PNAS - 3179

• (2025). Impactor relics of CI-like chondrites in chang’e-6 lunar samples. PNAS, 122(44), e2501614122. (www)

  @article{ , abstract = {The impact history of the Moon provides the opportunity to better understand mass transfer in the Solar System. While Earth’s meteorite collection serves as a key reference for material flux in the Earth–Moon system, it suffers from profound biases arising from Earth’s orbital dynamics and atmospheric filtering. Systematic identification and classification of meteorites on the airless Moon thus provide additional critical constraints for reconstructing the primordial accretion history and impactor population of the inner Solar System. However, identifying impactors on the Moon remains challenging due to their vaporization upon colliding at high velocities with the lunar surface. In situ remote sensing has previously detected chondritic impactor materials in the South-Pole-Aitken (SPA) basin of the far side of the Moon. The first opportunity to measure materials from the SPA basin has come via the Chang’e-6 (CE-6) mission, which returned samples from the Apollo basin inside the SPA basin. In this study, we screened seven olivine-porphyritic clasts as potential impactor relics in regolith returned by the CE-6 mission. These clasts were identified, via textural characterization, olivine Fe–Mn–Zn systematics, and in-situ triple oxygen isotopes, as impact relics solidified from melted chondritic parent bodies. Intriguingly, the parent body of all the identified impactor relics in this study resemble CI-like chondrites, a volatile-rich meteorite group that is relatively rare in Earth’s meteorite collection. The detection and classification of these impactor relics impose significant constraints on the proportions of meteoritic materials in the Earth–Moon system and their potential contributions to water inventories on the lunar surface.}, archive = {J_PNAS}, author = {Wang, Jintuan and Chen, Zhiming and Cui, Zexian and Yang, Qing and Zhang, Le and He, Pengli and Chen, Jingyou and Wang, Chengyuan and Zhang, Yan-Qiang and Wang, Jiangze and Cao, Yonghua and Head, James W. and O’Neill, Hugh and Tsuchiyama, Akira and Amelin, Yuri and Thiemens, Maxwell M. and Xing, Chang-ming and Wei, Bo and Lu, Wenhua and Lin, Mang and Xu, Yi-Gang}, doi = {10.1073/pnas.2501614122}, journal = {Proceedings of the National Academy of Sciences}, month = {11}, number = {44}, pages = {e2501614122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Impactor relics of CI-like chondrites in chang’e-6 lunar samples}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for milkman et al., a megastudy of text-based nudges encouraging patients to get vaccinated at an upcoming doctor’s appointment. PNAS, 122(43), e2527439122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2527439122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2527439122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for milkman et al., a megastudy of text-based nudges encouraging patients to get vaccinated at an upcoming doctor’s appointment}, volume = {122}, year = {2025}, }
• (2025). Correction for yu et al., tetraphenylethene-based highly emissive metallacage as a component of theranostic supramolecular nanoparticles. PNAS, 122(43), e2527010122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2527010122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2527010122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for yu et al., tetraphenylethene-based highly emissive metallacage as a component of theranostic supramolecular nanoparticles}, volume = {122}, year = {2025}, }
• (2025). Reply to bosten and franklin: Children’s color qualia structure is similar to adults’. PNAS, 122(43), e2525916122. (www)

  @article{ , archive = {J_PNAS}, author = {Moriguchi, Yusuke and Watanabe, Ryoichi and Sakata, Chifumi and Zeleznikow-Johnston, Ariel and Wang, Jue and Saji, Noburo and Tsuchiya, Naotsugu}, doi = {10.1073/pnas.2525916122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2525916122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to bosten and franklin: Children’s color qualia structure is similar to adults’}, volume = {122}, year = {2025}, }
• (2025). The moving mantle beneath hawaii: A new look at an old bend. PNAS, 122(43), e2524801122. (www)

  @article{ , archive = {J_PNAS}, author = {Müller, R. Dietmar}, doi = {10.1073/pnas.2524801122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2524801122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The moving mantle beneath hawaii: A new look at an old bend}, volume = {122}, year = {2025}, }
• (2025). A yellow warbler is for the climate as a canary is for the coal mine. PNAS, 122(43), e2524799122. (www)

  @article{ , archive = {J_PNAS}, author = {Grant, Peter R.}, doi = {10.1073/pnas.2524799122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2524799122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A yellow warbler is for the climate as a canary is for the coal mine}, volume = {122}, year = {2025}, }
• (2025). Reply to auspurg: On the limits of “justified” model spaces. PNAS, 122(43), e2523374122. (www)

  @article{ , archive = {J_PNAS}, author = {Ganslmeier, Michael and Vlandas, Tim}, doi = {10.1073/pnas.2523374122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2523374122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to auspurg: On the limits of “justified” model spaces}, volume = {122}, year = {2025}, }
• (2025). All the world’s a phage. PNAS, 122(43), e2523344122. (www)

  @article{ , abstract = {A renewed interest in bacteriophages has emerged from the explosive discovery of the complex pan-immune bacterial defense system and a revival of the therapeutic potential of phages in the age of widespread antimicrobial resistance to antibiotics. However, the road ahead is daunting because of the huge genetic diversity of phages and the vast numbers of genes of unknown function. A fully integrated approach that includes curiosity-driven exploration of phage biology, the development of integrated and inclusive research-education programs based on phage discovery and genomics (SEA-PHAGES), and the advancement of phage therapeutics provides a holistic structure for advancing the field. The phages of mycobacteria illustrate this model and a large mycobacteriophage collection reveals the enormous diversity of phages infecting a single bacterial strain and illuminates the evolutionary mechanisms giving rise to genomes with mosaic architectures. A set of 2,600 fully sequenced and annotated mycobacteriophage genomes and the development of tools for engineering them with desirable properties enable phage therapies for treating Mycobacterium infections for which antibiotics frequently fail. Technological advances in synthetic genomics and structural biology promise to rapidly advance this field and powerfully stimulate developments in all aspects of bacteriophage investigation and application. Here I describe what we have learned from the study of mycobacteriophages and how a holistic approach—integrating curiosity-driven research, inclusive education, and medicine—can serve as a model for advancing microbiology broadly.}, archive = {J_PNAS}, author = {Hatfull, Graham F.}, doi = {10.1073/pnas.2523344122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2523344122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {All the world’s a phage}, volume = {122}, year = {2025}, }
• (2025). Important design rules discovered for supramolecular multivalent ligands interacting with dynamic receptors. PNAS, 122(43), e2522205122. (www)

  @article{ , archive = {J_PNAS}, author = {Maynard, Heather D.}, doi = {10.1073/pnas.2522205122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2522205122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Important design rules discovered for supramolecular multivalent ligands interacting with dynamic receptors}, volume = {122}, year = {2025}, }
• (2025). Robustness is better assessed with a few thoughtful models than with billions of regressions. PNAS, 122(43), e2521917122. (www)

  @article{ , archive = {J_PNAS}, author = {Auspurg, Katrin}, doi = {10.1073/pnas.2521917122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2521917122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Robustness is better assessed with a few thoughtful models than with billions of regressions}, volume = {122}, year = {2025}, }
• (2025). Do color similarity judgments vary with age, and do they reveal anything about qualia?. PNAS, 122(43), e2521506122. (www)

  @article{ , archive = {J_PNAS}, author = {Bosten, Jenny M. and Franklin, Anna}, doi = {10.1073/pnas.2521506122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2521506122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Do color similarity judgments vary with age, and do they reveal anything about qualia?}, volume = {122}, year = {2025}, }
• (2025). Viscoelastic structural damping enables broadband low-frequency sound absorption. PNAS, 122(43), e2520808122. (www)

  @article{ , abstract = {Low-frequency sound absorption has traditionally relied on air-resonant structures, such as Helmholtz resonators, which are made of stiff materials that undergo negligible deformation. In these systems, energy dissipation arises primarily from air motion and thermal–viscous effects, resulting in inherently narrowband performance and bulky, complex designs for broadband absorption. Here, we presented a composite acoustic metamaterial that replaces the high-stiffness neck of a Helmholtz resonator with a soft, viscoelastic cylindrical shell. This structural modification enables material deformation and shifts the dominant energy dissipation mechanism from air resonance to intrinsic viscoelastic damping. A single unit achieves over 97% absorption across a broad low-frequency range (227 to 329 Hz) with deep-subwavelength thickness (λ/15 at 227 Hz). We developed a discretized impedance model that quantitatively links material properties and geometry to absorption behavior. Our results established a materials-centered design paradigm in which both material selection and geometry serve as coequal, tunable parameters for compact, broadband low-frequency sound control.}, archive = {J_PNAS}, author = {Zhang, Yanlin and Li, Junyin and Wu, Qiongying and Amabili, Marco and Misseroni, Diego and Jiang, Hanqing}, doi = {10.1073/pnas.2520808122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2520808122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Viscoelastic structural damping enables broadband low-frequency sound absorption}, volume = {122}, year = {2025}, }
• (2025). Full interhemispheric integration sustained by a fraction of posterior callosal fibers. PNAS, 122(43), e2520190122. (www)

  @article{ , abstract = {The dynamic integration of the lateralized and specialized capacities of the two cerebral hemispheres constitutes a hallmark feature of human brain function. This interhemispheric exchange of information critically depends upon the corpus callosum. Classical anatomical descriptions of callosal organization outline a topographic gradient from front to back, such that specific transcallosal fibers support distinct aspects of integrated brain function. Here, we present a challenge to this conventional model. Using neuroimaging data obtained from a new cohort of adult corpus callosotomy patients, we leverage modern network neuroscience techniques to show that full interhemispheric integration can be achieved via a small proportion of posterior callosal fibers. Partial callosotomy patients with spared callosal fibers retained widespread patterns of interhemispheric functional connectivity and showed no signs of behavioral disconnection, even with only 1 cm of the splenium intact. Conversely, only complete callosotomy patients demonstrated sweeping disruptions of interhemispheric network architectures, aligning with disconnection syndromes long-thought to reflect diminished information propagation and communication across the brain. These findings motivate an evolving mechanistic understanding of synchronized interhemispheric neural activity for large-scale human brain function and behavior.}, archive = {J_PNAS}, author = {Santander, Tyler and Bekir, Selin and Paul, Theresa and Simonson, Jessica M. and Wiemer, Valerie M. and Skinner, Henri Etel and Hopf, Johanna L. and Rada, Anna and Woermann, Friedrich G. and Kalbhenn, Thilo and Giesbrecht, Barry and Bien, Christian G. and Sporns, Olaf and Gazzaniga, Michael S. and Volz, Lukas J. and Miller, Michael B.}, doi = {10.1073/pnas.2520190122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2520190122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Full interhemispheric integration sustained by a fraction of posterior callosal fibers}, volume = {122}, year = {2025}, }
• (2025). On the scale of heterogeneity in composite electrodes of batteries. PNAS, 122(43), e2520136122. (www)

  @article{ , abstract = {An electrode in cylindrical or pouch cell batteries contains millions of active particles embedded in a conductive network. Battery performance, such as voltage, capacity, and cyclic efficiency, is a collective response of the particle network. We use optical microscopy to measure the local, heterogeneous state of charge of individual particles upon charging and discharging. The optical reflectivity is proportional to Li composition in the ternary oxide LiNi x Mn y Co z O 2 (NMC) cathode. Through clustering analysis, we determine the scale of heterogeneity where a representative volume in the composite electrode contains 100 to 1,000 particles. The heterogeneous activity in the particle network can be described by Weibull defect population at the particle interface with the conductive matrix.}, archive = {J_PNAS}, author = {Shrivastava, Aishwary and Sharma, Nikhil and He, Xiaomei and Liu, Yijin and Zhao, Kejie}, doi = {10.1073/pnas.2520136122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2520136122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {On the scale of heterogeneity in composite electrodes of batteries}, volume = {122}, year = {2025}, }
• (2025). Physical activity is directly associated with total energy expenditure without evidence of constraint or compensation. PNAS, 122(43), e2519626122. (www)

  @article{ , abstract = {The prevailing linear model of physical activity (PA) and total energy expenditure (TEE) has been challenged by models that predict an upper limit of TEE linked to a compensatory reduction elsewhere in the energy budget in response to increased PA. We determined the equation of best fit between PA and TEE and explored relationships between PA and behavioral and physiological compensation. Using linear and nonlinear modeling, we observed a positive linear relationship between PA and TEE either without or after adjustment for fat-free mass (R 2 = 0.3492, TEE = 0.00685*PA + 7.124: R 2 =0.3667, TEE_ADJ(FFM) = 0.00511*PA + 8.598). Higher PA was associated with lower sedentary time (R 2 = 0.7207, %SPA= −0.0211*X + 91.261). There was no association between PA, TEE, or resting metabolic rate and adjusted biomarkers of immune, reproductive, or thyroid function after Bonferroni correction. The findings of this observational study do not support the constrained/compensated model but affirm the conventional additive relationship between PA and TEE across a broad range of PA levels.}, archive = {J_PNAS}, author = {Howard, Kristen R. and Prado-Nóvoa, Olalla and Zorrilla-Revilla, Guillermo and Laskaridou, Eleni and Reid, Glen R. and Marinik, Elaina L. and Stamatiou, Marina and Hambly, Catherine and Davy, Brenda M. and Speakman, John R. and Davy, Kevin P.}, doi = {10.1073/pnas.2519626122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2519626122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Physical activity is directly associated with total energy expenditure without evidence of constraint or compensation}, volume = {122}, year = {2025}, }
• (2025). Exceptional diversity of allorecognition receptors in a nonvertebrate chordate reveals principles of innate allelic discrimination. PNAS, 122(43), e2519372122. (www)

  @article{ , abstract = {Highly polymorphic allorecognition systems have been characterized in numerous invertebrate species, and exhibit discriminatory capabilities reminiscent of vertebrate adaptive immunity. As these systems utilize germline encoded receptors, the mechanisms underlying allelic discrimination are unknown. The invertebrate chordate, Botryllus schlosseri, undergoes a natural transplantation reaction controlled by a highly polymorphic, polygenic locus (called the fuhc) with over 1,000 allelic haplotypes found worldwide. Two individuals are compatible if they share one or both fuhc alleles, and we had found that polymorphic discrimination is due to the integration of signals from two allorecognition receptors encoded within the fuhc locus, called fester and uncle fester. Here we show that these two receptors are members of an extended family consisting of >35 genes, now called the Fester family ( FF ), and coexpressed with members of another diverse gene family, the fester coreceptors ( FcoR ). Both FF and FcoR are Immunoglobulin superfamily members and each FcoR encodes conserved tyrosine signal transduction motifs, including ITIMs or hemITAMs. FF and FcoR are expressed and encoded as cognate pairs in two polymorphic haplotypes: one within the fuhc locus, and another on a separate chromosome, and remarkably, copy number variation between haplotypes is of gene pairs. Furthermore, two FcoR genes can swap ITIMs and hemITAMs by alternative splicing, suggesting that dynamic tuning of activating and inhibitory signaling is required for allelic discrimination. These results indicate that conserved signal processing mechanisms are the foundation of both allelic discrimination in Botryllus , and recurring convergent evolution of allorecognition receptors observed from invertebrates to mammals.}, archive = {J_PNAS}, author = {Rodriguez-Valbuena, Henry and Salcedo, Jorge and De Thier, Olivier and Flot, Jean Francois and Tiozzo, Stefano and De Tomaso, Anthony W.}, doi = {10.1073/pnas.2519372122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2519372122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exceptional diversity of allorecognition receptors in a nonvertebrate chordate reveals principles of innate allelic discrimination}, volume = {122}, year = {2025}, }
• (2025). Beyond adoption: The persistence of conservation and climate-smart agricultural practices in the united states. PNAS, 122(43), e2518373122. (www)

  @article{ , abstract = {Achieving sustainability goals requires that humans change their behavior not just once but persistently. Yet despite decades of research on the adoption of conservation and climate-smart agricultural practices, little is known about the extent to which these practices persist over time. One key reason is the lack of longitudinal, field-level data. Using ground-verified, longitudinal data on cover cropping across thousands of farm parcels in Indiana (USA), we find that persistence is low and contrasts sharply with the predictions made by Indiana conservation experts. We also find low persistence in a new national dataset of self-reported cover cropping by farm operators. The potential for low behavioral persistence in sustainable agricultural practices raises essential questions about the design of conservation programs and the modeling and valuation of ecosystem services.}, archive = {J_PNAS}, author = {Ferraro, Paul J. and Bowman, Maria and Correia, Hannah E. and Gao, Jing and Larson, Kelsey R. and Messer, Kent D. and Paul, Laura A. and Pratt, Bryan and Prokopy, Linda S.}, doi = {10.1073/pnas.2518373122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2518373122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Beyond adoption: The persistence of conservation and climate-smart agricultural practices in the united states}, volume = {122}, year = {2025}, }
• (2025). Genetic regulation of the estrogen receptor and inherited predisposition to breast cancer. PNAS, 122(43), e2517736122. (www)

  @article{ , abstract = {For many families severely affected with breast cancer, no inherited causal allele has been detected in any tumor suppressor gene. In an effort to understand the genetics underlying breast cancer in these families, we evaluated 136 such families for coinheritance of breast cancer with each of 79 common variants reported as high-confidence “risk alleles” for breast cancer by meta-analyses of genome-wide association studies. Simulations based on allele frequencies and family structures revealed one (and only one) of these 79 variants to cosegregate with breast cancer in the families significantly more frequently than expected by chance. This variant (rs2046210) is located 180 kb proximal to ESR1 , encoding the estrogen receptor alpha. Reporter assays in MCF7 cells revealed enhancement by the genomic segment at this site of activity of ESR1 promoters, but no difference in effect among alternative haplotypes. In contrast, the 600 kb genomic region including ESR1 and rs2046210 harbored 11 rare variants, each of which cosegregated with breast cancer in one or a few families. For 9 of these 11 variants, reporter assays indicated significant allele-specific effects on ESR1 promoters, with the breast-cancer-linked allele of each variant yielding higher promoter activity. At the site with the most striking effect, the breast-cancer-linked allele was associated with increased binding by transcription factor AP2-gamma TFAP2C in both MCF7 and T47D cells. These results demonstrate coinheritance with breast cancer of rare alleles that increase activity of ESR1 promoters, and suggest that rare ESR1 regulatory alleles may contribute to inherited predisposition to breast cancer.}, archive = {J_PNAS}, author = {Pierce, Sarah B. and Kortbawi, Hannah and Gulsuner, Suleyman and Mandell, Jessica B. and Lee, Ming K. and Walsh, Tom and King, Mary-Claire}, doi = {10.1073/pnas.2517736122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2517736122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genetic regulation of the estrogen receptor and inherited predisposition to breast cancer}, volume = {122}, year = {2025}, }
• (2025). HIF2α negatively regulates MYCN protein levels and promotes a low-risk noradrenergic phenotype in neuroblastoma. PNAS, 122(43), e2516922122. (www)

  @article{ , abstract = {The role of HIF2α, encoded by EPAS1 , in neuroblastoma remains controversial. Here, we demonstrate that induction of high levels of HIF2α in MYCN-amplified neuroblastoma cells results in a rapid and profound reduction of the oncoprotein MYCN. This is followed by an upregulation of genes characteristic of noradrenergic cells in the adrenal medulla. Additionally, upon induction of HIF2α, the proliferation rate drops substantially, and cells develop elongated neurite-like protrusions, indicative of differentiation. In vivo HIF2α induction in established xenografts significantly attenuates tumor growth. Notably, analysis of sequenced neuroblastoma patient samples, revealed a negative correlation between EPAS1 and MYCN expression and a strong positive correlation between EPAS1 expression, high expression levels of noradrenergic markers, and improved patient outcome. This was paralleled by analysis of human developing adrenal medulla datasets wherein EPAS1 expression was prominent in populations with high expression levels of genes characteristic of noradrenergic chromaffin cells. Our findings show that high levels of HIF2α in neuroblastoma, leads to drastically reduced MYCN protein levels, cell cycle exit, and noradrenergic cell differentiation. Taken together, our results challenge the dogma that HIF2α acts as an oncogene in neuroblastoma.}, archive = {J_PNAS}, author = {Yuan, Juan and Maitra, Subhamita and Antoniou, Eirini and Zhu, Jiacheng and Li, Wenyu and Demirel, Ilknur Safak and Toskas, Kostantinos and Martinez, Iria Laura and Ozcimen, Lacin and Lindehell, Henrik and Muhr, Jonas and Stenman, Jakob and Kogner, Per and Bedoya-Reina, Oscar C. and Schlisio, Susanne and Holmberg, Johan}, doi = {10.1073/pnas.2516922122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2516922122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {HIF2α negatively regulates MYCN protein levels and promotes a low-risk noradrenergic phenotype in neuroblastoma}, volume = {122}, year = {2025}, }
• (2025). Outrunning protein diffusion to the air–water interface in cryoEM. PNAS, 122(43), e2516900122. (www)

  @article{ , abstract = {Here, we report a series of measurements indicating that it is physically possible to thin and vitrify a specimen for electron cryomicroscopy (cryoEM) faster than proteins diffuse to the air–water interface. We achieved this by spraying picoliter volume droplets at speeds of hundreds of meters per second into a thin layer of liquid ethane coating the surface of a precooled specimen support. The droplets simultaneously collapsed and froze in microseconds into the amorphous phase as they landed on the surface. The atomic structure of the proteins was preserved and tomographic reconstructions of the vitrified specimens indicated adhesion to the interfaces was eliminated. Improved control of the final thickness of the specimen and the orientation distribution of the particles are now the limiting factors. This demonstration provides a basis for the development of specimen preparation methods and instruments that eliminate the detrimental effects of the air–water interface in cryoEM.}, archive = {J_PNAS}, author = {Gusach, Anastasiia and Sader, Kasim and Russo, Christopher J.}, doi = {10.1073/pnas.2516900122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2516900122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Outrunning protein diffusion to the air–water interface in cryoEM}, volume = {122}, year = {2025}, }
• (2025). Nir2 crystal structures reveal a phosphatidic acid–sensing mechanism at ER–PM contact sites. PNAS, 122(43), e2516849122. (www)

  @article{ , abstract = {Agonist-induced activation of phosphoinositide-specific phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] to diacylglycerol (DAG) at the inner leaflet of the plasma membrane (PM). DAG can be enzymatically transformed into phosphatidic acid (PA) and accumulated at the PM. PYK2 N-terminal domain-interacting receptor 2 (Nir2) mediates the formation of ER–PM membrane contact sites (MCSs) by specifically recognizing PA at the PM and directly interacting with ER membrane protein vesicle-associated membrane protein-associated proteins (VAPs). The N-terminal phosphatidylinositol transfer protein domain of Nir2 facilitates PI/PA exchange at ER–PM MCSs to maintain PI and PA levels. Here, we reveal the mechanisms by which Nir2 senses phosphatidic acid (PA) and associates with membranes, based on three crystal structures of its C-terminal Lipin/Ned1/Smp2 (LNS2) domain bound to PA, the diphenylalanine [FF]–containing acidic tract (FFAT) motif complexed with vesicle-associated membrane protein–associated protein B/C (VAPB), and the Asp-Asp-His-Asp (DDHD) domain. The C-terminal LNS2 domain of Nir2 directly interacts with the phosphate in the headgroup of PA via hydrogen bonds involving S1025, T1065, K1103, and K1126. Formation of a salt bridge between E355 in Nir2 and R55 in VAPB is essential for Nir2 FFAT–VAPB interaction. The central DDHD domain of Nir2 forms a twofold symmetric dimer, and this self-association contributes to stable and tight membrane association. These findings reveal how Nir2-mediated ER–PM MCS formation maintains continued PI(4,5)P 2 -dependent PLC signaling.}, archive = {J_PNAS}, author = {Kim, Dongyoung and Lee, Seowhang and Jun, Youngsoo and Lee, Changwook}, doi = {10.1073/pnas.2516849122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2516849122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nir2 crystal structures reveal a phosphatidic acid–sensing mechanism at ER–PM contact sites}, volume = {122}, year = {2025}, }
• (2025). Adipose cullin 3 mediates the antiobesity effect of pan neddylation inhibitors. PNAS, 122(43), e2515947122. (www)

  @article{ , abstract = {Cullin Ring E3 Ligases (CRLs) belong to the largest family of multisubunit ubiquitin E3 ligases. A cullin serves as the scaffold protein that recruits E3 ligases and substrate receptors in a CRL complex, whose activity requires cullin neddylation, a posttranslational modification that can be pharmacologically targeted by neddylation inhibitors. Elevated neddylation activity has been observed in the liver and adipose tissue of obese mice, implicating a pathogenic link between altered CRL activity and the development of metabolic disorders. Emerging evidence has also shown that neddylation inhibitors possess antiobesity and hypoglycemic property. However, the roles of cullin proteins in regulating adipocyte biology are still incompletely defined. Here, we report that pan neddylation inhibitor TAS4464 treatment reversed obesity and adipose inflammation, resulting in improved hepatic steatosis and insulin sensitivity in obese mice. Among all mammalian cullin proteins that were targeted by TAS4464, we identified that cullin 3 (Cul3) was required for adipogenesis and adipocyte hypertrophy. A complete absence of Cul3 in adipocytes caused severely inhibited adipose expansion associated with ectopic fat accumulation in the liver and brown adipose tissue and insulin resistance, while adipocyte-specific Cul3 haploinsufficiency attenuated obesity and improved overall metabolic homeostasis, which recapitulated the metabolic benefits of TAS4464. Mechanistically, we found that Cul3 inhibition caused adipose nuclear factor erythroid 2-related factor 2 (NRF2) stabilization, which contributed to impaired adipogenesis by inhibiting lipogenesis. Together, these findings demonstrate that Cul3 is required during adipogenesis and acts as a downstream mediator of the antiobesity effect of pan neddylation inhibitors.}, archive = {J_PNAS}, author = {Gu, Lijie and Du, Yanhong and Nazmul Hasan, Mohammad and Clayton, Yung-Dai and Li, Tiangang}, doi = {10.1073/pnas.2515947122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2515947122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Adipose cullin 3 mediates the antiobesity effect of pan neddylation inhibitors}, volume = {122}, year = {2025}, }
• (2025). HEIP1 orchestrates pro-crossover protein activity during mammalian meiosis. PNAS, 122(43), e2515747122. (www)

  @article{ , abstract = {Meiotic crossovers (COs) are needed to produce genetically balanced gametes. In mammals, CO formation is mediated by a conserved set of pro-CO proteins via mechanisms that remain unclear. Here, we characterize a mammalian pro-CO factor HEIP1. In mouse HEIP1 is essential for crossover and fertility of both sexes. HEIP1 promotes crossover by orchestrating the recruitment of other pro-CO proteins, including the MutSγ complex (MSH4-MSH5) and E3 ligases (HEI10, RNF212, and RNF212B), that are required to mature CO sites and recruit the CO-specific resolution complex MutLγ. Moreover, HEIP1 directly interacts with HEI10, suggesting a direct role in controlling the recruitment of pro-CO E3 ligases. During early stages of meiotic prophase I, HEIP1 interacts with the chromosome axes, independently of recombination, before relocalizing to the central region of the synaptonemal complex. We propose that HEIP1 is a conserved master regulator of CO proteins that controls different CO maturation steps.}, archive = {J_PNAS}, author = {De Muyt, Arnaud and Lee, Sunkyung and Khanal, Sushil and Dal Toe, Laurine and Adam, Céline and Mercier, Raphael and Borde, Valérie and Hunter, Neil and Robert, Thomas}, doi = {10.1073/pnas.2515747122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2515747122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {HEIP1 orchestrates pro-crossover protein activity during mammalian meiosis}, volume = {122}, year = {2025}, }
• (2025). Theta-nested gamma oscillations balance prediction and vigilance in spatial navigation. PNAS, 122(43), e2515493122. (www)

  @article{ , abstract = {Recent experimental findings challenge the traditional belief that vigilance is solely attributed to the sensorimotor system, suggesting instead that hippocampal activity, coupled with locomotor processes, enhances environmental sampling and planning. Here, we propose that hippocampal theta-nested gamma oscillations (TGOs), widely observed in experiments, play essential roles in both prediction and vigilance, in terms of recalling reward sites and avoiding unexpected dangers through synfire chains (SFCs). Despite the recognized importance of TGOs in navigation, their precise functional roles remain unclear. By building a biologically plausible spiking neuronal network model and reproducing experimental results, we leverage SFC properties-length and separation-to reveal that the positive correlation between theta frequency and motion velocity optimally balances planning for predictable events and staying alert to unexpected ones. Based on this adaptive mechanism, we further explain the distinct functional contributions of TGOs consistent with experimental findings: Theta oscillations facilitate self-location awareness, gamma oscillations enhance predictive capabilities, and their coupling ensures sufficient time windows for prediction. Our study provides insights into the functional roles of TGOs in the hippocampus, highlighting their importance in achieving both planning and vigilance during goal-directed navigation.}, archive = {J_PNAS}, author = {Li, Kwan Tung and Wang, Ziqun and Gong, Pulin and Yang, Dongping}, doi = {10.1073/pnas.2515493122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2515493122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Theta-nested gamma oscillations balance prediction and vigilance in spatial navigation}, volume = {122}, year = {2025}, }
• (2025). Precise gene editing of pathogenic lamin a mutations corrects cardiac disease. PNAS, 122(43), e2515267122. (www)

  @article{ , abstract = {Mutations in the Lamin A ( LMNA ) gene, which encodes the Lamin A and C proteins, cause severe human diseases collectively known as laminopathies. These conditions are often devastating and lack effective therapies. In this study, we developed precise base editing (BE) strategies targeting the human LMNA gene variants L35P and R249Q, which cause congenital muscular dystrophy (CMD) and dilated cardiomyopathy with conduction defects (DCM-CD), respectively. Induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) carrying the R249Q mutation displayed nuclear aberrations, DNA damage, and abnormal Ca 2+ transients. Similarly, L35P iPSC-CMs exhibited abnormal contraction, DNA damage, and reduced Lamin A/C protein expression. We also generated “humanized” mouse models carrying these pathogenic human mutations. R249Q homozygous mice exhibited cardiac conduction abnormalities, cardiac arrhythmias, and premature death. Mice with the homozygous L35P mutation displayed severe muscle-wasting and reduced lifespan, while heterozygous L35P mice displayed DCM. We developed an adenine base editing (ABE) approach for correcting the R249Q mutation and a cytosine base editing (CBE) strategy for the L35P variant. Precise correction of these mutations in iPSC-CMs successfully rescued all of the in vitro abnormalities. Furthermore, delivery of the BE components using adeno-associated virus prevented the pathological phenotypes and extended longevity of mice carrying the LMNA L35P and the R249Q mutations. These results demonstrate the efficacy of ABE and CBE in correcting pathogenic LMNA mutations that cause cardiac disease, highlighting BE as a promising therapeutic approach for human laminopathies.}, archive = {J_PNAS}, author = {Caravia, Xurde M. and Hayashi, Brian and Li, Hui and Gan, Peiheng and Alzhanov, Damir and Tan, Wei and Chen, Kenian and McAnally, John R. and Xu, Lin and Liu, Ning and Olson, Eric N.}, doi = {10.1073/pnas.2515267122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2515267122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Precise gene editing of pathogenic lamin a mutations corrects cardiac disease}, volume = {122}, year = {2025}, }
• (2025). Spatial gene expression analysis reveals pathological niches in japanese encephalitis virus neuroinvasion. PNAS, 122(43), e2515006122. (www)

  @article{ , abstract = {Japanese encephalitis virus (JEV) infection causes encephalitis in humans and animals. Following intradermal infection, JEV crosses the blood–brain barrier (BBB) and reaches target cells in the brain parenchyma. However, the cellular dynamics and pathological niches involved in JEV neuroinvasion remain poorly understood. In this study, we investigated the early stages of JEV infection in the mouse brain employing a highly multiplexed spatial transcriptomics platform to map viral RNA and host gene expressions in intact brain sections at a single-cell resolution. Although JEV RNA was undetectable in brain sections at 1-day postinfection (dpi), innate immune responses were transiently activated across the brain. At 4 dpi, we detected limited viral RNA and mapped its spatial distribution, identifying glial cells surrounding microvessels as early targets of brain infection. We further characterized transcriptional changes in infected and surrounding bystander cells, revealing cell-type–specific antiviral responses. Notably, JEV neuroinvasion led to the downregulation of endothelial tight junction genes, indicative of an early event that precedes BBB impairment during subsequent disease progression. Our spatial transcriptomic analysis provides insights into cell-type– and region-specific responses to JEV infection, and highlights the early role of glial cells in shaping the immune response landscape of the brain. These findings greatly improve our understanding of JEV pathogenesis before the onset of clinical encephalitis.}, archive = {J_PNAS}, author = {Orba, Yasuko and Kashima, Yukie and Tabata, Koshiro and Itakura, Yukari and Ariizumi, Takuma and Hall, William W. and Sawa, Hirofumi and Suzuki, Yutaka and Sasaki, Michihito}, doi = {10.1073/pnas.2515006122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2515006122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatial gene expression analysis reveals pathological niches in japanese encephalitis virus neuroinvasion}, volume = {122}, year = {2025}, }
• (2025). Morphological specializations of mosquito CO2-sensing olfactory receptor neurons. PNAS, 122(43), e2514666122. (www)

  @article{ , abstract = {Hematophagous mosquitoes use CO 2 as a key arousal signal that gates behavioral responses to host-derived cues. In Aedes aegypti , CO 2 is detected by olfactory receptor neurons (ORNs) housed in the sensory hairs (sensilla) on the maxillary palp. While the molecular mechanism and behavioral significance of CO 2 sensing have been well studied in mosquitoes, the nanoscale three-dimensional structures of their CO 2 -sensing ORNs and associated cells have remained unclear. Using serial block-face scanning electron microscopy, we characterize the CO 2 -sensing cpA neuron and its odor-sensitive neighbors, cpB and cpC, within the capitate sensilla of A. aegypti. Notably, cpA neurons are significantly larger, with an outer dendritic surface area 8 to 12 times greater than that of cpB and cpC neurons. This expanded CO 2 -sensing surface arises from its unique architecture, consisting of numerous flattened dendritic sheets folded into intricate lamellae. In contrast, cpB and cpC dendrites exhibit sparse, narrow cylindrical branches. Moreover, the cpA axon displays a prominent pearls-on-a-string morphology, with numerous mitochondria-rich, nonsynaptic varicosities connected by thin cables. Remarkably, a glial cell and an auxiliary cell together ensheathe the cpA soma but not cpB or cpC, suggesting a specialized role in supporting cpA function. Compared to Drosophila CO 2 -sensitive ORNs, a larger portion of the cpA outer dendrite is embedded within the sensillum cuticle, potentially improving access to environmental CO 2 . These findings reveal key morphological specializations of cpA neurons, thereby advancing our understanding of mosquito sensory biology and laying the groundwork for future studies on the molecular basis and functional ramifications of these anatomical adaptations.}, archive = {J_PNAS}, author = {Charara, Shadi and Choy, Jonathan and Cauwenberghs, Kalyani and Vijayakumar, Pawel and Ng, Renny and Kim, Keun-Young and Weng, Shih-Che and Akbari, Omar S. and Ellisman, Mark H. and Rifkin, Scott A. and Su, Chih-Ying}, doi = {10.1073/pnas.2514666122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2514666122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Morphological specializations of mosquito CO2-sensing olfactory receptor neurons}, volume = {122}, year = {2025}, }
• (2025). Evolutionary histories of functional mutations during the domestication and spread of japonica rice in asia. PNAS, 122(43), e2514614122. (www)

  @article{ , abstract = {Rice ( Oryza sativa ) was first domesticated beginning ~9,000 y ago in China as the japonica variety group/subspecies. Using genomic data from 456 japonica landraces, including data for 47 herbarium specimens collected over the last 167 y, we reconstruct how japonica rice moved from its center of origin to other parts of Asia beginning ~4,000 to 5,500 y ago. We observe an enrichment of pathogen resistance loci in selective sweeps associated with distinct geographic populations, suggesting that biotic interactions may be a key driver of local adaptation. We also find that the majority of 76 known functional mutations present in our japonica landraces—many of them associated with japonica rice domestication and diversification and important for modern breeding—had their origins in the Pleistocene >11,700 y ago and increased in allele frequency during key events in the evolution of rice.}, archive = {J_PNAS}, author = {Alam, Ornob and Gutaker, Rafal and Surya, Niketh and Castillo, Cristina and Fuller, Dorian and Guedes, Jade d’Alpoim and Purugganan, Michael}, doi = {10.1073/pnas.2514614122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2514614122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolutionary histories of functional mutations during the domestication and spread of japonica rice in asia}, volume = {122}, year = {2025}, }
• (2025). A universal thermal performance curve arises in biology and ecology. PNAS, 122(43), e2513099122. (www)

  @article{ , abstract = {Temperature has strong impacts on all biological and ecological processes, and thermal performance curves (TPCs) have been employed recurrently to assess them. TPCs almost always take a particular asymmetric shape across the biological hierarchy, with many different competing mechanisms and models doing a similarly good job of trying to explain the TPC phenomenon. Here, we reveal that the ubiquitous exponential scaling of biological processes with temperature creates a mechanistic tendency for TPC data and models to collapse onto a single curve (which we call the Universal TPC, UTPC), explaining mathematically why biological systems respond to temperature in such a consistent way. We illustrate that many seemingly different TPCs actually approximate rescaled versions of the same curve, even when thermal performance estimates vary widely across organisms, systems, and contexts. We demonstrate remarkable UTPC collapse across the tree of life, with diverse datasets spanning microbes to vertebrates, and individual physiology to population growth. UTPC phenomena also provide a strong theoretical basis for predicting performance of warm-adapted organisms will be more sensitive to- and less tolerant of- temperature fluctuations; an important consideration in the context of climate change.}, archive = {J_PNAS}, author = {Arnoldi, Jean-François and Jackson, Andrew L. and Peralta-Maraver, Ignacio and Payne, Nicholas L.}, doi = {10.1073/pnas.2513099122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2513099122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A universal thermal performance curve arises in biology and ecology}, volume = {122}, year = {2025}, }
• (2025). Neuronal plasticity at puberty in mouse hypothalamic kiss1 neurons that control fertility. PNAS, 122(43), e2512855122. (www)

  @article{ , abstract = {Puberty is a critical transition period to achieve reproductive capacity in all mammalian species. At puberty, hypothalamic Kiss1 neurons release kisspeptin, stimulating gonadotropin-releasing hormone (GnRH) release and activating the hypothalamic–pituitary–gonadal (HPG) axis. Here, we show that Kiss1 neurons in the arcuate nucleus of the hypothalamus ( Kiss1 ARC ) of female mice undergo profound intrinsic plasticity at puberty. Kiss1 ARC neurons in brain slices from 3-wk-old mice, when depolarized, typically fire a short high-frequency burst of action potentials before falling silent. This would make them unsuitable for the sustained activity that is required to activate pulsatile GnRH secretion and the HPG axis. At 4 wk of age and after puberty, Kiss1 ARC neurons can fire a sustained train of action potentials. There is a concomitant hyperpolarization in action potential threshold and postspike minimum voltage and larger medium after-hyperpolarizations (mAHP) and hyperpolarization-induced voltage sags. Transcriptomic profiling showed significant changes in ion channel expression after puberty. Using quantitative PCR, we confirmed changes in genes encoding voltage-gated sodium, calcium, potassium, and cation channels. Blocking hyperpolarization-induced cation channels caused Kiss1 ARC neurons from postpuberty mice to fire less sustained trains of action potentials. Recordings from Kiss1 ARC neurons in mice after ovariectomy and 17β-estradiol replacement revealed a critical window of estrogen-dependent plasticity between 3 and 6 wk, which is essential for the maturation of Kiss1 ARC neurons and the development of their adult electrophysiological activity. This represents an example of sex steroid–dependent plasticity in the mammalian brain at puberty.}, archive = {J_PNAS}, author = {Zhang, Yuanxin and Pakulat, Leonie M. and Takács, Szabolcs and Campbell, Lauren and Galliano, Elisa and Hrabovszky, Erik and Colledge, William H. and Jones, Susan}, doi = {10.1073/pnas.2512855122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2512855122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neuronal plasticity at puberty in mouse hypothalamic kiss1 neurons that control fertility}, volume = {122}, year = {2025}, }
• (2025). Asymmetric gating of a homopentameric ion channel GLIC revealed by cryo-EM. PNAS, 122(43), e2512811122. (www)

  @article{ , abstract = {Pentameric ligand-gated ion channels (pLGICs) are vital neurotransmitter receptors that are key therapeutic targets for neurological disorders. Although the high-resolution structures of these channels have been elucidated, capturing their dynamic conformational transitions remains challenging due to the transient nature of intermediate states. In this study, we investigated a prokaryotic proton-gated pLGIC, GLIC. In our cryo-EM data at pH 4.0, we identified and segregated asymmetric particles, which we precisely aligned to resolve high-resolution structures of several previously unresolved asymmetric intermediate states, in addition to symmetric closed and open states. Detailed structural analysis revealed systematic conformational changes at individual subunits driving the channel opening. Molecular dynamics simulations were used to assign the functional states. We further examined the roles of the F116 and Y251 residues, located at the domain interface, playing a central role in interdomain communication. In addition, patch-clamp experiments on GLIC I240A and L241A mutants, located in the M2 helix, demonstrated their importance in channel gating. Together, these results shed light on the sequential and asymmetric conformational transitions that occur during GLIC activation, offering a deeper mechanistic understanding of asymmetric gating in pLGICs.}, archive = {J_PNAS}, author = {Li, Zhuowen and Bharambe, Nikhil and Manishrao Lande, Kashmiri and Feddersen, Bjarne and Manikkoth Balakrishna, Asha and Biggin, Philip C. and Sahu, Giriraj and Basak, Sandip}, doi = {10.1073/pnas.2512811122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2512811122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Asymmetric gating of a homopentameric ion channel GLIC revealed by cryo-EM}, volume = {122}, year = {2025}, }
• (2025). Parallel shifts in differential gene expression reveal convergent miniaturization in fishes. PNAS, 122(43), e2512299122. (www)

  @article{ , abstract = {Body size variation in vertebrates is a complex polygenic trait, tightly correlated with numerous aspects of a species’ biology, ecology, and physiology. Miniaturization, the extreme reduction of adult body size, is a common phenomenon across the Tree of Life, yet the mechanisms underlying this process are poorly understood. Here, we investigate the molecular basis of body size evolution in goby fishes, a clade encompassing some of the smallest vertebrates on Earth. We generate a genome-wide phylogeny for 162 Gobioidei species and perform comparative transcriptomics across three clades with repeated instances of miniaturization and large-bodied forms. We identified 54 differentially expressed one-to-one orthologs between miniature and large-bodied species. These genes reveal distinct functional profiles, suggesting that regulation of cell numbers is a key mechanism governing body size control. Miniature species consistently overexpress growth inhibitors like CDKN1B and ING2 , associated with tighter cell cycle regulation and decreased proliferation rates, while large-bodied species upregulate growth-promoting genes such as TGFB3 , linked to tissue development and growth signaling. These enriched functional pathways, conserved since the Eocene (50 Ma), suggest macroevolutionary convergence in size regulation over deep time. Our findings provide insights into how size determination is governed at a genetic level and highlights the importance of exploring these factors in nonmodel organisms to uncover the fundamental processes regulating vertebrate body size evolution.}, archive = {J_PNAS}, author = {Troyer, Emily M. and White, William T. and Betancur-R, Ricardo and Arcila, Dahiana}, doi = {10.1073/pnas.2512299122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2512299122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Parallel shifts in differential gene expression reveal convergent miniaturization in fishes}, volume = {122}, year = {2025}, }
• (2025). Optimal disk packing of chloroplasts in plant cells. PNAS, 122(43), e2511696122. (www)

  @article{ , abstract = {Photosynthesis is essential for ecosystem survival, but while plants require light, excessive exposure can damage cells. Chloroplasts, photosynthetic organelles, respond via self-organized motion within cells to optimize light absorption. These disk-shaped organelles must balance two competing needs: dense packing to enhance absorption under dim light and rapid spatial rearrangement to avoid damage from excess light. Using microscopy, we show that plant cell shape and chloroplast size achieve both goals: dense monolayer packing for optimal absorption in low light and sidewall packing for light avoidance. We present a theoretical model using random close packing simulations of polydispersed hard disks in rectangular boxes and find optimal cell shapes that match plant cell measurements. Our findings highlight how particle packing principles under confinement enable light adaptation in plants, offering insights into organelle organization under confinement, a physical challenge relevant across biological systems.}, archive = {J_PNAS}, author = {Schramma, Nico and Weeks, Eric R. and Jalaal, Maziyar}, doi = {10.1073/pnas.2511696122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2511696122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Optimal disk packing of chloroplasts in plant cells}, volume = {122}, year = {2025}, }
• (2025). Oxygen isotopic evidence that gale crater, mars, was home to an early hesperian water reservoir that underwent significant evaporation. PNAS, 122(43), e2511627122. (www)

  @article{ , abstract = {Simultaneous measurements of HDO, H 2 18 O, and H 2 16 O in water evolved during pyrolysis of powdered rock samples acquired by the Curiosity rover within Gale crater’s clay-bearing units indicate extreme and variable heavy-isotope enrichments averaging ~4.5 times the D/H ratio and ~1.03 times the 18 O/ 16 O ratio of terrestrial seawater. These enrichments are recorded in water desorbed from mineral surfaces and evolved from poorly crystalline phases, hydrated salts, jarosite, and clays. All evolved waters are deuterium-enriched relative to common terrestrial waters, reflecting hydrogen loss to space. Because oxygen in structurally bound hydroxyl groups is least likely to exchange with other sources over geologic timescales, we focus on oxygen in water evolved during dehydroxylation of smectite clays. Several samples have 18 O/ 16 O ratios commensurate with precipitation from, or near-complete equilibration with, water moderately 18 O-enriched relative to terrestrial meteoric waters—consistent with other evidence that Mars’s hydrosphere is basically like Earth’s in terms of oxygen isotopes. Unlike hydrogen, oxygen atmospheric escape did not lead to extreme 18 O enrichments on Mars. Locally, however, most Gale smectites’ 18 O/ 16 O values require a pronounced 18 O-enrichment of their parental waters. On Earth, the most extreme 18 O enrichments in surface waters are found in closed basins having undergone significant evaporative loss into a low-humidity atmosphere, and the 18 O/ 16 O of authigenic clay minerals formed in these environs reflect those enrichments. A similar process acting on the hydrologic reservoir local to Gale at the time of clay formation and early diagenesis is a plausible explanation for the distinctive oxygen isotopic compositions of these clays.}, archive = {J_PNAS}, author = {Hofmann, Amy E. and Archer, P. Douglas and McAdam, Amy C. and Sutter, Brad and Bristow, Thomas F. and Eiler, John M. and Webster, Christopher R. and Flesch, Gregory J. and Fraeman, Abigail A. and Franz, Heather B. and House, Christopher H. and Rampe, Elizabeth B. and Stern, Jennifer C. and Mahaffy, Paul R. and Malespin, Charles A. and Grotzinger, John P. and Vasavada, Ashwin R.}, doi = {10.1073/pnas.2511627122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2511627122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Oxygen isotopic evidence that gale crater, mars, was home to an early hesperian water reservoir that underwent significant evaporation}, volume = {122}, year = {2025}, }
• (2025). A PHF19-YTHDC1 condensate switches EZH2-mediated gene suppression to activation for prostate cancer progression. PNAS, 122(43), e2510386122. (www)

  @article{ , abstract = {EZH2, a core component of PRC2 complex, silences global gene expression by tri-methylating histone H3K27. It remains an elusive question that EZH2 hyperexpression discords with its H3K27me3 activity of gene suppression in advanced prostate cancer. Here, we report a nascent RNA-dependent PHF19-YTHDC1 condensate capable of switching EZH2-mediated gene suppression to activation during prostate cancer progression. We found that the long isoform of PRC2 accessory subunit PHF19, PHF19L, was highly expressed in advanced prostate cancer that promoted the tumor progression and hormonal therapy resistance. Mechanistically, PHF19L was recruited to the m 6 A modified nascent RNA through YTHDC1 and formed a liquid-like YTHDC1-PHF19L condensate that pulled the EZH2 away from chromatin, resulting in reduced H3K27me3 deposition and the activated expression of EZH2-repressed genes. Therefore, our study reveals a biomolecular condensate that modulates the switch from EZH2-mediated epigenetic gene silence to activation during the progression of prostate cancer.}, archive = {J_PNAS}, author = {Yuan, Shuai and Ming, Dao-Jing and He, Jiapeng and Liu, Meng-Yang and He, Shao-Hua and Weng, Hong and Xi, Shu and Zhang, Jin-Hui and Shi, Ming-Hui and Cui, Jin-Long and Li, Lu-Yao and Zhang, Haozhe and Wang, Dan-Qi and Li, Fei and Guo, Meng-Meng and Cai, Yi and Tang, Shi-Di and Wang, Shuang-Ying and Wang, Xing-Huan and Zeng, Xian-Tao and Hu, Hailiang}, doi = {10.1073/pnas.2510386122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2510386122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A PHF19-YTHDC1 condensate switches EZH2-mediated gene suppression to activation for prostate cancer progression}, volume = {122}, year = {2025}, }
• (2025). Logarithmic coding leads to adaptive stabilization in the presence of sensorimotor delays. PNAS, 122(43), e2510385122. (www)

  @article{ , abstract = {Animals respond to sensory stimuli with motor actions, which in turn generate new sensory inputs. This sensorimotor loop is constrained by time delays that impose a trade-off between responsiveness and stability. Additionally, as the relationship between a motor command and the corresponding sensory feedback is context-dependent, the response must be adapted in real time. It is generally believed that this adaptation process relies on an internal model that is continuously updated through prediction error minimization. Here, we experimentally reveal an alternative strategy based on a simpler feedback mechanism that does not require any internal model. We developed a virtual reality system for the miniature transparent fish Danionella cerebrum that enables in vivo brain-wide imaging during fictive navigation. By systematically manipulating the feedback parameters, we dissected the motor control process that allows the animal to stabilize its position using optic flow. The sensorimotor loop can be fully described by a single delay differential equation, whose solutions quantitatively capture the observed behavior across all experimental conditions. Both behavioral and neural data indicate that the observed adaptive response arises from logarithmic nonlinearities at the sensory (Weber–Fechner law) and motor (Henneman’s size principle) ends. These fundamental properties of the nervous system, conserved across species and sensory modalities, have traditionally been interpreted in terms of efficient coding. Our findings unveil a distinct functional role for such nonlinear transformations: ensuring stability in sensorimotor control despite inherent delays and sensory uncertainty.}, archive = {J_PNAS}, author = {Demarchi, Leonardo and Coraggioso, Monica and Hubert, Antoine and Panier, Thomas and Morvan-Dubois, Ghislaine and Bormuth, Volker and Debrégeas, Georges}, doi = {10.1073/pnas.2510385122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2510385122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Logarithmic coding leads to adaptive stabilization in the presence of sensorimotor delays}, volume = {122}, year = {2025}, }
• (2025). Amyloid precursor protein and c99 are subunits in human microglial hv1 channels that enhance current and inflammatory mediator release. PNAS, 122(43), e2509903122. (www)

  @article{ , abstract = {In Alzheimer’s disease (AD), hyperactivated microglia produce inflammatory mediators that contribute to neuroinflammation and neuronal damage. Amyloid precursor protein (APP), a transmembrane protein expressed in many cell types, including neurons and microglia, plays a critical role in AD pathogenesis via its secretase-mediated processing to release the C-terminal 99-residue transmembrane fragment (C99) that is further cleaved to yield amyloid-β peptides. Voltage-gated proton channels (Hv1) have been implicated in microglial activation and release of inflammatory mediators, but the potential role of these channels in human microglia and AD pathogenesis remains unclear. Here, we demonstrate that human induced pluripotent stem cell–derived microglia (iMG) express native Hv1 channels with biophysical and pharmacological attributes determined by their coassembly with APP and that APP knockdown decreases Hv1 currents, suppressing cytokine and reactive oxygen species release. In HEK293T cells, APP is shown to increase current by favoring channel opening at more negative membrane potentials. C99 is sufficient to assemble with Hv1 and alters channel function even more significantly than APP. Coimmunoprecipitation, total internal reflection fluorescence microscopy, and altered pharmacology further demonstrate that C99 forms stable complexes with Hv1 in the plasma membrane. In addition, we find that two early-onset AD mutations in APP (E682K and D694N) that reside within C99 significantly increase voltage-dependent channel activity beyond that induced by wild type C99, rationalizing their enhanced mediation of neuroinflammation.}, archive = {J_PNAS}, author = {Zhao, Ruiming and Sophanpanichkul, Punyanuch and Chadarevian, Jean Paul and Ding, Yiwen and Dai, Hui and Nayak, Maha and Davtyan, Hayk and Blurton-Jones, Mathew and Goldstein, Steve A. N.}, doi = {10.1073/pnas.2509903122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2509903122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Amyloid precursor protein and c99 are subunits in human microglial hv1 channels that enhance current and inflammatory mediator release}, volume = {122}, year = {2025}, }
• (2025). Museum genomics suggests long-term population decline in a putatively extinct bumble bee. PNAS, 122(43), e2509749122. (www)

  @article{ , abstract = {Pollinator declines globally threaten ecosystem stability and agricultural productivity. Reconstructing pollinator historic demographies provides an evolutionary perspective to understand contemporary population declines. The Franklin bumble bee ( Bombus franklini ), once endemic to Oregon and California and last observed alive in 2006, is emblematic of this phenomenon. We collected whole-genome sequence data from museum specimens spanning four decades to elucidate the genetic and demographic history of this potentially extinct species. Heterozygosity estimates of 25 individuals were remarkably low, and runs of homozygosity (ROH) patterns identified short segments suggestive of historical inbreeding, with some individuals having almost entire chromosomes in ROH. Demographic reconstructions revealed a marked decline in effective population size beginning in the late Pleistocene, with further declines in the last 400 y, which may have been influenced by fire and drought stressors. We found little to no genomic evidence implicating pathogens in the species’ decline and used coalescent simulations to show that we would be able to detect recently reduced heterozygosity only when colony-level survival rates are 15 to 30%. We conclude that a combination of historically low effective population size and genetic diversity along with environmental stochasticity heightened this species’ extinction vulnerability prior to recent anthropogenic stressors. This study demonstrates the utility of museum collections for clarifying genetic and demographic dynamics of rare species and suggests that B. franklini may have already been on a trajectory of decline prior to human impacts.}, archive = {J_PNAS}, author = {Schweizer, Rena M. and Grummer, Jared A. and Tobin, Kerrigan B. and Corpuz, Renee and Geib, Scott M. and Cox-Foster, Diana and Kimsey, Lynn S. and Koch, Jonathan B. Uhuad and Branstetter, Michael G.}, doi = {10.1073/pnas.2509749122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2509749122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Museum genomics suggests long-term population decline in a putatively extinct bumble bee}, volume = {122}, year = {2025}, }
• (2025). Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors. PNAS, 122(43), e2509412122. (www)

  @article{ , abstract = {Myeloid-biased differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) occurs with aging or exhaustion. The molecular mechanism(s) responsible for this fate bias remain unclear. Here, we report that linker histone regulates HSPC fate choice at the lymphoid versus myeloid bifurcation. Linker histones package nucleosomes and compact chromatin. HSPCs expressing a doxycycline (dox)-inducible H1.0 transgene favor the lymphoid fate, display strengthened nucleosome organization, and reduced chromatin accessibility at subsets of genomic regions. The genomic regions showing reduced chromatin accessibility host many known marker genes of myeloid-biased HSCs. The transcription factor Hlf is located in one of the most differentially closed regions, whose chromatin accessibility and gene expression are reduced in H1.0 high HSPCs. Failure to reduce Hlf expression in multipotential HSPCs abrogates the H1.0-endowed lymphoid potential. Furthermore, HSPCs display aspartyl protease–dependent H1.0 decreases, especially in response to interferon alpha (IFNα). Aspartyl protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, our work elucidates a molecular scenario of how myeloid bias arises and uncovers a point of intervention for correcting myeloid skewed hematopoiesis.}, archive = {J_PNAS}, author = {Karatepe, Kutay and Mafra de Faria, Bruna and Zhang, Jian and Chen, Xinyue and Pinto, Hugo and Fyodorov, Dmitry and Sefik, Esen and Willcockson, Michael A. and Flavell, Richard A. and Skoultchi, Arthur I. and Guo, Shangqin}, doi = {10.1073/pnas.2509412122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2509412122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors}, volume = {122}, year = {2025}, }
• (2025). Dual-site cooperation for synergistic optimization of the band structure and spin state to facilitate C–N coupling reaction. PNAS, 122(43), e2508077122. (www)

  @article{ , abstract = {The emerging electrocatalytic C–N coupling reaction provides an attractive route toward green urea synthesis, but a lack of in-depth insight into the catalytic mechanism and the geometric/electronic configurations that determine the key C- and N-coupling intermediates formation hampers the exploration of efficient catalysts. Herein, we design a bimetallic oxide (Fe-Mo-O) with dual active sites of Fe and Mo for the adsorption and activation of NO 2 − and CO 2 , respectively. Constructing dual-metal catalyst leads to an upshift of the d-band center and the generation of an intermediate-spin Fe center, which not only favors the selective conversion of *CO 2 into the key intermediate *CO on Mo sites, but also facilitates the adsorption and reduction of NO 2 − on Fe sites. Operando characterizations and theoretical calculations together elucidate that urea generation is associated with the formation of *CONH 2 intermediate by coupling *CO and *NH 2 on the alternating Mo and intermediate-spin Fe active sites, ultimately synergistically lowering the C–N coupling energy barrier. Specifically, the Fe-Mo-O catalyst delivers a high urea yield rate of 681.8 μg h −1 mg −1 cat. and an excellent Faradaic efficiency of 60% at −0.5 V (vs. RHE). Furthermore, a C–N coupling paired with a glycerol oxidation system allows for energy-saving electrochemical coproduction of urea and formic acid. Our findings offer a feasible strategy to develop cutting-edge electrocatalysts for urea synthesis by active site design and electronic structure regulation.}, archive = {J_PNAS}, author = {Qian, Qizhu and Liu, Qilong and Wang, Mengxiang and Yang, Jingjing and Li, Huiyi and Bai, Wei and Wang, Wentao and Wu, Changzheng and Xiao, Chong and Xie, Yi}, doi = {10.1073/pnas.2508077122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2508077122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dual-site cooperation for synergistic optimization of the band structure and spin state to facilitate C–N coupling reaction}, volume = {122}, year = {2025}, }
• (2025). From retinotopic to ordinal coding: Dissecting the cortical stages of visual word recognition. PNAS, 122(43), e2507291122. (www)

  @article{ , abstract = {Fluent reading requires the brain to precisely encode the positions of letters within words, distinguishing for instance FORM and FROM across variations in size, position, and font. Early visual areas, however, are known to encode retinotopic positions, and how these representations get transformed into a position-invariant neural code remains unclear. Building upon a computational model of reading, we used 7T functional MRI and magnetoencephalography (MEG) to reveal a cortical hierarchy in which early visual areas (V1–V4) predominantly encode retinotopic information, whereas higher-level regions, including the visual word form area, transition to an ordinal letter-position code. MEG analyses confirm that retinotopic encoding emerges early (60 to 200 ms), followed by a shift toward ordinal representations in later time windows (220 to 450 ms). Despite this transition, word position remained a dominant factor across all time points, suggesting a concurrent coding of both retinotopic and abstract positional information. These findings uncover the spatiotemporal dynamics by which the human brain transforms visual input into structured prelexical representations, shedding light on the cortical stages of reading and their developmental and clinical implications.}, archive = {J_PNAS}, author = {Agrawal, Aakash and Dehaene, Stanislas}, doi = {10.1073/pnas.2507291122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2507291122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {From retinotopic to ordinal coding: Dissecting the cortical stages of visual word recognition}, volume = {122}, year = {2025}, }
• (2025). Magnon-induced electric polarization and magnon nernst effects. PNAS, 122(43), e2507255122. (www)

  @article{ , abstract = {Magnons offer a promising path toward energy-efficient information transmission and the development of next-generation classical and quantum computing technologies. However, efficiently exciting, manipulating, and detecting magnons remains a critical need. We show that magnons, despite their charge-neutrality, can induce electric polarization through their spin and orbital moments. This effect is governed by system symmetry, magnon band hybridization, and interactions with other quasiparticles. We calculate the electric polarization induced by magnons in two-dimensional collinear honeycomb and noncollinear antiferromagnets (AFMs), showing that the presence of the Dzyaloshinskii–Moriya interaction yields a finite net electric polarization. In NiPSe 3 , a collinear honeycomb AFM with Zigzag order, the induced net electric polarization is about three orders of magnitude greater than in MnPS 3 , a collinear honeycomb AFM with Néel phase. In the noncollinear AFM KFe 3 (OH) 6 (SO 4 ) 2 , the net electric polarization can be tuned via magnon hybridization, which can be controlled by external magnetic fields. These findings reveal that electric fields could be used to both detect and manipulate magnons under certain conditions by leveraging their spin and orbital angular moment. They also suggest that the discovery or engineering of materials with substantial magnon orbital moments could enhance practical uses of magnons for future computing and information transmission applications.}, archive = {J_PNAS}, author = {To, D. Quang and Garcia-Gaitan, Federico and Ren, Yafei and Zide, Joshua M. O. and Jungfleisch, M. Benjamin and Xiao, John Q. and Nikolić, Branislav K. and Bryant, Garnett W. and Doty, Matthew F.}, doi = {10.1073/pnas.2507255122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2507255122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Magnon-induced electric polarization and magnon nernst effects}, volume = {122}, year = {2025}, }
• (2025). Aberrant x chromosome dosage compensation causes hybrid male inviability in caenorhabditis. PNAS, 122(43), e2507166122. (www)

  @article{ , abstract = {Zygotic reproductive isolation frequently initiates with hybrid incompatibility in the heterogametic sex, such as males in XX/XY systems. The genetic basis of hybrid male incompatibility has long remained elusive. Here, we show that crosses of Caenorhabditis nigoni males with C. briggsae females result in insufficient expression of Cbr-xol-1 , an X-linked master switch responsible for intimately linked sex determination and dosage compensation pathways, consequently triggering aberrant X-chromosome repression in males, and ultimately leading to embryonic inviability. In contrast, male embryos from the reciprocal cross maintain normal expression level of C. nigoni xol-1 genes, consistent with their viability. We further demonstrate that the cis-regulatory regions of Cbr-xol-1 and Cni-xol-1 have functionally diverged. Finally, X transcription is also aberrantly repressed in lethal hybrid male embryos from crosses between gonochoristic species C. latens and C. remanei . Our results suggest an evolutionary scenario in which incompatibility of the dosage compensation system leads to reproductive isolation.}, archive = {J_PNAS}, author = {Li, Yongbin and Gao, Yimeng and Ma, Jiaonv and Gao, Yifan and Tang, Jiemei and Yang, Rui and Wang, Jiajia and Zhou, Wangyan and Zhang, Hantang and Shao, Wenhua and Liu, Zhijin and Zhao, Zhongying and Liu, Xiao}, doi = {10.1073/pnas.2507166122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2507166122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Aberrant x chromosome dosage compensation causes hybrid male inviability in caenorhabditis}, volume = {122}, year = {2025}, }
• (2025). Joint disruption of ret and ednrb transcription shifts cell fate trajectories in the enteric nervous system in hirschsprung disease. PNAS, 122(43), e2507062122. (www)

  @article{ , abstract = {Despite extensive genetic heterogeneity, 72% of pathogenic alleles for Hirschsprung disease (HSCR) arise from coding and regulatory variants in genes of the RET and EDNRB gene regulatory network (GRN) in the enteric nervous system (ENS). To elucidate the mechanisms leading to enteric neuronal loss from these genetic defects, we generated four strains of mice carrying reduced function alleles at Ret or Ednrb or both, along with their wild-type alleles. ENS tissue- and single-cell gene expression profiling of the developing and postnatal gastrointestinal tract in these five mouse models revealed three major insights: i) Ret and Ednrb deficiency, rather than complete loss, is sufficient to induce HSCR, ii) Ret and Ednrb demonstrate strong trans interactions, and iii) disruption of this interaction leads to cellular fate changes to compensate for neuronal loss. Critically, we show the combined reduction of signaling of these two receptors below a threshold in enteric neural crest-derived cells (ENCDCs) leads to a molecular tipping point at which otherwise lesser cellular defects result in aganglionosis. This study of targeted mouse models of a multifactorial disorder reveals how increasing dosage of genetic defects within a GRN leads to quantifiably increasing dysregulation from genotype to gene expression to cellular identity to function. Importantly, our studies establish that aganglionosis results only with severely reduced gene expression at both receptor genes and their consequent disruption of normal and compensatory cell fate trajectories.}, archive = {J_PNAS}, author = {Fine, Ryan D. and Chubaryov, Rebecca and Fu, Mingzhou and Grullon, Gabriel and Chakravarti, Aravinda}, doi = {10.1073/pnas.2507062122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2507062122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Joint disruption of ret and ednrb transcription shifts cell fate trajectories in the enteric nervous system in hirschsprung disease}, volume = {122}, year = {2025}, }
• (2025). A national randomized controlled trial of the impact of public montessori preschool at the end of kindergarten. PNAS, 122(43), e2506130122. (www)

  @article{ , abstract = {Although seminal studies from the early 1960s suggested quality preschool can have lasting positive effects, agreement is lacking on the efficacy of different preschool models. The Montessori model is longstanding but lacks rigorous impact studies; prior random lottery studies included just one or two schools, among other compromises. Here, we report on end-of-kindergarten (age 5 to 6) impacts from a national study of public Montessori preschool. We compared children offered a Montessori seat via competitive lottery admission processes at one of 24 public Montessori schools at age 3 ( n = 242 ) to children not offered a seat ( n = 346 ), estimating Montessori impacts with intention-to-treat and complier average causal effect models. Roughly half of the treatment sample still attended Montessori for kindergarten. Although there were no notable impacts at the end of PK3 or PK4, at the end of kindergarten, controlling for baseline scores and demographics, Montessori children had significantly higher reading, short-term memory, theory of mind, and executive function scores. Intention-to-treat effect sizes exceeded a fifth of a SD, considered large in field-based school research [M. A. Kraft, Educ. Res. 49 , 241–253 (2020)]. This contrasts sharply with the more typical finding, where impacts of preschool are observed immediately following the program but disappear by the end of kindergarten. Further, a cost analysis suggested three years of public Montessori preschool costs less per child than traditional programs, largely due to Montessori having higher child:teacher ratios in PK3 and PK4. Although sensitivity and robustness analyses yielded similar results, important limitations of the study should be noted.}, archive = {J_PNAS}, author = {Lillard, Angeline S. and Loeb, David and Berg, Juliette and Escueta, Maya and Manship, Karen and Hauser, Alison and Daggett, Emily D.}, doi = {10.1073/pnas.2506130122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2506130122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A national randomized controlled trial of the impact of public montessori preschool at the end of kindergarten}, volume = {122}, year = {2025}, }
• (2025). Therapeutic IgG- and IgM-specific proteases disarm the acetylcholine receptor autoantibodies that drive myasthenia gravis pathology. PNAS, 122(43), e2505984122. (www)

  @article{ , abstract = {Myasthenia gravis (MG) is an autoimmune disorder caused mainly by autoantibodies against the acetylcholine receptor (AChR), leading to muscle weakness. While treatments targeting AChR autoantibodies benefit many, some patients remain refractory, highlighting the need for personalized therapies. This study evaluates the therapeutic potential of S-1117, a pan-IgG-specific protease, in AChR autoantibody-mediated pathology. Using live cell-based assays, we examined AChR-specific monoclonal IgG autoantibodies (mAbs) and patient-derived serum samples for their effects on receptor binding, blockade, internalization, and complement activation, before and after treatment with S-1117. S-1117 effectively removed the crystallizable fragment (Fc)γ from both mAbs and serum IgG, impairing Fcγ-mediated complement activation in both soluble and antigen-bound forms. In cases with partial complement reduction, AChR-specific IgM contributed to complement deposition. AChR-IgM acted in concert with IgG in some patients to enhance complement deposition, while acting as main complement driver in others. An IgM-specific protease completely suppressed the pathogenic effects of AChR-IgM in two independent patient cohorts. These findings highlight the therapeutic potential of S-1117 in neutralizing AChR-IgG Fcγ-mediated effector functions and reveal an MG subset driven by IgM pathology. Our study shows that targeting both IgG- and IgM-mediated mechanisms with therapeutic proteases provides an approach to MG treatment and establishes a framework for patient stratification based on disease mechanisms, advancing precision medicine in MG.}, archive = {J_PNAS}, author = {Bayer, Alexandra C. and Sanmarco, Liliana M. and Pellerin, Alex and Masi, Gianvito and Plasencia, Agustin and Anderson, Jordan M. and Nowak, Richard J. and Damato, Valentina and Massacesi, Luca and Pham, Minh C. and Khani-Habibabadi, Fatemeh and Vital, Heather and Higginson-Scott, Nathan and Otipoby, Kevin L. and Xing, Yi and Mascanfroni, Ivan D. and O’Connor, Kevin C.}, doi = {10.1073/pnas.2505984122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2505984122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Therapeutic IgG- and IgM-specific proteases disarm the acetylcholine receptor autoantibodies that drive myasthenia gravis pathology}, volume = {122}, year = {2025}, }
• (2025). Proteolytically activated antibacterial toxins inhibit the growth of diverse gram-positive bacteria. PNAS, 122(43), e2505807122. (www)

  @article{ , abstract = {Many species of bacteria produce small-molecule antibiotics that enter and kill a wide range of competitor microbes. However, diffusible antibacterial proteins (ABPs) that share this broad-spectrum activity are not known to exist. Here, we report a family of proteins widespread in gram-positive bacteria that display potent antibacterial activity against a diverse range of target organisms. Upon entering susceptible cells, these ABPs enzymatically degrade essential cellular components including DNA, transfer ribonucleic acid (tRNA), and ribosomal ribonucleic acid (rRNA). Unlike previously characterized bactericidal proteins, which require a specific cell surface receptor and therefore display a narrow spectrum of activity, we find that ABPs act in a receptor-independent manner and consequently kill bacteria spanning multiple phyla. Target cell entry by ABPs requires proteolytic activation by a cognate, coexported serine protease, and the liberated toxin component of the cleaved ABP is driven across the target cell membrane by the proton motive force. By examining representative ABPs from diverse pathogenic, commensal, and environmental bacteria, we show that broad-spectrum antibacterial activity is a conserved property of this protein family. Collectively, our work demonstrates that secreted proteins can act as broad-spectrum antibiotics, suggesting that ABPs represent one of potentially many such families produced in nature.}, archive = {J_PNAS}, author = {Colautti, Jake and Garrett, Stephen R. and Whitney, John C.}, doi = {10.1073/pnas.2505807122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2505807122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Proteolytically activated antibacterial toxins inhibit the growth of diverse gram-positive bacteria}, volume = {122}, year = {2025}, }
• (2025). Impact of baleen whales on ocean primary production across space and time. PNAS, 122(43), e2505563122. (www)

  @article{ , abstract = {Primary production in the ocean is a fundamental process that supports marine food webs and global carbon sequestration. This process depends on nutrients that are often limited in surface waters. Whales are known to release essential elements such as nitrogen, phosphorus, and iron, yet the extent of their contribution to ocean primary production remains unclear. Here, we present daily estimates of nutrient input by baleen whales in high-latitude feeding grounds (Nordic and Barents Seas), based on multielement analyses of feces and urine. We then used end-to-end ecosystem models to assess the impact of these nutrients on primary production. We found that nitrogen is primarily excreted via urine, whereas phosphorus and trace elements are mainly released through feces. Ecosystem models indicate that baleen whales, including minke, fin, sei, humpback, blue, and bowhead whales, support annual and seasonal net primary production, with varying impacts across space and time. While the annual effects are modest (<2%) in most areas, the greatest impacts (up to 10%) occur during summer stratification and in offshore areas far from other nutrient sources. These increases in primary production have cascading effects on the food web, driving rises in mesozooplankton biomass. This study highlights the ecological significance of nutrient cycling by whales and underscores the value of integrating whale nutrient data into ecosystem modeling to assess the broader impacts of whales on marine productivity.}, archive = {J_PNAS}, author = {Freitas, Carla and Skogen, Morten D. and Sigurðsson, Guðjón M. and Biuw, Martin and Haug, Tore and Lindblom, Lotta and Gundersen, Kjell}, doi = {10.1073/pnas.2505563122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2505563122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Impact of baleen whales on ocean primary production across space and time}, volume = {122}, year = {2025}, }
• (2025). Differential O-glucose elongation on a specific EGF repeat within the canonical ligand–binding domain regulates DLL1/4-NOTCH1 signaling. PNAS, 122(43), e2504827122. (www)

  @article{ , abstract = {Three types of O -linked glycosylation— O -glucose, O -fucose, and O - N -acetylglucosamine— are crucial for the function of Notch receptors, which regulate critical cell fate determination processes in a wide variety of contexts. O -Glucose glycans are transferred to serine residues located between the first and second conserved cysteines within the epidermal growth factor-like (EGF) repeats in the Notch extracellular domain. Previously, O -glucose glycans were shown to be extended to a trisaccharide structure with two xyloses via α1-3 linkages. Our recent studies, however, indicated that the O -glucose glycan on NOTCH1 EGF10 can be extended by hexose and Neu5Ac. Here, we demonstrated that this hexose- and Neu5Ac-extended glycan has a 3’-sialyllactose-like structure synthesized by specific members of two isoenzyme families, B4GALT1 and ST3GAL4. Using mass spectrometry, we identified this modification exclusively on NOTCH1 EGF10 and the analogous NOTCH3 EGF9 domain, with no detection in any other EGF domains in NOTCH1, NOTCH2, and NOTCH3. Sequence comparison and mutagenesis experiments identified one amino acid at position -2 of the fourth cysteine (C 4 -2) in the EGF domain as crucial for the galactose elongation of O -glucose glycans. We further demonstrated that this site-specific elongation of O -glucose on NOTCH1 EGF10 significantly impacts ligand binding and signal transduction of NOTCH1. In the context of early T cell development, the C 4 -2 mutants NOTCH1 A396Y and A396F enhance T cell differentiation through DLL1- and DLL4-dependent NOTCH1 signaling. Our findings contribute to the understanding of the intricate regulatory mechanisms of Notch receptor function mediated by distinct positions and structures of O -glycans.}, archive = {J_PNAS}, author = {Tsukamoto, Yohei and Aoki, Kazuhiro and Kama, Yuichi and Hosokawa, Hiroyuki and Saiki, Wataru and Tsukamoto, Natsumi and Kato, Koki and Hosokawa, Yohei and Sato, Rie and Uesugi, Naoki and Fujita, Yuki and Fukazawa, Kana and Funada, Daichi and Suzuki, Fuga and Kurebayashi, Yuuki and Urata, Yusuke and Uchiyama, Sae and Wang, Weiwei and Minami, Akira and Takahashi, Tadanobu and Tiemeyer, Michael and Narimatsu, Yoshiki and Okajima, Tetsuya and Takeuchi, Hideyuki}, doi = {10.1073/pnas.2504827122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2504827122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Differential O-glucose elongation on a specific EGF repeat within the canonical ligand–binding domain regulates DLL1/4-NOTCH1 signaling}, volume = {122}, year = {2025}, }
• (2025). Driving forces of RNA condensation revealed through coarse-grained modeling with explicit mg2+. PNAS, 122(43), e2504583122. (www)

  @article{ , abstract = {RNAs are major drivers of phase separation in the formation of biomolecular condensates and can undergo protein-free phase separation in the presence of divalent ions or crowding agents. Much remains to be understood regarding how the complex interplay of base stacking, base pairing, electrostatics, ion interactions, and particularly structural propensities governs RNA phase behavior. Here, we develop an intermediate resolution model for condensates of RNAs (iConRNA) that can capture key local and long-range structural features of dynamic RNAs and simulate their spontaneous phase transitions with Mg 2+ . Representing each nucleotide using 6 to 7 beads, iConRNA accurately captures base stacking and pairing and includes explicit Mg 2+ . The model not only reproduces major conformational properties of poly(rA) and poly(rU) but also correctly folds small structured RNAs and predicts their melting temperatures. With an effective model of explicit Mg 2+ , iConRNA successfully recapitulates experimentally observed lower critical solution temperature phase separation of poly(rA) and triplet repeats, and critically, the nontrivial dependence of phase transitions on RNA sequence, length, concentration, and Mg 2+ level. Further mechanistic analysis reveals a key role of RNA folding in modulating phase separation as well as its temperature and ion dependence, besides other driving forces such as Mg 2+ –phosphate interactions, base stacking, and base pairing. These studies also support iConRNA as a powerful tool for direct simulation of RNA-driven phase transitions, enabling molecular studies of how RNA conformational dynamics and its response to complex condensate environments control the phase behavior and condensate material properties.}, archive = {J_PNAS}, author = {Li, Shanlong and Chen, Jianhan}, doi = {10.1073/pnas.2504583122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2504583122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Driving forces of RNA condensation revealed through coarse-grained modeling with explicit mg2+}, volume = {122}, year = {2025}, }
• (2025). Cytosolic proliferating cell nuclear antigen (PCNA) orchestrates neutrophil hyperactivation in COVID-19. PNAS, 122(43), e2503667122. (www)

  @article{ , abstract = {Neutrophils are central mediators of the hyperinflammatory response in severe SARS-CoV-2 infection. We report elevated cytosolic levels of proliferating cell nuclear antigen (PCNA) in neutrophils from patients with severe and critical COVID-19, correlating with enhanced NADPH oxidase–dependent reactive oxygen species (ROS) generation and neutrophil extracellular trap (NET) formation. Using T2AA, a small-molecule inhibitor of the PCNA scaffold, we demonstrate potent suppression of NADPH oxidase activation and NET release, particularly in response to SARS-CoV-2 RNA. Mechanistically, we identify a previously unrecognized interaction between PCNA and the heterodimeric S100A8/S100A9 (calprotectin), predominantly enriched in CD16 high CD62L low neutrophils expanded during COVID-19. PCNA binds the dimeric S100A8/S100A9 complex mediated via S100A8 subunit with micromolar affinity, and this interaction is abrogated by tetramerization, suggesting regulation by intracellular calcium. Disruption of this complex by T2AA inhibited ROS production in an S100A8/S100A9-dependent manner, implicating calprotectin as a functional regulator of neutrophil activation. In a betacoronavirus mouse model, T2AA treatment attenuated lung inflammation, reduced NET and calprotectin levels, and shifted pulmonary neutrophils away from hyperactivated and immunosuppressive phenotypes, consistent with immune reprogramming toward resolution. These findings establish cytosolic PCNA as a central scaffold in neutrophil hyperactivation during COVID-19 and highlight its pharmacological disruption as a promising host-directed strategy to limit inflammation and prevent organ damage.}, archive = {J_PNAS}, author = {Formiga, Rodrigo de Oliveira and Pesenti, Lucie and de la Héronnière, François Chable and Ladjemi, Maha Zohra and Stojkov, Darko and Yousefi, Shida and Frachet, Philippe and Krafft, Lisa and Tiberio, Laura and Bosisio, Daniela and Andrieu, Muriel and Many, Souganya and Karunanithy, Vaarany and Bailly, Karine and Dhôte, Théo and Saraceni-Tasso, Giovanni and Castel, Manon and Rousseau, Christophe and Starick, Marick Rodrigues and da Rocha, Edroaldo Lummertz and Lombardi, Emilia Puig and Almeida, Cicero José Luíz dos Ramos and Ramos, Anderson dos Santos and Cunha, Fernando Queiroz and Alves-Filho, José Carlos and Nóbrega, Natália Ribeiro Cabacinha and Gonçalves, Matheus Rodrigues and Queiroz-Junior, Celso Martins and Lima Batista, Viviane and Teixeira, Mauro Martins and Granger, Vanessa and Chollet-Martin, Sylvie and Chaisemartin, Luc De and Mouthon, Luc and Hosmalin, Anne and Hurtado-Nedelec, Margarita and Martin, Clémence and Spiller, Fernando and Simon, Hans-Uwe and Tamassia, Nicolas and Cassatella, Marco Antonio and Pène, Frédéric and Vogl, Thomas and Burgel, Pierre-Regis and Costa, Vivian Vasconcelos and Witko-Sarsat, Véronique}, doi = {10.1073/pnas.2503667122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2503667122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cytosolic proliferating cell nuclear antigen (PCNA) orchestrates neutrophil hyperactivation in COVID-19}, volume = {122}, year = {2025}, }
• (2025). Descattering and image restoration with a transformer-based neural network in deep tissue imaging. PNAS, 122(43), e2503576122. (www)

  @article{ , abstract = {Imaging biological structures deep inside tissues is crucial but challenging due to common light scattering. This study proposes a multiattention network that directly maps degraded scattering two-photon excitation fluorescence (TPEF) images to high-quality scattering-free images, thereby computationally extending the imaging depth for TPEF without requiring complex optical additions. The model relies solely on simulated data rather than well-registered real data pairs, and is trained to descatter and restore hidden spatial information at greater depths. Quantitative evaluations on simulated fluorescent beads and vasculature show significant performance improvements in peak signal-to-noise ratio (23 to 29 dB) and structural similarity index (23×) compared to the raw data. We also apply the framework to various ex vivo and in vivo experiments, achieving clear visualization of lipid droplets up to a depth of 1,300 μm and of vascular structure and astrocytes up to 950 μm and 500 μm, respectively, in live mouse brains at lower excitation powers.}, archive = {J_PNAS}, author = {Xu, Xiangcong and Zhang, Renlong and Luo, Chenggui and Zhang, Chi and Li, Yanping and Lin, Danying and Yu, Bin and Liu, Liwei and Weng, Xiaoyu and Wang, Yiping and Kong, Lingjie and Li, Jia and Qu, Junle}, doi = {10.1073/pnas.2503576122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2503576122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Descattering and image restoration with a transformer-based neural network in deep tissue imaging}, volume = {122}, year = {2025}, }
• (2025). Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer. PNAS, 122(43), e2503387122. (www)

  @article{ , abstract = {Lamin A/C ( LMNA ), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie et al. , Curr. Biol. 26 , 2651–2658 (2016)]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano et al. , Nucleus 9 , 258–275 (2018)]. Here, we define a mechanistic role for LMNA in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi et al. , Cancer Res. Commun. 2 , 503–517 (2022)]. LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. LMNA expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low LMNA levels correlate with poor clinical outcomes. These findings establish LMNA as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.}, archive = {J_PNAS}, author = {Schultz, Christopher W. and Saha, Sourav and Dhall, Anjali and Zhang, Yang and Desai, Parth and Pongor, Lorinc S. and Scheiblin, David A. and Magidson, Valentin and Shuklah, Ravi P. and Sebastian, Robin and Vekariya, Umeshkumar M. and Ahmed, Shahbaz and Sun, Yilun and Redon, Christophe and Kumar, Suresh and Krishnamurthy, Manan and Dias, Henrique B. and Aksenova, Vasilisa and Giordano, Elizabeth and Takahashi, Nobuyuki and Nirula, Michael and Arora, Mohit and Tabe, Chiori and Thomas, Maria Sebastian and Kumar, Rajesh and Arakawa, Yasuhiro and Jo, Ukhyun and Skorski, Tomasz and Teicher, Beverly A. and Shreshta, Roshan and Aladjem, Mirit I. and Lockett, Stephen and Dasso, Mary and Pommier, Yves and Sharma, Ajit K. and Thomas, Anish}, doi = {10.1073/pnas.2503387122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2503387122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer}, volume = {122}, year = {2025}, }
• (2025). Climate change impacts on tropical cyclone–induced power outage risk: Sociodemographic differences in outage burdens. PNAS, 122(43), e2502266122. (www)

  @article{ , abstract = {This research investigates the projected risks of future climate trends on tropical cyclone–induced power outages in the Gulf and Atlantic coast of the United States, focusing on the disproportionate impacts on vulnerable populations and the economic burdens associated with such events. Our methodology integrates four well-documented models to estimate changes in power outage rates, sociodemographic inequities, and economic costs due to tropical cyclone projections. Synthetic tropical cyclones were generated using data from seven global climate models (GCMs), used to compare power outage risks at the census tract level along two periods: hindcast (1995–2014) and late-century (2071–2100) using the SSP5-8.5 scenario. The late-century results from each model were scaled to align with a global warming scenario of 3 °C. We evaluated the uncertainty of these projections by considering the agreement among the GCMs outage projections. Results highlight a significant increase in power outage risks and high agreement in northern Florida, Georgia, the mid-Atlantic, and the North Atlantic coast. Distributional impact analyses indicate higher outage risks for Hispanic, non-White, and low-income populations, while economic projections show annual costs rising from $6.2 billion in the hindcast to over $11 billion for the 3 °C scenario. The findings highlight the need for adaptive strategies and equitable resource allocation to mitigate these growing risks due to future climate projections.}, archive = {J_PNAS}, author = {Guikema, Seth and Pagan-Cajigas, Zaira and Fant, Charles and Boehlert, Brent and Maier, C. X. and Emanuel, Kerry and Hartin, Corinne and Sarofim, Marcus C.}, doi = {10.1073/pnas.2502266122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2502266122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Climate change impacts on tropical cyclone–induced power outage risk: Sociodemographic differences in outage burdens}, volume = {122}, year = {2025}, }
• (2025). Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3. PNAS, 122(43), e2501825122. (www)

  @article{ , abstract = {Intracellular pH (pHi) influences diverse cellular processes, including cell proliferation, metabolism, and migration, and is linked to metabolic diseases and cancer. Protonation alters protein charge and conformation, modulating different aspects of protein function. How pHi fluctuations are sensed by signaling proteins and translated into cellular responses remains incompletely understood. Here, we reveal that pHi plays a key role in regulating the stability of the mitogen-activated protein kinase Extracellular signal-regulated kinase 3 (ERK3). Intracellular acidification markedly increases the half-life of ERK3, whereas alkalinization accelerates its degradation. The pH-dependent regulation of ERK3 is rapid, reversible, and consistent across cell types. Mechanistically, we identified a region in the C-terminus of ERK3 that contains pH-sensing motifs. We further show by quantitative proteomics that short-term acidification or alkalinization globally affects the cellular proteome. Our findings underscore the critical role of pHi in ERK3 turnover and suggest a broader role for pH in regulating protein stability and cell signaling.}, archive = {J_PNAS}, author = {Tesnière, Chloé and Boudghene-Stambouli, Fadia and Severin, Marc and Poët, Mallorie and Voisin, Laure and Ponniah, Muthulakshmi and Pascariu, Mirela and Bonneil, Eric and Trempe, Jean-François and Thibault, Pierre and Counillon, Laurent and Pedersen, Stine Falsig and Meloche, Sylvain}, doi = {10.1073/pnas.2501825122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2501825122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3}, volume = {122}, year = {2025}, }
• (2025). Hierarchical self-assembly for high-yield addressable complexity at fixed conditions. PNAS, 122(43), e2500245122. (www)

  @article{ , abstract = {There is evidence that the self-assembly of complex molecular systems often proceeds hierarchically, by first building subunits that later assemble in larger entities, in a process that can repeat multiple times. Yet, our understanding of this phenomenon and its performance is limited. Here, we introduce a simple model for hierarchical addressable self-assembly, where interactions between particles can be optimized to maximize the fraction of a well-formed target structure, or yield. We find that a hierarchical strategy leads to an impressive yield up to at least five generations of the hierarchy and does not require a cycle of temperatures as used in previous methods. High yield is obtained when the microscopic interaction decreases with the scale of units considered, such that the total interaction between intermediate structures remains identical at all scales. We provide thermodynamic and dynamical arguments constraining the interaction strengths where this strategy is effective. Overall, our work characterizes an alternative strategy for addressable self-assembly at a fixed temperature, and provides insight into the mechanisms sustaining hierarchical assembly in biological systems.}, archive = {J_PNAS}, author = {Holmes-Cerfon, Miranda and Wyart, Matthieu}, doi = {10.1073/pnas.2500245122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2500245122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hierarchical self-assembly for high-yield addressable complexity at fixed conditions}, volume = {122}, year = {2025}, }
• (2025). Single-cell sequencing uncovers sensory neuron–mediated CGRP signaling as a driver of sarcoma progression. PNAS, 122(43), e2500161122. (www)

  @article{ , abstract = {Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, skewed tumor associated macrophage polarization, reduced tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multiomics analyses of human OS bone samples further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. Next and in two parallel approaches to inhibit nerve ingrowth, we repurposed FDA-approved bupivacaine liposomes and separately blocked CGRP signaling using FDA-approved Rimegepant. Both strategies led to significant reductions in sarcoma growth, vascularity, and sarcoma-induced hyperalgesia. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition disrupts CGRP signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of OS represent an adjunctive therapy to improve clinical outcomes and survival.}, archive = {J_PNAS}, author = {Ramesh, Sowmya and Qin, Qizhi and Li, Zhao and Cherief, Masnsen and Zhong, Lingke and Archer, Mary and Xing, Xin and Thottappillil, Neelima and Balaji, Devadutta and Bae, Sam and Gomez-Salazar, Mario and Xu, Mingxin and Zhu, Manyu and Uniyal, Ankit and Chang, Leslie and Mazhar, Khadijah and Mittal, Monisha and Birbrair, Alexander and McCarthy, Edward F. and Morris, Carol D. and Levi, Benjamin and Guan, Yun and Clemens, Thomas L. and Price, Theodore J. and James, Aaron W.}, doi = {10.1073/pnas.2500161122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2500161122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Single-cell sequencing uncovers sensory neuron–mediated CGRP signaling as a driver of sarcoma progression}, volume = {122}, year = {2025}, }
• (2025). Smartphone use in a large US adult population: Temporal associations between objective measures of usage and mental well-being. PNAS, 122(43), e2427311122. (www)

  @article{ , abstract = {Smartphones are essential tools in daily life yet concerns persist about their potential effects on mental health and well-being. Research on these relationships often relies on subjective measures of smartphone use, which can lack validity. These studies are also often limited by small, homogenous samples and the inability to differentiate between types of smartphone activities (e.g., social media vs. other applications). In this study, we analyzed 250,000 d of smartphone usage data from 10,099 adults, using objective measures of smartphone usage collected over 4 wk. We examined normative usage patterns and the temporal relationships between smartphone use and mood. Our findings reveal weak or null associations between smartphone use and mood, both cross-sectionally and longitudinally, and at both individual and group levels. Demographic factors, such as age and gender, were stronger predictors of mood than smartphone use. Statistically significant results that were observed showed that younger adults demonstrated a stronger association between social media use and lower mood cross-sectionally, but not longitudinally. Non-social app use was linked to lower mood in between-subjects analyses, but better mood in within-subjects analyses. However, all effects were small (or null), indicating minimal practical significance. These findings suggest that smartphone use has a limited or negligible impact on mood and well-being over a 4-wk period and do not support claims of a strong or causal relationship between smartphone use and mental well-being across this timeframe.}, archive = {J_PNAS}, author = {Winbush, Ari and McDuff, Daniel and Hernandez, John and Barakat, Andrew and Jiang, Allen and Heneghan, Conor and Nelson, Benjamin W. and Allen, Nicholas B.}, doi = {10.1073/pnas.2427311122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2427311122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Smartphone use in a large US adult population: Temporal associations between objective measures of usage and mental well-being}, volume = {122}, year = {2025}, }
• (2025). Invariant HVC size in female canaries singing under testosterone: Unlocking function through neural differentiation, not growth. PNAS, 122(43), e2426847122. (www)

  @article{ , abstract = {Testosterone administration to nonsinging adult female canaries induces song, making this a model for behavioral plasticity and its underlying neural mechanisms in vertebrates. The song control nucleus HVC is traditionally believed to undergo a substantial size change when transitioning from a nonfunctional to a functional (song-producing) state. Using 2-photon in vivo imaging, we tracked the spatial distribution and anatomical properties of HVC neurons over several weeks of testosterone-induced song development. Surprisingly, despite ultrastructural changes of HVC neurons, testosterone did neither alter neuronal spacing nor HVC size. Instead, spatial transcriptomics revealed that testosterone modulates gene networks throughout HVC, aligning transcriptomic profiles between its peripheral and central HVC regions in singing birds, thereby mimicking the histological appearance of an enlarging HVC. Our results demonstrate that changes in HVC size in adults reflect phenotypic changes in neurons within a stable framework. Importantly, the nonfunctional state is not associated with a reduced brain area volume, preserving HVC’s capacity for functional differentiation throughout life.}, archive = {J_PNAS}, author = {Ma, Shouwen and Frankl-Vilches, Carolina and Gahr, Manfred}, doi = {10.1073/pnas.2426847122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2426847122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Invariant HVC size in female canaries singing under testosterone: Unlocking function through neural differentiation, not growth}, volume = {122}, year = {2025}, }
• (2025). Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway–dependent Rho/ROCK signaling. PNAS, 122(43), e2424904122. (www)

  @article{ , abstract = {Certain TP53 mutations can confer neomorphic gain of function (GOF) activities to the p53 protein that affect cancer progression. Yet the concept of mutant p53 GOF has been challenged. Here, using various strategies to alter the status of mutant versions of p53 in different cell lines, we demonstrate that mutant p53 stimulates cancer cell invasion in three-dimensional environments. Mechanistically, mutant p53 enhances RhoA/ROCK-dependent cell contractility and cell-mediated extracellular matrix (ECM) reorganization via increasing mevalonate pathway–dependent RhoA localization to the membrane. In line with this, RhoA-dependent proinvasive activity is also mediated by IDI-1, a mevalonate pathway product. Further, the invasion-enhancing effect of mutant p53 is dictated by the biomechanical properties of the surrounding ECM, thereby adding a cell-independent layer of regulation to mutant p53 GOF activity that is mediated by dynamic reciprocal cell–ECM interactions. Together our findings link mutant p53 metabolic GOF activity with a context-dependent invasive cellular phenotype.}, archive = {J_PNAS}, author = {Guzman, Asja and Kawase, Tatsuya and Devanny, Alexander J. and Efe, Gizem and Navaridas, Raúl and Yu, Karen and Regunath, Kausik and Mercer, Iris G. and Avard, Rachel C. and Muniz de Queiroz, Rafaela and Rustgi, Anil K. and Kaufman, Laura J. and Prives, Carol}, doi = {10.1073/pnas.2424904122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2424904122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway–dependent Rho/ROCK signaling}, volume = {122}, year = {2025}, }
• (2025). Rewarding touch limits lifespan through neural to intestinal signaling. PNAS, 122(43), e2423780122. (www)

  @article{ , abstract = {In multicellular organisms, sensory perception affects many aspects of behavior and physiology. Perception of environmental stressors like food scarcity often leads to physiological changes that promote survival and slow aging. However, recent work shows that perception of attractive food smells can block the health benefits of dietary restriction in multiple model organisms. While it is known that sensory perception and cell nonautonomous signaling can modulate health and longevity, our knowledge of the specific sensory cues and mechanistic pathways that define this signaling is still limited. Here we find that the sense of touch interacts with nutritional state to modulate lifespan in Caenorhabditis elegans . Worms subjected to dietary restriction are shorter-lived when they perceive tactile stimuli that mimic bacterial food and/or protective soil. Touch modulation of dietary restriction requires putative mechanoreceptor proteins, the neurotransmitters dopamine and tyramine/adrenaline, and the neuropeptides INS-11 and GnRH. Ultimately, the touch circuit regulates the longevity effectors DAF-2/IGF1R and FMO-2/FMO5. These results establish a physiological touch circuit and connect neural reward pathways to the growth and reproductive axes. Finding that texture mechanosensation can modulate longevity suggests a role for touch in lifespan.}, archive = {J_PNAS}, author = {Kitto, Elizabeth S. and Beydoun, Safa and Leiser, Scott F.}, doi = {10.1073/pnas.2423780122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2423780122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rewarding touch limits lifespan through neural to intestinal signaling}, volume = {122}, year = {2025}, }
• (2025). Capillary self-thinning of threads of polyelectrolyte solutions with axial electric fields. PNAS, 122(43), e2422879122. (www)

  @article{ , abstract = {A theory of solutions of charged polyelectrolyte (PE) macromolecules, treating them as electric dipoles, is proposed. In a thin thread of PE solution sustained between two disks—whether wettable or nonwettable—these dipoles are reoriented by an axial electric field, aligning themselves with the field direction. This alignment causes significant axial elastic stresses and affects capillary self-thinning dynamics of the thread, slowing the process and potentially arresting it entirely, and even leading to oscillatory regimes. Accordingly, the evolution of the thread radius deviates significantly from the exponential decay characteristic of solutions of flexible polymer macromolecules and the linear decay characteristic of Newtonian fluids. At relatively high electric field strengths, in a thread where elastic stresses become dominant, an oscillatory regime emerges. Here, the cross-sectional radius not only decreases but also increases and oscillates in time—a behavior rooted in an ill-posedness of the problem reducing to the Laplace equation in case of strong electric fields. This indicates a manifestation of Hadamard instability. The theory is supported by experimental data acquired in this work.}, archive = {J_PNAS}, author = {Martin, Patrick and Vasilyev, Gleb and Zussman, Eyal and Yarin, Alexander L.}, doi = {10.1073/pnas.2422879122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2422879122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Capillary self-thinning of threads of polyelectrolyte solutions with axial electric fields}, volume = {122}, year = {2025}, }
• (2025). Disrupted developmental signaling induces novel transcriptional states. PNAS, 122(43), e2418351122. (www)

  @article{ , abstract = {Signaling pathways induce stereotyped transcriptional changes as stem cells progress into mature cell types during embryogenesis. Signaling perturbations are necessary to discover which genes are responsive or insensitive to pathway activity. However, gene regulation is additionally dependent on cell state-specific factors like chromatin modifications or transcription factor binding. Thus, transcriptional profiles need to be assayed in single cells to identify potentially multiple, distinct perturbation responses among heterogeneous cell states in an embryo. In perturbation studies, comparing heterogeneous transcriptional states among experimental conditions often requires samples to be collected over multiple independent experiments, which can introduce confounding batch effects. We present Design-Aware Integration of Single Cell ExpEriments (DAISEE), a new algorithm that models perturbation responses in single-cell datasets collected according to complex experimental designs. We demonstrate that DAISEE improves upon a previously available integrative nonnegative matrix factorization framework, more efficiently separating perturbation responses from confounding variation. We use DAISEE to integrate newly collected single-cell RNA sequencing datasets from 5-h-old zebrafish embryos expressing optimized photoswitchable MEK (psMEK), which globally activates the extracellular signal-regulated kinase (ERK), a signaling molecule involved in many cell specification events. psMEK drives some cells that are normally not exposed to ERK signals toward other wild type states and induces novel states expressing early-acting endothelial genes. Overactive signaling is therefore capable of producing unexpected gene expression states in developing embryos.}, archive = {J_PNAS}, author = {Patel, Aleena L. and Gonzalez, Vanessa and Menon, Triveni and Shvartsman, Stanislav Y. and Burdine, Rebecca D. and Avdeeva, Maria}, doi = {10.1073/pnas.2418351122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2418351122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Disrupted developmental signaling induces novel transcriptional states}, volume = {122}, year = {2025}, }
• (2025). Squamous cell carcinoma antigen-1/SerpinB3 is an endogenous skin injury response element. PNAS, 122(43), e2415164122. (www)

  @article{ , abstract = {The squamous cell carcinoma antigen SerpinB3 is a serum-circulating biomarker of epithelial cancers associated with high metastasis, treatment resistance, and poor prognosis. Despite its clinical significance, the endogenous role of SerpinB3 has remained undefined. Here, we identify SerpinB3 as a mediator of epithelial wound healing. Injury induces SerpinB3 expression in vitro and in vivo in the migrating epidermal tongue; overexpression of the protein promotes epithelial-to-mesenchymal transition–like changes. Recombinant Serpinb3a, the mouse ortholog, enhances re-epithelialization in vitro and accelerates wound closure and collagen remodeling in vivo. These findings reveal a physiological function for SerpinB3 in epithelial repair and suggest that its expression in cancer, chronic wounds, and inflammatory diseases may reflect reactivation of a conserved wound response program—positioning SerpinB3 as a compelling therapeutic target.}, archive = {J_PNAS}, author = {Yaron, Jordan R. and Pallod, Shubham and Nezhadi, Sepideh and Gildar, Holly M. and Hylton-Pelaia, Jayda and Roberts, Jordan and Kilbourne, Jacquelyn and Rege, Kaushal}, doi = {10.1073/pnas.2415164122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2415164122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Squamous cell carcinoma antigen-1/SerpinB3 is an endogenous skin injury response element}, volume = {122}, year = {2025}, }
• (2025). Foot placement control underlies stable locomotion across species. PNAS, 122(43), e2413958122. (www)

  @article{ , abstract = {Animals navigate their environment stably without inefficient course corrections despite unavoidable errors. In humans, this stability is achieved by modulating the placement of the foot on each step such that recent errors are corrected. However, it is unknown whether animals with diverse nervous systems and body mechanics use such foot placement control; foot trajectories of many-legged animals are considered to be stereotypical velocity-driven patterns, as opposed to error-driven. Here, we put forth a unified “feedforward-feedback” control structure for stable locomotion that combines velocity-driven and body state error-driven foot placement. We provide empirical support for this control structure across flies, mice, and humans by mining their natural locomotor variability, finding that a competing control structure with purely velocity-driven foot placement is not supported by the data. This work finds shared behavioral signatures of foot placement control in flies, mice, and humans. We find that key characteristics of these signatures, such as their urgency and centralization, vary with neuromechanical embodiment across species. For example, more inherently stable multilegged animals exhibit less urgent control with a lower control magnitude and a slower correction timescale compared to humans. Furthermore, many-legged animals display modular, direction-, and leg-specific control signatures, whereas humans exhibit common signatures across both legs. Overall, our findings provide insight into stable locomotion across species, revealing how species with diverse neuromechanics achieve a shared functional goal: foot placement control.}, archive = {J_PNAS}, author = {De Comite, Antoine and Seethapathi, Nidhi}, doi = {10.1073/pnas.2413958122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {43}, pages = {e2413958122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Foot placement control underlies stable locomotion across species}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(42), eiti4225122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti4225122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {eiti4225122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). In the wake of wildfires, toxic smoke is a lasting health concern. PNAS, 122(42), e2527308122. (www)

  @article{ , archive = {J_PNAS}, author = {McDermott, Amy}, doi = {10.1073/pnas.2527308122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2527308122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In the wake of wildfires, toxic smoke is a lasting health concern}, volume = {122}, year = {2025}, }
• (2025). Profile of jean-philippe avouac. PNAS, 122(42), e2527289122. (www)

  @article{ , abstract = {Jean-Philippe Avouac, elected to the National Academy of Sciences in 2025, explores deformations in Earth’s surface in an effort to understand the formation and behavior of earthquakes. Using geology, satellite data, radar imagery, and modeling, Avouac has characterized the strain along the Himalayan Arc and at other faults. In his Inaugural Article, Avouac characterizes the magnitude 7.7 earthquake along the Sagaing fault in Myanmar in 2025. The enormous 510 km rupture traversed a section of the fault assumed to be under strain since it had not erupted since 1839. However, the rupture also included sections of the fault that were not part of this seismic gap.}, archive = {J_PNAS}, author = {Davis, Tinsley H.}, doi = {10.1073/pnas.2527289122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2527289122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profile of jean-philippe avouac}, volume = {122}, year = {2025}, }
• (2025). Correction for bassiouni et al., observed declines in leaf nitrogen explained by photosynthetic acclimation to CO2. PNAS, 122(42), e2527000122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2527000122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2527000122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for bassiouni et al., observed declines in leaf nitrogen explained by photosynthetic acclimation to CO2}, volume = {122}, year = {2025}, }
• (2025). Correction for lu et al., a theoretical framework for scaling ecological niches from individuals to species. PNAS, 122(42), e2526938122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2526938122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2526938122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for lu et al., a theoretical framework for scaling ecological niches from individuals to species}, volume = {122}, year = {2025}, }
• (2025). Correction for bonetti et al., decoding the elite soccer player’s psychological profile. PNAS, 122(42), e2526834122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2526834122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2526834122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for bonetti et al., decoding the elite soccer player’s psychological profile}, volume = {122}, year = {2025}, }
• (2025). Correction for garzon et al., MicroRNA fingerprints during human megakaryocytopoiesis. PNAS, 122(42), e2526161122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2526161122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2526161122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for garzon et al., MicroRNA fingerprints during human megakaryocytopoiesis}, volume = {122}, year = {2025}, }
• (2025). Reply to maleszka et al.: DNA methylation signals persist across insect metamorphosis. PNAS, 122(42), e2524479122. (www)

  @article{ , archive = {J_PNAS}, author = {Foley, Erin E. B. and Thomas, Christian L. and Kyriacou, Charalambos P. and Mallon, Eamonn B.}, doi = {10.1073/pnas.2524479122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2524479122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to maleszka et al.: DNA methylation signals persist across insect metamorphosis}, volume = {122}, year = {2025}, }
• (2025). Medicine on the menu: When illness informs appetite. PNAS, 122(42), e2524005122. (www)

  @article{ , archive = {J_PNAS}, author = {Han, Ji Heon and Ja, William W.}, doi = {10.1073/pnas.2524005122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2524005122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Medicine on the menu: When illness informs appetite}, volume = {122}, year = {2025}, }
• (2025). Gating of immune-triggered cell death is a redox rhythm–specific output. PNAS, 122(42), e2523642122. (www)

  @article{ , archive = {J_PNAS}, author = {Su, Jianbin and Gassmann, Walter}, doi = {10.1073/pnas.2523642122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2523642122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Gating of immune-triggered cell death is a redox rhythm–specific output}, volume = {122}, year = {2025}, }
• (2025). Guardians at the border: Peritumoral macrophages fight breast cancer. PNAS, 122(42), e2523640122. (www)

  @article{ , archive = {J_PNAS}, author = {Erdogmus, Serap and Srinivas, Neha and Mollaoglu, Gurkan}, doi = {10.1073/pnas.2523640122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2523640122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Guardians at the border: Peritumoral macrophages fight breast cancer}, volume = {122}, year = {2025}, }
• (2025). Still no evidence for an environmentally responsive epigenetic clock in an insect. PNAS, 122(42), e2523241122. (www)

  @article{ , archive = {J_PNAS}, author = {Maleszka, Ryszard and Cardoso-Junior, Carlos A. M. and Pellegrini, Matteo}, doi = {10.1073/pnas.2523241122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2523241122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Still no evidence for an environmentally responsive epigenetic clock in an insect}, volume = {122}, year = {2025}, }
• (2025). Reply to brandes et al.: A first step, not a final word, on modeling microplastics-induced crop losses. PNAS, 122(42), e2523194122. (www)

  @article{ , archive = {J_PNAS}, author = {Dang, Fei and Li, Chengjun and Zhu, Ruijie and Zhong, Huan and Xing, Baoshan}, doi = {10.1073/pnas.2523194122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2523194122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to brandes et al.: A first step, not a final word, on modeling microplastics-induced crop losses}, volume = {122}, year = {2025}, }
• (2025). Unisexual reproduction in the global human fungal pathogen cryptococcus neoformans. PNAS, 122(42), e2521779122. (www)

  @article{ , abstract = {The human fungal pathogen Cryptococcus species complex (encompassing Cryptococcus neoformans , Cryptococcus deneoformans , and the Cryptococcus gattii species complexes) exhibits diversity in sexual reproduction, including α- a mating, pseudosexual reproduction, as well as unisexual reproduction initiated from a single isolate or between isolates of the same mating type. A central conundrum is that while most Cryptococcus natural populations exhibit significant α mating-type bias, genetic and genomic analyses show recombination occurs in nature. The discovery of unisexual reproduction in C. deneoformans provided insight; however, thus far, unisexual reproduction has never been directly observed in the predominant global pathogenic species C. neoformans . Here, we provide evidence that mutating the RIC8 gene, which encodes a conserved guanine nucleotide exchange factor (GEF) involved in both chaperoning and activating Gα proteins, enables unisexual reproduction in C. neoformans . Additionally, we show that genetic variation in the natural population promotes unisexual reproduction, and unisexual reproduction in C. neoformans involves canonical meiotic recombination. Finally, we found that deletion of both GPA2 and GPA3 in the MAT α background leads to self-filamentation without sporulation, suggesting that differential modulation of the Gα proteins, likely involving Ric8, could underlie the switch between different modes of sexual reproduction in Cryptococcus . Our study further highlights that the highly conserved Ric8 GEF can act as an important regulator of cellular development in response to environmental stimuli and could modulate sexual reproduction in nature. We hypothesize that unisexual reproduction occurs much more frequently in nature than currently appreciated, and possibly in other fungi and microbial eukaryotes as well.}, archive = {J_PNAS}, author = {Sun, Sheng and Bian, Zhuyun and Xu, Ziyan and Choi, Yeseul and Heitman, Joseph}, doi = {10.1073/pnas.2521779122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2521779122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unisexual reproduction in the global human fungal pathogen cryptococcus neoformans}, volume = {122}, year = {2025}, }
• (2025). High-magnetic-field phases in u1-xThxTe2. PNAS, 122(42), e2521261122. (www)

  @article{ , abstract = {At temperatures T much lower than its superconducting critical temperature T c = 2.1 K, the heavy fermion superconductor UTe 2 has a unique phase diagram of magnetic field H vs. φ and θ, angles H is tilted from the b -axis toward the a - and c -axes, respectively, of its orthorhombic unit cell. The phase diagram contains three distinct superconducting phases: SC 1 in which φ and θ extend from 0 to 90° and H ≤ ~15 T; SC 2 for φ ≤ ~7°, θ ≤ ~4° and ~15 T ≤ H ≤ H m = ~35 T, the onset of the magnetic field polarized (FP) phase, and SC FP which resides entirely within the FP phase in a pocket of superconductivity extending from θ ≈ 20° to 40° and from ~40 T to above 60 T. We studied the evolution of the H vs. θ phase diagram for Th concentrations 0.005 ≤ x ≤ 0.047 in the U 1-x Th x Te 2 system at ~0.6 K. Within this range of x values, SC 1 extends over 0 ≤ θ ≤ 90° and H ≤ ~10 T for x = 0.047, while SC 2 is suppressed. The SC FP and FP phases are unaffected to x = 0.02 but are completely suppressed in the region x = 0.025 to 0.047 where the residual resistance ratio RRR ~3 indicates a significant amount of disorder. These results complement recent studies of nonsuperconducting disordered UTe 2 single crystals in which the SC 1 and SC 2 phases are absent, but the FP and so-called “orphan” SC FP phases are retained.}, archive = {J_PNAS}, author = {Moir, Camilla M. and Singleton, John and Blawat, Joanna and Lee-Wong, Eric and Deng, Yuhang and Feng, Keke and Wannamaker, Tyler and Baumbach, Ryan E. and Maple, M. Brian}, doi = {10.1073/pnas.2521261122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2521261122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High-magnetic-field phases in u1-xThxTe2}, volume = {122}, year = {2025}, }
• (2025). Phylogenomics redefines the evolutionary history of mosquitoes. PNAS, 122(42), e2519291122. (www)

  @article{ , abstract = {Mosquitoes have a substantial impact on human and animal health, but their deeper evolutionary relationships have been difficult to resolve. We inferred a time-calibrated phylogenetic history of mosquitoes using conserved genome-wide markers from representatives of major lineages. Our analyses revealed that codon bias and positive selection in subfamily Anophelinae contributed to a substantial level of branch attraction bias between Anophelinae and outgroup taxa, which in our view has misled previous phylogenetic analyses of mosquitoes. Accounting for this systematic phylogenetic bias led to a revised view of mosquito evolution, including the nonmonophyly of subfamily Culicinae. Similarly, we dated the origin of mosquitoes to the mid-Cretaceous (~106 Mya) and most extant genera to after the KPg boundary <66 Mya, 100 My younger than previous estimates and coincident with the origin of Plasmodium parasites. Our study provides a foundation for future analyses of the evolution of mosquito-borne disease.}, archive = {J_PNAS}, author = {Pierce, Mac P. and Worthington, Brian M. and Han, Shaolin and Ni, Xue-Bing and Liao, Yunshi and Shum, Marcus H. and Guan, Yi and Holmes, Edward C. and Lam, Tommy T.}, doi = {10.1073/pnas.2519291122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2519291122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phylogenomics redefines the evolutionary history of mosquitoes}, volume = {122}, year = {2025}, }
• (2025). Elevated virus infection of honey bee queens reduces methyl oleate production and destabilizes colony-level social structure. PNAS, 122(42), e2518975122. (www)

  @article{ , abstract = {Pathogenic threats to reproductive individuals pose a profound challenge to the stability of insect societies. In honey bees ( Apis mellifera L.), severe virus infections in queens can trigger worker-initiated supersedure, a socially coordinated replacement of the queen that, while risky, is essential when her reproductive competence is compromised. How viruses impact the physiology of queen hosts, who bear unique reproductive burdens within their colonies, and how this perturbs colony social order remains poorly understood. We hypothesized that the supersedure response is mediated by pathogen-induced, intensity-dependent changes in queen pheromonal signaling. Laboratory infection experiments revealed that queens challenged with deformed wing virus B and black queen cell virus infections demonstrated a reduction in methyl oleate, a key component of the queen retinue pheromone, and field data corroborated this association. Lipidomics analysis demonstrated that infection coincides with a systemic lipid deficiency, especially in triacylglycerides (major energy reserves), providing a physiological link among viral stress, ovarian atrophy, and altered pheromone output. Notably, artificial suppression of ovary investment via restricted laying also caused methyl oleate production to decline; therefore, high virus infection likely indirectly suppresses methyl oleate production by reducing ovary mass. In field trials, we further show that synthetic pheromone blends containing methyl oleate significantly suppressed queen cell rearing compared to no-pheromone controls, whereas blends lacking this compound yielded an intermediate effect. These results demonstrate that virus-induced reproductive decline disrupts pheromone signaling, revealing a plausible mechanistic pathway by which pathogens can erode social cohesion.}, archive = {J_PNAS}, author = {McAfee, Alison and Chapman, Abigail and Alcazar Magaña, Armando and Marshall, Katie E. and Hoover, Shelley E. and Tarpy, David R. and Foster, Leonard J.}, doi = {10.1073/pnas.2518975122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2518975122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Elevated virus infection of honey bee queens reduces methyl oleate production and destabilizes colony-level social structure}, volume = {122}, year = {2025}, }
• (2025). The simulation of judgment in LLMs. PNAS, 122(42), e2518443122. (www)

  @article{ , abstract = {Large Language Models (LLMs) are increasingly embedded in evaluative processes, from information filtering to assessing and addressing knowledge gaps through explanation and credibility judgments. This raises the need to examine how such evaluations are built, what assumptions they rely on, and how their strategies diverge from those of humans. We benchmark six LLMs against expert ratings—NewsGuard and Media Bias/Fact Check—and against human judgments collected through a controlled experiment. We use news domains purely as a controlled benchmark for evaluative tasks, focusing on the underlying mechanisms rather than on news classification per se. To enable direct comparison, we implement a structured agentic framework in which both models and nonexpert participants follow the same evaluation procedure: selecting criteria, retrieving content, and producing justifications. Despite output alignment, our findings show consistent differences in the observable criteria guiding model evaluations, suggesting that lexical associations and statistical priors could influence evaluations in ways that differ from contextual reasoning. This reliance is associated with systematic effects: political asymmetries and a tendency to confuse linguistic form with epistemic reliability—a dynamic we term epistemia, the illusion of knowledge that emerges when surface plausibility replaces verification. Indeed, delegating judgment to such systems may affect the heuristics underlying evaluative processes, suggesting a shift from normative reasoning toward pattern-based approximation and raising open questions about the role of LLMs in evaluative processes.}, archive = {J_PNAS}, author = {Loru, Edoardo and Nudo, Jacopo and Di Marco, Niccolò and Santirocchi, Alessandro and Atzeni, Roberto and Cinelli, Matteo and Cestari, Vincenzo and Rossi-Arnaud, Clelia and Quattrociocchi, Walter}, doi = {10.1073/pnas.2518443122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2518443122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The simulation of judgment in LLMs}, volume = {122}, year = {2025}, }
• (2025). Mitotic recombination events and single-base mutations induced by ultraviolet light in g1-arrested yeast cells. PNAS, 122(42), e2518046122. (www)

  @article{ , abstract = {Ultraviolet light (UV) is a potent inducer of both single-base mutations and mitotic recombination. Although these genomic alterations are often attributed to the action of error-prone DNA polymerases on UV-induced DNA lesions during replicative DNA synthesis, UV damage can also result in mutagenic and recombinogenic DNA damage in nondividing cells. We examined the effects of UV on cells of the yeast Saccharomyces cerevisiae arrested in G 1 of the cell cycle. By mating an irradiated haploid with an unirradiated haploid, we found that recombination was initiated only on the irradiated chromosome. This result indicates that trans effects of UV on recombination (for example, induction of recombinogenic proteins stimulating DNA breaks on the unirradiated homolog) are small or negligible. In addition, we show that most of the UV-induced mutations produced in G 1 -irradiated cells result in mutations at identical positions in both strands of the duplex. As observed for recombination events, mutations are almost exclusively on the irradiated chromosome, indicating the near absence of a trans effect on mutations.}, archive = {J_PNAS}, author = {Zhu, Ying-Xuan and Li, Ke-Jing and He, Min and Zhang, Ke and Zheng, Dao-Qiong and Petes, Thomas D.}, doi = {10.1073/pnas.2518046122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2518046122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mitotic recombination events and single-base mutations induced by ultraviolet light in g1-arrested yeast cells}, volume = {122}, year = {2025}, }
• (2025). Temperature adaptation in structure and function in lactate dehydrogenase-A reflects convergent evolution in a few key protein regions. PNAS, 122(42), e2517759122. (www)

  @article{ , abstract = {Adaptive differences in the thermal stabilities of enzyme structure and function play critical roles in establishing the thermal optima and limits of all organisms. Thus, understanding the mechanisms underlying these adaptations can yield insights into protein structure–function relationships, protein evolution, and the consequences of temperature shifts on species distributions. Past studies have suggested that only a small number of amino acid substitutions are needed for adaptive change, but whether similar sites in the sequence, which we term thermal adaptation–related sequence sites (TRSS), and similar changes in amino acid content at these TRSS occur across widely different taxa remains to be elucidated. For detecting TRSS among orthologs of species adapted to a wide range of temperatures, we investigated 277 lactate dehydrogenase-A (LDH-A) orthologs in marine fish from diverse habitats. We validated the importance of several TRSS variants using site-directed mutagenesis on zebrafish LDH-A, effectively recreating the variants in the zebrafish ortholog. Our results indicate that enzyme thermal adaptation arises primarily from a few substitutions that influence hydrophobicity in functionally important regions of secondary structures. These findings reveal striking convergence in the sites (the TRSS) of temperature-adaptive evolution of LDH-As and provide insights into the types of amino acid substitutions that foster adaptation to temperature. Furthermore, the patterns of convergent evolution identified in this study supported development of a deep learning model for predicting thermal limits. This model can provide an important tool for predicting thermal ranges of species and the potential effects of temperature change on distribution patterns.}, archive = {J_PNAS}, author = {Zhu, Xiao-Lu and Liao, Ming-Ling and Ma, Lin-Xuan and Somero, George N. and Dong, Yun-Wei}, doi = {10.1073/pnas.2517759122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2517759122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Temperature adaptation in structure and function in lactate dehydrogenase-A reflects convergent evolution in a few key protein regions}, volume = {122}, year = {2025}, }
• (2025). Information sampling and bayesian belief formation in statistical judgment. PNAS, 122(42), e2517302122. (www)

  @article{ , abstract = {The statistical properties of data are often communicated using visual graphs, like scatterplots. However, decision makers make systematic errors when processing these graphs, with important consequences for statistical communication in science, medicine, and policy. We propose that decision makers are Bayesian learners, who learn optimally given the data points that they attend to. Accordingly, judgment errors arise from biased sampling of information from graphs. We tested our theory in four eye-tracking experiments (total N = 421), in which participants made correlation judgments from scatterplots of both experimentally manipulated data (Experiment 1) and real data (Experiment 2), as well as plots with different display formats (Experiments 3 and 4). Participants’ judgments displayed several known biases, including underestimation of absolute correlations and sensitivity to irrelevant visual features. Importantly, the (optimal) Bayesian belief updating model, trained on the sensory inputs from visual information search, predicted both participants’ judgments and associated biases with high accuracy in all the experiments. Additionally, a computational model of participants’ information sampling processes, combined with the Bayesian model, reproduced all behavioral regularities. These results shed light on the cognitive mechanisms of belief formation, show how statistical judgments can be quantitatively predicted and manipulated, and provide insights for data visualization and statistical communication.}, archive = {J_PNAS}, author = {He, Lisheng and Wang, Hongyi and Bian, Yiwen and Zhang, Xiumei and Bhatia, Sudeep}, doi = {10.1073/pnas.2517302122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2517302122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Information sampling and bayesian belief formation in statistical judgment}, volume = {122}, year = {2025}, }
• (2025). Global conformation of the rag GTPase heterodimer governs eukaryotic amino acid sensing. PNAS, 122(42), e2517050122. (www)

  @article{ , abstract = {The Rag GTPase heterodimer is a central mediator of amino acid sensing in eukaryotic cells. When amino acids are abundant, it binds to the mechanistic target of rapamycin complex 1 to activate cellular programs for growth and proliferation. In its functional cycle, besides local conformational changes near the nucleotides that are commonly observed in monomeric signaling GTPases, the relative positioning of the two Rag subunits, i.e., the global conformation, is unique due to the heterodimeric architecture. Although various global conformations have been captured in static structural models, dynamic transitions between these conformations and their biological relevance remain unclear. Here, we visualize the global conformation of the Rag GTPase heterodimer using single-molecule Förster resonance energy transfer. By tracking the movement of individual protein molecules, we found that the two subunits explore a wide conformational space, which is strictly dictated by the bound nucleotides, regulators, and mutations. Additionally, we demonstrate that proper modulation of the global conformation is crucial for correctly interpreting amino acid signals. Our results defined a checkpoint of amino acid sensing in eukaryotic cells.}, archive = {J_PNAS}, author = {Doxsey, Dylan D. and Shen, Kuang}, doi = {10.1073/pnas.2517050122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2517050122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global conformation of the rag GTPase heterodimer governs eukaryotic amino acid sensing}, volume = {122}, year = {2025}, }
• (2025). The persistence of cross-cutting discussion in a politicized public sphere. PNAS, 122(42), e2516942122. (www)

  @article{ , abstract = {Although studies of Americans’ general discussant networks have been repeated over time, research that assesses change in the nature of Americans’ political discussion networks has yet to be conducted in nationally representative probability surveys. In this study I answer two questions about the quality of the American public sphere that have generated widespread speculation, but little evidence to date. First, how have Americans’ political discussion networks changed over the past 25 y? Second, are the consequences of these changes what one would expect based on previous theory linking Americans’ interpersonal information environments to political tolerance and political participation? I resolve competing claims suggesting that people feel less free to discuss politics, with claims suggesting instead that political discussion now permeates everyday life to a greater extent than in the past. Findings suggest widespread increases in political discussion, changes driven almost entirely by increases in like-minded political discussion partners. Surprisingly, Americans are no more or less likely to engage in conversations across lines of political difference. The predicted consequences of these fluctuations confirm an intrinsic tension between characteristics valued in democratic citizens. Political tolerance has declined significantly, along with decreased awareness of rationales for others’ relative to one’s own views. Political participation is significantly higher on average than 25 y ago. Few people reported engaging with online political discussants, despite efforts to make sure they were included in network measures.}, archive = {J_PNAS}, author = {Mutz, Diana C.}, doi = {10.1073/pnas.2516942122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2516942122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The persistence of cross-cutting discussion in a politicized public sphere}, volume = {122}, year = {2025}, }
• (2025). Mot1 regulation of promoter binding by TBP varies with stress and gene expression levels independently of coactivator dependence. PNAS, 122(42), e2516926122. (www)

  @article{ , abstract = {Mot1 in budding yeast regulates transcription by dissociating general initiation factor TBP (TATA-binding protein) from DNA. Previous studies suggested that Mot1 preferentially removes TBP from stress-responsive promoters containing consensus TATA elements that utilize coactivator SAGA while enhancing TBP binding at “house-keeping” genes with TATA-like elements that employ TFIID for TBP recruitment. In stress conditions of amino acid starvation, by contrast, we found that Mot1 promotes TBP binding at genes activated by transcription factor Gcn4, enriched for TATA/SAGA-dependent promoters, and at SAGA-dependent genes expressed constitutively at high-levels, while suppressing TBP binding at SAGA-dependent genes only expressed at lower levels. Importantly, Mot1’s influence on genes induced by starvation or oxidative stress switches from increased to decreased TBP binding when transcribed at low levels in nonstressed cells. Mot1’s role at TFIID-dependent promoters also scales with transcription level, enhancing TBP binding only for the highly expressed subset. Notably, reduced TBP binding on Mot1 depletion impairs transcription of highly expressed TFIID genes but not highly expressed SAGA/stress-activated genes, suggesting that SAGA produces a surfeit of incomplete preinitiation complexes dependent on Mot1 for assembly.}, archive = {J_PNAS}, author = {Mittal, Priyanka and Hinnebusch, Alan G.}, doi = {10.1073/pnas.2516926122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2516926122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mot1 regulation of promoter binding by TBP varies with stress and gene expression levels independently of coactivator dependence}, volume = {122}, year = {2025}, }
• (2025). Sperm and offspring production in a nonobstructive azoospermia mouse model via testicular mRNA delivery using lipid nanoparticles. PNAS, 122(42), e2516573122. (www)

  @article{ , abstract = {Microsurgical testicular sperm extraction (microTESE) with intracytoplasmic sperm injection (ICSI) represents the current standard treatment for nonobstructive azoospermia (NOA). However, cures remain unavailable for NOA patients lacking retrievable haploid cells. mRNA supplementation could be a potential treatment for genetic defects leading to impaired spermatogenesis. Lipid nanoparticles (LNPs) have emerged as mRNA delivery vehicles with minimal risk of genome integration; however, their ability to selectively deliver mRNA to specific cell types remains limited. To overcome this, microRNA (miRNA) target sequences were incorporated into mRNA constructs to restrict expression specifically to germ cells. Using pyruvate dehydrogenase E1 subunit alpha 2 (PDHA2) knockout mice as an NOA model with meiotic arrest, we demonstrate that LNP-mediated delivery of Pdha2 mRNA enables the resumption and completion of meiosis, restores sperm production, and facilitates the generation of healthy fertile offspring via ICSI. Whole-genome sequencing of the offspring confirmed the absence of large-scale genomic abnormalities. Our results provide proof of concept for a safe and effective chemically synthesized LNP-based mRNA therapy with miRNA-regulated germ cell specificity, offering a promising therapeutic approach to treating male infertility caused by spermatogenesis arrest.}, archive = {J_PNAS}, author = {Mashiko, Daisuke and Emori, Chihiro and Hatanaka, Yuki and Motooka, Daisuke and Pan, Chen and Kaneda, Yuki and Matzuk, Martin M. and Ikawa, Masahito}, doi = {10.1073/pnas.2516573122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2516573122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sperm and offspring production in a nonobstructive azoospermia mouse model via testicular mRNA delivery using lipid nanoparticles}, volume = {122}, year = {2025}, }
• (2025). Scaling laboratory results with machine learning is no silver bullet to strengthen global (micro)plastic mitigation policy. PNAS, 122(42), e2515836122. (www)

  @article{ , archive = {J_PNAS}, author = {Brandes, Elke and Fiener, Peter and Gessler, Arthur}, doi = {10.1073/pnas.2515836122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2515836122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Scaling laboratory results with machine learning is no silver bullet to strengthen global (micro)plastic mitigation policy}, volume = {122}, year = {2025}, }
• (2025). Bridging microscopic dynamics and rheology in the yielding of charged colloidal suspensions. PNAS, 122(42), e2514216122. (www)

  @article{ , abstract = {The yielding of soft materials is critical to many natural and industrial processes, yet experimental insights into microscopic aspects of yielding are limited. This study combines angle X-ray scattering, X-ray photon correlation spectroscopy, and in situ rheology (Rheo-SAXS-XPCS) with fast lubrication dynamics simulations to examine how interparticle interactions influence yielding in charged colloidal suspensions. By tuning attraction through salt addition, we compare repulsive and attractive systems under deformation. Repulsive suspensions yield uniformly with Andrade-like creep and minimal structural change. In contrast, attractive suspensions show complex behaviors, including shear banding, delayed yielding, and resolidification, governed by transient dynamics at shear band interfaces. These results directly link microscopic particle dynamics to macroscopic flow and demonstrate how interaction potentials control rheological behavior. This work offers a framework for designing soft materials with tailored properties for applications in coatings, food processing, drug delivery, and other technologies requiring precise mechanical control.}, archive = {J_PNAS}, author = {He, Hongrui and Liang, Heyi and Chu, Miaoqi and Jiang, Zhang and de Pablo, Juan J. and Tirrell, Matthew V. and Narayanan, Suresh and Chen, Wei}, doi = {10.1073/pnas.2514216122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2514216122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bridging microscopic dynamics and rheology in the yielding of charged colloidal suspensions}, volume = {122}, year = {2025}, }
• (2025). Temporal and spatial coordination of DNA segregation and cell division in an archaeon. PNAS, 122(42), e2513939122. (www)

  @article{ , abstract = {Cells must coordinate DNA segregation with cytokinesis to ensure that each daughter cell inherits a complete genome. Here, we explore how DNA segregation and division are mechanistically coupled in archaeal relatives of eukaryotes, which lack Cyclin-dependent kinase (CDK)/Cyclins. Using live cell imaging, we first describe the series of sequential changes in DNA organization that accompany cell division in Sulfolobus, which computational modeling shows likely aid genome segregation. Through a perturbation analysis we identify a regulatory checkpoint which ensures that the compaction of the genome into two spatially segregated nucleoids only occurs once cells have assembled a division ring—which also defines the axis of DNA segregation. Finally, we show that DNA compaction and segregation depend, in part, on a ParA homologue, SegA, and its partner SegB, whose absence leads to bridging DNA. Taken together, these data show how regulatory checkpoints like those operating in eukaryotes aid high-fidelity division in an archaeon.}, archive = {J_PNAS}, author = {Parham, Joe and Sorichetti, Valerio and Cezanne, Alice and Foo, Sherman and Kuo, Yin-Wei and Hoogenberg, Baukje and Radoux-Mergault, Arthur and Mawdesley, Eloise and Gatward, Lydia Daniels and Boulanger, Jerome and Schulze, Ulrike and Šarić, Anđela and Baum, Buzz}, doi = {10.1073/pnas.2513939122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2513939122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Temporal and spatial coordination of DNA segregation and cell division in an archaeon}, volume = {122}, year = {2025}, }
• (2025). Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility. PNAS, 122(42), e2513924122. (www)

  @article{ , abstract = {Sperm motility is essential for male fertility and is tightly controlled by signaling events in the flagellum. Slc9c1 encodes a sperm-specific Na + /H + exchanger (sNHE/SLC9C1) that localizes to the flagellum and is indispensable for sperm motility and male fertility. SLC9C1 is unique among Na + /H + exchangers in that it possesses a voltage-sensing domain (VSD), the physiological function of which remains poorly understood in mammals. Here, by analyzing coevolving genes with Slc9c1 , we identified Tmem217 , which encodes a transmembrane protein that is localized in the sperm flagellum. Knockout (KO) of Tmem217 in mice resulted in sperm motility defects and male infertility, phenocopying Slc9c1 KO mice. Coimmunoprecipitation and structural prediction analyses indicated that TMEM217 binds to SLC9C1 via its VSD. Further analyses indicated that the amounts of SLC9C1 and its associated protein, soluble adenylyl cyclase (sAC), were lost in mature Tmem217 KO spermatozoa, leading to disrupted 3′,5′-cyclic monophosphate (cAMP) signaling pathways. Remarkably, cAMP analogs restored the impaired motility and fertilizing ability of Tmem217 KO spermatozoa in vitro, validating the essential role of TMEM217 in regulating cAMP production. Our findings indicate that the association of TMEM217 with SLC9C1 via its VSD is critical for the proper organization and function of the SLC9C1–sAC–cAMP axis in mature spermatozoa.}, archive = {J_PNAS}, author = {Iida-Norita, Rie and Miyata, Haruhiko and Ninomiya, Akinori and Emori, Chihiro and Kamoshita, Maki and Pan, Chen and Wang, Haoting and Ikawa, Masahito}, doi = {10.1073/pnas.2513924122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2513924122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility}, volume = {122}, year = {2025}, }
• (2025). TMEM16F phospholipid scramblase regulates tumorigenesis by modulating the tumor immune microenvironment. PNAS, 122(42), e2513910122. (www)

  @article{ , abstract = {The immunosuppressive tumor microenvironment enables immune evasion through mechanisms beyond canonical immune checkpoints. While phosphatidylserine (PS) externalization coordinates apoptotic clearance under physiological conditions, tumors hijack this mechanism through apoptotic mimicry to subvert antitumor immunity. Here, we identify TMEM16F, a calcium-activated phospholipid scramblase, as a driver of tumor-intrinsic PS externalization. TMEM16F-mediated PS scrambling polarized macrophages to an immunosuppressive M2 phenotype, which promotes TGF-β1 secretion and regulatory T cell expansion to suppress cytotoxic lymphocytes. Genetic ablation of TMEM16F abolished PS exposure, systemically reprogrammed the tumor microenvironment and primary immune organs toward immune activation, and suppressed tumor growth across cancer models. Pharmacological scramblase inhibition produced these effects, demonstrating therapeutic potential. Our findings establish TMEM16F-dependent phospholipid scrambling as a critical immune evasion axis and propose targeting this pathway for cancer treatment.}, archive = {J_PNAS}, author = {Wu, Menghan and Shi, Peishang and Huang, Jianmin and Ni, Xiaomin and Lai, Ruijia and Cao, Kun and Cai, Mengya and Yu, Hao and Zhao, Wenshan and Zhang, Yang}, doi = {10.1073/pnas.2513910122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2513910122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TMEM16F phospholipid scramblase regulates tumorigenesis by modulating the tumor immune microenvironment}, volume = {122}, year = {2025}, }
• (2025). Synthetic bottlebrush block copolymer prevents disease onset in duchenne muscular dystrophy. PNAS, 122(42), e2513599122. (www)

  @article{ , abstract = {Duchenne muscular dystrophy (DMD) is a fatal genetic disease of progressive muscle deterioration with no cure. DMD treatment requires a body-wide approach to target all diseased striated muscles: limb, respiratory, and heart. To address this, we focus studies on blocking the onset of muscle membrane instability, the primary defect in DMD, as a promising yet unmet druggable target. Here, data show the remarkable potency of a synthetic poly(ethylene oxide)/poly(propylene oxide) side chain–based bottlebrush block copolymer, ~150,000 times more potent than linear polymers, to rapidly restore contractile function to DMD skeletal muscle fibers in vitro. Strikingly, upon bottlebrush polymer delivery to DMD animals, results show highly efficacious prevention of the onset of skeletal and diaphragm muscle damage and the blocking of stress-induced cardiac injury and death in vivo. These data suggest bottlebrush polymers as a potent stand-alone muscle membrane-stabilizing therapeutic for DMD. Given DMD’s early childhood onset, together with newborn screening for DMD, bottlebrush macromolecules could be envisioned as an early therapy to preserve and protect viable muscle and potentially for other acquired or inherited diseases involving membrane damage.}, archive = {J_PNAS}, author = {Cohen, Houda and Angulski, Addeli Bez Batti and Quick, Joseph D. and Kuebler, Taylor S. and Thompson, Brian R. and Bauer, John and Hahn, Dongwoo and Townsend, DeWayne and Hassler, Joseph F. and Hackel, Benjamin J. and Lodge, Timothy P. and Sham, Yuk Y. and Bates, Frank S. and Metzger, Joseph M.}, doi = {10.1073/pnas.2513599122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2513599122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synthetic bottlebrush block copolymer prevents disease onset in duchenne muscular dystrophy}, volume = {122}, year = {2025}, }
• (2025). Shapes of ideal stalagmites. PNAS, 122(42), e2513263122. (www)

  @article{ , abstract = {Stalagmites are isolated columns of calcium carbonate growing on a cave floor; their growth is driven by the constant dripping of supersaturated solutions from the roof of the cave. In this paper, we derive a closed-form expression for the shape of a steadily growing stalagmite. Our analysis gives rise to three distinct shapes, all of them observable in nature, with the shape characterized by a single dimensionless parameter. Transitions between different shapes occur at a specific value of this parameter, with additional selection rules determining the shape and size of stalagmites evolving under specific cave conditions. Our theory shows that the stalagmite shape influences the 13 C isotope shifts, which are an important source of paleoclimatic information.}, archive = {J_PNAS}, author = {Szymczak, Piotr and Ladd, Anthony J. C. and Lipar, Matej and Pekarovič, Dean}, doi = {10.1073/pnas.2513263122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2513263122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Shapes of ideal stalagmites}, volume = {122}, year = {2025}, }
• (2025). Emergence of antiphage functions from random sequence libraries reveals mechanisms of gene birth. PNAS, 122(42), e2513255122. (www)

  @article{ , abstract = {De novo gene birth—the emergence of genes from nongenic sequences—drives biological innovation, yet its adaptive potential remains poorly understood. To investigate this issue, we screened libraries of ~100 million short (semi-)random sequences, mimicking early stages of gene birth, for genes that promote Escherichia coli survival during phage infection. This selection uncovered thousands of functional genes that confer viral resistance through at least two distinct mechanisms: 1) activation of a bacterial regulatory system that remodels the outer membrane, which provides broad-spectrum defense, and 2) transcriptional repression of bacterial outer membrane receptors required for phage adsorption, which provides phage-specific protection. Remarkably, unrelated random genes with no sequence similarity produced similar protective phenotypes, revealing that diverse sequences can converge on equivalent functions. We further showed that T4 phage rapidly evolves to counter these novel defenses, acquiring baseplate mutations that enhance adsorption to resistant hosts. Together, these findings demonstrate that random sequences can rapidly evolve into functional genes with direct fitness benefit, highlighting the evolutionary potential of de novo gene birth in the microbial world.}, archive = {J_PNAS}, author = {Frumkin, Idan and Vassallo, Christopher N. and Chen, Yi Hua and Laub, Michael T.}, doi = {10.1073/pnas.2513255122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2513255122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Emergence of antiphage functions from random sequence libraries reveals mechanisms of gene birth}, volume = {122}, year = {2025}, }
• (2025). Exploring bacteria–surface interactions with a fluorescent membrane tension probe. PNAS, 122(42), e2512977122. (www)

  @article{ , abstract = {Understanding how bacteria interact with surfaces is critical for advancing applications in biofilm and biofouling prevention, biomaterial development, or biosensing. However, the biophysical mechanisms underlying these interactions remain poorly characterized, and novel microscopy strategies are needed to specifically address the biointerface. In this study, we employ fluorescence lifetime imaging microscopy (FLIM) with the tension reporter Flipper-TR to investigate membrane tension in live bacteria interacting with various surfaces. We show that Flipper-TR stains both Gram-positive and Gram-negative bacterial membranes, exhibiting fluorescence lifetimes shorter than those in eukaryotic cells, with slight variations between bacterial types and likely reflecting differences in membrane composition. Flipper-TR displays lifetime variations along the vertical axis of bacterial cells, suggesting spatial differences in membrane tension influenced by cell wall architecture. Our results further demonstrate that Flipper-TR is responsive to the nature of bacterial interactions with surfaces. By comparing bacterial immobilization on surfaces with different coatings, we show that Flipper-TR can sensitively distinguish differences in membrane tension arising from distinct adhesion mechanisms. Additionally, Flipper-TR detects changes in membrane tension when bacteria are exposed to engineered nanostructured substrates. Overall, this work expands the toolbox to study the mechanical aspects of bacterial–material interactions and contributes to providing design rules for novel materials that influence bacterial behavior.}, archive = {J_PNAS}, author = {Gonzalez-Garcia, M. Carmen and Ballesteros, Daniel and Hernández, Jaime J. and Pazos, Manuel and Rodríguez, Isabel and Requejo-Isidro, Jose and Flors, Cristina}, doi = {10.1073/pnas.2512977122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2512977122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exploring bacteria–surface interactions with a fluorescent membrane tension probe}, volume = {122}, year = {2025}, }
• (2025). Iron limitation differentially affects viral replication in key marine microbes. PNAS, 122(42), e2512910122. (www)

  @article{ , abstract = {Viral lysis accounts for much of microbial mortality in the ocean, and iron (Fe) is a critical micronutrient that can limit phytoplankton growth. However, interactions between Fe nutrition of microbes, including both heterotrophic bacteria and phytoplankton, and viral lysis are not well known. Here, we present viral infection dynamics under Fe-limited and Fe-replete conditions for isolates of three types of marine picoplankton, the photosynthetic picoeukaryote Ostreococcus , the cyanobacterium Synechococcus , and the heterotrophic bacterium Vibrio . Iron limitation of Ostreococcus resulted in slowed growth and reduced viral burst sizes; this is similar to prior results from studies of larger eukaryotic phytoplankton, where reduced viral replication under Fe limitation is attributed to the viral reliance on host metabolism and replication machinery. Fe limitation of one Vibrio impacted dynamics of its virus similarly, lengthening the latent period before infected cells burst to release new viruses, and reducing the number of infective particles released upon lysis. In contrast, for another Vibrio isolate, Fe limitation had no discernible effect on replication of its virus. Furthermore, dynamics of three cyanophages that infect the same Synechococcus isolate were not affected by Fe limitation of the host, either in terms of latent period or burst size. The results show that some marine viruses, particularly cyanophages, can replicate efficiently even when host growth is compromised. These findings have implications for marine ecology and carbon cycling in Fe-limited regions of the global ocean.}, archive = {J_PNAS}, author = {Yung, Charmaine C. M. and Kelly, Rachel L. and Kauffman, Kathryn M. and Cunningham, Brady R. and Zimmerman, Amy E. and Worden, Alexandra Z. and John, Seth G.}, doi = {10.1073/pnas.2512910122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2512910122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Iron limitation differentially affects viral replication in key marine microbes}, volume = {122}, year = {2025}, }
• (2025). Droplet outbursts from onion cutting. PNAS, 122(42), e2512779122. (www)

  @article{ , abstract = {Cutting onions often leads to tear-inducing aerosol release, yet the underlying mechanics remain poorly understood. In this work, via high-speed characterizations, we show that droplet formation occurs via a two-stage process: an initial high-speed outburst followed by slower ligament fragmentation. By systematically varying blade sharpness and speed, we find that faster or blunter blades significantly increase both the number and energy of ejected droplets. Strain mapping reveals that the onion’s tough epidermis acts as a barrier to fracture, enabling the underlying mesophyll to undergo significant compression before rupture. Developing a simplified bilayer model, we experimentally and theoretically capture the mechanism behind, with numerical calculations of the onion critical fracture forces matching independent Instron results. The work highlights the importance of blade sharpening routines to limiting ejected droplets infected with pathogens in the kitchen, which pack additional outburst energy due to vegetables’ outer strong casings.}, archive = {J_PNAS}, author = {Wu, Zixuan and Hooshanginejad, Alireza and Wang, Weilun and Hui, Chung-Yuen and Jung, Sunghwan}, doi = {10.1073/pnas.2512779122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2512779122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Droplet outbursts from onion cutting}, volume = {122}, year = {2025}, }
• (2025). Modeling the rise and demise of classic maya cities: Climate, conflict, and economies of scale. PNAS, 122(42), e2512325122. (www)

  @article{ , abstract = {Urbanization was one of the most significant transitions in human history, yet explanations for the rise and expansion of early cities remain contentious. Here, we propose that simple models from population ecology can integrate existing theories for the development of early cities. Using newly synthesized paleoclimatological, paleoecological, demographic, and historical data from across the Classic Period Maya Lowlands (250–1000 CE) integrated with piece-wise structural equation models, we show that climate downturns, intergroup conflict, and strong economies of scale interact to promote the coevolution of urbanism and patron–client relationships, fueling city expansion, urban institutions, and systemic inequality. In addition, we elucidate how these nonlinear pathways structure the persistence or dissolution of cities. This study underscores the importance of robust economies of scale in the development of early cities and provides a comprehensive framework for understanding the conditions that promote or hinder urbanization, offering insights applicable to both ancient and contemporary urban dynamics.}, archive = {J_PNAS}, author = {McCool, Weston C. and Codding, Brian F. and Degnan, Bridgette and Ebert, Claire E. and Johnson, Emily S. and Vernon, Kenneth Blake and Wilson, Kurt M. and Beach, Timothy and Prufer, Keith M. and Kennett, Douglas J.}, doi = {10.1073/pnas.2512325122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2512325122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Modeling the rise and demise of classic maya cities: Climate, conflict, and economies of scale}, volume = {122}, year = {2025}, }
• (2025). Prehistoric hunting megastructures in the adriatic hinterland. PNAS, 122(42), e2511908122. (www)

  @article{ , abstract = {Airborne laser scanning survey of the Karst Plateau in the Adriatic hinterland has revealed four monumental dry-stone structures, characterized by long, low stone alignments converging into concealed enclosures. These features, strategically placed along natural movement corridors, appear to have been designed to guide and trap herds of wild animals. Their architectural scale, complexity, and integration with the terrain suggest a high degree of communal organization, landscape knowledge, and planning. Although direct dating remains inconclusive, associated stratigraphy indicates they were abandoned before the Late Bronze Age, pointing to a potentially earlier origin. These structures may represent the westernmost examples of a broader tradition of large-scale hunting installations previously known only from the arid zones of Southwest Asia and North Africa. Their finding challenges prevailing models of prehistoric subsistence in Europe and opens broad perspectives on social organization, mobility, and human–animal relations in complex landscapes.}, archive = {J_PNAS}, author = {Vrhovnik, Dimitrij Mlekuž and Fabec, Tomaž}, doi = {10.1073/pnas.2511908122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2511908122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prehistoric hunting megastructures in the adriatic hinterland}, volume = {122}, year = {2025}, }
• (2025). Dynamic control of NMDA receptor ca2+ permeability by endogenous and synthetic modulators. PNAS, 122(42), e2511783122. (www)

  @article{ , abstract = {NMDA receptors are principal sources of postsynaptic Ca 2+ in central neurons. It is widely assumed that the content of Ca 2+ in the glutamate-elicited ionic flux is determined by the molecular composition of the NMDA receptors, whose expression varies developmentally and across brain regions and can change on a scale of minutes to hours. Here, we report that rather than being a fixed property of a given receptor assembly, the amount of Ca 2+ in the NMDA receptor current can fluctuate in real time over a wide dynamic range in response to endogenous and synthetic allosteric modulators. We identify the extracellular N-terminal domain of the receptor as a structural modulator of its Ca 2+ permeability and demonstrate that the mechanism involves changes in the receptor’s unitary Ca 2+ conductance. These results reveal an unsuspected lever controlling the NMDA receptor–mediated Ca 2+ transients and, implicitly, the many physiological and pathological processes influenced by these currents.}, archive = {J_PNAS}, author = {Weaver, Mae G. and Popescu, Gabriela K.}, doi = {10.1073/pnas.2511783122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2511783122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic control of NMDA receptor ca2+ permeability by endogenous and synthetic modulators}, volume = {122}, year = {2025}, }
• (2025). Engineered 3D immuno-glial-neurovascular human miBrain model. PNAS, 122(42), e2511596122. (www)

  @article{ , abstract = {Patient-specific, human-based cellular models integrating a biomimetic blood–brain barrier, immune, and myelinated neuron components are critically needed to enable accelerated, translationally relevant discovery of neurological disease mechanisms and interventions. To construct a human cell-based model that includes these features and all six major brain cell types needed to mimic disease and dissect pathological mechanisms, we have constructed, characterized, and utilized a multicellular integrated brain (miBrain) immuno-glial-neurovascular model by engineering a brain-inspired 3D hydrogel and identifying conditions to coculture these six brain cell types, all differentiated from patient induced pluripotent stem cells. miBrains recapitulate in vivo – like hallmarks inclusive of neuronal activity, functional connectivity, barrier function, myelin-producing oligodendrocyte engagement with neurons, multicellular interactions, and transcriptomic profiles. We implemented the model to study Alzheimer’s Disease pathologies associated with APOE4 genetic risk. APOE4 miBrains differentially exhibit amyloid aggregation, tau phosphorylation, and astrocytic glial fibrillary acidic protein. Unlike the coemergent fate specification of glia and neurons in other organoid approaches, miBrains integrate independently differentiated cell types, a feature we harnessed to identify that APOE4 in astrocytes promotes neuronal tau pathogenesis and dysregulation through crosstalk with microglia.}, archive = {J_PNAS}, author = {Stanton, Alice E. and Bubnys, Adele and Agbas, Emre and James, Benjamin and Park, Dong Shin and Jiang, Alan and Pinals, Rebecca L. and Liu, Liwang and Truong, Nhat and Loon, Anjanet and Staab, Colin and Cerit, Oyku and Wen, Hsin-Lan and Mankus, David and Bisher, Margaret E. and Lytton-Jean, Abigail K. R. and Kellis, Manolis and Blanchard, Joel W. and Langer, Robert and Tsai, Li-Huei}, doi = {10.1073/pnas.2511596122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2511596122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Engineered 3D immuno-glial-neurovascular human miBrain model}, volume = {122}, year = {2025}, }
• (2025). Anomalous grain dynamics and grain locomotion of odd crystals. PNAS, 122(42), e2511350122. (www)

  @article{ , abstract = {Crystalline or polycrystalline systems governed by odd elastic responses are known to exhibit complex dynamical behaviors involving self-propelled dynamics of topological defects with spontaneous self-rotation of chiral crystallites. Unveiling and controlling the underlying mechanisms require studies across multiple scales. We develop such a type of approach that bridges between microscopic and mesoscopic scales, in the form of a phase field crystal model incorporating transverse interactions. This continuum density field theory features two-dimensional parity symmetry breaking and odd elasticity, and generates a variety of interesting phenomena that agree well with recent experiments and particle-based simulations of active and living chiral crystals, including self-rotating crystallites, dislocation self-propulsion and proliferation, and fragmentation in polycrystals. We identify a distinct type of surface cusp instability induced by self-generated surface odd stress that results in self-fission of single-crystalline grains. This mechanism is pivotal for the occurrence of various anomalous grain dynamics for odd crystals, particularly the predictions of a transition from normal to reverse Ostwald ripening for self-rotating odd grains, and a transition from grain coarsening to grain self-fragmentation in the dynamical polycrystalline state with an increase of transverse interaction strength. We also demonstrate that the single-grain dynamics can be maneuvered through the variation of interparticle transverse interactions. This allows to steer the desired pathway of grain locomotion and to control the transition between grain self-rotation, self-rolling, and self-translation. Our results provide insights for the design and control of structural and dynamical properties of active odd elastic materials.}, archive = {J_PNAS}, author = {Huang, Zhi-Feng and Vrugt, Michael te and Wittkowski, Raphael and Löwen, Hartmut}, doi = {10.1073/pnas.2511350122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2511350122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Anomalous grain dynamics and grain locomotion of odd crystals}, volume = {122}, year = {2025}, }
• (2025). Post-reproductive lifespan in wild mountain gorillas. PNAS, 122(42), e2510998122. (www)

  @article{ , abstract = {Animals can typically maximize their fitness by reproducing throughout adulthood. Yet, in a handful of species, females cease reproduction long before death, highlighting an apparent evolutionary paradox. We used over three decades of life-history and behavioral data to examine the prevalence of postreproductive lifespan in wild mountain gorillas ( Gorilla beringei beringei ). Almost one third of females in our study population (7/25) have been “postreproductive” according to a commonly used criterion and have lived more than a decade past their age of last reproduction, representing at least a fourth of their adult lifespan. Additionally, using conservative estimates of female ages, we found a significant post-reproductive representation (a common population-level measure of post-reproductive lifespan) equal to 0.10. Our results add to observations of postreproductive lifespan in chimpanzees and humans and thus, they represent a critical addition to our understanding of hominid life-history evolution.}, archive = {J_PNAS}, author = {Smit, Nikolaos and Robbins, Martha M.}, doi = {10.1073/pnas.2510998122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2510998122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Post-reproductive lifespan in wild mountain gorillas}, volume = {122}, year = {2025}, }
• (2025). WUSCHEL-d1 upregulation enhances grain number by inducing formation of multiovary-producing florets in wheat. PNAS, 122(42), e2510889122. (www)

  @article{ , abstract = {Innovative genetic improvements in food crops are needed to maintain global food security. Here, we report the map-based cloning of TaWUSCHEL-D1 ( WUS-D1 ) as the gene responsible for the multiovary phenotype in wheat, which produces three fertile ovaries and grains per floret. We generated a 14.5 Gbp chromosome-level assembly of multiovary wheat line “MOV” that shows unique structural variation in the Mov-1 physical region, resulting in widespread gene upregulation. High-resolution genetic mapping refined the locus to a 135 kbp region that contains two genes. We used nine independent deletion mutants, eight TILLING mutants, and genetic complementation of these genotypes to show that a WUSCHEL ortholog, WUS-D1 , is the causal gene of the Mov-1 locus. Expression studies showed that WUS-D1 is highly expressed during early inflorescence development in MOV, whereas the gene is inactive in wild-type wheat. The higher WUS-D1 expression is associated with the formation of larger meristems and floret primordia that are competent to produce multiple ovaries. These insights provide a foundation to manipulate floral organ numbers to enhance breeding capabilities of bread wheat.}, archive = {J_PNAS}, author = {Schoen, Adam and Yoshikawa, Guilherme V. and Sharma, Parva Kumar and Mahlandt, Alex and Chen, Yi and Sheng, Huajin and Kochian, Leon and Gao, Peng and Xiang, Daoquan and Quilichini, Teagen D. and Venglat, Prakash and Wang, Sheng and Yadav, Inderjit Singh and Sablowski, Robert and Wang, Yuqi and Zhang, Peng and Whibley, Annabel and Hill, Amy and Gu, Yong and Rodriguez-Leal, Daniel and Luo, Weifeng and Qi, Yiping and Meier, Nathan and Kajla, Anmol and Willman, Matthew and Brown-Guedira, Gina and Simpson, Sheron A and Youngblood, Ramey C. and Hulse-Kemp, Amanda and Murphy, Angus and Gill, Bikram and Uauy, Cristobal and Datla, Raju and Rawat, Nidhi and Boden, Scott A. and Tiwari, Vijay}, doi = {10.1073/pnas.2510889122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2510889122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {WUSCHEL-d1 upregulation enhances grain number by inducing formation of multiovary-producing florets in wheat}, volume = {122}, year = {2025}, }
• (2025). Apusomonad rhodopsins: A new family of ultraviolet to blue light–absorbing rhodopsin channels. PNAS, 122(42), e2510619122. (www)

  @article{ , abstract = {Apusomonads are sediment-dwelling bacterivorous protists that are sister to all Opisthokonta. They have been found to show a negative phototactic response to blue light, mediated by an as-yet unidentified photoreceptive system. Here, by screening available apusomonad omics data we found genes of a distinct group of microbial rhodopsins, apusomonad rhodopsins (ApuRs). ApuRs, heterologously expressed in mammalian cells, absorbed near-UV or violet light, suggesting that ApuRs could be involved in apusomonads’ photoavoidance response toward short-wavelength light. Electrophysiological measurements indicate that ApuRs are anion-selective rhodopsin channels which evolved independently of the family of channelrhodopsins widespread in other unicellular eukaryotes. In ApuRs, channel opening is triggered by photoisomerization of the retinal from its all- trans form to 13- cis and 11- cis forms. We found that intracellular proton transfer is involved in channel opening and determines the channel’s open/close kinetics. These findings expand our understanding of the photobiology of heterotrophic flagellates and demonstrate that UV-absorbing ApuRs are in fact the most blue-shifted rhodopsin channels known to date.}, archive = {J_PNAS}, author = {Galindo, Luis Javier and Takaramoto, Shunki and Nagata, Takashi and Rozenberg, Andrey and Takahashi, Hiroto and Béjà, Oded and Inoue, Keiichi}, doi = {10.1073/pnas.2510619122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2510619122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Apusomonad rhodopsins: A new family of ultraviolet to blue light–absorbing rhodopsin channels}, volume = {122}, year = {2025}, }
• (2025). High-resolution geostationary satellite observations of free tropospheric NO2 over north america and implications for lightning emissions. PNAS, 122(42), e2510535122. (www)

  @article{ , abstract = {Free tropospheric (FT) nitrogen dioxide (NO 2 ) plays a critical role in atmospheric oxidant chemistry as a source of tropospheric ozone and of the hydroxyl radical (OH). It also contributes significantly to satellite-observed tropospheric NO 2 columns, which should be considered when using these columns to quantify surface emissions of nitrogen oxide radicals (NO x ≡ NO + NO 2 ). But large uncertainties remain in the sources and chemistry of FT NO 2 because observations are sparse. Here, we construct a cloud-sliced FT NO 2 (700 to 300 hPa) product from the Tropospheric Emissions: Monitoring of Pollution (TEMPO) geostationary satellite instrument over North America. This product provides higher data density and quality than previous products from low Earth orbit instruments, including the first observations of the FT NO 2 diurnal cycle in different seasons. Combined with coincident observations from the Geostationary Lightning Mapper, the TEMPO data imply that lightning is the dominant source of FT NO x in nonwinter seasons. Comparison of TEMPO FT NO 2 data with the Goddard Earth Observation System-Composition Forecasts (GEOS-CF) atmospheric chemistry model shows overall consistent magnitudes, seasonality, and diurnal variation, with a midday minimum in nonwinter seasons from photochemical loss. However, there are major discrepancies that we attribute to GEOS-CF’s use of a standard cloud-top-height-based scheme for the lightning NO x source. We find that this scheme underestimates offshore lighting flash density and misrepresents the diurnal cycle of lightning over land. Our FT NO 2 product provides a unique resource for improving the lightning NO x parameterization in atmospheric models and the ability to use NO 2 observations from space to quantify surface NO x emissions.}, archive = {J_PNAS}, author = {Dang, Ruijun and Jacob, Daniel J. and Wang, Huiqun and Nowlan, Caroline R. and Gonzalez Abad, Gonzalo and Chong, Heesung and Liu, Xiong and Shah, Viral and Yang, Laura H. and Oak, Yujin J. and Marais, Eloise A. and Horner, Rebekah P. and Rollins, Andrew W. and Crawford, James H. and Li, Ke and Liao, Hong}, doi = {10.1073/pnas.2510535122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2510535122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High-resolution geostationary satellite observations of free tropospheric NO2 over north america and implications for lightning emissions}, volume = {122}, year = {2025}, }
• (2025). Small-molecule allosteric activator of ubiquitin-specific protease 7 (USP7). PNAS, 122(42), e2510496122. (www)

  @article{ , abstract = {Ubiquitin-specific protease 7 (USP7) is a deubiquitylase essential for cell homeostasis, DNA repair, and regulation of both tumor suppressors and oncogenes. Recently, haploinsufficiency of USP7 has been associated with Hao–Fountain syndrome (HAFOUS), a rare neurodevelopmental disorder. Although a range of USP7 inhibitors have been developed over the last decade, in the context of HAFOUS, USP7 activators may represent a more relevant approach. To address this challenge, we report the identification and characterization of a small-molecule activator of USP7 called MS-8. Structural and functional studies show that MS-8 allosterically activates USP7, mimicking the endogenous autoactivation mechanism of the enzyme. We observed that MS-8 engages and activates mutant USP7 in a cellular context, impacting downstream proteins. Taken together, our study provides validation of the USP7 activator that paves the way toward activation-driven USP7 pharmacology.}, archive = {J_PNAS}, author = {Jaen Maisonet, Isabella and Sharafi, Mona and Korchak, Emilie J. and Salazar-Chaparro, Andres and Bratt, Ariana S. and Parikh, Tvesha and Varca, Anthony C. and Shah, Binita and Darnowski, Michael and Chung, Mia and Teh, Wei Pin and Che, Jianwei and Bezsonova, Irina and Buhrlage, Sara J.}, doi = {10.1073/pnas.2510496122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2510496122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Small-molecule allosteric activator of ubiquitin-specific protease 7 (USP7)}, volume = {122}, year = {2025}, }
• (2025). Sex differences in healthy brain aging are unlikely to explain higher alzheimer’s disease prevalence in women. PNAS, 122(42), e2510486122. (www)

  @article{ , abstract = {As Alzheimer’s disease (AD) is diagnosed more frequently in women, understanding the role of sex has become a key priority in AD research. However, despite aging being the primary risk factor for AD, it remains unclear whether men and women differ in the extent of brain decline with age. Using 12,638 longitudinal brain MRIs from 4,726 participants aged 17 to 95 y across 14 cohorts, we examined sex differences in structural brain changes over time, controlling for differences in head size. Men showed greater cortical thickness (CT) decline in the cuneus, lingual, parahippocampal, and pericalcarine regions; surface area decline in the fusiform and postcentral regions; and in older adults, greater subcortical decline in the caudate, nucleus accumbens, putamen, and pallidum. In contrast, women only showed greater surface area decline in the banks of the superior temporal sulcus and greater ventricular expansion in older adults. These results suggest that sex differences in age-related brain decline are unlikely to contribute to the higher AD diagnosis prevalence in women, necessitating research into alternative explanations.}, archive = {J_PNAS}, author = {Ravndal, Anne and Fjell, Anders M. and Vidal-Piñeiro, Didac and Sørensen, Øystein and Falch, Emilie S. and Kropiunig, Julia and Garrido, Pablo F. and Roe, James M. and Alatorre-Warren, José-Luis and Sneve, Markus H. and Bartrés-Faz, David and Pascual-Leone, Alvaro and Brandmaier, Andreas M. and Düzel, Sandra and Kühn, Simone and Lindenberger, Ulman and Nyberg, Lars and Watne, Leiv Otto and Henson, Richard N. and null, null and Walhovd, Kristine B. and Grydeland, Håkon}, doi = {10.1073/pnas.2510486122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2510486122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sex differences in healthy brain aging are unlikely to explain higher alzheimer’s disease prevalence in women}, volume = {122}, year = {2025}, }
• (2025). Parkinsonism disrupts the balance between excitatory and inhibitory activity within the primary motor cortex during movement. PNAS, 122(42), e2510287122. (www)

  @article{ , abstract = {Parkinson’s disease (PD) has been associated with alterations in neuronal activity in the basal ganglia-thalamocortical (BGTC) network. Previous studies have suggested that cortical disinhibition is a feature of PD, but there has been little direct evidence of the changes in cortical neuronal spiking activity to support this hypothesis. To test the hypothesis that activity in the motor cortex is enhanced in PD, we investigated the effects of parkinsonism on movement-related neuronal activity in the primary motor cortex (M1). Microelectrode arrays were chronically implanted in M1 of two nonhuman primates and populations of cells were collected before and after the induction of parkinsonism using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In both animals, we found that during the reaching task in the parkinsonian state, the proportion of M1 neurons that were activated (excited) during movement were increased, while those that were suppressed (inhibited) decreased. These data support the concept that dopaminergic loss in parkinsonism promotes a loss of inhibition in the motor cortex, leading to overactivity in M1 and a disruption in spatial-temporal processing of information within the BGTC circuit that contributes to the motor dysfunction observed in PD.}, archive = {J_PNAS}, author = {Mohanty, Biswaranjan and Guo, Zheshan and Johnson, Luke A. and Wang, Jing and Vitek, Jerrold L.}, doi = {10.1073/pnas.2510287122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2510287122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Parkinsonism disrupts the balance between excitatory and inhibitory activity within the primary motor cortex during movement}, volume = {122}, year = {2025}, }
• (2025). Hydrothermal vent temperatures track magmatic inflation and forecast eruptions at the east pacific rise, 9°50’N. PNAS, 122(42), e2510245122. (www)

  @article{ , abstract = {Hydrothermal vent temperatures fluctuate in response to transient magmatic and tectonic activity at the axis of mid-ocean ridges (MORs) and modulate energy fluxes from the deep Earth to the ocean. Such fluctuations have thus far only been documented on time scales of minutes to years, because of the scarcity of long, continuous observations. Here, we assemble a ~35-year-long time series of exit fluid temperatures from five hydrothermal vents on the East Pacific Rise axis, between 9°46’-51’N. This dataset reveals a steady increase in maximum venting temperatures atop the central part of the axial magma lens (AML), from ~350 °C to ~390 °C between the 1991–92 and 2005–06 eruptions. Temperatures decreased back to ~350 °C shortly after the 2005–06 eruption and have been rising ever since. We interpret the temperature increase as a result of a steady decrease in upflow zone permeability caused by the steady inflation of the AML compressing the oceanic upper crust. Using laboratory-determined pressure–permeability relations, we estimate crustal pressurization rates of 0.38 MPa/y (1992–2005) and 0.33 MPa/y (post-2006), consistent with geodetic observations from 2009–2011. Decadal fluctuations in hydrothermal vent temperatures likely mimic the rate of AML pressurization, yielding valuable new constraints on the dynamics of magmatic replenishment and eruptions at MORs. Notably, this temperature time series underpinned our forecast of the April 2025 eruption at the study site.}, archive = {J_PNAS}, author = {Barreyre, Thibaut and Olive, Jean-Arthur and Fornari, Daniel J. and McDermott, Jill M. and Parnell-Turner, Ross and Moutard, Kim and Wu, Jyun-Nai and Marjanović, Milena}, doi = {10.1073/pnas.2510245122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2510245122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hydrothermal vent temperatures track magmatic inflation and forecast eruptions at the east pacific rise, 9°50’N}, volume = {122}, year = {2025}, }
• (2025). Safety versus performance: How multi-objective learning reduces barriers to market entry. PNAS, 122(42), e2510004122. (www)

  @article{ , abstract = {Emerging marketplaces for large language models and other large-scale machine learning models appear to exhibit market concentration, which has raised concerns about whether there are insurmountable barriers to entry in such markets. In this work, we study this issue from both an economic and an algorithmic point of view, focusing on a phenomenon that reduces barriers to entry. Specifically, an incumbent company risks reputational damage unless its model is sufficiently aligned with safety objectives, whereas a new company can more easily avoid reputational damage. To study this issue formally, we define a multi-objective high-dimensional regression framework that captures reputational damage, and we characterize the number of data points that a new company needs to enter the market. Our results demonstrate how multi-objective considerations can fundamentally reduce barriers to entry—the required number of data points can be significantly smaller than the incumbent company’s dataset size. En route to proving these results, we develop scaling laws for high-dimensional linear regression in multi-objective environments, showing that the scaling rate becomes slower when the dataset size is large, which could be of independent interest.}, archive = {J_PNAS}, author = {Jagadeesan, Meena and Jordan, Michael I. and Steinhardt, Jacob}, doi = {10.1073/pnas.2510004122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2510004122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Safety versus performance: How multi-objective learning reduces barriers to market entry}, volume = {122}, year = {2025}, }
• (2025). Electrical and thermal conductivity of earth’s iron-enriched basal magma ocean. PNAS, 122(42), e2509771122. (www)

  @article{ , abstract = {The Earth’s earliest magnetic field may have originated in a basal magma ocean, a layer of silicate melt surrounding the core that could have persisted for billions of years. Recent studies show that the electrical conductivity of liquid with a bulk silicate Earth composition exceeds 10 4 S/m at basal magma ocean conditions, potentially surpassing the threshold for dynamo activity. Over most of its history however, the basal magma ocean is more enriched in iron than the bulk silicate Earth, due to iron’s incompatibility in the mineral assemblages of the lower mantle. Using ab-initio molecular dynamics calculations, we examine how iron content affects the silicate dynamo hypothesis. We investigate how the electrical conductivity of silicate liquid changes with iron enrichment, at pressures and temperatures relevant for Earth’s basal magma ocean. We also compute the electronic contribution to the thermal conductivity, to evaluate convective instability of basal magma oceans. Finally, we apply our results to model the thermal and magnetic evolution of Earth’s basal magma ocean over time.}, archive = {J_PNAS}, author = {Dragulet, Francis and Stixrude, Lars}, doi = {10.1073/pnas.2509771122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2509771122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electrical and thermal conductivity of earth’s iron-enriched basal magma ocean}, volume = {122}, year = {2025}, }
• (2025). Adaptable microplastic classification using similarity learning on µFTIR spectra collected from µFTIR focal plane array imaging. PNAS, 122(42), e2509745122. (www)

  @article{ , abstract = {Deep learning on micro-Fourier transform infrared (µFTIR) spectra has the potential to provide a reliable, automated approach to classify and identify microplastics. However, deep learning models often come with certain limitations, including exhaustive dataset requirements, overfitting, and the need to retrain when new classes are introduced or new data are substantially different from the training set. This work explores a similarity learning approach to training deep learning models to address these issues for microplastic classification. A one-dimensional convolutional neural network (CNN) was trained by similarity learning on a dataset of µFTIR spectra acquired from 45 manufactured microplastic samples of 11 plastic compositions and compared with cross-entropy training of the same CNN architecture as well as classical machine learning algorithms. The CNN trained by similarity learning consistently yielded the highest accuracies (up to a 0.973 F1-score) across the multiple classes of microplastics. Notably, despite only training on microplastic spectra collected under pristine conditions, the CNN trained via similarity learning maintained the highest accuracy (up to a 0.905 F1-score) on a “noisy” dataset consisting of microplastics spiked onto filters with high amounts of exogenous background material. Furthermore, similarity learning combined with support-vector classifiers also allowed for the detection and separation of microplastic polymer-composition classes not contained in the training set. Overall, this approach is able to achieve high accuracy in microplastic classification despite challenges posed by the diversity of microplastic polymer compositions, limited time and resources for dataset preparation, and high amounts of background noise that are common in FTIR spectra collected from real-world microplastic samples.}, archive = {J_PNAS}, author = {Smolen, Justin A. and Moore, Gavin E. and Perez, Nicholas D. and Wooley, Karen L.}, doi = {10.1073/pnas.2509745122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2509745122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Adaptable microplastic classification using similarity learning on µFTIR spectra collected from µFTIR focal plane array imaging}, volume = {122}, year = {2025}, }
• (2025). Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival. PNAS, 122(42), e2509222122. (www)

  @article{ , abstract = {Cancer cells exhibit accelerated protein production to accommodate their high rates of growth and proliferation. Elevated protein synthesis creates a dependency on endoplasmic reticulum (ER)-resident proteins and chaperones, which are required to maintain proteostasis. In this study, we identified the protein disulfide isomerases (PDIs) PDIA1 and PDIA5, which play a critical role in folding of client proteins in the ER, as important regulators of prostate cancer growth and response to therapy. PDIA1 and PDIA5 are upregulated in prostate cancer and induced by the androgen receptor (AR) signaling axis. Genetic or pharmacological disabling of PDIA1/PDIA5 caused redox stress, mitochondrial dysfunction, growth inhibition, and death of prostate cancer cells in vitro and in vivo. The critical functions of these enzymes in redox homeostasis and cell survival were observed in both AR-driven and AR-independent models of prostate cancer. Loss of PDIA1/PDIA5 activity led to ubiquitination and degradation of the AR, revealing a feedback loop between these chaperones and the AR pathway. Mechanistically, PDIA1/PDIA5 regulated AR stability by mediating disulfide bond formation, an activity that required cysteines 669 and 844 in AR’s ligand-binding domain. Importantly, targeting PDIAs sensitized prostate cancer cells to the AR antagonist, enzalutamide. This study reveals a mechanism governing AR proteostasis in prostate cancer and positions PDIA1/5 as viable therapeutic targets.}, archive = {J_PNAS}, author = {Xie, Jianling and Shen, Kaikai and Liang, Wenken and Kuang, Zijian and Shrestha, Raj K. and Hanson, Adrienne R. and Townley, Scott L. and He, Meiling and Yu, Sishu and Zhou, Peiwen and Zhu, Liangzhen and Gong, Zhiwen and Ao, Xiang and Rao, Sushma R. and Zhang, Qing and Chen, Kaijie and Wei, Jinfen and Marri, Shashikanth and Snel, Marten F. and Irani, Swati and Chen, Liye and Wang, Ling and McDougal, Daniel P. and Bruning, John B. and Ou, Minglin and Wang, Shaobo and Proud, Christopher G. and Du, Hongli and Butler, Lisa M. and Selth, Luke A.}, doi = {10.1073/pnas.2509222122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2509222122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival}, volume = {122}, year = {2025}, }
• (2025). A generalizable deep learning framework for structure-based protein–ligand affinity ranking. PNAS, 122(42), e2508998122. (www)

  @article{ , abstract = {Rapid and accurate estimation of protein–ligand binding affinities is crucial for early-stage drug discovery, yet hindered by a trade-off between the accuracy of gold-standard physics-based methods and the speed of simpler empirical scoring functions. Machine learning (ML) promised to bridge this gap, but its potential is unrealized due to limited model generalizability. Current ML models often fail when predicting affinities for novel proteins or chemical series unseen during training. We hypothesize that this failure stems from a competition within these models during training, where the learning of spurious correlations from structural motifs prevalent in the training data competes with the learning of transferable, physicochemical principles governing molecular interaction. Here, we introduce COnvolutional Representation of Distance-dependent Interactions with Attention Learning (CORDIAL), a deep learning framework designed with an inductive bias toward learning the distance-dependent physicochemical interaction signatures between proteins and ligands, explicitly avoiding direct parameterization of their chemical structures. This interaction-only approach proves effective. Through leave-superfamily-out validation that simulates encounters with novel protein families, we demonstrate that CORDIAL maintains predictive performance and calibration. This contrasts with diverse contemporary ML models, whose predictive ability is degraded under these conditions. Our results highlight the value of encoding appropriate task-specific physicochemical principles into ML architectures and offer a validated strategy for developing generalizable models for structure-based drug discovery.}, archive = {J_PNAS}, author = {Brown, Benjamin P.}, doi = {10.1073/pnas.2508998122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2508998122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A generalizable deep learning framework for structure-based protein–ligand affinity ranking}, volume = {122}, year = {2025}, }
• (2025). Polycomb repressive complex 1 and USP16 localize to the mitochondrion and influence its function. PNAS, 122(42), e2508812122. (www)

  @article{ , abstract = {Polycomb Repressive Complex 1 (PRC1) represses gene expression by ubiquitinating histone H2A or physically compacting chromatin. USP16, one of the histone H2A deubiquitinases, antagonizes PRC1-mediated H2A ubiquitination (H2Aub). Here, we report that both PRC1 and USP16 are also localized in mitochondria and influence mitochondrial function directly. Our findings are based on immunofluorescence and proximity ligation assays, cell fractionation, and biochemical analyses of isolated or affinity-purified mitochondria. We further showed that PRC1 and USP16 function with the ubiquitin pathway. Auxin-induced, mitochondria-specific depletion of the PRC1 subunit RING2 altered the ubiquitination status of mitochondrial proteins, including H2Aub. Disruption of PRC1, either through double knockout (KO) of RING1 and RING2 or through mitochondria-specific deletion of RING2 in the RING1 KO background, caused profound alterations in mitochondrial proteome and led to disturbances in mitochondrial integrity and impaired respiratory function. Thus, in addition to their canonical functions in the nucleus, PRC1 and USP16 also translocate into mitochondria and directly impact mitochondrial integrity and function.}, archive = {J_PNAS}, author = {Shi, Lei and Chen, Chunxu and Jian, Xiaokun and Wang, Qiushi and Shen, Yuan and Alajmi, Asmaa and Zhang, Hao and Shock, Lisa S. and Chow, Louise T. and Wang, Hengbin}, doi = {10.1073/pnas.2508812122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2508812122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Polycomb repressive complex 1 and USP16 localize to the mitochondrion and influence its function}, volume = {122}, year = {2025}, }
• (2025). Microbial oxidation significantly reduces methane export from global groundwaters. PNAS, 122(42), e2508773122. (www)

  @article{ , abstract = {Methane is ubiquitous in groundwater, and its release to surface environments through pumping, discharge, or diffusion is an emerging environmental concern. Microbial oxidation consumes methane and mitigates its release, but quantitative constraints in groundwater remain unknown. Using ultra-low-level 14 C-labeling, we estimate in situ microbial methane oxidation rates in shallow carbonate and sandy aquifers from central and northern Germany with methane concentrations spanning 5 orders of magnitude, from 0.15 ± 0.04 to 36,250 ± 1,390 µg L −1 . Oxidation rates ranged from 0.001 ± 0.0003 to 74.28 ± 46.94 µgC L −1 d −1 and were highly correlated with groundwater methane concentrations. Oxidation-based methane turnover was rapid at low methane concentrations, with complete consumption requiring days to weeks. In contrast, microbial oxidation at high methane sites required months to decades for complete methane turnover, indicating the potential for unconsumed methane to leak into local streams or wetlands. High oxidation rates were associated with gammaproteobacterial methanotrophs that typically thrive in suboxic conditions and anaerobic methane-oxidizing archaea, while uncultivated methanotrophs of the Methylomirabilota and Verrucomicrobiota dominated low-rate sites. Based on globally distributed groundwater methane concentration data, we extrapolated the strong observed correlation between methane concentrations and oxidation rates to global groundwater volumes, estimating that microbial oxidation removes ~66% of groundwater methane globally, equivalent to 167 to 778 Tg CH 4 y −1 . This highlights the groundwater microbiome as a crucial subsurface methane filter that reduces methane release to surface waters, soils, and the atmosphere.}, archive = {J_PNAS}, author = {Heinze, Beatrix M. and Schwab, Valérie F. and Küsel, Kirsten and Schloemer, Stefan and Roskam, Andreas and Xu, Xiaomei and Trumbore, Susan}, doi = {10.1073/pnas.2508773122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2508773122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Microbial oxidation significantly reduces methane export from global groundwaters}, volume = {122}, year = {2025}, }
• (2025). Oil–water interfaces drive gold precipitation via microdroplet chemistry in thermal geological systems. PNAS, 122(42), e2508673122. (www)

  @article{ , abstract = {Sedimentary basins host high-grade gold mineralization at intersections of auriferous hydrothermal fluids and hydrocarbons. However, the precise mechanism of native gold formation associated with organic matter remains poorly understood. Here, we investigate gold precipitation at oil–water interfaces through in situ thermal experiments using various combinations of oil and HAuCl 4 -bearing solutions. Our results reveal that gold particles form spontaneously following the extensive generation and evolution of water microdroplets at oil–water interfaces at temperatures of 140 to 400 °C. We propose that electrons (e − ), released from the conversion of hydroxide ions (OH − ) to hydroxyl radicals (·OH) in water microdroplets, together with H atoms (·H) formed through electron transfer involving H 3 O + , and spontaneously generated H 2 O 2 from·OH recombination, drive the reduction of Au 3+ to Au 0 . The atomic gold progressively aggregates into Au 0 clusters and Au nanoparticles (AuNPs), ultimately forming micrometer-scale gold particles and wires. This precipitation process occurs within minutes at temperatures above 350 °C and within hours below 200 °C. The experimentally produced gold particles exhibit textures like those in natural ore deposits. This interfacial microdroplet–induced mechanism provides a unique perspective on native gold formation in hydrocarbon-rich geosystems. Beyond its geological significance, this mechanism offers a potentially simplified approach for gold recovery from electronic waste without the need to introduce complex adsorbents or reducing agents into the waste stream.}, archive = {J_PNAS}, author = {Yuan, Guanghui and Wang, Jixuan and Cao, Yingchang and Jin, Zihao and Hao, Fang and Liu, Keyu and Li, Yang and Schulz, Hans-Martin and Gluyas, Jon and Zare, Richard N.}, doi = {10.1073/pnas.2508673122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2508673122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Oil–water interfaces drive gold precipitation via microdroplet chemistry in thermal geological systems}, volume = {122}, year = {2025}, }
• (2025). Reuniting crystallography with real space: Ab initio structure elucidation with 4D-STEM. PNAS, 122(42), e2508185122. (www)

  @article{ , abstract = {Structure elucidation via single-crystal methods has historically lacked experimental access to real-space information, instead relying exclusively on diffraction-space measurements of Bragg reflections. Here we exploit the dual-space imaging power of 4D scanning transmission electron microscopy to meaningfully integrate real-space information into the crystallographic workflow. We show that virtual apertures assembled by segmentation of high-angle annular dark-field images enable i) pixel-by-pixel separation of coherent Bragg signal from clusters of closely spaced nanocrystals and ii) selective extraction of integrated intensities from thinner subregions of individual specimens, facilitating retroactive tuning of multiple scattering artifacts. This strategy empowers us to simply pick and choose whichever nanoscale regions of interest generate the highest-quality diffraction patterns, allowing us to solve several independent structures of the metal-organic framework UiO-66 from specimens whose agglomerated morphology proved intractable for conventional microcrystal electron diffraction. Our method is compatible with both rotational and serial approaches to data processing, ultimately divulging the first scanning nanobeam electron diffraction structures determined by direct methods at subangstrom resolution.}, archive = {J_PNAS}, author = {Saha, Ambarneil and Pattison, Alexander J. and Bustillo, Karen C. and Mittan-Moreau, David W. and Brewster, Aaron S. and Zhang, Jian and Ercius, Peter}, doi = {10.1073/pnas.2508185122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2508185122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reuniting crystallography with real space: Ab initio structure elucidation with 4D-STEM}, volume = {122}, year = {2025}, }
• (2025). The FKF1–ELF3–PRC2 module regulates flowering time in response to light in temperate grasses. PNAS, 122(42), e2508103122. (www)

  @article{ , abstract = {The precise timing of flowering is critical to ensure reproductive success in plants. This process is coordinated by both endogenous and environmental cues. Light is a pivotal environmental cue fundamentally regulating plant growth and development. In temperate grasses, how light regulates flowering time remains largely unknown. Here, we characterize a blue-light photoreceptor, FLAVIN-BINDING, KELCH REPEAT, F-BOX 1 (FKF1), which functions as a flowering promoter in Brachypodium distachyon . Loss-of-function mutations in FKF1 result in delayed flowering under long-day conditions, whereas overexpression of FKF1 strongly accelerates flowering. We show that FKF1 controls the stability of floral repressor EARLY FLOWERING 3 (ELF3) in response to blue light. FKF1 directly interacts with and catalyzes the ubiquitination of ELF3, leading to protein degradation of ELF3 via the 26S proteasome pathway. Blue light can strengthen the interaction between FKF1 and ELF3, thereby accelerating degradation of ELF3. Moreover, ELF3 physically interacts with SWINGER and CURLY LEAF, two core subunits of Polycomb repressive complex 2 (PRC2), and mediates the subsequent deposition of histone H3 lysine 27 trimethylation (H3K27me3) for stable transcriptional silencing of the flowering activator PHOTOPERIOD 1 . Remarkably, the FKF1–ELF3–PRC2 regulatory module-mediated flowering time control in response to light is likely conserved across temperate grasses. Our study elucidates the mechanism by which light modulates H3K27me3 deposition to regulate flowering time in temperate grasses. This mechanism also allows plants to adapt to dynamically changing environments.}, archive = {J_PNAS}, author = {Zeng, Siying and Qin, Zhengrui}, doi = {10.1073/pnas.2508103122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2508103122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The FKF1–ELF3–PRC2 module regulates flowering time in response to light in temperate grasses}, volume = {122}, year = {2025}, }
• (2025). Quantifying cell traction forces at the single-fiber scale in 3D: An approach based on deformable photopolymerized fiber arrays. PNAS, 122(42), e2507677122. (www)

  @article{ , abstract = {The forces exerted by cells upon the fibers of the extracellular matrix play a decisive role in cell motility in physiopathology. How the local physical properties of the matrix (density, stiffness, orientation) affect cellular forces remains, however, poorly understood. Existing approaches to measure cell three-dimensional (3D) traction forces within fibrous substrates lack control over the local properties and rely on continuum approaches, not suited for measuring forces at the scale of individual fibers. Herein, an approach is proposed to fabricate multilayer arrays of suspended deformable fibers spanning a wide range of fine-tunable geometrical and mechanical properties using two-photon polymerization. Atomic Force Microscopy is used to thoroughly investigate the properties of individual fibers, including Young’s modulus and stiffness. This approach is combined with a reference-free method for measuring traction forces in 3D, which relies on automated segmentation of the fibers coupled with finite element modeling. The force measurement pipeline is applied to study forces exerted by endothelial cells, fibroblasts, or macrophages, and reveals how these forces are influenced by fiber density and stiffness. Additionally, coupling to fast volumetric imaging with lattice light-sheet microscopy enables the measurement of the low-intensity and short-lived tractions exerted by amoeboid cells, such as dendritic cells. Our technology will be instrumental for monitoring and studying cell behavior at the single-fiber level at extracellular matrix density interfaces, which play a crucial role in both physiological and pathological contexts, such as tumor boundaries.}, archive = {J_PNAS}, author = {Ucla, Pierre and Lê-Chesnais, Joanne and Ver Hulst, Henri and Ju, Xingming and Calvente, Isabel and Nematollahi, Elnaz and Leconte, Ludovic and Salamero, Jean and Bonnet, Isabelle and Monnot, Catherine and Moreau, Hélène D. and Landoulsi, Jessem and Semetey, Vincent and Coscoy, Sylvie}, doi = {10.1073/pnas.2507677122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2507677122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantifying cell traction forces at the single-fiber scale in 3D: An approach based on deformable photopolymerized fiber arrays}, volume = {122}, year = {2025}, }
• (2025). Integrative mapping reveals molecular features underlying the mechanism of nucleocytoplasmic transport. PNAS, 122(42), e2507559122. (www)

  @article{ , abstract = {Nuclear pore complexes (NPCs) enable rapid, selective, and robust nucleocytoplasmic transport. To explain how transport emerges from the system components and their interactions, we used experimental data and theoretical information to construct an integrative Brownian dynamics model of transport through an NPC, coupled to a kinetic model of transport in the cell. The model recapitulates key aspects of transport for a wide range of molecular cargoes, including preribosomes and viral capsids. Our model quantifies how flexible phenylalanine-glycine (FG) repeat proteins create an entropic barrier to passive diffusion and how this barrier is selectively lowered in facilitated diffusion by the many transient interactions of nuclear transport receptors with the FG repeats. Selective transport is enhanced by “fuzzy” multivalent interactions, redundant FG repeat mass, coupling to the energy-dependent RanGTP concentration gradient, and exponential dependence of transport kinetics on the transport barrier. Our model will facilitate rational modulation of the NPC and its artificial mimics.}, archive = {J_PNAS}, author = {Raveh, Barak and Eliasian, Roi and Rashkovits, Shaked and Russel, Daniel and Hayama, Ryo and Sparks, Samuel and Singh, Digvijay and Lim, Roderick Y. H. and Villa, Elizabeth and Rout, Michael P. and Cowburn, David and Sali, Andrej}, doi = {10.1073/pnas.2507559122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2507559122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Integrative mapping reveals molecular features underlying the mechanism of nucleocytoplasmic transport}, volume = {122}, year = {2025}, }
• (2025). Invasin-functionalized PIC hydrogels enable long-term 3D culture of epithelial organoids. PNAS, 122(42), e2507500122. (www)

  @article{ , abstract = {Tissue stem cell (TSC)-derived epithelial organoids are typically cultured in Matrigel [T. Sato et al. , Nature 459 , 262–265 (2009)], an extracellular matrix-like hydrogel produced from Engelbreth–Holm–Swarm sarcoma cells. This tumor is grown in the mouse abdomen [R. W. Orkin et al. , J. Exp. Med. 145 , 204–220 (1977)]. Previously, we demonstrated that the Yersinia membrane protein Invasin, coated on transwells, replaces Matrigel by activating β1-integrins, allowing long-term expansion of primary epithelial cells as 2D organoid sheets [J. J. A. P. M. Wijnakker et al. , Proc. Natl. Acad. Sci. U.S.A. 122 , e2420595121 (2025)]. Here, we functionalize a synthetic polyisocyanide (PIC) hydrogel with the integrin-activating domain of Invasin (INV). PIC hydrogels are soluble at 4 °C and form a gel at 37 °C [P. H. J. Kouwer et al. , Nature 493 , 651–655 (2013)]. When INV is covalently linked to PIC, the resulting hydrogel supports multipassage 3D growth of human intestinal and airway organoids. Self-renewal, polarization, and differentiation are maintained. The 3D swelling assay for cystic fibrosis drug testing (S. F. Boj et al. , J. Vis. Exp. (2017), 10.3791/55159] was validated using PIC-INV. With PIC-INV hydrogels, we establish a fully defined and animal-free system for 3D TSC-derived organoid culture.}, archive = {J_PNAS}, author = {Wijnakker, Joost J. A. P. M. and Lim, Sangho and Schreurs, Robin and Faria, João Ferreira and Korving, Jeroen and Begthel, Harry and Iyer, Kirti K. and Kouwer, Paul H. J. and Clevers, Hans}, doi = {10.1073/pnas.2507500122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2507500122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Invasin-functionalized PIC hydrogels enable long-term 3D culture of epithelial organoids}, volume = {122}, year = {2025}, }
• (2025). TCR signal–enhancing mutation alters lipid metabolism of thymocytes and impairs antitumor immunity of mature t cells. PNAS, 122(42), e2507154122. (www)

  @article{ , abstract = {The T cell receptor (TCR), a master regulator of adaptive immunity, serves as a molecular transducer that converts antigen recognition into precisely modulated intracellular signals, orchestrating both T cell development and effector functions. In this study, we leveraged a germline CD3ε I173A mutation, a previously characterized alteration that amplifies TCR signaling through the disruption of inhibitory lipid interactions, to dissect how thymocyte-intrinsic TCR signaling amplification influences the fate of mature T cells. Remarkably, thymic double-positive cells in CD3ε I173A mice with altered TCR repertoires demonstrated a significant downregulation of the phosphatidylserine decarboxylase homolog gene AC149090.1 . This modulation triggered a comprehensive rewiring of lipid metabolic pathways, establishing a systemic compensatory mechanism to counterbalance excessive TCR signaling. These metabolic adaptations culminated in functionally compromised mature T cells, characterized by diminished activation potential, reduced proliferative capacity, and impaired antitumor efficacy in CD3ε I173A mice. Our results underscore the critical role of thymic TCR signaling in T cell development for sustaining immune homeostasis and orchestrating mature T cell functionality, unveiling the lipid metabolic plasticity during thymocyte development that acts as a critical regulatory checkpoint for maintaining immune homeostasis.}, archive = {J_PNAS}, author = {Liang, Wenhua and Liang, Yuge and Yu, Mingzhu and Ji, Chenshuang and Wang, Feng}, doi = {10.1073/pnas.2507154122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2507154122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TCR signal–enhancing mutation alters lipid metabolism of thymocytes and impairs antitumor immunity of mature t cells}, volume = {122}, year = {2025}, }
• (2025). Virulence hierarchies within the mycobacterium tuberculosis complex. PNAS, 122(42), e2507104122. (www)

  @article{ , abstract = {The Mycobacterium tuberculosis complex (MTBC) includes M. tuberculosis ( M. tb ), the primary cause of human tuberculosis, M. bovis, the classical zoonotic pathogen and cause of bovine tuberculosis, and M. orygis, a recently recognized multihost pathogen. Given that M. tb, M. bovis, and M. orygis pose significant threats to the health of humans and animals, we sought to understand fundamental differences in pathogenicity among these closely related organisms. Building upon historical observations, we conducted a comparative virulence assessment of these pathogens using both bovine and murine infection models. Holstein calves were infected via aerosol with M. tb, M. bovis, or M. orygis , and pathology was analyzed through macroscopic and microscopic assessments of lungs and lymph nodes, along with quantitative tissue bacterial burden measurements. In C57BL/6 mice, we compared virulence using three readouts, namely survival, lethal dose determination, and detailed pathological assessments. Despite genomic similarity, animal-adapted MTBCs consistently showed dramatically enhanced virulence compared to M. tb with distinct immunopathology and, in the murine model, mortality within 24 days. Using gene disruption studies guided by proteomic comparisons, we determined that these infection outcomes were dependent on shared (ESAT-6) and lineage-associated (MPT70) virulence factors, the route of infection, and prior infection or immunization. Our findings reveal unexpected virulence hierarchies within the MTBC, with fundamental and translational implications for tuberculosis research.}, archive = {J_PNAS}, author = {Danchuk, Sarah N. and Duffy, Shannon C. and Sullivan, Jaryd and Beenish Rufai, Syed and McIntosh, Fiona A. and Lupien, Andréanne and Harrison, Luke B. and Ghasemi Goojani, Hojjat and Taylor, Lorne and Wei, Yuhong and Joubert, Philippe and Mortensen, Rasmus and Chen, Jeffrey M. and Niroula, Nirajan and Stevens, Robin and Norleen, Carla and Kapur, Vivek and Behr, Marcel A.}, doi = {10.1073/pnas.2507104122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2507104122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Virulence hierarchies within the mycobacterium tuberculosis complex}, volume = {122}, year = {2025}, }
• (2025). A species interaction kick-starts ecological speciation in allopatry. PNAS, 122(42), e2506625122. (www)

  @article{ , abstract = {Adaptation to different environments is thought to play a key role in speciation. However, speciation typically begins in allopatry, where reproductive isolation can also arise through neutral processes or selection unrelated to ecological differences. Disentangling the role of adaptive ecological divergence in the early stages of speciation therefore remains an important challenge in understanding the origin of new species. Here, we study threespine stickleback populations that have recently evolved in isolated postglacial lakes either in the presence or absence of prickly sculpin—a resource competitor that also shares ubiquitous trout predators with stickleback. We simulated secondary contact between several stickleback populations from these two ecological contexts in large, seminatural ponds, and genotyped offspring from 411 mating events to assess the strength of premating isolation associated with this biotic factor. Assortative mating between populations of the same ecological type (i.e., both sculpin-sympatric or both solitary) was moderate on average but ranged from weak to complete. Strikingly, and in line with a central premise of ecological speciation, the strength of premating isolation increased with increasing morphological and genomic population divergence shaped by sculpin-mediated selection. In contrast, overall phenotypic and genomic population divergence agnostic to sculpin presence/absence only poorly explained premating isolation, highlighting how ecological speciation in allopatry can be obscured by other sources of divergence. More broadly, our findings demonstrate how interactions with other ecologically similar species can play a major role in initiating and driving evolutionary trajectories toward new species, even in allopatry.}, archive = {J_PNAS}, author = {Roesti, Marius and Groh, Jeffrey S. and Jones, Felicity C. and Peichel, Catherine L. and Schluter, Dolph}, doi = {10.1073/pnas.2506625122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2506625122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A species interaction kick-starts ecological speciation in allopatry}, volume = {122}, year = {2025}, }
• (2025). Fundamental features of social environments determine rate of social affiliation. PNAS, 122(42), e2506243122. (www)

  @article{ , abstract = {Humans start new friendships and social connections throughout their lives and such relationships foster mental and physical well-being. While friendship initiation may depend on alignment of subtle and complex personal variables, here we investigated whether it also depends on basic features of social environments. In a preregistered online study (n = 783) using a novel social-affiliation seeking paradigm, we found people were more likely to send friend requests as the density of friendship opportunities decreased and frequency of success increased. Further, we found task-related measures, like overall friend requests, were correlated with mental health dimensions like social thriving and anhedonia. Next, in an ultra-high-field fMRI study (n = 24), we found that both fundamental features of social environments--opportunity density and frequency of success--affected neural activity across a network of regions linked to foraging including dorsal raphe nucleus, substantia nigra, and anterior insula. Thus, humans consider the background statistics of an environment while making social decisions and these decisions are linked to activity in cortico-subcortical circuits mediating the influence of environmental statistics on other aspects of behavior. Moreover, individual differences in how environmental features influence social behavior are associated with variation in mental health dimensions, offering key insights into interindividual variability in social functioning.}, archive = {J_PNAS}, author = {Garud, Sankalp and Rascu, Miruna and Hamilton, Sorcha and Yu, Ingrid and Rushworth, Matthew F. S. and Klein-Flügge, Miriam C.}, doi = {10.1073/pnas.2506243122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2506243122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fundamental features of social environments determine rate of social affiliation}, volume = {122}, year = {2025}, }
• (2025). Reconfiguration of brain-wide neural activity after early life adversity. PNAS, 122(42), e2506140122. (www)

  @article{ , abstract = {Early life adversity (ELA) predisposes individuals to physical and mental disorders lifelong. How ELA affects brain functions, leading to these vulnerabilities, is a mystery. To understand ELA’s impacts, investigations into neural activity affected by ELA must go beyond localized areas toward simultaneous recordings from multiple widely distributed regions over time. Such studies will expose relative activity between regions and discover shifts in regional activity in response to different experiences. Here, we performed longitudinal manganese-enhanced MRI (MEMRI) to measure degrees of brain-wide neural activity in ELA-exposed mice across a series of experiences in adulthood. To ascertain whether ELA resulted in atypical brain activity, results were compared to those of the standard mouse (Std). MEMRI captured activity in the freely moving home cage condition, and short- and long-term after exposure to TMT, a naturalistic predator threat. Images were normalized and aligned then analyzed with statistical mapping and automated segmentation. We found that neural activity in the home cage was greater in ELA compared to Std in multiple striatal-pallidal and hypothalamic regions. Upon acute threat, neural activity in Std increased in these regions to become more similar to that in ELA, while new hyperactive responses in ELA emerged in the midbrain and hindbrain. Nine days after acute threat, heightened neural activity in ELA persisted within locus coeruleus and increased within the posterior amygdala, ventral hippocampus, and dorsomedial and ventromedial hypothalamus. These results reveal functional imbalances that arise between multiple brain-systems after ELA, which are dependent upon context and cumulative experiences into adulthood.}, archive = {J_PNAS}, author = {Uselman, Taylor W. and Jacobs, Russell E. and Bearer, Elaine L.}, doi = {10.1073/pnas.2506140122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2506140122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reconfiguration of brain-wide neural activity after early life adversity}, volume = {122}, year = {2025}, }
• (2025). Uncovering functional connectivity patterns predictive of cognition in youth using interpretable predictive modeling. PNAS, 122(42), e2505600122. (www)

  @article{ , abstract = {Brain-wide association studies using functional MRI have advanced our understanding of how behavioral traits relate to individual variability in brain function. These studies typically identify functional connectivity (FC) patterns linked to behavioral traits using either whole-brain or region-wise predictive models. However, whole-brain models often struggle with generalizability and interpretability due to the high dimensionality of FC data, while region-wise models isolate predictions, limiting their ability to capture the integrated contributions of brain-wide FC patterns. In this study, we introduce an interpretable predictive model that learns fine-grained FC patterns predictive of behavioral traits, jointly at the regional and participant levels, to characterize the overall association of FC patterns with a target trait. Our model jointly learns a relevance score and a dedicated prediction function for each brain region, then integrates the regional predictions using the relevance scores as weights to generate a participant-level prediction, capturing the collective association of FC patterns with the trait. We validated our method using FC data from 6,798 participants in the Adolescent Brain and Cognitive Development (ABCD) study to predict cognition. Our model identified the cingulo-parietal, retrosplenial-temporal, dorsal attention, and cingulo-opercular networks as collectively predictive of cognitive traits, achieved competitive prediction accuracy, and enabled detailed characterization of fine-grained FC differences across cognitive domains. The learned relevance scores enhanced region-wise predictions of longitudinal cognitive measures in the ABCD cohort and cognitive traits in the Human Connectome Project Development cohort. These findings suggest that our method effectively characterizes generalizable and fine-grained FC patterns linked to cognition in youth.}, archive = {J_PNAS}, author = {Li, Hongming and Cieslak, Matthew and Salo, Taylor and Shinohara, Russell T. and Oathes, Desmond J. and Davatzikos, Christos and Satterthwaite, Theodore D. and Fan, Yong}, doi = {10.1073/pnas.2505600122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2505600122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Uncovering functional connectivity patterns predictive of cognition in youth using interpretable predictive modeling}, volume = {122}, year = {2025}, }
• (2025). T cell receptor specificity landscape revealed through de novo peptide design. PNAS, 122(42), e2504783122. (www)

  @article{ , abstract = {T cells play a key role in adaptive immunity by mounting specific responses against diverse pathogens. Effective bindings between T cell receptors (TCRs) and pathogen derived peptides presented on major histocompatibility complexes (MHCs) mediate immune responses. However, predicting these interactions remains challenging due to limited functional data on T cell reactivities. Here, we introduce a computational approach to predict TCR interactions with peptides presented on MHC-I alleles, and to design immunogenic peptides for specified TCR–MHC complexes. Our method leverages HERMES, a structure-based machine learning model trained on the protein universe to predict amino acid preferences based on local structural environments. Despite no direct training on TCR-pMHC data, HERMES’s implicit physical reasoning enables us to make accurate predictions of both TCR–pMHC binding affinities and T cell activities across diverse viral and cancer epitopes, achieving up to 0.72 correlation with experimental data. Leveraging our TCR recognition model, we develop a computational protocol for de novo design of immunogenic peptides. Through experimental validation in three TCR–MHC systems, we demonstrate that our designs—with up to five substitutions from the native sequence—activate T cells at success rates of up to 50%. Last, we use our generative framework to quantify the diversity of the peptide recognition landscape for various TCR–MHC’s, offering key insights into T cell specificity. Our approach provides a platform for immunogenic peptide and neoantigen design, as well as for evaluating TCR specificity, offering a computational framework to inform design of engineered T cell therapies and vaccines.}, archive = {J_PNAS}, author = {Visani, Gian Marco and Pun, Michael N. and Minervina, Anastasia A. and Bradley, Philip and Thomas, Paul G. and Nourmohammad, Armita}, doi = {10.1073/pnas.2504783122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2504783122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {T cell receptor specificity landscape revealed through de novo peptide design}, volume = {122}, year = {2025}, }
• (2025). Identification of CCR4C as a chloroplast-localized NADP(H) phosphatase regulating NAD(P)(H) balance in arabidopsis. PNAS, 122(42), e2504605122. (www)

  @article{ , abstract = {NAD(P)(H) metabolism plays a crucial role in plant development and growth. NADK2, a chloroplast-localized NAD kinase, supplies NADP + to the photosynthetic electron transport chain. The Arabidopsis T-DNA insertion mutant of NADK2 ( nadk2 ) exhibits a reduced NADP + /NAD + ratio, slow growth, and pale green leaves. To gain further insights into NAD(P)(H) metabolism in chloroplasts, nadk2 revertant mutants ( nkr ) were screened from the M2 generation of EMS (ethyl methane sulfonate)-treated nadk2 seeds. Among them, nkr1 displayed greener leaves and improved growth compared to nadk2 . Genetic mapping and genomic sequencing identified At3g18500 ( CCR4C ) as the causal gene. The nkr1 mutant carried a single nucleotide substitution, introducing a stop codon within the predicted N-terminal chloroplast localization signal, resulting in the loss of CCR4C protein function. The nadk2 ccr4c double mutant restored leaf color and growth to near wild-type levels. To investigate the function of CCR4C, recombinant CCR4C protein was purified and shown to directly convert NADP(H) to NAD(H). Localization analysis with CCR4C-GFP fusion proteins confirmed chloroplast targeting. Furthermore, ccr4c single mutants exhibited disrupted NAD(P)(H) balance and enhanced tolerance to ROS stress (e.g., H 2 O 2 , methyl viologen). These findings reveal CCR4C as a chloroplast-localized NADP(H) phosphatase crucial for maintaining NAD(P)(H) balance, providing insights into how plant cells manage chloroplast metabolism.}, archive = {J_PNAS}, author = {Akashi, Kazuki and Kodama, Yutaka and Sakaguchi, Hiroaki and Hashida, Shin-Nosuke and Miyagi, Atsuko and Ishikawa, Toshiki and Yamaguchi, Masatoshi and Kawai-Yamada, Maki}, doi = {10.1073/pnas.2504605122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2504605122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identification of CCR4C as a chloroplast-localized NADP(H) phosphatase regulating NAD(P)(H) balance in arabidopsis}, volume = {122}, year = {2025}, }
• (2025). Neural predictors of hidden, persistent psychological states at work. PNAS, 122(42), e2504382122. (www)

  @article{ , abstract = {Common workplace challenges such as feeling overwhelmed, burned out, or disengaged often remain hidden due to fear of judgment or social norms, contributing to rising mental health crises and organizational dysfunction. This study presents a brain-based framework for predicting these hidden and persistent psychological states through noninvasive neuroimaging. We used functional near-infrared spectroscopy to record neural activity from 67 executives in the field as they watched a video about workplace attitudes. We then applied a multitimepoint pattern analysis (MTPA) approach to reduce timeseries dimensionality and successfully classify whether individuals were feeling overwhelmed (72.8% accuracy) or in need of a new or different challenge (79.1% accuracy) in their careers using the temporal parietal junction (TPJ) and dorsal medial prefrontal cortex (dmPFC), respectively. The MTPA framework also allowed us to reverse-engineer specific thematic properties of the stimulus that evoked differential neural responses linked to these predicted outcomes. Emotional content in the video (e.g., reported distress) corresponded to the selected TPJ features that predicted whether someone was overwhelmed, while socially relevant content (e.g., missing social gatherings) aligned with the selected features from the dmPFC that predicted the need for a new or different challenge. These findings demonstrate the ability of neural measures to unobtrusively identify hidden and persistent psychological states in real-world settings, enabling targeted interventions that can improve well-being and engagement.}, archive = {J_PNAS}, author = {Goldstein, Bear M. and Burns, Shannon M. and Binnquist, Ashley L. and Dieffenbach, Macrina C. and Konkoly, Csaba and Abramowitz, Shira and Lieberman, Matthew D.}, doi = {10.1073/pnas.2504382122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2504382122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neural predictors of hidden, persistent psychological states at work}, volume = {122}, year = {2025}, }
• (2025). Ubiquitin-mediated degradation restricts spatiotemporal accumulation of the cytoplasmic male sterility protein WA352 to anthers in rice. PNAS, 122(42), e2504381122. (www)

  @article{ , abstract = {Cytoplasmic male sterility (CMS) is caused by mitochondrial genes that are constitutively expressed in plant tissues, although the encoded proteins preferentially accumulate in anthers. The mechanisms regulating CMS protein accumulation remain unclear. Here, we explored this process using wild-abortive CMS (CMS-WA) rice ( Oryza sativa ). We show that WA352, the causal protein of CMS-WA, is degraded by the ubiquitin–proteasome system (UPS). Structural analysis and protein truncation assays revealed that the N terminus of WA352 is critical for its anchoring to the inner mitochondrial membrane and its UPS-mediated degradation. Functional complementation confirmed that WA352 151–352 , lacking the N-terminal domain, accumulates constitutively in vegetative tissues, causing a reactive oxygen species burst and retarding rice growth. We further identified three mitochondrion-localized F-box proteins that participate in WA352 ubiquitination and degradation. Our findings demonstrate that UPS-mediated regulation restricts WA352 accumulation to anthers, allowing it to specifically disrupt anther development, thus helping to explain the male-specific effects of CMS genes in plants.}, archive = {J_PNAS}, author = {Zhang, Zixu and Ding, Zhi and Feng, Xueye and Huang, Jingjing and Peng, Xu and Xiao, Yubin and Zong, Wubei and Zhao, Zhe and Liu, Yao-Guang and Xie, Yongyao and Chen, Letian}, doi = {10.1073/pnas.2504381122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2504381122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ubiquitin-mediated degradation restricts spatiotemporal accumulation of the cytoplasmic male sterility protein WA352 to anthers in rice}, volume = {122}, year = {2025}, }
• (2025). Electrostatics facilitate midair host attachment in parasitic jumping nematodes. PNAS, 122(42), e2503555122. (www)

  @article{ , abstract = {Jumping can be hazardous for entomopathogenic nematodes (EPNs) as those that fail to attach to an insect host face death by predation or starvation. Recently, it has been shown that electrostatic charges on large insects can prompt a close-range detachment of free-living nematodes, which are nonparasitic and unable to jump. However, it remains unclear if static electricity can influence aerial interactions between parasitic jumping worms and their insect hosts. Here, we analyze and model the trajectories of jumping EPNs in still air as they approach fruit flies with varying electrostatic charge. We find that the nematodes’ attachment to the host is facilitated by an electrical potential of a few hundred volts, a magnitude commonly found in flying insects. A model combining electrostatics, aerodynamics, and Bayesian inference indicates that the electrostatic charge on jumping nematodes is ∼ 0.1 pC, which aligns with theoretical predictions for electrostatic induction. Drag coefficients based on host–nematode interactions in the presence of horizontal wind show differences at both low and high jumping velocities. Numerical simulations show that intermediate wind speeds ( ∼ 0.2 m/s) can further increase the likelihood of host attachment, as wind-driven aerial drifting allows the worms to reach hosts at greater distances. Our results suggest that submillimeter parasites that become airborne may exploit the electric charge carried by their host to facilitate attachment and thus enhance survival. The use of quantitative physical models provides valuable insights into understanding complex airborne infectious diseases mediated by natural environmental forces.}, archive = {J_PNAS}, author = {Ran, Ranjiangshang and Burton, Justin C. and Kumar, Sunny and Bhamla, Saad and Dillman, Adler R. and Ortega-Jimenez, Victor M.}, doi = {10.1073/pnas.2503555122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2503555122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electrostatics facilitate midair host attachment in parasitic jumping nematodes}, volume = {122}, year = {2025}, }
• (2025). FETCH enables fluorescent labeling of membrane proteins in vivo with spatiotemporal control in drosophila. PNAS, 122(42), e2503166122. (www)

  @article{ , abstract = {Fluorescent labeling approaches are crucial for elucidating protein function and dynamics. While robust methods to monitor gene transcription are widespread, the visualization of proteins in vivo is more elusive. To meet this challenge, we developed Fluorescent Endogenous Tagging with a Covalent Hook (FETCH) to label cell surface proteins (CSPs) in vivo through a stable covalent bond mediated by the DogTag-DogCatcher peptide partner system. FETCH leverages a spontaneous covalent isopeptide bond that forms between the 23-amino acid DogTag and the 15-kDa DogCatcher. Unlike most tags that work best at protein termini, DogTag functions well in protein loops, expanding the range of sites that can be targeted in proteins. In FETCH, DogTag is introduced into extracellular loops of CSPs through genome engineering, enabling covalent bond formation with a genetically encoded DogCatcher-GFP fusion protein that can be secreted from a variety of cell types in intact animals. To identify optimal DogTag insertions into CSPs, we describe a flow cytometry–based platform for rapidly screening candidates in vitro. We demonstrate the ability to tag and visualize three members of the immunoglobulin superfamily (IgSF) in vivo: the transmembrane protein mCD8 and two GPI-anchored proteins belonging to the DIP-Dpr interactome that interact biophysically to facilitate neuronal target recognition at Drosophila neuromuscular and brain synapses. FETCH enables precise temporal and spatial control to visualize tagged proteins in vivo, features that are adaptable to a multitude of applications for modifying any cell surface protein.}, archive = {J_PNAS}, author = {Rostam, Kevin D. and Morano, Nicholas C. and Menon, Kaushiki P. and Lopez, Davys H. and Shapiro, Lawrence and Zinn, Kai and Feng, Siqian and Mann, Richard S.}, doi = {10.1073/pnas.2503166122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2503166122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {FETCH enables fluorescent labeling of membrane proteins in vivo with spatiotemporal control in drosophila}, volume = {122}, year = {2025}, }
• (2025). Linking the production of reactive oxygen species to the expression of antimicrobial peptides through aquaporin in an arthropod. PNAS, 122(42), e2502570122. (www)

  @article{ , abstract = {In arthropods, bacterial infection activates dual oxidase 2 (Duox2) to produce extracellular reactive oxygen species (ROS), while stimulating the expression of antimicrobial peptides (AMPs) through immune deficiency (Imd)/Relish pathway. Although both strategies contribute significantly to antibacterial immunity, the Duox2/ROS system and Relish/AMPs pathway are generally considered separate branches. In the present study, we report that these two branches are connected by an aquaporin 4 (Aqp4) in a crustacean, the red swamp crayfish Procambarus clarkii . Aqp4 is found to be critical for the crayfish antibacterial response. The significance of Aqp4 is achieved by transporting extracellular ROS into the intracellular compartment after bacterial infection. The increase in intracellular ROS levels, mediated by the c-Jun N-terminal kinase, promotes the nuclear translocation and thereby the transcriptional activity of FoxO. As the key transcription factor of Relish, FoxO regulates the upregulation of Relish and ultimately the expression of Relish-targeting AMPs. By linking ROS production to AMP expression, the sequential ROS/Aqp4/FoxO/Relish/AMPs axis makes a relatively significant, yet previously unnoticed, contribution to the antibacterial response. Therefore, this study reveals the intriguing association between ROS production and AMP expression, the two central antibacterial strategies and provides insights into the regulatory mechanisms of arthropod immunity.}, archive = {J_PNAS}, author = {Wei, Zhe and Liu, Ping-Ping and Wang, Wei-Guang and Wang, Xian-Wei}, doi = {10.1073/pnas.2502570122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2502570122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Linking the production of reactive oxygen species to the expression of antimicrobial peptides through aquaporin in an arthropod}, volume = {122}, year = {2025}, }
• (2025). A protein dynamics–based deep learning model enhances predictions of fitness and epistasis. PNAS, 122(42), e2502444122. (www)

  @article{ , abstract = {Deep learning has advanced our ability to assess the effects that individual mutations have on protein function; however, predicting the complex interplay between two or more mutations remains challenging. Here, we seek to address this challenge by building a deep learning framework that incorporates information related to protein dynamics. Namely, we build a neural network architecture using a physics-based metric called the Asymmetric Dynamic Coupling Index (DCI asym ), which quantifies the degree to which each member of a pair of residues influences the flexibility of the other. DCI asym enables us to train models through an allosteric Graph Neural Network (GNN) in which each residue is linked to its distant dynamic influencers. Despite not being trained on experimental epistasis data, our GNN consistently outperforms existing approaches on deep mutational scanning datasets across four distinct proteins, highlighting its enhanced capacity to model epistatic interactions. Our GNN model was then challenged to predict the functions of 37 novel, computationally designed TEM-1 β-lactamase variants of unknown function, and it demonstrated excellent predictive accuracy for these variants. Thus, our GNN provides a pathway for better assessing the impact of multiple mutations on protein function, including epistatic relationships and mutations that have profound effects on activity despite being spatially far from the active site.}, archive = {J_PNAS}, author = {Huynh, Ngoc and Kazan, I. Can and Lu, Jin and Kolbaba-Kartchner, Bethany and Mills, Jeremy H. and Ozkan, S. Banu}, doi = {10.1073/pnas.2502444122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2502444122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A protein dynamics–based deep learning model enhances predictions of fitness and epistasis}, volume = {122}, year = {2025}, }
• (2025). Spontaneous activity of astrocytes is a stochastic functional signal for memory consolidation. PNAS, 122(42), e2500511122. (www)

  @article{ , abstract = {In the absence of explicit neuronal inputs, the glial cell astrocytes exhibit recurring intracellular Ca 2+ fluctuations, primarily localized at thin processes, known as Ca 2+ microdomains (MDs). Although spontaneous Ca 2+ MDs are present throughout the brain, their putative role is unknown. Here, we question whether, owing to their recurring signaling mode, spontaneous Ca 2+ MDs contribute to slowly evolving phenomena in the brain, such as memory consolidation. We demonstrate that, in the perirhinal cortex, a central region in recognition memory, these events promote Ca 2+ -dependent gliotransmission and modulate synaptic strengthening. Their recurring activity extends the release of the gliotransmitter brain-derived neurotrophic factor (BDNF) over time, ensuring the sustained Tropomyosin Receptor Kinase B (TrkB)-signaling required for the consolidation of long-term synaptic potentiation and lasting memories. We also show that Ca 2+ MDs, which are stochastic events, preserve their random behavior during gliotransmission, introducing an element of unpredictability into the process of memory retention. Our study assigns to spontaneous, stochastic activity in astrocytes a unique functional role in shaping and stabilizing memory circuits.}, archive = {J_PNAS}, author = {Losi, Gabriele and Vignoli, Beatrice and Granata, Rocco and Lia, Annamaria and Zonta, Micaela and Sansevero, Gabriele and Pischedda, Francesca and Chiavegato, Angela and Santi, Spartaco and Zentilin, Lorena and Berardi, Nicoletta and Ratto, Gian Michele and Carmignoto, Giorgio and Canossa, Marco}, doi = {10.1073/pnas.2500511122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2500511122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spontaneous activity of astrocytes is a stochastic functional signal for memory consolidation}, volume = {122}, year = {2025}, }
• (2025). Broadband topological transitions in twisted elastodynamic metasurfaces. PNAS, 122(42), e2427049122. (www)

  @article{ , abstract = {In the last decade, the connection between physics and topology has resulted in the discovery of several new phenomena. A celebrated example is the field of topological insulators [X.-L. Qi, S.-C. Zhang, Rev. Mod. Phys. 83 , 1057–1110 (2011)]., in which topological quantities describing the bulk medium response in reciprocal space dictate the presence of protected transport states at the boundary of a finite sample. Broken symmetries in the microscopic structure of a material play a prominent role in determining its topological features relevant to these phenomena. As another landmark phenomenon driven by broken symmetries, twistronics leverages the rotation angle between coupled layers to control in extreme ways the dispersion topology, leading to flat-band superconductivity [Y. Cao et al. , Nature 556 , 43–50 (2018)] and topological transitions for polaritons [G. Hu et al. , Nature 582 , 209–213 (2020)]. Here, we apply these concepts to elastodynamic waves, and exploit the twist degree-of-freedom to control broken symmetries in the microscopic structure of elastic metasurfaces, demonstrating extreme wave control. We predict and experimentally demonstrate topological transitions within twisted elastodynamic metasurfaces, which we harness for broadband, reconfigurable, and robust manipulation of phonons. Our twist-elastic approach opens alternative directions in microelectronics, microfluidics, and ultrasound sensing, leveraging precise multifunctional engineering of mechanical vibrations of relevance to many modern technologies.}, archive = {J_PNAS}, author = {Yves, Simon and Peng, Yu-Gui and Alù, Andrea}, doi = {10.1073/pnas.2427049122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2427049122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Broadband topological transitions in twisted elastodynamic metasurfaces}, volume = {122}, year = {2025}, }
• (2025). The insulin-like peptides dilp2 and dilp6 exhibit divergent responses to dietary sugar and protein in drosophila larvae. PNAS, 122(42), e2426930122. (www)

  @article{ , abstract = {Nutrient intake drives secretion of insulin and insulin-like peptides that stimulate anabolic metabolism and tissue growth. Eight Drosophila insulin-like peptides (Dilps) are encoded in the Drosophila genome; whether these Dilps respond uniformly to changes in dietary nutrients is unknown. Here, we investigate the endocrine responses of Dilp2, secreted by brain insulin-producing cells, and Dilp6, produced by the fat body, to dietary sugar and protein in mid-third instar Drosophila larvae. Starvation leads to a profound reduction in circulating Dilp2 without affecting circulating Dilp6 levels. Diets containing sugar alone drive nutrient storage and increase hemolymph Dilp6, but do not promote Dilp2 release. In contrast, dietary protein drives growth and restores hemolymph Dilp2 but strongly reduces circulating Dilp6. Furthermore, circulating levels of Dilp2 and Dilp6 are modulated by the ratio of sugar to protein in the diet. We find that depleting circulating Dilp6 via fat body specific knockdown or increasing insulin receptor (InR) levels in fat body leads to increased levels of triglyceride storage but decreased peripheral growth. Our results suggest that Dilp6, a hormone produced in response to dietary sugar, may direct the use of sugar for growth instead of fat storage at the end stage of larval development. Our findings reveal different modes of regulation for Dilp2 and Dilp6 and raise the question of how the single known Drosophila InR integrates divergent signals from distinct Dilps to control growth and metabolism.}, archive = {J_PNAS}, author = {Suzawa, Miyuki and McPherson, W. Kyle and Dunham, Kelly E. and Van Gorder, Elizabeth E. and Reddy, Shivani and Jamali, Leila A. and Bland, Michelle L.}, doi = {10.1073/pnas.2426930122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2426930122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The insulin-like peptides dilp2 and dilp6 exhibit divergent responses to dietary sugar and protein in drosophila larvae}, volume = {122}, year = {2025}, }
• (2025). Functional organization of the primary motor cortex in psychosis and the potential role of intereffector regions in psychomotor slowing. PNAS, 122(42), e2425388122. (www)

  @article{ , abstract = {Altered psychomotor behavior in psychosis is poorly understood. Novel insights into the physiology of the motor cortex prompted a revision of the motor homunculus. Next to core motor effector areas, the primary motor cortex (M1) contains intereffector regions with more integrative connectivity patterns, suggestive of serving psychomotor behavior. Here, we test whether patterns of connectivity differ between patients with and without psychomotor slowing and which cortical areas are associated with aberrant motor behavior in psychosis. This resting-state functional MRI study included 83 patients with psychosis and psychomotor slowing, 43 patients without psychomotor slowing, and 63 matched healthy subjects. We tested group differences in connectivity and regressed motor behavior measures with connectivity in patients with psychomotor slowing. Across subjects, we found distinct rs-fMRI connectivity profiles of the intereffector areas in M1, extending to premotor cortices and cerebellum. Patients with psychomotor slowing had stronger connectivity from the intereffectors than controls or patients without slowing. Finally, motor behavior correlated with connectivity from M1 intereffector regions in patients. Connectivity profiles of intereffectors suggest a role in planning and controlling complex behavioral repertoires. Collectively, these findings in patients with psychomotor slowing stress the importance of intereffector regions in shaping psychomotor behaviors in mental disorders.}, archive = {J_PNAS}, author = {Walther, Sebastian and Wüthrich, Florian and Pavlidou, Anastasia and Nadesalingam, Niluja and Heckers, Stephan and Nuoffer, Melanie G. and Chapellier, Victoria and Stegmayer, Katharina and Maderthaner, Lydia V. and Kyrou, Alexandra and von Känel, Sofie and Lefebvre, Stephanie}, doi = {10.1073/pnas.2425388122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2425388122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Functional organization of the primary motor cortex in psychosis and the potential role of intereffector regions in psychomotor slowing}, volume = {122}, year = {2025}, }
• (2025). Citrullination negatively regulates the functions of the p53 protein and opposes its ubiquitination and degradation. PNAS, 122(42), e2423526122. (www)

  @article{ , abstract = {This study investigates the regulatory role of peptidylarginine deiminase 4 (PAD4)-mediated citrullination on the tumor suppressor protein p53. We demonstrate that p53 serves as a substrate for PAD4, undergoing citrullination at multiple arginine residues, including critical sites within its DNA-binding domain. Mass spectrometry identified eight citrullination sites, notably R158, R282, and R283, which were further validated in various cancer cell lines. Functional studies revealed that citrullination significantly impairs p53’s ability to form stable tetramers, essential for high-affinity DNA binding. Electrophoretic mobility shift assays and analytical ultracentrifugation confirmed reduced binding to consensus sequences in the p21 and MDM2 promoters. As a result, citrullination led to marked reductions in p21 and MDM2 transcriptional activation and altered regulation of ME2, as demonstrated by reporter assays and quantitative PCR. In addition, citrullination compromised p53’s roles in cell cycle control and apoptosis. Supporting these findings, citrulline-mimic mutants (arginine-to-glutamine substitutions) exhibited diminished transcriptional activity relative to wild-type p53. Furthermore, citrullination disrupted the interaction between p53 and its E3 ubiquitin ligase MDM2, reducing p53 ubiquitination and degradation, as shown by in vitro ubiquitination assays and cycloheximide chase experiments. Importantly, replacing glutamine with lysine at these key sites largely restored p53 activity, indicating that the loss of positive charge is central to the functional consequences of citrullination. Together, these findings identify PAD4-catalyzed citrullination as a regulatory mechanism that modulates p53 function and highlight PAD4 as a potential therapeutic target in cancer.}, archive = {J_PNAS}, author = {Yang, Yi-Fang and Lee, Chien-Yun and Liu, Guang-Yaw and Hsieh, Ju-Yi and Lin, Yi-Chun and Wang, Li-Wei and Chan, Kai-Han and Yen, Won-Shin and Chen, Yin-Chu and Lin, Chi-Li and Hung, Hui-Chih}, doi = {10.1073/pnas.2423526122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2423526122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Citrullination negatively regulates the functions of the p53 protein and opposes its ubiquitination and degradation}, volume = {122}, year = {2025}, }
• (2025). Hierarchical dynamic coding coordinates speech comprehension in the human brain. PNAS, 122(42), e2422097122. (www)

  @article{ , abstract = {Speech comprehension involves transforming an acoustic waveform into meaning. To do so, the human brain generates a hierarchy of features that converts the sensory input into increasingly abstract language properties. However, little is known about how rapid incoming sequences of hierarchical features are continuously coordinated. Here, we propose that each language feature is supported by a dynamic neural code, which represents the sequence history of hierarchical features in parallel. To test this “hierarchical dynamic coding” (HDC) hypothesis, we use time-resolved decoding of brain activity to track the construction, maintenance, and update of a comprehensive hierarchy of language features spanning phonetic, word form, lexical–syntactic, syntactic, and semantic representations. For this, we recorded 21 native English participants with magnetoencephalography (MEG), while they listened to two hours of short stories in English. Our analyses reveal three main findings. First, the brain represents and simultaneously maintains a sequence of hierarchical features. Second, the duration of these representations depends on their level in the language hierarchy. Third, each representation is maintained by a dynamic neural code, which evolves at a speed commensurate with its corresponding linguistic level. This HDC preserves the maintenance of information over time while limiting destructive interference between successive features. Overall, HDC reveals how the human brain maintains and updates the continuously unfolding language hierarchy during natural speech comprehension, thereby anchoring linguistic theories to their biological implementations.}, archive = {J_PNAS}, author = {Gwilliams, Laura and Marantz, Alec and Poeppel, David and King, Jean-Rémi}, doi = {10.1073/pnas.2422097122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2422097122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hierarchical dynamic coding coordinates speech comprehension in the human brain}, volume = {122}, year = {2025}, }
• (2025). Forest recovery after deforestation is fueled by mineral weathering at the expense of ecosystem buffering capacity. PNAS, 122(42), e2419123122. (www)

  @article{ , abstract = {The pace and trajectory of ecosystem development are governed by the availability and cycling of limiting nutrients, and anthropogenic disturbances such as acid rain and deforestation alter these trajectories by removing substantial quantities of nutrients via titration or harvest. Here, we use six decades of continuous chemical and hydrologic data from three adjacent headwater catchments in the Hubbard Brook Experimental Forest, New Hampshire—one deforested (W5), one CaSiO 3 -enriched (W1), and one reference (W6)—to quantify long-term nutrient and mineral fluxes. Acid deposition since 1900 drove pronounced depletion and export of base cations, particularly calcium, across all watersheds. Experimental deforestation of W5 intensified loss of biomass and nutrient cations and triggered sustained increases in streamwater pH, Ca 2+ , and SiO 2 exports over nearly four decades, greatly exceeding the effects of direct CaSiO 3 enrichment in both duration and magnitude. We detect no long-term changes in water yield or water flow paths in the experimental watersheds, and we attribute this multidecadal increase in weathering rates following deforestation to biological responses to severe nutrient limitation. Our evidence suggests that in the regrowing forest, plants are investing photosynthate into belowground processes that amplify mineral weathering to access phosphorus and micronutrients, consequently elevating the export of less limiting elements present in silicate parent material. Throughout decades of forest regrowth, enhanced biotic weathering has continued to deplete the acid buffering capacity of the terrestrial ecosystem while the export of weathering products has elevated the pH of the receiving stream.}, archive = {J_PNAS}, author = {Bernhardt, Emily S. and Rosi, Emma J. and Solomon, Christopher T. and Campbell, John and Driscoll, Charles T. and Green, Mark B. and Likens, Gene E. and McDowell, William H.}, doi = {10.1073/pnas.2419123122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2419123122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Forest recovery after deforestation is fueled by mineral weathering at the expense of ecosystem buffering capacity}, volume = {122}, year = {2025}, }
• (2025). Mapping subnational gender gaps in internet and mobile adoption using social media data. PNAS, 122(42), e2416624122. (www)

  @article{ , abstract = {The digital revolution has ushered in many societal and economic benefits. Yet access to digital technologies such as mobile phones and internet remains highly unequal, especially by gender in the context of low- and middle-income countries (LMICs). While national-level estimates are increasingly available for many countries, reliable, quantitative estimates of digital gender inequalities at the subnational level are lacking. These estimates, however, are essential for monitoring gaps within countries and implementing targeted interventions within the global sustainable development goals, which emphasize the need to close inequalities both between and within countries. We develop estimates of internet and mobile adoption by gender and digital gender gaps at the subnational level for 2,075 regions in 117 LMICs from 2015 through 2025, a context where digital penetration is low and national-level gender gaps disfavoring women are large. We construct these estimates by applying machine-learning algorithms to Facebook user counts, geospatial data, development indicators, and population composition data. We calibrate and assess the performance of these algorithms using ground-truth data from subnationally representative household survey data from 33 LMICs. Our results reveal striking disparities in access to mobile and internet technologies between and within LMICs. These disparities imply that as of 2025, women are 19% less likely to use the internet and 8% less likely to own a mobile phone in LMICs, corresponding to over 190 million fewer women owning a mobile phone and over 320 million fewer women using the internet.}, archive = {J_PNAS}, author = {Breen, Casey F. and Fatehkia, Masoomali and Yan, Jiani and Zhao, Xinyi and Leasure, Douglas R. and Weber, Ingmar and Kashyap, Ridhi}, doi = {10.1073/pnas.2416624122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2416624122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mapping subnational gender gaps in internet and mobile adoption using social media data}, volume = {122}, year = {2025}, }
• (2025). Substrate-dependent activation of LONP1 informs on proteolytic regulation and ATPase motor function. PNAS, 122(42), e2415153122. (www)

  @article{ , abstract = {AAA+ enzymes use energy from ATP hydrolysis to remodel diverse cellular targets. Structures of substrate-bound AAA+ complexes suggest that these enzymes employ a conserved hand-over-hand mechanism to thread substrates through their central pore. However, the fundamental aspects of the mechanisms governing motor function and substrate processing within specific AAA+ families remain unresolved. We used cryoelectron microscopy to structurally interrogate reaction intermediates from in vitro biochemical assays to inform the underlying regulatory mechanisms of the human mitochondrial AAA+ protease, LONP1. Our results demonstrate that substrate binding, rather than nucleotide binding, activates the assembly and allosterically regulates proteolytic activity. The N-terminal domain plays a critical role in this process and facilitates the initial stages of substrate selection and engagement. Moreover, structures of LONP1 actively degrading a substrate in the presence of ATP provide important context to the conventional understanding of the hand-over-hand translocation mechanism, suggesting that ATP hydrolysis is likely not limited to a single position in the right-handed spiral during the hand-over-hand translocation mechanism.}, archive = {J_PNAS}, author = {Mindrebo, Jeffrey T. and Lander, Gabriel C.}, doi = {10.1073/pnas.2415153122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {42}, pages = {e2415153122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Substrate-dependent activation of LONP1 informs on proteolytic regulation and ATPase motor function}, volume = {122}, year = {2025}, }
• (2025). Correction for quintero, the diffused evolutionary dynamics of morphological novelty. PNAS, 122(41), e2526425122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2526425122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2526425122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for quintero, the diffused evolutionary dynamics of morphological novelty}, volume = {122}, year = {2025}, }
• (2025). Correction for kolomenskiy et al., scaling and mechanical optimality of bristled wings in microinsects. PNAS, 122(41), e2526142122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2526142122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2526142122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for kolomenskiy et al., scaling and mechanical optimality of bristled wings in microinsects}, volume = {122}, year = {2025}, }
• (2025). Correction for bawa et al., prevalence of monogamy at the level of flowers in plants. PNAS, 122(41), e2525723122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2525723122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2525723122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for bawa et al., prevalence of monogamy at the level of flowers in plants}, volume = {122}, year = {2025}, }
• (2025). Retraction for safdar et al., endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. PNAS, 122(41), e2525608122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2525608122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2525608122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Retraction for safdar et al., endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice}, volume = {122}, year = {2025}, }
• (2025). Guanine storage vacuoles sequester guanine crystals and serve as nitrogen reserves in chlamydomonas reinhardtii. PNAS, 122(41), e2522352122. (www)

  @article{ , abstract = {Nitrogen cycles in Chlamydomonas reinhardtii have historically been studied in the context of exogenous ammonium/nitrate availability and uptake. Recently, crystalline guanine has been identified, using Raman microscopy, in the cytoplasm of numerous microalgae, including C. reinhardtii . The signal level is influenced by availability of exogenous nitrogen, suggesting that the deposits serve as a nitrogen store. We report the visualization of these guanine crystals in C. reinhardtii and other microalgae using quick-freeze deep-etch electron microscopy. They prove to reside within cytoplasmic vacuoles: A membrane with a high density of small intramembranous particles surrounds a uniform, coarsely granular interior matrix within which stacks of flat crystals assemble, often in stunning abundance. We designate these as guanine storage vacuoles (GSVs). In C. reinhardtii and other members of the Chlamydomonadales, a discrete disc-shaped granular domain occupies the center of each GSV, and the crystals arise within or at the edges of this domain, suggesting that it represents an amorphous form of guanine. In C. reinhardtii , GSVs are numerous in log-phase cells, are not found in cells maintained in nitrogen-free medium, and reappear within 8 h after the cells are provided with nitrogen, initially as small disc-containing vacuoles. We compare this cycle with that of the polyphosphate granules localized in acidocalcisomes. Nineteen enzyme families and 10 transporters are predicted to participate in guanine-related pathways in C. reinhardtii , many showing strong upregulation with nitrogen starvation. These understandings will inform future studies on the contributions made by GSVs to the metabolism and physiology of eukaryotic microalga.}, archive = {J_PNAS}, author = {Goodenough, Ursula and Roth, Robyn and Lee, Jae-Hyeok}, doi = {10.1073/pnas.2522352122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2522352122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Guanine storage vacuoles sequester guanine crystals and serve as nitrogen reserves in chlamydomonas reinhardtii}, volume = {122}, year = {2025}, }
• (2025). The timeframe of prediction for eco-evolutionary dynamics. PNAS, 122(41), e2522204122. (www)

  @article{ , archive = {J_PNAS}, author = {Chevin, Luis-Miguel}, doi = {10.1073/pnas.2522204122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2522204122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The timeframe of prediction for eco-evolutionary dynamics}, volume = {122}, year = {2025}, }
• (2025). Turning mass support for environmental goals into action. PNAS, 122(41), e2521545122. (www)

  @article{ , archive = {J_PNAS}, author = {Bouman, Thijs}, doi = {10.1073/pnas.2521545122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2521545122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Turning mass support for environmental goals into action}, volume = {122}, year = {2025}, }
• (2025). Unveiling ignis fatuus: Microlightning between microbubbles. PNAS, 122(41), e2521255122. (www)

  @article{ , abstract = {Will-o’-the-wisps, ghostly blue flames seen at night in marshlands and long attributed to methane cool flames, have remained scientifically unexplained, a mystery caused by the lack of a known ignition mechanism. Here, we demonstrate that spontaneous electrical discharges, termed “microlightning”, can occur between rising methane-containing microbubbles in water. High-speed optical imaging reveals brief flashes between charged bubbles, arising from strong electric fields at curved gas–liquid interfaces. These discharges initiate nonthermal oxidation of methane, producing luminescence and measurable heat under ambient conditions. Our findings offer a scientific basis for ignis fatuus and reveal a general mechanism by which electrified interfaces can drive redox reactions in natural environments without the need for external ignition sources.}, archive = {J_PNAS}, author = {Xia, Yu and Meng, Yifan and Shi, Jianbo and Zare, Richard N.}, doi = {10.1073/pnas.2521255122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2521255122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unveiling ignis fatuus: Microlightning between microbubbles}, volume = {122}, year = {2025}, }
• (2025). A new era of understanding of the control of thick filament states in the heartbeat. PNAS, 122(41), e2521205122. (www)

  @article{ , archive = {J_PNAS}, author = {Solaro, R. John}, doi = {10.1073/pnas.2521205122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2521205122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A new era of understanding of the control of thick filament states in the heartbeat}, volume = {122}, year = {2025}, }
• (2025). Activity-dependent citrate dynamics in neurons. PNAS, 122(41), e2519902122. (www)

  @article{ , abstract = {Glycolytic enzymes sense metabolite levels to adapt rapidly to changing energy demands, but measuring the levels of these effectors with spatiotemporal precision in live cells has been challenging. We addressed this question in the context of neuronal depolarization, which activates glycolysis, focusing on the glycolysis inhibitor citrate. We engineered a pair of quantitative fluorescent biosensors for citrate that address several limitations (affinity, pH, Mg 2+ , and temperature) of existing citrate biosensors. Using two-photon fluorescence lifetime imaging, we found that free citrate in the cytosol of neurons in acute mouse brain slices declines two-to-threefold within seconds of neuronal activation and then returns to baseline over a few minutes. The stimulation-dependent citrate transient depends at least in part on the mitochondrial calcium uniporter. These types of live metabolite measurements are essential for achieving a nuanced understanding of the fast control of glycolysis.}, archive = {J_PNAS}, author = {Rosen, Paul C. and Fu, Panhui and Ferrán, Beatriz and Kim, Erica and Brooks, Daniel J. and Lim, Daniel C. and Díaz-García, Carlos Manlio and Yellen, Gary}, doi = {10.1073/pnas.2519902122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2519902122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Activity-dependent citrate dynamics in neurons}, volume = {122}, year = {2025}, }
• (2025). Taking evo-devo to the next level. PNAS, 122(41), e2519801122. (www)

  @article{ , archive = {J_PNAS}, author = {Hlusko, Leslea J.}, doi = {10.1073/pnas.2519801122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2519801122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Taking evo-devo to the next level}, volume = {122}, year = {2025}, }
• (2025). 5′-terminal glycosylation of protein-coding transcripts: An epitranscriptomic modification that prolongs mRNA lifetimes. PNAS, 122(41), e2519788122. (www)

  @article{ , abstract = {Glycosylation is among the most common molecular modifications in living organisms, one that affects the function of myriad macromolecules: mostly proteins, lipids, and polysaccharides of various kinds but also a few specific noncoding RNAs that undergo glycosylation at an internal site. Here we expand the glycome by showing that protein-coding transcripts can also be glycosylated, but in the form of a 5′-terminal glucose cap. These caps are present on up to 30 to 40% of the 5′ ends of U-initiated mRNAs in Escherichia coli , a remarkably high level of noncanonical capping that requires no transcript or promoter characteristic other than a 5′-terminal U. By contrast, no N -acetylglucosamine caps are evident. Due to their resistance to enzymatic removal, glucose caps can greatly prolong the cellular lifetime of mRNA by impeding its degradation via a 5′-end-dependent mechanism. The prevalence and protective impact of glucose caps set them apart from other bacterial RNA caps. This epitranscriptomic modification has the potential to selectively increase the synthesis of bacterial proteins encoded by U-initiated transcripts, especially after transcription is downregulated.}, archive = {J_PNAS}, author = {Banerjee, Tithi and Luciano, Daniel J. and Belasco, Joel G.}, doi = {10.1073/pnas.2519788122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2519788122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {5′-terminal glycosylation of protein-coding transcripts: An epitranscriptomic modification that prolongs mRNA lifetimes}, volume = {122}, year = {2025}, }
• (2025). Electing amateur politicians reduces cross-party collaboration. PNAS, 122(41), e2519787122. (www)

  @article{ , abstract = {Public trust in democratic institutions has dropped to historic lows, prompting electorates in major democracies to turn to “amateur” politicians with the expectation that these political outsiders will cut through stalemates to deliver policy results. Amateurs are often seen as pragmatic “doers,” but also uncompromising, a combination at odds with governing systems where legislative progress depends on cross-party coalitions. Using the US Congress as a critical case, we evaluate these competing expectations by linking over four decades of election data with 2.2 million bill (co)sponsorship records. We find that electing amateurs intensifies partisan divisions: Districts that send amateurs to Congress yield representatives who attract fewer opposing-party collaborators to their bills and less often support other-party legislation. Our results suggest that amateurs are unlikely to deliver on their promise for pragmatic governance, as they resist or undervalue the compromises essential to lawmaking.}, archive = {J_PNAS}, author = {Porter, Rachel and Harden, Jeffrey J. and Dobson, Mackenzie R.}, doi = {10.1073/pnas.2519787122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2519787122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electing amateur politicians reduces cross-party collaboration}, volume = {122}, year = {2025}, }
• (2025). Multisensory electronic skin with decoupled pressure–temperature-sensing capabilities for similar object recognition. PNAS, 122(41), e2519693122. (www)

  @article{ , abstract = {Multisensory electronic skin (e-skin), which mimics the tactile capabilities of human skin, is pivotal in equipping robots with intelligent perceptual functions. Despite numerous advances in multifunctional perceptions, e-skin with combined mechano- and thermosensation capabilities for accurately recognizing objects with similar characteristics is still challenging. Here, we report a multisensory e-skin with a skin-like multilayer construction for smart perceptions, which features the patterned protrusion texture mimicking the skin texture to enhance the pressure-sensing sensitivity, the temperature-sensing component mimicking the thermoreceptors, the pressure-sensing component mimicking the mechanoreceptors, and the heater mimicking the body heat source. This multisensory e-skin exhibits excellent decoupled sensing performances of pressure and temperature, enabling the development of a haptic perception system for evaluating some discernible characteristics (e.g., shape and size) and experience-driven features (e.g., modulus and thermal conductivity) of objects through a simple grasp. Demonstrations of accurate recognition and automatic classification of various objects even with extremely similar surface features highlight the significant potential of this multisensory e-skin in applications such as intelligent soft robotics, prosthetics, and other related fields.}, archive = {J_PNAS}, author = {Ji, Jin and Luo, Hongyu and Su, Jiangtao and Wang, Suhao and Chen, Xiaodong and Song, Jizhou}, doi = {10.1073/pnas.2519693122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2519693122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multisensory electronic skin with decoupled pressure–temperature-sensing capabilities for similar object recognition}, volume = {122}, year = {2025}, }
• (2025). Supply–demand strategies for near-term climate benefits from hydrogen in the united states. PNAS, 122(41), e2519606122. (www)

  @article{ , abstract = {Hydrogen (H 2 ) is a promising energy carrier for decarbonization. However, the greenhouse gas (GHG) mitigation potential of the H 2 supply and its adoption across various demand sectors in the US remains unclear. Here, we couple prospective life cycle assessment with a process-based integrated assessment model to evaluate the GHG mitigation of H 2 from supply and demand perspectives. Our results show the critical role of H 2 production mix in determining supply-side GHG mitigation potential. Without national carbon pricing or large-scale electrolysis in the near future, biomass-based H 2 (Bio-H 2 ) emerges as a critical transitional clean H 2 production technology. Bio-H 2 reduces the life cycle GHG emission intensity of the H 2 supply mix by 1.8 to 5.5 kg CO 2 kg −1 H 2 , resulting in a national reduction of 606 to 1,706 Mt CO 2 e from 2025 to 2050. This represents 1.6 to 2 times greater mitigation potential compared to scenarios without Bio-H 2 . On the demand side, we identify a misalignment: industrial sectors with high mitigation intensity (e.g., iron and steel, 147 Mt CO 2 e EJ −1 ) receive limited H 2 deployment (0.8 EJ), while the transportation sector accounts for 75% of H 2 use (e.g., passenger and light-duty vehicles, 10 EJ) despite their lower mitigation intensities (54 Mt CO 2 e EJ −1 ). While economy-wide climate policies (e.g., carbon prices) could direct more industrial H 2 usages, implementing these policies is challenging; sector-specific strategies can be more practical. Our results highlight the importance of near-term support for Bio-H 2 and sector-specific demand strategies to enhance the climate effectiveness of US H 2 deployment.}, archive = {J_PNAS}, author = {Xu, Youyi and Peng, Wei and Yao, Yuan}, doi = {10.1073/pnas.2519606122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2519606122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Supply–demand strategies for near-term climate benefits from hydrogen in the united states}, volume = {122}, year = {2025}, }
• (2025). Structure of a transient protein-folding intermediate by pressure-jump NMR spectroscopy. PNAS, 122(41), e2519493122. (www)

  @article{ , abstract = {Protein folding, as commonly portrayed, involves exploration of a rough, high-dimensional landscape, ending with a final descent into a low-energy folded state. During that journey, the protein may visit shallow basins corresponding to metastable structures, potentially of biological importance. Structural characterization of transiently populated metastable states is challenging due to their low population, which limits traditional NMR, and also makes crystallization for X-ray diffraction difficult without stabilizing mutations, covalent modifications, or the addition of antibodies. Here, we report the structural characterization of the on-pathway folding intermediate of a pressure-sensitized ubiquitin mutant. The obtained non-native β-sheet registry was previously shown to be necessary in the PINK1 mitophagy pathway. We used fast pressure jumps to repeatedly initiate folding and advanced NMR measurements to probe the evolving ensemble of protein conformations. The results reported here demonstrate that the non-native β-sheet hydrogen bond registry can act as a metastable trap during protein folding. This work provides a template for future investigation of metastable conformations and protein folding with rich structural detail.}, archive = {J_PNAS}, author = {Masoumzadeh, Elahe and Courtney, Joseph M. and Charlier, Cyril and Ying, Jinfa and Anfinrud, Philip and Bax, Adriaan}, doi = {10.1073/pnas.2519493122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2519493122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure of a transient protein-folding intermediate by pressure-jump NMR spectroscopy}, volume = {122}, year = {2025}, }
• (2025). Reply to koplenig and wolfer: Global language analyses must account for relationships, location, and unbalanced binary data. PNAS, 122(41), e2518837122. (www)

  @article{ , archive = {J_PNAS}, author = {Hua, Xia and Bromham, Lindell}, doi = {10.1073/pnas.2518837122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2518837122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to koplenig and wolfer: Global language analyses must account for relationships, location, and unbalanced binary data}, volume = {122}, year = {2025}, }
• (2025). Statistical errors undermine claims about the evolution of polysynthetic languages. PNAS, 122(41), e2518416122. (www)

  @article{ , archive = {J_PNAS}, author = {Koplenig, Alexander and Wolfer, Sascha}, doi = {10.1073/pnas.2518416122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2518416122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Statistical errors undermine claims about the evolution of polysynthetic languages}, volume = {122}, year = {2025}, }
• (2025). Reply to buttersack et al.: Challenges in contactless temperature determination of supercooled aqueous droplets. PNAS, 122(41), e2518363122. (www)

  @article{ , archive = {J_PNAS}, author = {Biswas, Souvick and Paul, Dababrata and Mondal, Koushik and Kaiser, Ralf I.}, doi = {10.1073/pnas.2518363122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2518363122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to buttersack et al.: Challenges in contactless temperature determination of supercooled aqueous droplets}, volume = {122}, year = {2025}, }
• (2025). Chimeric RNA isoforms generated by diverse mechanisms from two C-type lectins modulate innate immunity in arthropods. PNAS, 122(41), e2518148122. (www)

  @article{ , abstract = {Chimeric RNA formation represents a critical mechanism for expanding protein functional diversity, yet its role in invertebrate immune adaptation remains poorly characterized. Here, we report that two C-type lectin genes ( MnLec2 and MnLec3 ) from distinct genomic loci in the oriental river prawn Macrobrachium nipponense undergo positionally flexible chimeric RNA formation via alternative trans-splicing and transcriptional slippage, generating 11 structurally diverse chimeric isoforms ( MnLec1 , MnLec4–13 ) with bidirectional exon joining. Crucially, pathogen challenges reprogram chimeric RNA frequencies to shift immune equilibrium, universally suppressing detrimental MnLec9 while promoting protective MnLec7 formation. Functional dissection confirms dual-action pathogen suppression, recombinant MnLec7 (rMnLec7) suppresses white spot syndrome virus replication by upregulating antimicrobial peptides and RNAi effectors, while accelerating Vibrio parahaemolyticus clearance and improving survival. Conversely, suppression of MnLec9 removes its immunosuppressive activity, synergistically enhancing host defense. This coordinated isoform rebalancing enables effective pathogen clearance. Thus, positional flexibility in chimeric RNA formation generates antagonistic isoforms that maintain immune homeostasis and deploy targeted defense upon infection, revealing an adaptive transcriptional strategy in arthropods.}, archive = {J_PNAS}, author = {Huang, Ying and Huang, Xin and Zhang, Li-Hua and Ren, Qian}, doi = {10.1073/pnas.2518148122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2518148122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chimeric RNA isoforms generated by diverse mechanisms from two C-type lectins modulate innate immunity in arthropods}, volume = {122}, year = {2025}, }
• (2025). A time-gated PKA–CREB signaling circuit licenses IL-12 responsiveness and th1 fate in CD4+ t cells. PNAS, 122(41), e2517132122. (www)

  @article{ , abstract = {Naïve CD4 + T cells differentiate into Th1 cells upon T-cell Receptor (TCR) stimulation in the presence of Interferon gamma (IFN-γ) and Interleukin 12 (IL-12). However, the intracellular signaling networks that temporally coordinate these inputs to reinforce Th1 lineage commitment remain incompletely defined. Here, we identify protein kinase A (PKA) as a time-gated regulator of IL-12 responsiveness and Th1 differentiation. Using a conditional knockout mouse model that deletes both catalytic PKA subunits in CD4 + T cells, we show that PKA is dispensable for early T cell activation but is essential for the late-phase induction of IL-12 receptor β2 ( Il12rb2 ) and signal transducer and activator of transcription (STAT4). PKA-deficient CD4 + T cells fail to differentiate into Th1 cells in vitro and cannot induce Th1-mediated colitis in vivo. Instead, they adopt a Th2-skewed phenotype and drive eosinophilic lung inflammation and fibrosis. Mechanistically, prolonged TCR stimulation induces the expression of the peptide hormone Adrenomedullin and its receptor component Ramp3, which activate PKA and its downstream effector cAMP response element binding protein (CREB). Activated CREB drives Il12rb2 and Stat4 transcription, establishing a feedforward circuit that integrates signal duration with cytokine responsiveness. In the absence of PKA, this transcriptional program fails to initiate, leading to impaired IL-12 signaling and a loss of Th1 identity. These findings define a PKA–CREB signaling module that links sustained antigen stimulation to transcriptional and epigenetic commitment in CD4 + T cells, offering a mechanistic explanation for the temporal gating of Th1 differentiation and the prevention of Th2-driven tissue pathology.}, archive = {J_PNAS}, author = {Zhao, Jingyao and Dainichi, Teruki and Guichard, Vincent and Zhang, Yingyu and Shirley, Simon and Leão, Felipe Batista and Tian, Ruxiao and Huang, Yuefeng and Ghosh, Sankar}, doi = {10.1073/pnas.2517132122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2517132122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A time-gated PKA–CREB signaling circuit licenses IL-12 responsiveness and th1 fate in CD4+ t cells}, volume = {122}, year = {2025}, }
• (2025). Machine learning in chemistry. PNAS, 122(41), e2517062122. (www)

  @article{ , archive = {J_PNAS}, author = {Debenedetti, Pablo G. and de Pablo, Juan J. and Schatz, George C.}, doi = {10.1073/pnas.2517062122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2517062122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Machine learning in chemistry}, volume = {122}, year = {2025}, }
• (2025). Disulfide cross-linked redox-sensitive peptide condensates are efficient cell delivery vehicles of molecular cargo. PNAS, 122(41), e2515427122. (www)

  @article{ , abstract = {Biomolecular condensates (BCs) are phase-separated viscoelastic hubs within demixed solutions enriched in proteins and nucleic acids. Such condensates, also called membraneless organelles, are increasingly observed in cells and serve as transient hubs for spatial organization and compartmentalization of biomolecules. Along with the transiency of formation and dissolution, their ability to sequester molecules has inspired us to develop BCs as potential vehicles to transport and deliver molecular cargo. We recently reported the design of disulfide bond cross-linked phase-separating peptide (PSP) condensates that spontaneously dissolve in reducing conditions. Based on the premise that the highly reducing cytoplasm could dissolve PSP condensates and release partitioned cargo, here, we demonstrate the ability of PSP condensates to deliver molecular cargo to the cytoplasm of HeLa cells. We show that PSP condensates deliver a variety of cargos that differ in their sizes and chemistries, including small molecules, peptides, GFP (31 kDa), DNA (1.7 kbp), and mRNA. The transfection efficiencies of PSP condensates for delivering DNA and mRNA were also significantly greater than those of a commercial transfection agent. With room to tailor the condensate properties based on cargo and cell types, these results showcase the potential of disulfide-cross-linked PSPs as effective and customizable cellular delivery vehicles, filling a critical demand gap for such delivery systems.}, archive = {J_PNAS}, author = {Mondal, Malay and Swetman, Windfield S. and Karim, Shazeed-Ul and Shrestha, Sabin and Davis, Ashe M. and Bai, Fengwei and Huang, Faqing and Clemons, Tristan D. and Rangachari, Vijayaraghavan}, doi = {10.1073/pnas.2515427122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2515427122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Disulfide cross-linked redox-sensitive peptide condensates are efficient cell delivery vehicles of molecular cargo}, volume = {122}, year = {2025}, }
• (2025). A midbrain-to-ventral-striatum dopaminergic pathway orchestrates odor-guided insect predation in mice. PNAS, 122(41), e2514847122. (www)

  @article{ , abstract = {Foraging and food consumption are fundamental for the survival of animals. In natural environments, wild rodents feed on insects, including moth larvae, and odor-guided evaluation of potential food resources is a critical step in initiating feeding behavior. However, the mechanisms by which rodents seek and feed on insect prey remain poorly understood. Herein, we employed a laboratory-based predator–prey interaction system using mice and cotton bollworm larvae to investigate the neural mechanisms underlying food-seeking and feeding behaviors at both cellular and neural circuit levels. We demonstrate that mice exhibit a strong preference for consuming fed larvae, and this preference is dependent on the main olfactory system. Gas chromatography-mass spectrometry analysis revealed significant differences in the chemical profiles of fed and unfed larvae, with fed larvae containing a higher level of linoleic acid (LA) and a lower level of (Z)-9-tricosene [(Z)-9-TE]. Behavioral assays showed that mice, as well as Brand’s voles and brown rats, are attracted to LA but avoid (Z)-9-TE in a two-choice odor preference test. Furthermore, we identified that the dopaminergic pathway from the ventral tegmental area (VTA) to the medial olfactory tubercle (mOT) plays a central role in mediating this preference. Chemogenetic inhibition of this pathway abolished the preference for LA over (Z)-9-TE, while chemogenetic activation reversed this effect. Additionally, fiber photometry recordings and pharmacology revealed that mOT D1 and D2 spiny projection neurons preferentially mediate attraction to LA and avoidance of (Z)-9-TE, respectively. These findings uncover a neurobiological system in rodents that supports insect predation based upon chemosignals.}, archive = {J_PNAS}, author = {Wang, Wenqiang and Zhong, Yanbiao and Tan, Ruiyi and Wang, Maoyuan and Liu, Jia and Wang, Ding and Wang, Haiping and Li, Yue and Li, Guanqing and Yang, Jian and Wang, Peng and Wu, Jialiang and Zhang, Jianxu and Wang, Chen-Zhu and Shi, Haishui and Ma, Minghong and Yu, Yiqun and Zhang, Yun-Feng}, doi = {10.1073/pnas.2514847122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2514847122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A midbrain-to-ventral-striatum dopaminergic pathway orchestrates odor-guided insect predation in mice}, volume = {122}, year = {2025}, }
• (2025). Methanogenesis inhibition remodels microbial fermentation and stimulates acetogenesis in ruminants. PNAS, 122(41), e2514823122. (www)

  @article{ , abstract = {Rumen microbiota enable ruminants to grow on fibrous plant materials, but also produce methane, driving 5% of global greenhouse gas emissions and leading to a loss of gross energy content. Methanogenesis inhibitors such as 3-nitrooxypropanol (3-NOP) decrease methane emissions in ruminants when supplemented in feed. Yet we lack a system-wide, species-resolved understanding of how the rumen microbiota remodels following inhibition and how this influences animal production. Here, we conducted a large-scale trial with 51 dairy calves to analyze microbiota responses to 3-NOP, pairing host performance, emissions, and nutritional profiles with genome-resolved metagenomic and metatranscriptomic data. 3-NOP supplementation decreased methane emissions by 62%, modulated short-chain fatty acid and H 2 levels, and did not affect dietary intake or animal performance. We created a rumen microbial genome catalogue (27,884 genomes) that mapped to the meta-omic data at high rates. There was a strong reduction of methanogens and stimulation of reductive acetogens, primarily uncultivated lineages such as “ Candidatus Faecousia.” However, there was a shift in major fermentative communities away from acetate production in response to hydrogen gas accumulation. In vitro incubations recapitulated these results and showed an enrichment of acetate from reductive acetogenesis. Altogether, the divergent responses of the fermentative and hydrogenotrophic communities lead to net hydrogen build-up and limit potential productivity gains from methane reduction. By linking ruminant greenhouse gas emissions and productivity to specific microbial species, this study emphasizes the importance of microbiota-wide analysis for optimizing methane mitigation strategies and identifies promising strategies to simultaneously reduce emissions while increasing animal production.}, archive = {J_PNAS}, author = {Ni, Gaofeng and Wang, Min and Walker, Nicola and Muetzel, Stefan and Schmidt, Oliver and Fischer, André and Stemmler, René T. and Leung, Pok Man and Zhang, Xiumin and Li, Qiushuang and Jain, Surbhi and Jespersen, Marion and Grinter, Rhys and Archer, Stephen D. J. and Pacheco, David and Lowe, Katherine and Pope, Phillip B. and Müller, Volker and Pitta, Dipti W. and Janssen, Peter H. and Watson, Mick and Attwood, Graeme T. and Ver Loren van Themaat, Emiel and Kindermann, Maik and Greening, Chris}, doi = {10.1073/pnas.2514823122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2514823122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Methanogenesis inhibition remodels microbial fermentation and stimulates acetogenesis in ruminants}, volume = {122}, year = {2025}, }
• (2025). Turning the FeFe hydrogenase from clostridium beijerinckii into an efficient h2 oxidation catalyst using a redox-active matrix. PNAS, 122(41), e2514698122. (www)

  @article{ , abstract = {Hydrogenases are Nature’s sustainable and efficient catalysts for the conversion between H + and H 2 . The obstacles that prevented their use as H 2 oxidation catalysts in fuel cells are being removed one by one, thanks to the continuous discovery of hydrogenases that have unexpected catalytic properties, the development of new methods for their scalable production and matrices that protect them. Obtaining an efficient biohybrid electrode that is scalable and robust under a large range of experimental conditions is still challenging. The FeFe hydrogenase of Clostridium beijerinckii is a very active catalyst of H 2 evolution and can be handled under O 2 , and its production can potentially be scaled up. However, it was believed that it cannot be used for H 2 oxidation, as it is easily oxidized to an O 2 -stable but inactive state. Here, we show that when the enzyme is embedded into a redox-active film whose reduction potential is finely tuned to the equilibrium potential of the H + /H 2 couple, the potential that the enzyme experiences can be buffered in a sharp window that is actually compatible with enzyme-catalyzed H 2 oxidation and prevents anaerobic inactivation. This leads us to provide the demonstration of an FeFe hydrogenase-based system that can be used for H 2 oxidation and that can be repeatedly exposed to O 2 during and between operational cycles.}, archive = {J_PNAS}, author = {Filmon, Dawit T. and Jaenecke, Jan and Winkler, Martin and Fourmond, Vincent and Léger, Christophe and Plumeré, Nicolas}, doi = {10.1073/pnas.2514698122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2514698122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Turning the FeFe hydrogenase from clostridium beijerinckii into an efficient h2 oxidation catalyst using a redox-active matrix}, volume = {122}, year = {2025}, }
• (2025). A phosphoinositide-mediated switch of GET pathway receptor dimerization in arabidopsis. PNAS, 122(41), e2514354122. (www)

  @article{ , abstract = {The Guided Entry of Tail-Anchored Proteins (GET) pathway facilitates the insertion of tail-anchored (TA) proteins into the ER membrane, but its regulation in plants remains unclear. In Arabidopsis , we identify phosphatidylinositol 4-phosphate (PI4P) as an anchor that brings the receptors At GET1 and At GET2 into proximity within the ER membrane. At GET2 binds PI4P via an arginine residue in its transmembrane domain. Mutation of this residue disrupts At GET1 and At GET2 proximity at the ER, impairing GET complex function. This defect can be rescued by synthetic dimerization of A tGET1 and At GET2. The PI4P phosphatase RHD4 acts as a gatekeeper, converting PI4P to PI and enabling At GET1– At GET2 interaction, which influences TA protein insertion and root hair growth. Our findings establish the PI4P-RHD4 module as a crucial regulator of GET receptor dynamics, highlighting the interplay between phospholipids and protein trafficking in plants.}, archive = {J_PNAS}, author = {Zhang, Lei and Struß, Aron and Qin, Miaojing and Dombrowski, Annika and Li, Tingting and Viebahn, Stefanie and Mehlhorn, Dietmar and Grefen, Christopher}, doi = {10.1073/pnas.2514354122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2514354122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A phosphoinositide-mediated switch of GET pathway receptor dimerization in arabidopsis}, volume = {122}, year = {2025}, }
• (2025). Single-cell lysis patterns morphogenesis of eDNA in the matrix of pseudomonas aeruginosa biofilms. PNAS, 122(41), e2514210122. (www)

  @article{ , abstract = {When bacteria form a biofilm, complex behaviors emerge. Biofilm bacteria differ from their free-living counterparts, exhibiting heterogenous, spatiotemporally patterned behavior. Can we explain these patterns by defining the rules that govern single-cell behavior in biofilms? By understanding these rules, can we explain emergent functions at the biofilm scale? Here we reveal how the architecture of extracellular DNA (eDNA) in the biofilm matrix is controlled by single-cell lysis during Pseudomonas aeruginosa biofilm development. We extend single-cell imaging methods to capture complete biofilm development over 5+ d, characterizing the stages of biofilm development and visualizing eDNA matrix morphogenesis from start to finish. Mapping the spatiotemporal distribution of single-cell lysis events shows that cell lysis is spatiotemporally patterned, concentrated in a region 5 µm below the biofilm surface that moves with the biofilm as it grows. Using analytical modeling, we examined the consequences of patterning at the biofilm scale. Cell lysis patterning defines eDNA in the matrix: Patterned lysis is sufficient to explain the final eDNA distribution. Cell lysis and biofilm growth are coupled such that the amount of eDNA in the biofilm scales with its volume; this patterning results in a predominantly uniform eDNA matrix architecture, which could not occur without patterning. Finally, we find that patterning of cell lysis is self-organized by nutrient gradients, with maximal lysis occurring in regions where oxygen is present and carbon is limited. The ability of cells to use self-generated nutrient gradients as positioning cues to establish depth-based patterning is a striking feature of bacterial biofilm development.}, archive = {J_PNAS}, author = {Squyres, Georgia R. and Newman, Dianne K.}, doi = {10.1073/pnas.2514210122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2514210122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Single-cell lysis patterns morphogenesis of eDNA in the matrix of pseudomonas aeruginosa biofilms}, volume = {122}, year = {2025}, }
• (2025). Goblet cells dictate viral tropism and pathogenesis in nasal and intestinal mucosae. PNAS, 122(41), e2514150122. (www)

  @article{ , abstract = {Host determinants are critical for shaping the outcomes of viral mucosal infections and developing effective antiviral strategies. However, the regulatory roles of “nonsusceptible” mucosal cells remain unclear. Here, we show that while swine influenza and porcine epidemic diarrhea (PEDV) viruses infect piglet nasal and intestinal epithelia, each virus establishes efficient infection only in its preferred mucosal niche. Goblet cell activity significantly influences mucosal infection outcomes; increased mucus secretion effectively blocks viral entry, while its reduction facilitates viral dissemination. Notably, PEDV activates acetylcholine-cholinergic receptor muscarinic 3 signaling in submucosal enteric neurons to induce goblet cell-associated antigen passages. This mechanism enables the translocation of intestinal bacteria to the lamina propria in early infection, even when the epithelial barrier remains intact, triggering inflammation and exacerbating mucosal damage. Our findings emphasize the crucial role of goblet cells in controlling viral tropism and their potential as targets for developing effective broad-spectrum antiviral approaches.}, archive = {J_PNAS}, author = {Wang, Wenqian and Chao, Wenwen and Zeng, Hui and Tang, Rongfeng and Liu, Ruiling and Wang, Chengcheng and Wu, Xuan and Qi, Jiaxin and Cao, Yunlei and Li, Yuchen and Yang, Qian}, doi = {10.1073/pnas.2514150122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2514150122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Goblet cells dictate viral tropism and pathogenesis in nasal and intestinal mucosae}, volume = {122}, year = {2025}, }
• (2025). Reassessment of kepler’s habitable zone earth-like exoplanets with data-driven null signal templates. PNAS, 122(41), e2513927122. (www)

  @article{ , abstract = {One of the primary mission goals of the Kepler space telescope is to detect Earth-like terrestrial planets in the habitable zone around Sun-like stars. Unfortunately, such planets are at the detection limit. Estimating their statistical significance via false alarm probability (FAP) is crucial for their validation and has a large impact on the estimate of their occurrence rate, which is of central importance for future spectroscopic missions searching for life signatures. Current methods estimate FAP by light curve inverting or scrambling, but we show that both of these approaches are unsatisfactory. Here, we propose to modify the planet transit template by randomly shifting the transit times by small amounts. We show that the exoplanet search with the resulting null signal template (NST) has the same statistical properties as with the true periodic template, which enables assigning a reliable star-specific FAP to every candidate. We show on simulations and on the real data that the method is robust to unmodeled noise contamination. We reevaluate the statistical significance of all 47 previously proposed habitable Earth-like and super Earth Kepler candidates and assign them star-specific NST based FAP. We identify 29 candidates with FAP below 1%, 7 of whom are currently not considered confirmed. Among these are Kepler 452b with radius 1.5 R ⊕ , a period of 384 d, and KOI 2194.03 with radius 1.8 R ⊕ and a period of 445 d, both around Sun-like G stars. Several well-known candidates should be considered marginal or likely false alarms, including Kepler 186f with 20% FAP.}, archive = {J_PNAS}, author = {Robnik, Jakob and Seljak, Uroš}, doi = {10.1073/pnas.2513927122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2513927122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reassessment of kepler’s habitable zone earth-like exoplanets with data-driven null signal templates}, volume = {122}, year = {2025}, }
• (2025). A nonenzymatic effector disrupts bacteroides cell wall homeostasis via OmpA targeting to mediate interbacterial competition. PNAS, 122(41), e2513207122. (www)

  @article{ , abstract = {The human gut microbiome is a dynamic ecosystem where bacteria engage in interspecies competition using molecular weapons such as the type VI secretion system (T6SS). Here, we characterize BteO–BtiO, a unique effector–immunity pair in Bacteroides fragilis that mediates antagonism via a nonenzymatic mechanism. Microscopy reveals that BteO exposure leads to cell elongation, membrane blebbing, and lysis in sensitive strains. Structural and biochemical analyses demonstrate that BteO disrupts cell wall homeostasis by binding to conserved C-terminal domains of OmpA-family proteins (OmpAs), which are critical for outer membrane integrity. The immunity protein BtiO neutralizes BteO by mimicking the OmpA-binding interface. We further show that bile salts enhance BteO-mediated killing in vitro and that BteO confers a competitive advantage in the mammalian gut. Remarkably, BteO exhibits broad-spectrum activity across Bacteroides species. These findings reveal a nonenzymatic strategy of bacterial antagonism and broaden our understanding of T6SS effector diversity within Bacteroides .}, archive = {J_PNAS}, author = {He, Jing and Chen, Zhe and Jiang, Kun and Yang, Yan and Li, Weixun and Wang, Xiaotong and Xu, Xiaoning and Zheng, Shuaining and Jiao, Xuyao and Chen, Xudong and Huo, Liujie and Lim, Bentley and Liu, Shuang-Jiang and Gao, Xiang}, doi = {10.1073/pnas.2513207122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2513207122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A nonenzymatic effector disrupts bacteroides cell wall homeostasis via OmpA targeting to mediate interbacterial competition}, volume = {122}, year = {2025}, }
• (2025). Freezing enhances CO2 mineralization in ca2+-containing solutions. PNAS, 122(41), e2512544122. (www)

  @article{ , abstract = {Natural carbon sinks and the factors influencing them are critical to the global carbon budget. Here, we identify the freezing process as an important factor. It greatly contributes to natural carbon sinks by enhancing atmospheric CO 2 sequestration/mineralization in mineral ion-rich aqueous systems, which is demonstrated by freezing the solutions of Ca(OH) 2 , binary NaCl–CaCl 2 solutions, and artificial seawater. The acceleration is caused by the impacts of freezing on nucleation and growth processes of CaCO 3 crystals. Freezing accelerates nucleation by concentrating reactants within ice crystal boundaries, increasing supersaturation, and thus lowering the nucleation energy barrier. At the post–thaw stage where nuclei already form and reactant concentration is decreased, the crystals undergo the barrier-free growth process. Our findings reveal the freezing-enhanced CO 2 sequestration that is omitted in the current global carbon budget models and signal an urgent need to integrate cryogenic mineralization into climate predictions.}, archive = {J_PNAS}, author = {Sun, Minghao and Gao, Dong and Li, Bowen and Francisco, Joseph S. and Bai, Guoying and Zhang, Xinxing}, doi = {10.1073/pnas.2512544122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2512544122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Freezing enhances CO2 mineralization in ca2+-containing solutions}, volume = {122}, year = {2025}, }
• (2025). Search for a parity-violating long-range spin-dependent interaction. PNAS, 122(41), e2512538122. (www)

  @article{ , abstract = {High-sensitivity quantum sensors are a promising tool for experimental searches for beyond-Standard-Model interactions. Here, we demonstrate an atomic comagnetometer operating under a resonantly-coupled hybrid spin-resonance (HSR) regime to probe P-odd, T-even interactions. The HSR regime enables robust nuclear-electron spin coupling, enhancing measurement bandwidth and stability without compromising the high sensitivity of spin-exchange relaxation-free magnetometers. To minimize vibration-related noise from velocity-modulated sources, we implement a multistage vibration isolation system, achieving a vibration-related noise reduction exceeding 700-fold. We establish new constraints on vector-boson-mediated parity-violating interactions, improving experimental sensitivity by three orders of magnitude compared to previous limits. The new constraints complement existing astrophysical and laboratory studies of potential extensions to the Standard Model.}, archive = {J_PNAS}, author = {Heng, Xing and Xu, Zitong and Huang, Xiaofei and Gong, Dinghui and Tian, Guoqing and Ji, Wei and Fang, Jiancheng and Budker, Dmitry and Wei, Kai}, doi = {10.1073/pnas.2512538122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2512538122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Search for a parity-violating long-range spin-dependent interaction}, volume = {122}, year = {2025}, }
• (2025). Platelets engage mast cells in a bilateral IL-33-driven feed-forward loop. PNAS, 122(41), e2512193122. (www)

  @article{ , abstract = {Platelets amplify type 2 inflammation (T2I) through incompletely understood mechanisms. Depletion of platelets markedly attenuated mast cell (MC) activation in a model of aspirin exacerbated respiratory disease (AERD) that depends on IL-33 and cysteinyl leukotrienes (cysLTs). We demonstrate an IL-33-driven feed-forward loop between platelets and MCs. IL-33 neutralization prevented increases in cysLTs and CXCL7, a platelet activation marker, in bronchoalveolar lavage (BAL) fluid from AERD-like mice in response to aspirin challenges. BAL fluid concentrations of PGD 2 correlated strongly with both CXCL7 and MC tryptase in subjects with severe asthma. Platelets amplified PGD 2 and LTC 4 productions by IL-33-stimulated mouse bone marrow–derived MCs (BMMCs), which induced release of CXCL7 and expression of CD62P by platelets. Deletions of MC-specific LTC 4 or platelet-specific type 2 cysLT receptor (CysLT 2 R) completely eliminated both platelet activation and the amplification of PGD 2 and LTC 4 generation by MCs. Platelet-derived ADP/ATP and MC-associated P2Y 1 receptors were essential. These findings identify an innate immune pathway involving MC–platelet interplay that may drive IL-33-dependent immunopathology in asthma.}, archive = {J_PNAS}, author = {Nishida, Airi and Nagai, Jun and Hastings, Madeline and Zaleski, Kendall and Sasaki, Marie and Samir, Omar and Lai, Juying and Marshall, Sofia A. and Hayashi, Hiroaki and Majumdar, Sreyashi and Alhallak, Kinan and Feng, Chunli and Liu, Tao and Boyce, Joshua A.}, doi = {10.1073/pnas.2512193122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2512193122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Platelets engage mast cells in a bilateral IL-33-driven feed-forward loop}, volume = {122}, year = {2025}, }
• (2025). The integrated stress response suppresses antiviral RNA interference by autophagy-mediated degradation of the RNA-induced silencing complex. PNAS, 122(41), e2511857122. (www)

  @article{ , abstract = {The small interfering RNA (siRNA) pathway is a highly conserved antiviral defense mechanism in vertebrates and invertebrates. Although the core components of this pathway are well characterized, its upstream regulatory networks remain poorly understood. Here, we identify the integrated stress response (ISR) as a negative regulator of the siRNA pathway, and demonstrate that the picorna-like virus CrPV (Cricket Paralysis Virus) exploits this mechanism for immune evasion. Mechanistically, the picorna-like virus triggers the ISR through transcriptional suppression of ppp1r15 , a key regulator of eukaryotic initiation factor 2α (eIF2α) dephosphorylation. ISR activation subsequently induces the autophagy-lysosomal pathway by up-regulating Atg1 transcription in an ATF4-dependent manner. This process leads to selective degradation of Argonaute 2 (Ago2) and other core components of the RNA-induced silencing complex (RISC), thereby suppressing the host RNA interference (RNAi) machinery and enhancing viral replication. Our findings uncover an unconventional immune evasion strategy employed by a picorna-like virus and establish a previously unrecognized crosstalk between the ISR and siRNA pathways.}, archive = {J_PNAS}, author = {Wang, Qiyu and Chen, Lingyue and Wang, Jiayin and Chen, Zhijian and Ma, Zixian and Xie, Xuan and Zeng, Xiaohui and Bie, Yuanyuan and Wang, Zhaowei}, doi = {10.1073/pnas.2511857122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2511857122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The integrated stress response suppresses antiviral RNA interference by autophagy-mediated degradation of the RNA-induced silencing complex}, volume = {122}, year = {2025}, }
• (2025). Endosome transcriptomics reveal trafficking of cajal bodies into multivesicular bodies. PNAS, 122(41), e2511840122. (www)

  @article{ , abstract = {All eukaryotic cells secrete exosomes, a type of extracellular vesicles derived from the endocytic compartments known as multivesicular bodies (MVBs), or late endosomes (LEs). Exosomes contain a diverse range of cargo such as nucleic acids, proteins, lipids, and small molecules but whether these contents have a biological function remains an area of intense investigation. Over the last decade, numerous studies have described the transcriptome of exosomes but very little is known about the RNA content of the MVBs, the source compartment for exosome biogenesis. Here, we determine the small-RNA transcriptome of highly purified MVBs and report that various classes of nuclear small regulatory RNAs such as small-Cajal body associated RNAs, small-nucleolar RNAs, and small-nuclear RNAs traffic to MVBs. We show that this RNA-trafficking requires the function of endosomal sorting complexes required for transport (ESCRT) machinery but is independent of canonical LC3 lipidation mediated selective autophagy. Furthermore, blocking the activity of a PI3K Class 3 enzyme, VPS34, required for recruitment of the ESCRT machinery to the endosome, prevents the turnover of these nuclear RNAs in MVBs. Our results provide a mechanism for targeting nuclear ribonucleoprotein complexes, such as Cajal bodies, for degradation and turnover by the cytoplasmic endo-lysosomal pathway.}, archive = {J_PNAS}, author = {Singh, Jasleen and Williams, Justin Krish and Elliott, Quinn and Jhawar, Rohit and Ferguson, Lucas and Collins, Kathleen and Schekman, Randy}, doi = {10.1073/pnas.2511840122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2511840122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Endosome transcriptomics reveal trafficking of cajal bodies into multivesicular bodies}, volume = {122}, year = {2025}, }
• (2025). Short-term experimental flooding impacts soil biogeochemistry but not aboveground vegetation in a coastal forest. PNAS, 122(41), e2511756122. (www)

  @article{ , abstract = {Rising sea levels and intensifying storms increase flooding pressure on coastal forests, triggering tree mortality, ecosystem transitions, and changes to the coastal carbon cycle. However, the mechanisms that drive coastal forest mortality remain elusive due to the complex interplay between belowground and aboveground processes during flooding disturbances and limitations of observations typically reported in coastal forest mortality studies. We used an ecosystem-scale manipulation to simulate hurricane-level flooding of a coastal forest and explore the individual and interactive impacts of inundation and salinity. Monitoring real-time soil conditions and tree physiological responses, we observed consistent impacts on soil biogeochemistry aligned with belowground drivers of tree mortality, but no consistent responses in aboveground vegetation immediately following flooding. Our findings provide empirically based insight into the earliest stages of a hypothesized forest mortality spiral and offer critical benchmarks for predicting coastal forest resilience in the face of accelerating climate change.}, archive = {J_PNAS}, author = {Regier, Peter and Bond-Lamberty, Ben and Ward, Nicholas and Bailey, Vanessa and Peixoto, Roberta Bittencourt and Machado-Silva, Fausto and McDowell, Nate and Morris, Kendalynn A. and Myers-Pigg, Allison and Pennington, Stephanie C. and Rahman, Mizanur and Rich, Roy and Smith, Richard W. and Wilson, Stephanie J. and Woodard, Stella C. and Stearns, Alice and Day, Donnie and Doro, Kennedy and Emmanuel, Efemena and Grossiord, Charlotte and Hopple, Anya and Ogunsola, Olawale and Patel, Kaizad and Phillips, Evan and Megonigal, J. Patrick}, doi = {10.1073/pnas.2511756122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2511756122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Short-term experimental flooding impacts soil biogeochemistry but not aboveground vegetation in a coastal forest}, volume = {122}, year = {2025}, }
• (2025). Challenges in contactless temperature determination of supercooled aqueous droplets. PNAS, 122(41), e2511453122. (www)

  @article{ , archive = {J_PNAS}, author = {Buttersack, Tillmann and Bauerecker, Sigurd and Leisner, Thomas}, doi = {10.1073/pnas.2511453122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2511453122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Challenges in contactless temperature determination of supercooled aqueous droplets}, volume = {122}, year = {2025}, }
• (2025). Inequality in air pollution–attributable mortality by income level between and within countries. PNAS, 122(41), e2511394122. (www)

  @article{ , abstract = {Air pollution is a major global health threat, with exposure exhibiting substantial heterogeneity across and within regions. While disparities in air pollution exposure by income groups are well documented, how these inequalities translate into differential burdens of pollution-attributable premature mortality remains understudied. We utilize high-resolution estimates of secondary air pollutants, combined with income data, to investigate the relationship between global air pollution–attributable mortality and poverty across urban–rural contexts and air pollutants. We show that high-income countries face higher air pollution–attributable mortality owing to population aging, in contrast to the established exposure inequality pattern. While affluent populations within most countries also face higher mortality burdens, in several low-income countries, this pattern is reversed due to elevated exposures among impoverished rural populations. South Asia and Africa exhibit the highest levels of vulnerability to coincident mortality and poverty, where populations living in periurban transition zones bear disproportionate dual burdens. In many low-income countries, those living near wealthier urban centers also face elevated health burdens from air pollution: a “cost of opportunity” when air pollutant regulations are weak. Our findings emphasize the imperative for tailored policy interventions to mitigate amplified health risks in vulnerable communities.}, archive = {J_PNAS}, author = {Tao, Chenliang and Zhang, Yuqiang and Shindell, Drew and Zhang, Hongliang}, doi = {10.1073/pnas.2511394122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2511394122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inequality in air pollution–attributable mortality by income level between and within countries}, volume = {122}, year = {2025}, }
• (2025). Soil microbial life history strategies covary with ecosystem multifunctionality across aridity gradients. PNAS, 122(41), e2511071122. (www)

  @article{ , abstract = {Aridity thresholds shape ecosystem functions worldwide. Despite the importance of soil microbiomes in engineering ecosystem processes, the specific strategies employed by soil microbiomes to support ecosystem multifunctionality (EMF) across aridity gradients remain virtually unknown. Here, we investigated 474 soil samples across a continental-scale aridity gradient and identified an aridity threshold beyond which plot-level EMF declines sharply. Microbial habitat and decomposition functions were among the last to respond to aridity, with thresholds occurring under more arid conditions compared to plant productivity and soil fertility. Combining metagenomic sequencing with physiological assays to characterize microbial life history strategies of high yield (Y), resource acquisition (A), and stress tolerance (S), we introduce a microbial trait-based framework to mechanistically link community-level microbial life history strategies to EMF. Our results reveal that microbial Y-strategy is positively correlated with EMF across aridity gradients, A-strategy exhibits a negative association with EMF across aridity gradients, and S-strategy is negatively correlated with EMF in arid ecosystems. Collectively, this study offers empirical evidence and insights into how aridification interacts with soil microbiomes in shaping EMF, highlighting the pivotal role of microbial life history strategies in understanding the mechanisms behind EMF variation in an increasingly arid world.}, archive = {J_PNAS}, author = {Zhou, Tao and Delgado-Baquerizo, Manuel and Ren, Chengjie and He, Nianpeng and Zhou, Zhenghu and He, Yanghui}, doi = {10.1073/pnas.2511071122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2511071122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Soil microbial life history strategies covary with ecosystem multifunctionality across aridity gradients}, volume = {122}, year = {2025}, }
• (2025). Metabolic controls on the carbon isotope fractionations of bacterial fermentation. PNAS, 122(41), e2511040122. (www)

  @article{ , abstract = {Microbial fermentation facilitates the initial breakdown of organic matter into small molecules and is thought to be the rate-limiting step of anoxic organic mineralization. However, fermentation is understudied in modern and ancient biogeochemistry due to a lack of environmental biomarkers. It has long been assumed that fermentation, like respiration, does not express significant carbon isotope fractionations, precluding isotopic signals as a means of studying it in nature. Here, we tested this idea by growing pure cultures of four fermenting bacteria on glucose and measuring the carbon isotope compositions of the organic acids and alcohols produced. We found that fermentation exhibits a strong carbon isotope fractionation, ranging from − 6‰ to + 16‰, depending on the fermentation product. With bioisotopic models that track site-specific isotope enrichments through metabolism, we constrained the enzymes responsible for these fractionations. Our models reproduced in vivo organic acid δ 13 C values in all four organisms. These findings demonstrate that acetate 13 C-enrichment is likely a widespread signature of fermentation. They also challenge traditional notions of controls on the isotope composition of lipids. Finally, our study suggests that fermentation imposes a trophic carbon isotope fractionation as organic carbon is passed from fermenters to secondary degraders like sulfate reducers. Looking to the geologic past, this trophic fractionation could have imprinted isotopic signals on the three billion year record of sedimentary organic carbon, specifically the inverse δ 13 C pattern of Precambrian acyclic isoprenoid and n-alkane biomarkers. Pervasive evidence of fermentation in the rock record would suggest its underappreciated role in biogeochemical cycles throughout Earth history.}, archive = {J_PNAS}, author = {Mueller, Elliott P. and Heuer, Verena B. and Leadbetter, Jared R. and Hinrichs, Kai-Uwe and Sessions, Alex L.}, doi = {10.1073/pnas.2511040122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2511040122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Metabolic controls on the carbon isotope fractionations of bacterial fermentation}, volume = {122}, year = {2025}, }
• (2025). Heterochronic shifts in a timing-keeping microRNA are associated with multiple instances of neoteny in plants. PNAS, 122(41), e2510697122. (www)

  @article{ , abstract = {The prolonged production of juvenile traits and an associated reduction or loss of adult traits during development (neoteny) can either arise from a change in genes that mediate the timing of the shift between juvenile and adult traits (timing genes) or from changes in genes that are necessary for the development of adult traits (target genes). To date, the relative contribution of each developmental mechanism to the origins of neoteny remain unclear. We examined this question in the plant genus, Acacia Mill., which contains species that undergo the juvenile-to-adult vegetative transition (vegetative phase change) early in shoot development, as well as species that remain permanently juvenile, or have delayed vegetative phase change. Mapping the timing of vegetative phase change onto a molecular phylogeny of Acacia revealed that permanent juvenility has evolved multiple times and is sometimes associated with a delay in vegetative phase change in related species. In three cases, the absence or delay in vegetative phase change was associated with either higher amounts or a delayed decline in the level of miR156, the master regulator of vegetative phase change in plants. These findings support the hypothesis that neoteny in Acacia has evolved not by a loss in the capacity to produce the adult leaf phenotype but by a change in the timing of genes that promote juvenile leaf identity.}, archive = {J_PNAS}, author = {Leichty, Aaron R. and Poethig, R. Scott}, doi = {10.1073/pnas.2510697122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2510697122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Heterochronic shifts in a timing-keeping microRNA are associated with multiple instances of neoteny in plants}, volume = {122}, year = {2025}, }
• (2025). An orc6 tether mediates ORC binding-site switching during replication origin licensing. PNAS, 122(41), e2510685122. (www)

  @article{ , abstract = {During origin licensing, the origin recognition complex (ORC) loads two Mcm2-7 helicases onto DNA in a head-to-head conformation, establishing the foundation for subsequent bidirectional replication. Single-molecule experiments support a helicase-loading model in which one ORC loads both Mcm2-7 helicases at origins. For this to occur, ORC must release from its initial Mcm2-7 and DNA binding sites, flip over the helicase, and bind the opposite end of the Mcm2-7 complex and adjacent DNA to form the MO complex. Importantly, this binding-site transition occurs without ORC releasing into solution. Using a single-molecule FRET assay, we show that the N-terminal half of Orc6 tethers ORC to the N-terminal region of Mcm2 during ORC’s binding-site transition. This interaction involves both the folded Orc6 N-terminal domain (Orc6N) and the adjacent unstructured linker and forms before ORC releases from its initial Mcm2-7 interaction. The absence of this interaction increases the rate of ORC release into solution, consistent with a tethering function. CDK phosphorylation of ORC inhibits the tethering interaction, providing a mechanism for the known CDK inhibition of MO complex formation. Interestingly, we identify mutations in the Orc6 linker region that support MO complex formation but prevent double-hexamer formation by inhibiting stable second Mcm2-7 recruitment. Our study provides a molecular explanation for a one-ORC mechanism of helicase loading and demonstrates that Orc6 is involved in multiple stages of origin licensing.}, archive = {J_PNAS}, author = {Driscoll, David and Friedman, Larry J. and Gelles, Jeff and Bell, Stephen P.}, doi = {10.1073/pnas.2510685122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2510685122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An orc6 tether mediates ORC binding-site switching during replication origin licensing}, volume = {122}, year = {2025}, }
• (2025). A multilayered gap junction network is essential for social decision-making. PNAS, 122(41), e2510579122. (www)

  @article{ , abstract = {Early-life social experiences can shape adult behavior, yet the underlying neural mechanisms of this plasticity remain incompletely understood. Here, we show that Caenorhabditis elegans larvae reared at high density develop into adults that exhibit exploratory behavior in the associative-learning paradigm known as thermotaxis. While animals grown at low density prefer the temperature previously associated with food, those exposed to high density during larval stages instead disperse from this temperature. The high-density experience alters the neural representation of thermal valence, a process that requires a gap junction network spanning multiple neural circuit layers. This network connects density-sensing neurons to the circuit that processes temperature information. Furthermore, these gap junction components also control the decision to enter developmental diapause in response to high density. Our results suggest that the multilayered gap junction network enables early social experience to influence adult behavior and is essential for developmental and behavioral plasticity in social contexts.}, archive = {J_PNAS}, author = {Nakayama, Airi and Kuroyanagi, Hiroo and Matsuyama, Hironori J. and Mori, Ikue and Hisamoto, Naoki and Nakano, Shunji}, doi = {10.1073/pnas.2510579122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2510579122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A multilayered gap junction network is essential for social decision-making}, volume = {122}, year = {2025}, }
• (2025). EFCAB10 anchors AK8 to the radial spoke for proper ciliary motility. PNAS, 122(41), e2510243122. (www)

  @article{ , abstract = {Radial spokes in motile cilia and flagella regulate rhythmic ciliary motility, which is essential for rapid cell movement and extracellular fluid flow. In humans, defective radial spokes can cause a genetic disorder known as primary ciliary dyskinesia (PCD), resulting in respiratory defects and infertility. Despite their critical role in ciliary motility, the molecular composition and related physiological functions remain to be elucidated. Here, we identify EF-hand calcium-binding domain protein 10 (EFCAB10) and adenylate kinase (AK8) as radial spoke proteins and describe their roles in mouse motile cilia. Using Efcab10 −/− and Ak8 −/− mice, we show that loss of either protein can affect ciliary motility and lead to PCD-related phenotypes in mice. Interestingly, ciliary AK8 is completely absent in Efcab10 −/− cilia, but the loss of AK8 has no effect on ciliary EFCAB10. Further biochemical analyses reveal that EFCAB10 interacts with AK8 and RSPH3B, which fastens AK8 to the radial spoke. Overall, our findings demonstrate the essential role of EFCAB10 as a radial spoke protein in maintaining the integrity of the radial spoke and provide valuable insights into the molecular basis of related ciliopathies.}, archive = {J_PNAS}, author = {Song, Ting and Li, Qingchao and Lyu, Qian and Zhao, Junkui and Zi, Xirui and Ma, Shuxiang and Luo, Jiajun and Li, Shushen and Nai, Shanshan and Liu, Hongbin and Zhu, Xueliang and Li, Te and Zhou, Jun and Zhao, Huijie}, doi = {10.1073/pnas.2510243122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2510243122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {EFCAB10 anchors AK8 to the radial spoke for proper ciliary motility}, volume = {122}, year = {2025}, }
• (2025). Intrinsically disordered linkers and terminal domains codrive aciniform spidroin self-assembly through liquid–liquid phase separation. PNAS, 122(41), e2510216122. (www)

  @article{ , abstract = {Aciniform silk is a remarkably tough and elastic protein fiber primarily used by spiders to wrap prey and construct the inner layers of egg sacs. While the formation of ampullate and eggcase silks has been extensively studied, the molecular mechanism underlying the self-assembly of the aciniform spidroin, AcSp1, remains poorly understood. Here, we demonstrate that the intrinsically disordered linkers of AcSp1 play a critical role in driving spidroin assembly through liquid–liquid phase separation in solution. The N-terminal domain (NTD) exhibits pH-independent dimerization over a physiological pH range (5.0 to 7.0) and undergoes concentration-dependent tetramerization. Quaternary structure of AcSp1-NTD shows a hierarchical assembly process mediated by both hydrophobic and electrostatic interactions, which enhances phase separation in both salt-free and salt-containing solutions. Finally, inspired by this mechanistic insight, we developed a fully aqueous spinning method to fabricate artificial aciniform fibers with excellent extensibility and toughness. These findings uncover a pivotal molecular strategy that transforms our understanding of diverse molecular mechanisms governing spidroin assembly and establish a foundation for designing and manufacturing elastic and tough silk-based biomaterials.}, archive = {J_PNAS}, author = {Qin, Ruiqi and Yang, Runze and Yu, Shuixin and Guo, Wei and Cong, Hailong and Ning, Yuzhe and Chen, Cheng and Yang, Daiwen and Yuan, Wensu and Lin, Zhi}, doi = {10.1073/pnas.2510216122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2510216122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intrinsically disordered linkers and terminal domains codrive aciniform spidroin self-assembly through liquid–liquid phase separation}, volume = {122}, year = {2025}, }
• (2025). Functional genetic elements of a butterfly mimicry supergene. PNAS, 122(41), e2509864122. (www)

  @article{ , abstract = {Development requires the coordinated action of many genes across space and time, yet numerous species can develop discrete, alternate phenotypes. Such complex balanced polymorphisms are often controlled by supergenes: multiple tightly linked loci that function together to control development of a complex phenotype. Supergenes are widespread in nature. However, the evolution and functions of supergene alleles remain obscure because the identities of the functional loci, and the causative variation between them, remain essentially unknown. The doublesex supergene controls mimicry polymorphism in the swallowtail butterflies Papilio polytes and Papilio alphenor. Alternate alleles cause development of discrete mimetic or nonmimetic wing patterns. We found that the mimetic allele evolved by gaining six new cis -regulatory elements (CREs) and an inversion that locked those CREs together with dsx and the novel noncoding gene U3X . At least four of these new CREs are essential for dsx expression and mimetic pattern development. Genome-wide assays of DSX binding suggest that dsx controls mimetic pattern development by directly regulating the expression of both itself and a handful of unlinked genes. The dsx supergene thus contains multiple functional genetic elements, each required for the phenotype switch and linked together by an inversion, and likely exerts its effects on color pattern development through direct regulation of unlinked “modifier” genes. Our results therefore support classic theories of supergene evolution, but update those ideas to match what we have learned about gene regulation since their development over a half century ago.}, archive = {J_PNAS}, author = {VanKuren, Nicholas W. and Sheikh, Sofia I. and Fu, Claire L. and Massardo, Darli and Service, Namiko N. and Lu, Wei and Kronforst, Marcus R.}, doi = {10.1073/pnas.2509864122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2509864122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Functional genetic elements of a butterfly mimicry supergene}, volume = {122}, year = {2025}, }
• (2025). Human deep sleep facilitates cerebrospinal fluid dynamics linked to spontaneous brain oscillations and neural events. PNAS, 122(41), e2509626122. (www)

  @article{ , abstract = {How sleep maintains our healthy brain function has remained one of the biggest mysteries in neuroscience, medical settings, and daily lives. While cerebrospinal fluid (CSF) during sleep has been implicated in metabolic waste reduction in animals, how CSF dynamics are driven in the healthy human brain during deep sleep remains elusive. A myriad of research has shown that crucial cognitive processing manifests in slow-wave and rapid-eye movement (REM) sleep, suggesting that a key to maintaining brain functions lies in deep sleep. By leveraging a simultaneous sparse-functional MRI and polysomnography method, we demonstrate that deep sleep–specific CSF dynamics are associated with spontaneous brain oscillations in healthy young human participants. Slow waves and sleep spindles during slow-wave sleep are tightly linked to short-cycle, frequent, and moderate CSF fluctuations. In contrast, slow waves during light sleep and arousals produce slow, infrequent, and steep CSF signal changes. Rapid eye movements and sawtooth waves during REM sleep are also linked to CSF signal changes. Furthermore, CSF signals are significantly faster in frequency during deep than light sleep. These brain oscillations during light and deep sleep recruit essentially different brain networks, with deep sleep involving memory and homeostatic circuits. Thus, human deep sleep has a unique way of facilitating CSF dynamics that are distinctive from arousal mechanisms.}, archive = {J_PNAS}, author = {Uji, Makoto and Li, Xuemei and Saotome, An and Katsumata, Ryosuke and Waggoner, R. Allen and Suzuki, Chisato and Ueno, Kenichi and Aritake, Sayaka and Tamaki, Masako}, doi = {10.1073/pnas.2509626122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2509626122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Human deep sleep facilitates cerebrospinal fluid dynamics linked to spontaneous brain oscillations and neural events}, volume = {122}, year = {2025}, }
• (2025). Predicting forced responses of probability distributions via the fluctuation–dissipation theorem and generative modeling. PNAS, 122(41), e2509578122. (www)

  @article{ , abstract = {We present a flexible data-driven framework for estimating the response of higher-order moments of nonlinear stochastic systems to small external perturbations. The classical generalized fluctuation–dissipation theorem (GFDT) links the unperturbed steady-state distribution to the system’s linear response. While standard implementations relying on Gaussian approximations can predict the mean response, they often fail to capture changes in higher-order moments. To overcome this, we combine GFDT with score-based generative modeling to estimate the system’s score function directly from data. We demonstrate the framework’s versatility by employing two complementary score estimation techniques tailored to the system’s characteristics: i) a clustering-based algorithm (K-means Gaussian Mixture Modeling) for systems with low-dimensional effective dynamics, and ii) a denoising score matching method implemented with a U-Net architecture for high-dimensional, spatially extended systems where reduced-order modeling is not feasible. Our method is validated on several stochastic models relevant to climate dynamics: three reduced-order models of increasing complexity and a 2D Navier–Stokes model representing a turbulent flow with a localized perturbation. In all cases, the approach accurately captures strongly nonlinear and non-Gaussian features of the system’s response, significantly outperforming traditional Gaussian approximations.}, archive = {J_PNAS}, author = {Giorgini, Ludovico T. and Falasca, Fabrizio and Souza, Andre N.}, doi = {10.1073/pnas.2509578122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2509578122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Predicting forced responses of probability distributions via the fluctuation–dissipation theorem and generative modeling}, volume = {122}, year = {2025}, }
• (2025). Evolutionary consideration of serial order processing by the normal rodent brain. PNAS, 122(41), e2509426122. (www)

  @article{ , abstract = {The granular mid-dorsolateral prefrontal cortex of the primate brain is the final stage in the evolutionary development from the phylogenetically older agranular frontal cortex that lies above the anterior part of the corpus callosum, i.e., the anterior part of the cingulate gyrus. In the rodent brain, the prefrontal cortex is limited to this earlier agranular stage and is often referred to as the “medial prefrontal cortex.” The primate mid-dorsolateral prefrontal cortex is critical for the monitoring of information in working memory, including the monitoring of the precise serial order of flexible randomly varying sequences of stimuli. Thus, a fundamental question arises: what are the functional limits of serial order processing in the rodent brain which, anatomically, possesses only the earlier stage in the evolution of the prefrontal cortex? The present study examined the ability of normal rats to monitor the serial order of sequences of spatial stimuli (locations). The normal rodent brain can code accurately the order of directional left-to-right or right-to-left sequences of locations. However, the serial order of nondirectional randomly varying sequences can be processed only to a limited extent: when performance relies considerably on the salient memory of the most recent stimulus to code an approximate order of the earlier stimuli within working memory. Thus, the development of the granular prefrontal cortex in the primate brain provides an additional higher level of executive control permitting precise coding of the order of stimuli in working memory that is essential to manipulate information to plan action.}, archive = {J_PNAS}, author = {Zlatkina, Veronika and Martakis, Katherine and Azizi, Houman and Petrides, Michael}, doi = {10.1073/pnas.2509426122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2509426122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolutionary consideration of serial order processing by the normal rodent brain}, volume = {122}, year = {2025}, }
• (2025). Multispecies sensory networks and social foraging strategies: Implications for population decline in procellariiform seabirds. PNAS, 122(41), e2509317122. (www)

  @article{ , abstract = {Multispecies sensory networks, where different species prioritize different sensory modalities and then use heterospecific information in a likely noncooperative fashion, may allow animals to improve foraging over large areas for cryptic prey. We test this hypothesis in procellariiform seabirds that forage in mixed flocks, where both prey odors and visual cues provided by other foraging hetero- and conspecifics might improve success rates. Using agent-based models, we explored the impact of social strategies on olfactory foraging for Antarctic krill ( Euphausia superba ). Our results suggest that social foraging enables species with different sensory adaptations to achieve similar success rates. Additionally, our results indicate that foraging is more successful in mixed-species rather than single-species flocks, where individuals can monitor the activity of other birds that are using different sensory foraging strategies than themselves to find prey. These results suggest that sensory-based foraging networks may be more critical to their survival than previously assumed. Finally, we show that success rates decrease at low population densities. As seabird populations continue to decline, understanding and preserving these social foraging networks may be essential for their conservation and ecological success. Overall, our study provides insights into the critical role of multispecies sensory networks to foraging success, wherein different species have different sensory adaptations for locating prey. While we used empirical anatomical and behavioral data specific to procellariiforms to inform our models, our approach and results may have broader implications for other species as well.}, archive = {J_PNAS}, author = {Granger, Jesse and Nevitt, Gabrielle and Johnsen, Sönke}, doi = {10.1073/pnas.2509317122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2509317122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multispecies sensory networks and social foraging strategies: Implications for population decline in procellariiform seabirds}, volume = {122}, year = {2025}, }
• (2025). STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy. PNAS, 122(41), e2508809122. (www)

  @article{ , abstract = {The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the alternate pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet rapid mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process have remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.}, archive = {J_PNAS}, author = {Koganti, Prasanthi P. and Zhao, Amy H. and Kern, Michael C. and Fassinou, Auriole C. R. and Selvaraj, Vimal}, doi = {10.1073/pnas.2508809122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2508809122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy}, volume = {122}, year = {2025}, }
• (2025). Disorder-driven non-anderson transition in a weyl semimetal. PNAS, 122(41), e2508569122. (www)

  @article{ , abstract = {For several decades, it was widely believed that a noninteracting disordered electronic system could only undergo an Anderson metal–insulator transition due to Anderson localization. However, numerous recent theoretical works have predicted the existence of a disorder-driven non-Anderson phase transition that differs from Anderson localization. The frustration lies in the fact that this non-Anderson disorder-driven transition has not yet been experimentally demonstrated in any system. Here, using angle-resolved photoemission spectroscopy, we present a case study of observing the non-Anderson disorder-driven transition by visualizing the electronic structure of the Weyl semimetal NdAlSi on surfaces with varying amounts of disorder. Our observations reveal that strong disorder can effectively suppress all surface states in the Weyl semimetal NdAlSi, including the topological surface Fermi arcs. This disappearance of surface Fermi arcs is associated with the vanishing of the topological invariant, indicating a quantum phase transition from a Weyl semimetal to a diffusive metal. These observations provide direct experimental evidence of the non-Anderson disorder-driven transition occurring in real quantum systems, a finding long anticipated by theoretical physicists.}, archive = {J_PNAS}, author = {Li, Cong and Wang, Yang and Zhang, Jianfeng and Liu, Hongxiong and Chen, Wanyu and Liu, Guowei and Deng, Hanbin and Kim, Timur K. and Polley, Craig and Thiagarajan, Balasubramanian and Yin, Jiaxin and Shi, Youguo and Xiang, Tao and Tjernberg, Oscar}, doi = {10.1073/pnas.2508569122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2508569122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Disorder-driven non-anderson transition in a weyl semimetal}, volume = {122}, year = {2025}, }
• (2025). When noncanonical olfaction is optimal. PNAS, 122(41), e2508439122. (www)

  @article{ , abstract = {The early olfactory system is canonically described by a “one-receptor-to-one-neuron” model: each olfactory sensory neuron (OSN) expresses a single type of olfactory receptor (OR). Although the olfactory systems of many model organisms approximately follow this canonical organization, a number of exceptions are known. In particular, Aedes aegypti mosquitoes coexpress multiple types of ORs in many OSNs. Why do some olfactory systems follow the canonical organization while others violate it? We approach this question from the normative perspective of efficient coding. We find that the canonical and noncanonical organizations optimally encode odor signals in different types of olfactory environment. Noncanonical olfaction is beneficial when relevant sources emit correlated odorants and the environment contains odorants from ethologically irrelevant odor sources. Our theory explains previous observations of receptor coexpression and provides a framework from which to understand the structure of early olfactory systems.}, archive = {J_PNAS}, author = {Lienkaemper, Caitlin and Younger, Meg A. and Ocker, Gabriel Koch}, doi = {10.1073/pnas.2508439122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2508439122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {When noncanonical olfaction is optimal}, volume = {122}, year = {2025}, }
• (2025). Unexpected heterogeneity and tissue-specific properties of the thymic hematopoietic antigen–presenting cell network. PNAS, 122(41), e2508184122. (www)

  @article{ , abstract = {Thymic hematopoietic antigen–presenting cells (hAPCs) play critical roles in regulating T cell development, but the identity, diversity, and transcriptional regulation of these cells are poorly understood. To address this, we characterized mouse thymic hAPCs in an unbiased manner utilizing physical interactions. Transcriptional profiling revealed the presence of CD8α + cDC1, SIRPα + cDC2, mature dendritic cells (DC), plasmacytoid DCs, macrophage, and B cell lineages in both mouse and human thymus. Notably, the composition and activation profile of DCs was altered in autoimmune mouse strains. Further, we found that the SIRPα + DCs are in fact a heterogeneous population consisting of DC3, transitional DCs, and true DC2s, all of which express a thymus-specific signature. Surprisingly, the differentiation of these thymic DC2s does not depend on IRF4. Finally, we described a thymic hematopoietic autoimmune regulator-expressing APC population resembling Janus cells that appear to express peripheral tissue antigens. Our findings thus reveal complexity of the thymic hAPC network.}, archive = {J_PNAS}, author = {Wang, Yi and Liu, Xin and Bond, Amelie C. and Oh, Seungyoul and Ochiai, Sotaro and Larson, Abbie R. and Qualls, Anita E. and Sun, Im Hong and Chopin, Michaël and Gardner, James M. and Nutt, Stephen L. and Ronchese, Franca and Pellicci, Daniel G. and Chong, Mark M. W.}, doi = {10.1073/pnas.2508184122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2508184122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unexpected heterogeneity and tissue-specific properties of the thymic hematopoietic antigen–presenting cell network}, volume = {122}, year = {2025}, }
• (2025). The intestinal environment potentiates bacteriophage adaptation in response to phenotypic resistance in salmonella typhimurium. PNAS, 122(41), e2507909122. (www)

  @article{ , abstract = {Heterogeneous gene expression enables the coexistence of virulent phages with populations of isogenic bacteria comprising both phenotypically phage-resistant and susceptible cells. However, the evolvability of phages and the fitness cost they impose on susceptible bacteria challenge the evolutionary stability of the coexistence. Understanding this dynamic is critical for predicting phage–bacteria coevolution with implications for phage therapy, where resistance hinders treatment success. To address this point, we built on the discovery that heterogeneously expressed alterations of the O-antigen (phase variation) enable phenotypic resistance in Salmonella Typhimurium ( S .Tm) against the T5-like phage 37 (Φ37). We observed that phase variation allowed prolonged phage–bacteria coexistence in liquid medium. In contrast, phase variation only delayed the fixation of genetically phage-resistant S .Tm mutants when the phage–bacteria interaction took place in the gut of infected mice. The emergence of evolved phages capable of infecting both phenotypically susceptible and resistant phase variants of wild-type S .Tm selected for genetically resistant S .Tm mutants. Experimental in vitro evolution in a viscous medium recapitulated the short-lived coexistence of phages with susceptible S .Tm observed in the gut. This demonstrates that conditions in the gut increase the evolvability of phages by potentiating the effect of mutations that increase the phage host range, thereby negating the protection conferred by phase variation.}, archive = {J_PNAS}, author = {Wenner, Nicolas and Bertola, Anouk and Larsson, Louise and Rocker, Andrea and Amare Bekele, Nahimi and Sauerbeck, Chris and Lemos Rocha, Leonardo F. and Druelle, Valentin and Molari, Marco and Harms, Alexander and Diard, Médéric}, doi = {10.1073/pnas.2507909122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2507909122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The intestinal environment potentiates bacteriophage adaptation in response to phenotypic resistance in salmonella typhimurium}, volume = {122}, year = {2025}, }
• (2025). Collagen-disrupting attIL12 TIL therapy boosts deep t cell infiltration via dual signaling activation and CCKAR reduction in sarcomas. PNAS, 122(41), e2507542122. (www)

  @article{ , abstract = {Tumor-targeted T cell therapies of various types have been booming, but T cell therapy is limited by its inability to penetrate the collagen barrier surrounding tumors. The destruction of tumor collagen is significant because collagen both suppresses T cells and contributes to the formation of the extracellular matrix. Our previously reported cell-surface vimentin (CSV)–targeted and membrane-anchored interleukin 12-armed (attIL12) T cells can reduce collagen production by killing cancer-associated fibroblasts, but fail to reduce collagen expression by tumor cells, resulting in resistance to attIL12-T cell treatment. In this study, we found that CCKAR directly boosts collagen production by tumor cells in vitro and in vivo. attIL12-modified tumor-infiltrating lymphocytes (TILs) disabled collagen production by CCKAR-high autologous tumor cells in vitro and sarcoma patient-derived xenografts (PDXs) in vivo. This disruption of collagen production by tumor cells by attIL12-TILs overcomes resistance to attIL12-T cell treatment and required a simultaneous interaction between the CSV on autologous tumor cells, which is targeted by attIL12, and human leukocyte antigen-T cell receptor on attIL12-TILs; When either interaction was abrogated, collagen production and CCKAR expression were not shut down. Mechanistically, the interaction between attIL12-TILs and autologous tumor cells induced interferon gamma production synergistically, which in combination with CCKAR downregulation reduced collagen expression through suppression of both transforminggrowth factor beta-stimulated SMAD activation and CCKAR-AKT signaling. Diminishing collagen expression from tumor cells significantly increased T cell infiltration and improved tumor growth inhibition in PDX sarcomas. Thus, this attIL12-TIL therapy holds great clinical potential for boosting T cell infiltration in high-grade, collagen-rich tumors.}, archive = {J_PNAS}, author = {Hu, Jiemiao and Singh, Harjeet and Jin, Yining and Zhang, Wendong and Wang, Jian and Xia, Xueqing and Somaiah, Neeta and Gorlick, Richard and Li, Shulin}, doi = {10.1073/pnas.2507542122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2507542122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Collagen-disrupting attIL12 TIL therapy boosts deep t cell infiltration via dual signaling activation and CCKAR reduction in sarcomas}, volume = {122}, year = {2025}, }
• (2025). Deciphering the determinants of recombinant protein expression across the human secretome. PNAS, 122(41), e2506036122. (www)

  @article{ , abstract = {Protein secretion is an essential process of mammalian cells. In biomanufacturing, this process can be optimized to enhance production yields and biotherapeutic quality. While cell line engineering and bioprocess optimization have yielded high protein titers for some recombinant proteins, many remain difficult to express. Here, we investigated factors influencing protein expression in Chinese hamster ovary (CHO) cells, expressing 2,135 Human Secretome Project proteins. While the abundance of mRNA from recombinant proteins explained less than 1% of observed variation in secretion titers, analysis of 218 biochemical and biophysical descriptors uncovered intrinsic protein features that account for ~15% of secretion variability, pinpointing key drivers such as molecular weight, cysteine content, and N-linked glycosylation, and establishing a roadmap for rational design of difficult-to-express proteins. We subsequently analyzed RNA-Seq data from 95 CHO cell cultures, each expressing a distinct recombinant protein, spanning a wide range of titers. Host cell transcriptomic signatures showed strong correlations with titer, thereby providing insights into cellular processes that covary with expression. Cells failing to produce proteins exhibited increased ubiquitin-mediated proteasomal degradation, including ER-associated degradation; whereas high-producing cells demonstrated enhanced lipid metabolism and a stronger response to oxidative stress, suggesting these factors may support successful recombinant protein productions. Together, using this resource, we quantified the contributions of various protein and cellular factors that correlate with the expression of diverse recombinant human proteins in a heterologous host, thereby providing insights for next-generation CHO cell engineering.}, archive = {J_PNAS}, author = {Masson, Helen O. and Di Giusto, Pablo and Kuo, Chih-Chung and Malm, Magdalena and Lundqvist, Magnus and Sievertsson, Åsa and Berling, Anna and Tegel, Hanna and Hober, Sophia and Uhlen, Mathias and Grassi, Luigi and Robasky, Kimberly and Hsieh, Chen-Lin and Hatton, Diane and Rockberg, Johan and Lewis, Nathan E.}, doi = {10.1073/pnas.2506036122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2506036122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deciphering the determinants of recombinant protein expression across the human secretome}, volume = {122}, year = {2025}, }
• (2025). Augmenting rice ANNEXIN expression to counter planthopper NlAnnexin-like5 as an antivirulence strategy against a major crop pest. PNAS, 122(41), e2505698122. (www)

  @article{ , abstract = {The brown planthopper (BPH) is the most devastating insect pest in rice, posing a serious threat to global rice production. One attractive control strategy would be based on the understanding of the virulence mechanisms of BPH at the molecular level and then designing targeted methods to neutralize such mechanisms. Salivary proteins of BPH are important players in mediating rice–BPH interactions. Here, we describe a pivotal role of a watery saliva protein, Nilaparvata lugens Annexin-like5 ( Nl ANX5), in the rice–BPH interaction. RNA interference (RNAi) of NlANX5 greatly compromised BPH feeding performance and survival rate on rice plants. NlANX5 -RNAi BPH triggered a rapid calcium ion influx in rice cells. The feeding and survival defects of NlANX5 -RNAi BPH can be restored in NlANX5 -expressing transgenic rice plants. Nl ANX5 targets rice annexin ( Os ANN) proteins, including Os ANN2 and Os ANN8. Further analysis with Nl ANX5 and Os ANN2 as well as Os ANN8 showed that Nl ANX5 displaces Os ANN2 and Os ANN8 from the rice cell membrane. The osann2 osann8 mutant rice plants are hypersusceptible to BPH infestation. In contrast, enhanced expression of OsANN2 and OsANN8 genes resulted in robust rice resistance against BPH. This study highlights a successful example of identifying and augmenting the expression of the host targets of a major BPH virulence effector as a promising antivirulence strategy against an important crop pest.}, archive = {J_PNAS}, author = {Zhang, Xiao-Ya and Li, Shaoqin and Opachaloemphan, Comzit and Zhang, Chuan-Xi and He, Sheng Yang and Jiang, Yanjuan}, doi = {10.1073/pnas.2505698122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2505698122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Augmenting rice ANNEXIN expression to counter planthopper NlAnnexin-like5 as an antivirulence strategy against a major crop pest}, volume = {122}, year = {2025}, }
• (2025). Gene age shapes functional and evolutionary properties of the drosophila seminal fluid proteome. PNAS, 122(41), e2505490122. (www)

  @article{ , abstract = {Seminal fluid proteins (Sfps) are crucial for animal reproductive success, with Sfp-encoding genes believed to be evolutionarily young due to heightened rates of gene loss and gain and rapidly evolving at the sequence level relative to other genes. Using estimates of the phylogenetic origin of each Drosophila melanogaster Sfp gene, based on genomic resources that include outgroup species to the Drosophila genus, we examined the functional attributes and evolutionary characteristics of 357 Sfp genes relative to their evolutionary age. Contrary to the perception that many Sfp genes are evolutionarily young, 62% existed in the genome of the ancestor to this genus. These ancient genes have broader expression profiles, more expansive biological roles, and have more interactions with non-Sfp genes. This increased pleiotropy has imposed constraints on the rate of sequence evolution in ancient Sfp genes compared to younger ones. Notably, these younger Sfp genes evolve substantially faster as a result of both adaptive and nonadaptive evolutionary forces. Within the Sfp interactome, we identified a fast-evolving core subnetwork of younger genes with more restricted tissue expression and functions. Our systematic approach has uncovered a large set of ancient Sfp genes with distinct genomic, functional, and evolutionary characteristics compared to the younger, more commonly studied Sfp genes. With increased refined genomic and functional data acquisition across a wider variety of taxa, our approach and results serve as proof of the importance of systemic strategies applied to broadly defined gene sets based on their time of evolutionary origination.}, archive = {J_PNAS}, author = {Ranz, Jose M. and Flacchi, Carolina and Hariyani, Imtiyaz E. and Civetta, Alberto}, doi = {10.1073/pnas.2505490122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2505490122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Gene age shapes functional and evolutionary properties of the drosophila seminal fluid proteome}, volume = {122}, year = {2025}, }
• (2025). Distinct and convergent effects of SF3B1 mutations in human breast cancer. PNAS, 122(41), e2505374122. (www)

  @article{ , abstract = {Tumor genomic profiling has uncovered many cancer drivers whose implications in terms of tumor biology and therapeutic actionability remain understudied. Hotspot mutations in SF3B1 induce widespread transcriptomic alterations and occur across multiple cancer types. Despite this, the biological and clinical consequences of SF3B1 mutations remain elusive. Characterization of the largest SF3B1 mutant breast cancer clinical cohort to date identifies SF3B1 driver mutations in approximately 2.5% of HR+ HER2- breast cancer, with strong enrichment of K700E substitutions, substantial variation in variant allele fraction (VAF), and significantly improved overall survival due to enrichment in Luminal A disease. In vitro and in vivo studies in representative cell models suggest several of the most prevalent SF3B1 mutations have deleterious effects on cell growth, leading to selective loss of the mutation over time, providing a rationale for the low frequency and low VAF of SF3B1 mutations in breast cancer. Though all introduced hotspot mutations limit growth and are reverted to wildtype (WT) over time, mutations at position R625 have a more pronounced phenotype than K700E, providing an explanation for the clinically observed skew in mutation frequencies. RNA and DNA sequencing analyses were used to identify characteristic pathway-level transcriptomic changes in SF3B1 -mutant cells and identify copy number alterations as a mechanism of both improved mutation tolerability and a means to eliminate the mutation over time. These data suggest that while SF3B1 mutations are enriched in some clinical contexts, their role in breast tumorigenesis is highly complex and dependent on secondary events that overcome their deleterious effects on cell growth and survival.}, archive = {J_PNAS}, author = {Bergman, Riley E. and Keeton, Christin I. and Sinha, Irika R. and Ling, Jonathan P. and Wang, Yu and Ha, Lauren and Mehta, Eshani P. and Reed, Sarah C. and Fox, Ethan K. and O’Grady, Tina M. and Yu, Yingying and Fragkogianni, Stamatina and Chao, Calvin and Davidson, Brad A. and Miranda, Adam X. and Croessmann, Sarah and Zhao, Shilin and Liu, Qi and Shyr, Yu and Dalton, W. Brian and Hurley, Paula J. and Park, Ben H.}, doi = {10.1073/pnas.2505374122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2505374122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Distinct and convergent effects of SF3B1 mutations in human breast cancer}, volume = {122}, year = {2025}, }
• (2025). Microtubule remodeling by the innate immune factor trim69 compromises dynein-dependent migration of HIV virion cores toward the nucleus. PNAS, 122(41), e2505128122. (www)

  @article{ , abstract = {Like many viruses, HIV relies on the microtubule (MT) cytoskeleton for successful infection. MT-associated proteins (MAPs) regulate MT functions and thus bear the potential to modulate viral infection. However, while several MAPs are known to exert proviral effects on HIV, little is known about antiviral ones. We previously described the Tripartite motif protein 69 (Trim69) as an innate immune factor that remodels MTs, leading to inhibition of a broad spectrum of viruses, including HIV. Through in silico modeling, TIRF microscopy, and cell-based assays, we determine that Trim69 binding to MTs is determined by a basic surface in its SPRY domain that interacts with the C-terminal tails of tubulins. This surface is conserved among mammalian Trim69s and is critical for its functions. We demonstrate that by binding and remodeling MTs, Trim69 inhibits the docking and the migration of virion cores on MTs by promoting the stalling of the dynein/dynactin motor complexes. Altogether, these findings shed light on a mechanism of viral defense that involves an innate immune regulation of the MT cytoskeleton.}, archive = {J_PNAS}, author = {Vadon, Charlotte and Nguyen, Xuan-Nhi and Siahaan, Valerie and Song, Yuxin and Krishnan, Arya and Henriot, Veronique and Chantharath, Amandine and Burlaud-Gaillard, Julien and Roingeard, Philippe and Janke, Carsten and Etienne, Lucie and Fiorini, Francesca and Magiera, Maria M. and Cimarelli, Andrea}, doi = {10.1073/pnas.2505128122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2505128122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Microtubule remodeling by the innate immune factor trim69 compromises dynein-dependent migration of HIV virion cores toward the nucleus}, volume = {122}, year = {2025}, }
• (2025). Total cancer risk estimates from measured concentrations of volatile organic compounds in industrialized southeastern louisiana. PNAS, 122(41), e2504770122. (www)

  @article{ , abstract = {Communities in southeastern Louisiana are subject to disproportionate environmental health burdens, including elevated risk for cancer, from emissions of industrial hazardous air pollutants (HAPs). However, there are few ambient measurements (or none) of various HAPs in the heavily industrialized corridor between Baton Rouge and New Orleans (BR-NO). We measured 17 carcinogenic volatile organic compounds using fast-response in situ instrumentation aboard a mobile laboratory. Using spatially resolved concentrations, we estimate cancer risk in 15 census tracts along an 81 km-long stretch of the BR-NO corridor. In 14 of 15 tracts, our estimates of total cancer risk were higher (range: 0.9 to 11.6 × ; median: 5 × ) than those from the U.S. Environmental Protection Agency’s (USEPA) 2020 Air Toxics Screening Assessment (AirToxScreen). Our maximum estimate for total tract-level cancer risk was 560-in-one million excess cancer cases, far exceeding the upper limit of USEPA’s acceptable risk range (100-in-one million). This discrepancy is largely explained by differences between measured vs. modeled ethylene oxide concentrations, though there are important contributions from a number of additional HAPs. Our risk estimates are dominated by ethylene oxide, which contributes between 39.5 and 92.2% of total cancer risk across all tracts; chloroprene (0.2 to 36.8%); and formaldehyde (4.1 to 14.6%). AirToxScreen also identifies these three compounds as primary drivers of risk in this location. Together, these three compounds account for between 63 and 96.9% of total cancer risk. There is substantial spatial variability in total cancer risk and the relative contribution of each HAP, both between and within tracts. These data substantiate claims that the region has high HAPs-related cancer risk and quantify which individual HAPs are of highest concern.}, archive = {J_PNAS}, author = {Robinson, Ellis S. and Yassine, Amira and Agarwal, Shivang and Tehrani, Mina W. and Lupolt, Sara N. and Chiger, Andrea A. and Gigot, Carolyn and Claflin, Megan S. and Lerner, Brian M. and Yacovitch, Tara I. and Roscioli, Joseph R. and Herndon, Scott C. and Avery, Anita M. and Daube, Conner and Lunny, Elizabeth M. and Fortner, Edward C. and Werden, Benjamin S. and Burke, Thomas A. and Rule, Ana M. and Koehler, Kirsten and Nachman, Keeve E. and DeCarlo, Peter F.}, doi = {10.1073/pnas.2504770122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2504770122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Total cancer risk estimates from measured concentrations of volatile organic compounds in industrialized southeastern louisiana}, volume = {122}, year = {2025}, }
• (2025). A molecular probe for detecting cholinesterase activity in MRI. PNAS, 122(41), e2504547122. (www)

  @article{ , abstract = {Cholinesterase (ChE) enzymes terminate action of the neurotransmitter acetylcholine at synapses and neuromuscular junctions throughout the body. Noninvasive strategies for monitoring these enzymes could be important for studying basic biology of cholinergic systems and disorders that affect their function. To address this goal, we developed an imaging probe that allows activity of ChE to be detected using MRI. The probe, called ChERT, undergoes enzymatic processing that reduces its solubility, promoting accumulation near sites of cholinesterase activity. Following wide-field brain delivery, ChERT produces MRI contrast changes in brain regions known to be enriched in cholinesterases; these are suppressed in the presence of a selective enzymatic inhibitor, confirming their specificity. After abdominal delivery, ChERT labels regions of the gut where ChE expression is expected. In both the brain and periphery, colocalization of ChERT with ChE could be confirmed and visualized at higher resolution by fluorescence microscopy, owing to optical properties of the probe architecture. The ChERT agent thus provides a potentially versatile basis for assessment of cholinergic phenotypes throughout the body.}, archive = {J_PNAS}, author = {Sen, Sajal and Dawson, Miranda and Thiabaud, Gregory D. and Backman, Kyle and Fayer, Itay and Das, Sayani and Whitmire, Eliza and Kung, Catherine and Barandov, Ali and Jasanoff, Alan}, doi = {10.1073/pnas.2504547122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2504547122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A molecular probe for detecting cholinesterase activity in MRI}, volume = {122}, year = {2025}, }
• (2025). Causes and consequences of disordered hyperuniformity in global drylands. PNAS, 122(41), e2504496122. (www)

  @article{ , abstract = {Self-organization of individual organisms at a very small scale may result in recognizable functional ecosystem structures at a larger spatial scale. Drylands, which cover almost half of emerged lands, host some of the most remarkable vegetation patterns on Earth, including “disordered hyperuniformity,” a recently defined class of such emergent self-organization structures. Yet, the extent, causes, and consequences of disordered hyperuniform vegetation patterns in drylands remain virtually unknown. Here, we analyzed high-resolution remote sensing images of 425 spot-like drylands across the globe and found that disordered hyperuniformity shapes vegetation patterns in about one out of ten drylands, with the distribution of plants appearing to be “disordered” to the naked eye, but supporting highly recognizable (uniform) patterns at larger scales ( ca. 50 to 500 m). Using mathematical models, we identify three potential mechanisms that can generate disordered hyperuniform vegetation patterns. These mechanisms are not limited to the well-studied Turing patterns and represent key general processes with respect to plant–plant or plant–sediment interactions. Further modeling indicates that disordered hyperuniformity enhances ecosystem functioning in terms of water retention use, and expands the range of aridity conditions under which the system can maintain itself, but may slow recovery of vegetation structure from disturbances. In a wider context, we also show that disordered hyperuniformity is likely to pertain to diverse dryland systems, such as termite-mound or fairy-circle landscapes. Our findings highlight that exploring disordered hyperuniformity of vegetation pattern of drylands (and potentially other large-scale systems) offers insights into the organization and resilience of ecosystems globally.}, archive = {J_PNAS}, author = {Hu, Wensi and Cui, Lijuan and Delgado-Baquerizo, Manuel and Solé, Ricard and Kéfi, Sonia and Berdugo, Miguel and Xu, Nuo and Wang, Bo and Liu, Quan-Xing and Xu, Chi}, doi = {10.1073/pnas.2504496122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2504496122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Causes and consequences of disordered hyperuniformity in global drylands}, volume = {122}, year = {2025}, }
• (2025). Biologically grounded neocortex computational primitives implemented on neuromorphic hardware improve vision transformer performance. PNAS, 122(41), e2504164122. (www)

  @article{ , abstract = {Understanding the computational principles of the brain and translating them into neuromorphic hardware and modern deep learning architectures is critical for advancing neuro-inspired AI (NeuroAI). Here, we develop an experimentally constrained, biophysically realistic model of neocortical microcircuits in the mouse primary visual cortex (layers 2 to 3) to examine how four major interneuron classes—Parvalbumin, Somatostatin, vasoactive intestinal peptide, and LAMP5—interact within a competitive–cooperative motif to implement soft winner-take-all (sWTA) circuit dynamics. In a conductance-based network grounded in in vitro physiology, we show that this circuit motif selectively amplifies strong inputs while suppressing, without silencing, weaker ones, enabling gain modulation, signal restoration, and context-dependent multistability. Using a gain-matching strategy, we mapped the motif onto IBM’s TrueNorth neuromorphic chip, revealing a principled correspondence between cell-type-specific roles and hardware primitives. Sparse coupling of sWTA modules generated persistent up-states and a two-state neural machine approximating working memory. We then embedded the sWTA circuit as a preprocessing filter in a Vision Transformer, which significantly enhanced out-of-distribution generalization across diverse tasks, including zero-shot digit classification, cross-domain transfer between digit datasets, and nighttime semantic segmentation. The sWTA filter boosted accuracy on unseen data by up to ~20% and reduced training compute by directing learning toward salient features, without additional data or architectural changes. By unifying biophysically grounded circuit models, neuromorphic implementation, and state-of-the-art AI architectures, this work outlines a generalizable roadmap for embedding cortical computation into next-generation NeuroAI systems that combine biological principles with practical AI performance gains.}, archive = {J_PNAS}, author = {Iqbal, Asim and Mahmood, Hassan and Stuart, Greg J. and Fishell, Gord and Honnuraiah, Suraj}, doi = {10.1073/pnas.2504164122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2504164122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biologically grounded neocortex computational primitives implemented on neuromorphic hardware improve vision transformer performance}, volume = {122}, year = {2025}, }
• (2025). GeoEvoBuilder: A deep learning framework for efficient functional and thermostable protein design. PNAS, 122(41), e2504117122. (www)

  @article{ , abstract = {While deep learning has advanced protein sequence and function design, engineering highly active and stable proteins still requires labor-intensive iterative computational design and experimentation. There is a critical need for methods capable of directly generating protein sequences with the required properties. Here, we present GeoEvoBuilder, an advanced deep learning framework that adaptively integrates structural and evolutionary constraints for protein sequence design. GeoEvoBuilder accurately recapitulates functional sites and generates sequences that fold correctly with enhanced activity and thermal stability. GeoEvoBuilder has been applied to redesign green fluorescent protein, glutathione peroxidase 4 (GPX4), and dihydrofolate reductase (DHFR), yielding variants with significantly improved thermal stability and activity. Notably, the top DHFR design demonstrated a 20-fold increase in catalytic efficiency and a 10 °C gain in thermal stability. Crystal structure determination confirmed that the designed proteins form correct structures. Further analysis of residue dynamic correlations in GPX4 variants provides insights into how remote sites regulate enzymatic activity. Unlike conventional methods that focus on single mutation and their combinations with iterative design and experiment cycles, GeoEvoBuilder explores a large sequence space that enables successful designs with over 30% residue changes in one run. GeoEvoBuilder not only provides a transformative tool for protein engineering but also can be applied to uncover the intricate relationships between protein sequence, structure, function, and evolution. GeoEvoBuilder is publicly available at https://github.com/PKUliujl/GeoEvoBuilder .}, archive = {J_PNAS}, author = {Liu, Jiale and You, Hantian and Guo, Zheng and Xu, Qin and Zhang, Changsheng and Lai, Luhua}, doi = {10.1073/pnas.2504117122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2504117122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {GeoEvoBuilder: A deep learning framework for efficient functional and thermostable protein design}, volume = {122}, year = {2025}, }
• (2025). Mineral dissolution by dimeric complexes. PNAS, 122(41), e2504109122. (www)

  @article{ , abstract = {Mineral dissolution is typically thought to occur by the detachment of monomeric building blocks of the crystal structure, although direct evidence is rare. Using in situ high-speed atomic force microscopy to examine step-edge retreat dynamics at high resolution, we report that the dissolution of gibbsite in alkaline solutions occurs mainly by the release of aluminate dimers, which subsequently dissociate into the monomeric species that dominate the solution. The observed dissolution anisotropy is readily explained by this mechanism, which was further supported by density functional tight-binding simulations of detachment activation energies. Recognition that such polynuclear dissolution mechanisms exist may enable an improved understanding of processes regulating mineral dissolution rates in nature and industry.}, archive = {J_PNAS}, author = {Li, Xiaoxu and Guo, Qing and Zhao, Yatong and Qian, Chang and Pouvreau, Maxime and Graham, Trent R. and Chen, Ping and Liu, Lili and Liu, Chang and Legg, Benjamin A. and Chen, Qian and Miao, Aijun and Wang, Zheming and De Yoreo, James J. and Pearce, Carolyn I. and Clark, Aurora E. and Rosso, Kevin M. and Zhang, Xin}, doi = {10.1073/pnas.2504109122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2504109122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mineral dissolution by dimeric complexes}, volume = {122}, year = {2025}, }
• (2025). Spatial self-organization of confined bacterial suspensions. PNAS, 122(41), e2503983122. (www)

  @article{ , abstract = {Lab studies of bacteria usually focus on cells in spatially extended, nutrient-replete settings, such as in liquid cultures and on agar surfaces. By contrast, many biological and environmental settings—ranging from mucus in the body to ocean sediments and the soil beneath our feet—feature multicellular bacterial populations that are confined to tight spots where essential metabolic substrates (e.g., oxygen) are scarce. What influence does such confinement have on a bacterial population? Here, we address this question by studying suspensions of motile Escherichia coli confined to quasi two-dimensional (2D) droplets. We find that when the droplet size and cell concentration are both large enough, the initially uniform suspension spatially self-organizes into a concentrated, immotile inner “core” that coexists with a more dilute, highly motile surrounding “shell.” By simultaneously measuring cell concentration, oxygen concentration, and motility-generated fluid flow, we show that this behavior arises from the interplay between oxygen transport through the droplet from its boundary, uptake by the cells, and corresponding changes in their motility in response to oxygen variations. Furthermore, we use biophysical theory and simulations to quantitatively describe this interplay. Our work thus sheds light on the rich collective behaviors that emerge for bacterial populations in confined environments, with implications for understanding ecological niches and engineering artificial systems.}, archive = {J_PNAS}, author = {Hokmabad, Babak Vajdi and Martínez-Calvo, Alejandro and Gonzalez La Corte, Sebastian and Datta, Sujit S.}, doi = {10.1073/pnas.2503983122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2503983122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatial self-organization of confined bacterial suspensions}, volume = {122}, year = {2025}, }
• (2025). Inter- and intrahemispheric sources of vestibular signals to v1. PNAS, 122(41), e2503181122. (www)

  @article{ , abstract = {Head movements are sensed by the vestibular organs. Unlike classical senses, signals from vestibular organs are not selectively conveyed to a dedicated cortical area but are broadcast throughout the cortex. This distributed processing pattern reflects the fundamental role of vestibular information in contextual modulation across diverse cortical computations. Surprisingly, the routes taken by vestibular signals to reach the cortex are still largely uncharted. Here, we show that the primary visual cortex (V1) receives real-time head movement signals—direction, velocity, and acceleration—from the ipsilateral pulvinar and contralateral visual cortex (VC). The ipsilateral pulvinar provides the main head movement signal, with a bias toward contraversive movements (e.g., clockwise movements in left V1). Conversely, the contralateral VC provides head movement signals during ipsiversive movements. Crucially, head movement variables encoded in V1 are already encoded in the pulvinar, suggesting that those variables are computed subcortically. Thus, the convergence of inter- and intrahemispheric signals endows V1 with a rich representation of the animal’s head movements.}, archive = {J_PNAS}, author = {Bouvier, Guy and Sanzeni, Alessandro and Hamada, Elizabeth and Brunel, Nicolas and Scanziani, Massimo}, doi = {10.1073/pnas.2503181122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2503181122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inter- and intrahemispheric sources of vestibular signals to v1}, volume = {122}, year = {2025}, }
• (2025). Design principles of the common gly-x6-gly membrane protein building block. PNAS, 122(41), e2503134122. (www)

  @article{ , abstract = {Protein behavior in lipids is poorly understood and inadequately represented in current computational models. Design and prediction abilities for bilayer-embedded molecular structures may be improved by characterizing membrane proteins’ most frequent, favored structural features to glean both context-specific and general principles. We used protein design to proactively interrogate the sequence–structure relationship and stabilizing atomic details of two highly prevalent antiparallel transmembrane (TM) motifs with Small-X 6 -Small consensus sequences. A fragment-based data-mining and sequence statistical inference method including cross-evolutionary structure-aligned covariance enabled engineering of de novo TM protein assemblies by successfully encoding Gly-X6-Gly and Ala-X6-Ala building blocks. A highly stable glycine-based design’s X-ray structure hosts Cα-H∙∙∙O = C H-bonding alongside extensive backbone-directed van der Waals packing, idealizing features of this motif in Nature. Data-driven design navigates sequence space to directly inquire upon how to encode and stabilize vital membrane protein structural elements, facilitating efficacious construction of lipid-embedded architectures of increasing complexity.}, archive = {J_PNAS}, author = {Golden, Kiana and Avarvarei, Catalina and Anderson, Charlie T. and Holcomb, Matthew and Tang, Weiyi and Dai, Xiaoping and Zhang, Minghao and Mailie, Colleen A. and Sanchez, Brittany B. and Chen, Jason S. and Forli, Stefano and Mravic, Marco}, doi = {10.1073/pnas.2503134122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2503134122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Design principles of the common gly-x6-gly membrane protein building block}, volume = {122}, year = {2025}, }
• (2025). Chemical characterization of c31 sterols from sponges and neoproterozoic fossil sterane counterparts. PNAS, 122(41), e2503009122. (www)

  @article{ , abstract = {Putative metazoan body fossils from the Precambrian are curiously lacking morphological characteristics that link them unambiguously to extant animal phyla, including sponges. Chemical fossils such as the rare C 30 hydrocarbons 24- iso -propylcholestane (24- i pc) and 26-methylstigmastane (26-mes), however, have been proposed as evidence for the Neoproterozoic emergence of the Demospongiae (Porifera) due to their prevalence in rocks of this age and the occurrence of their sterol precursors in contemporary demosponges. However, there are alternative hypotheses which posit that diagenetic alteration products of algal sterols, or those from Rhizaria or other protists, account for the enigmatic steroid distributions observed in these ancient sedimentary rocks. Here, we report additional support for the Neoproterozoic rise of demosponges through the chemical characterization of two previously unrecognized C 31 hydrocarbons—24- n -butylcholestane (24- n bc) and 24- sec -butylcholestane (24- sec bc). Precursor C 31 sterols from contemporary demosponges, as well as a suite of synthesized C 31 sterol standards were reduced to their sterane counterparts. Gas chromatography-tandem mass spectrometry analysis and collisionally activated dissociation mass spectra confirmed the presence of 24- n bc and 24- sec bc in well-preserved early Ediacaran rocks, and the coelution of these compounds with synthetic standards enhances the robustness of these findings. Co-occurrence of abundant 24- i pc and 24- sec bc was found for numerous Neoproterozoic-Cambrian rock/oil samples, closely mimicking the abundance patterns and high structural selectivity of major C 30 and C 31 sterols detected in numerous species of modern demosponges. These findings support the hypothesized first emergence of sponges during the Neoproterozoic Era.}, archive = {J_PNAS}, author = {Shawar, Lubna and Love, Gordon D. and Uveges, Benjamin T. and Zumberge, J. Alex and Cárdenas, Paco and Giner, José-Luis and Summons, Roger E.}, doi = {10.1073/pnas.2503009122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2503009122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chemical characterization of c31 sterols from sponges and neoproterozoic fossil sterane counterparts}, volume = {122}, year = {2025}, }
• (2025). Apparent learning biases emerge from optimal inference: Insights from master equation analysis. PNAS, 122(41), e2502761122. (www)

  @article{ , abstract = {Recent studies [S. Palminteri, G. Lefebvre, E. J. Kilford, S. J. Blakemore, PLoS Comput. Biol. 13 , e1005684 (2017); G. Lefebvre, M. Lebreton, F. Meyniel, S. Bourgeois-Gironde, S. Palminteri, Nat. Hum. Behav. 1 , 0067 (2017).] among others claim that human behavior in a two armed Bernoulli bandit task is described by positivity and confirmation bias, thereby implying [S. Palminteri, M. Lebreton, Trends Cogn. Sci. 26 , 607–621 (2022).] that “Humans do not integrate new information objectively.” The claim is based on fitting to human data a Q -learning model with different (and temporally constant) learning rates for positive and negative reward prediction errors. However, we find that even if the agent updates its belief via, arguably objective, Bayesian inference, fitting the above model demonstrates both the biases. This finding seems particularly surprising, as Bayesian inference, when written as an effective Q -learning algorithm, is described by unbiased (and temporally decreasing) learning rates. In this article, we explain the reasons behind this observation, by studying the stochastic dynamics of these learning systems using Master equations. In particular, we show that both confirmation bias and unbiased but temporally decreasing learning rates have the same behavioral signature: decreased action switching probabilities, as compared to temporally constant and unbiased learning rates. Our analysis underscores the need for modeling temporally varying learning rates in subjects before any claims can be made about their choices being biased.}, archive = {J_PNAS}, author = {Godara, Prakhar}, doi = {10.1073/pnas.2502761122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2502761122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Apparent learning biases emerge from optimal inference: Insights from master equation analysis}, volume = {122}, year = {2025}, }
• (2025). Regulation of an lncRNA irf8 by the Ikzf1/Myb complex drives neutrophil development. PNAS, 122(41), e2502741122. (www)

  @article{ , abstract = {As critical executors of the immune system, neutrophils provide an immediate inflammatory response for the clearance of debris and microbes, which is essential for the protection of health. Developmentally, neutrophils and macrophages share common progenitors, whose fate is tightly controlled by transcriptional programs. Dysregulation of these programs causes severe hematological disorders, including neutropenia, neutrophilia, leukemia, and inflammatory disorders. However, the mechanisms underlying the generation of neutrophils through these programs are poorly understood. Here, we revealed that Ikzf1 and Myb were enriched in neutrophils. Overactivation of Ikzf1 promoted neutrophil generation while suppressing macrophage emergence. Conversely, the simultaneous loss of Ikzf1 and Myb, but not the individual mutations, drastically impaired neutrophil production and enlarged the macrophage pool in both zebrafish and mice. Mechanistically, Ikzf1 and Myb formed a complex that targeted irf8 and induced the expression of a long noncoding RNA (lncRNA), irf8-2 , through a regulatory element. LncRNA irf8-2 biased neutrophil commitment by modulating irf8 dosage via Zfp36l1. The deletion of irf8-2 resulted in defective neutrophil development and enhanced macrophage production. However, a partial ratio of neutrophils and macrophages was restored when Ikzf1, Myb, and Irf8 were all compromised. Overall, our study reveals that Ikzf1 and Myb cooperatively bias neutrophil development against Irf8 via the lncRNA irf8 -2 and Zfp36l. This study provides previously uncharacterized insights into the conserved molecular balance between neutrophil and macrophage development during myelopoiesis, with potential implications for understanding and treating myeloid disorders.}, archive = {J_PNAS}, author = {He, Yuepeng and Li, Yang and Shao, Yibo and Huang, Xue and He, Jiangyong and Liu, Shengnan and Xiao, Yalan and Li, Zhigang and Hou, Yu and Luo, Lingfei and Zhao, Fangying and Li, Li}, doi = {10.1073/pnas.2502741122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2502741122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Regulation of an lncRNA irf8 by the Ikzf1/Myb complex drives neutrophil development}, volume = {122}, year = {2025}, }
• (2025). BTK autoinhibition analyzed by high-throughput swaps of SH2 domains. PNAS, 122(41), e2502688122. (www)

  @article{ , abstract = {Bruton’s Tyrosine Kinase (BTK), a Tec-family tyrosine kinase, resembles the Src and Abl kinases in that an SH2-SH3 module regulates the activity of the kinase domain, principally through an inhibitory interaction between the SH3 and kinase domains. In Src-family kinases, phosphorylation of a C-terminal tail latches the SH2 domain onto the kinase domain, stabilizing the inhibitory conformation of the SH3 domain; in Abl, interaction between the kinase domain and a myristoyl group on the N-terminal segment provides a similar latching function. The structure of autoinhibited BTK resembles that of the Src and Abl kinases, but BTK lacks an obvious SH2-kinase latch. To assess the role of the SH2 domain in autoinhibition of BTK, we generated hundreds of chimeric BTK molecules in which the native SH2 domain is replaced by other SH2 domains. We measured the fitness of these chimeric proteins using a high-throughput assay in T and B cells. Surprisingly, many SH2 domains increased fitness when substituted into BTK. Analysis of one set of chimeric proteins indicates that the increase in fitness stems from the ability of the substituted SH2 domains to disrupt BTK autoinhibition while maintaining phosphotyrosine targeting. Thus, although BTK lacks a specialized latch, distributed interactions between the SH2 and kinase domains stabilize the autoinhibitory conformation of BTK. While phosphotyrosine recognition can be conferred on BTK by evolutionarily distant SH2 domains, autoinhibition requires specific interactions with the kinase domain that arose through evolutionary refinement of the regulatory mechanism, and is less easily mimicked by heterologous SH2 domains.}, archive = {J_PNAS}, author = {Eisen, Timothy J. and Ghaffari-Kashani, Sam and Hung, Chien-Lun and Groves, Jay T. and Kuriyan, John}, doi = {10.1073/pnas.2502688122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2502688122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {BTK autoinhibition analyzed by high-throughput swaps of SH2 domains}, volume = {122}, year = {2025}, }
• (2025). Exceedingly low genetic diversity in snow leopards due to persistently small population size. PNAS, 122(41), e2502584122. (www)

  @article{ , abstract = {Snow leopards ( Panthera uncia ) serve as an umbrella species whose conservation benefits their high-elevation Asian habitat. Their numbers are believed to be in decline due to numerous anthropogenic threats; however, their conservation is hindered by numerous knowledge gaps. In particular, the dearth of genetic data, unique among all big cat species, hinders a full understanding of their population structure, historical population size, and current levels of genetic diversity. Here, we use whole-genome sequencing data for 41 snow leopards (37 newly sequenced) to offer insights into these unresolved aspects of snow leopard biology. Among our samples, we find evidence of a primary genetic divide between the northern and southern part of the range around the Dzungarian Basin—as previously identified using landscape models and fecal microsatellite markers—and a secondary divide south of Kyrgyzstan around the Taklamakan Desert. Most noteworthy, we find that snow leopards have the lowest genetic diversity of any big cat species, likely due to a persistently small population size throughout their evolutionary history rather than recent inbreeding. We also find that snow leopards have significantly less highly deleterious homozygous load compared to numerous Panthera species, suggesting effective purging during their evolutionary history at small population sizes. Without a large population size or ample standing genetic variation to help buffer them from any forthcoming anthropogenic challenges, snow leopard persistence may be more tenuous than currently appreciated.}, archive = {J_PNAS}, author = {Solari, Katherine A. and Morgan, Simon and Poyarkov, Andrey D. and Weckworth, Byron and Samelius, Gustaf and Sharma, Koustubh and Ostrowski, Stephane and Ramakrishnan, Uma and Kubanychbekov, Zairbek and Kachel, Shannon and Johansson, Örjan and Lkhagvajav, Purevjav and Hemmingmoore, Heather and Alexandrov, Dmitry Y. and Bayaraa, Munkhtsog and Grachev, Alexey and Korablev, Miroslav P. and Hernandez-Blanco, Jose A. and Munkhtsog, Bariushaa and Rosenbaum, Barry and Rozhnov, Viatcheslav V. and Madad Rajabi, Ali and Noori, Hafizullah and Suryawanshi, Kulbhushansingh R. and Armstrong, Ellie E. and Petrov, Dmitri A.}, doi = {10.1073/pnas.2502584122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2502584122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exceedingly low genetic diversity in snow leopards due to persistently small population size}, volume = {122}, year = {2025}, }
• (2025). Association of affirmative action with health and education outcomes and services in india. PNAS, 122(41), e2502290122. (www)

  @article{ , abstract = {Structural and social inequalities are determinants of poor human development outcomes in low- and middle-income countries. In a quasi-experimental, regression discontinuity design study, we examined associations of affirmative action in local governments for a historically marginalized group in India with health and education outcomes, using administrative health data, primary data in schools, and interviews. Exposure was 60 village clusters with, and nonexposure was 60 village clusters without, local leadership reserved for scheduled caste (SC) in 2021 local elections. Primary outcomes were infant mortality rate (IMR) and student test scores. Secondary outcomes were prenatal visits, mother tetanus vaccinations, prenatal supplement, infant vaccination, and teacher engagement in schools. Groups did not differ on socioeconomic, geographic, and service delivery indicators in 2020 (baseline). In 2023, 2.5 y after elections, exposure village clusters had lower IMR (0.46 IRR; [0.30 to 0.69]; P < 0.001), and exposure village clusters had significantly higher odds of two prenatal visits, two tetanus vaccinations, and prenatal supplement received by the second trimester. Exposure was not associated with maternal care in the first trimester or infant vaccination. Exposure was not associated with test scores, but teacher engagement was lower in exposure village clusters. Exposure group leaders reported higher discrimination than nonexposure group, and in follow-up interviews, they described more difficulty in working with teachers. Affirmative action in local governments in India predicted greater infant survival and improved prenatal health services, indicating benefits of addressing structural inequities. Lack of benefits for education outcomes might reflect social inequity of discrimination experienced by SC leaders.}, archive = {J_PNAS}, author = {Pandey, Priyanka and Sahadevan, K G and Hastings, Paul David}, doi = {10.1073/pnas.2502290122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2502290122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Association of affirmative action with health and education outcomes and services in india}, volume = {122}, year = {2025}, }
• (2025). Predicting the way forward for the global biodiversity framework. PNAS, 122(41), e2501695122. (www)

  @article{ , archive = {J_PNAS}, author = {Zurell, Damaris and Bocedi, Greta and Velazco, Santiago J. E. and Gonzalez, Andrew and Purvis, Andy and Wintle, Brendan and Merow, Cory and Lundquist, Carolyn and Guillera-Arroita, Gurutzeta and Settele, Josef and Serra-Diaz, Josep M. and Cabral, Juliano Sarmento and Travis, Justin M. J. and Schifferle, Katrin and Buckley, Lauren and Briscoe, Natalie J. and Isaac, Nick J. B. and Peres-Neto, Pedro R. and Keuth, Raya and Gascoigne, Samuel J. L. and Ferrier, Simon and Urban, Mark C.}, doi = {10.1073/pnas.2501695122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2501695122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Predicting the way forward for the global biodiversity framework}, volume = {122}, year = {2025}, }
• (2025). Dynamic sensor selection for biomarker discovery. PNAS, 122(41), e2501324122. (www)

  @article{ , abstract = {Recent advances in biotechnologies enable monitoring of biological systems with unprecedented resolution, yet identifying and interpreting biological signals remains a major challenge in clinical and research settings. Classically, biomarkers are measurable indicators of the state of biological processes. Given the large number of molecules in modern datasets, a major challenge is identifying the best biomarkers for a particular setting. Here, we apply observability theory to establish a general methodology for biomarker selection. We demonstrate that observability identifies biologically meaningful sensors in a range of time series transcriptomics data. To address unique biological constraints, we introduce the method of dynamic sensor selection to maximize observability over time, thus enabling observability over regimes where system dynamics themselves are subject to change. Our observability-guided biomarker discovery framework extends to multiple data modalities, as demonstrated with the joint use of transcriptomics and chromosome conformation data. We demonstrate the generality of this approach by evaluating the observability of neural activity measured in movies and electroencephalograms. These applications highlight the broad utility of observability-guided biomarker selection, spanning agriculture, biomanufacturing, and neural systems.}, archive = {J_PNAS}, author = {Pickard, Joshua and Stansbury, Cooper and Surana, Amit and Muir, Lindsey and Bloch, Anthony and Rajapakse, Indika}, doi = {10.1073/pnas.2501324122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2501324122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic sensor selection for biomarker discovery}, volume = {122}, year = {2025}, }
• (2025). Visualization of spin–orbit-entangled 4f electrons in crystalline materials. PNAS, 122(41), e2500251122. (www)

  @article{ , abstract = {Lanthanide 4f electrons are strongly influenced by spin–orbit coupling, resulting in well-defined J multiplets, which are further split by the crystalline electric field in condensed matter. While the anisotropy of 4f electrons is closely linked to material properties, direct experimental observation of the 4f electron distribution in real space remains a significant challenge. Here, we present an approach for visualizing the anisotropic distribution of lanthanide 4f electrons in pyrochlore oxides by combining high-photon-energy X-ray diffraction and valence electron density (VED) analysis based on the core differential Fourier synthesis (CDFS) method. The observed VED distributions around the lanthanide site reveal the parameters of the ground-state wavefunction, which roughly agree with point-charge calculations for the trigonal crystal electric field under the LS coupling scheme. This CDFS-based VED observation method not only provides insights into the anisotropic nature of 4f electrons but also opens a pathway for studying the 4f states in a wide range of crystalline materials.}, archive = {J_PNAS}, author = {Kitou, Shunsuke and Ueda, Kentaro and Nakamura, Yuiga and Sugimoto, Kunihisa and Nomura, Yusuke and Arita, Ryotaro and Tokura, Yoshinori and Arima, Taka-hisa}, doi = {10.1073/pnas.2500251122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2500251122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Visualization of spin–orbit-entangled 4f electrons in crystalline materials}, volume = {122}, year = {2025}, }
• (2025). Statistical physics of large-scale neural activity with loops. PNAS, 122(41), e2426926122. (www)

  @article{ , abstract = {As experiments advance to record from tens of thousands of neurons, statistical physics provides a framework for understanding how collective activity emerges from networks of fine-scale correlations. While modeling these populations is tractable in loop-free networks, neural circuitry inherently contains feedback loops of connectivity. Here, for a class of networks with loops, we present an exact solution to the maximum entropy problem that scales to very large systems. This solution provides direct access to information-theoretic measures like the entropy of the model and the information contained in correlations, which are usually inaccessible at large scales. In turn, this allows us to search for the optimal network of correlations that contains the maximum information about population activity. Applying these methods to 45 recordings of approximately 10,000 neurons in the mouse visual system, we demonstrate that our framework captures more information—providing a better description of the population—than existing methods without loops. For a given population, our models perform even better during visual stimulation than spontaneous activity; however, the inferred interactions overlap significantly, suggesting an underlying neural circuitry that remains consistent across stimuli. Generally, we construct an optimized framework for studying the statistical physics of large neural populations, with future applications extending to other biological networks.}, archive = {J_PNAS}, author = {Carcamo, David P. and Lynn, Christopher W.}, doi = {10.1073/pnas.2426926122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2426926122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Statistical physics of large-scale neural activity with loops}, volume = {122}, year = {2025}, }
• (2025). Skillful heat-related mortality forecasting during recent deadly european summers. PNAS, 122(41), e2426516122. (www)

  @article{ , abstract = {Europe is a heatwave hotspot: numerous temperature records have been broken in recent summers, and roughly 60,000 and 50,000 heat-related deaths occurred in the summers of 2022 and 2023, respectively. With recent summers, like that of 2022, projected to become the new norm, there is a pressing need to further develop heat-health warning systems to help society adapt to a warming climate. Here, we forecast heat-related mortality by applying a statistical epidemiological framework to temperature forecasts extending up to 2 wk in advance. Focusing on two recent and exceptional summers in Europe, namely 2022 and 2023, we evaluate the skill of the daily heat-related mortality forecasts, and assess its association with temperature. For most of Europe, milder temperatures, close to the minimum mortality temperature, are associated with more skillful heat-related mortality forecasts. However, some of the hottest regions in Europe instead showed enhanced forecast skill associated with higher temperatures. This suggests that heat-related mortality forecasts can provide valuable information in European regions associated with high levels of heat-related mortality. Consequently, we advocate for local health authorities to include information from forecasts of heat-related mortality in their heat warning systems.}, archive = {J_PNAS}, author = {Holmberg, Emma and Quijal-Zamorano, Marcos and Ballester, Joan and Messori, Gabriele}, doi = {10.1073/pnas.2426516122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2426516122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Skillful heat-related mortality forecasting during recent deadly european summers}, volume = {122}, year = {2025}, }
• (2025). The autophagy-specific exocyst subcomplex contributes to phagophore assembly site integrity by promoting phagophore expansion. PNAS, 122(41), e2426476122. (www)

  @article{ , abstract = {Autophagy is a crucial intracellular pathway for maintaining cellular homeostasis. It involves forming double-membrane vesicles called autophagosomes, which deliver cytosolic cargoes to the lysosomes/vacuoles for degradation. Biogenesis of autophagosomes is a membrane-intensive process wherein the membrane expansion steps are poorly understood. The tethering complex, exocyst, canonically implicated in secretion, also participates in autophagosome biogenesis in yeast, plants, and mammals. However, the contribution of the exocyst complex in autophagosome biogenesis is unclear. In this study, using yeast temperature-sensitive mutants of the exocyst, we observed the accumulation of multiple abortive PAS incapable of autophagosome biogenesis. These dysfunctional abortive structures were enriched with core autophagy proteins involved in initiation and membrane expansion. However, the membrane expansion ability required for cargo capture was severely compromised in these mutants. Further investigations, including a comprehensive epistasis analysis, revealed that the exocyst plays a role downstream of the Atg1 complex. However, it was required at a stage before phosphatidylinositol 3-kinase (PI3K complex I), Atg2–Atg18, and Atg12–Atg5–Atg16 complexes. Taken together, we show that productive PAS formation and membrane expansion during autophagosome biogenesis are exquisitely orchestrated by the autophagy-specific exocyst subcomplex, which excludes Exo70.}, archive = {J_PNAS}, author = {Kumari, Ruchika and Nath, Titikhya and Pflaum, Jeremy and R, Inchara and Vinay, Sannannagari and Wilfling, Florian and Manjithaya, Ravi}, doi = {10.1073/pnas.2426476122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2426476122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The autophagy-specific exocyst subcomplex contributes to phagophore assembly site integrity by promoting phagophore expansion}, volume = {122}, year = {2025}, }
• (2025). Transpupillary in vivo two-photon imaging reveals enhanced surveillance of retinal microglia in diabetic mice. PNAS, 122(41), e2426241122. (www)

  @article{ , abstract = {The retina, located outside the cranium, serves as an ideal structure for investigating information processing within the central nervous system due to its well-organized neurovascular unit comprising diverse cell types, including neurons, glial cells (such as microglia, Müller glia, and astrocytes), pericytes, and vascular endothelial cells. Disrupted retinal homeostasis contributes to various ocular diseases such as diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa. However, noninvasive in vivo imaging methods to study the pathogenesis of these disorders remain limited. Here, we developed a two-photon microscopy technique for real-time, transpupillary in vivo visualization of the retinal neurovascular unit in mice. Our approach integrates systematic head fixation, a custom-made polymethyl methacrylate contact lens, and a glycerin immersion objective lens with an extended working distance and a higher numerical aperture, specifically designed for two-photon microscopy. This method enabled us to visualize dynamic microglial process activity around retinal blood vessels. Our results revealed that retinal microglia exhibit enhanced surveillance under diabetic conditions, which is undetectable by static confocal microscopy. Furthermore, we demonstrated that liraglutide, a glucagon-like peptide-1 receptor agonist commonly used for the treatment of diabetes and obesity, reversed the enhanced microglial behaviors in the diabetic retina. Our simple yet effective approach mitigates the need for advanced optical systems like adaptive optics, providing an effective tool for real-time imaging of the retina. This method offers a valuable resource for visual neuroscience research and holds great potential for clinical applications, particularly in the early diagnosis, intervention, and monitoring of retinal diseases.}, archive = {J_PNAS}, author = {Sotani, Noriyuki and Kusuhara, Sentaro and Nishisho, Ryuto and Kuno, Hiroto and Shima, Hidenori and Haruwaka, Koichiro and Mori, Yuka and Kishi, Maya and Furuyashiki, Tomoyuki and Kobayashi, Kenta and Wake, Hiroaki and Takumi, Toru and Nakamura, Makoto and Tachibana, Yoshihisa}, doi = {10.1073/pnas.2426241122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2426241122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transpupillary in vivo two-photon imaging reveals enhanced surveillance of retinal microglia in diabetic mice}, volume = {122}, year = {2025}, }
• (2025). Impact of extreme weather events on the US domestic supply chain of food manufacturing. PNAS, 122(41), e2424715122. (www)

  @article{ , abstract = {In the United States, like in other countries, the agrifood supply chain faces challenges from a growing population and less predictable weather conditions. Extreme weather events such as droughts decrease agricultural yield and harvested areas, impact the domestic trade of agricultural products and, in turn, food manufacturing. We investigate this relationship at the state level by estimating the food manufacturing production function in a two-stage instrumental variable estimation process. We first assess how drought affects trade in animals and fish, cereal grains, and all other crop products. Next, we estimate a nested production function for processed food. Our findings indicate that the impact of a drought is far from being confined to the area where it happens. At the national level, we find that a 1% increase in drought in the states producing agricultural commodities reduces their exports to other states by 0.5% to 0.7% which, in turn, reduces food manufacturing production by an average of 0.04%. The capacity to shift the origin of import flows, adjust their volume, and substitute agricultural inputs supports the resilience of the food manufacturing sector. We further estimate the 48 × 48 pairwise dependence across states and by commodity group. While cereal grain production is more spatially concentrated than other crops, the agrifood supply chain can enhance its resilience by sourcing from geographically diverse counties within key supplier states and improving multistate coordination. These findings provide important insights for policymakers and industry stakeholders willing to reduce the food system vulnerability to extreme weather events.}, archive = {J_PNAS}, author = {Yim, Hyungsun and Dall’erba, Sandy}, doi = {10.1073/pnas.2424715122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2424715122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Impact of extreme weather events on the US domestic supply chain of food manufacturing}, volume = {122}, year = {2025}, }
• (2025). Natural history of liver fluke infection underpins epidemiological patterns of biliary cancer. PNAS, 122(41), e2423536122. (www)

  @article{ , abstract = {Pathogens are major drivers of cancer globally and the processes of infection and carcinogenesis unfold over decades making them difficult to observe in human or natural populations. We investigate these hidden dynamics for the foodborne trematode Opisthorchis viverrini , which is a primary cause of biliary cancer (cholangiocarcinoma) and infects 12 million people in Southeast Asia. In tumors from patients exposed to O. viverrini , we find that the earliest chromosomal amplifications carrying driver genes occurred at 30 y old on average, two to four decades before cancer diagnosis, and disproportionately contain TP53 , PTEN and FGFR2 genes. We then fitted transmission models to parasitological data from Thailand spanning 27 y ( n = 11,517) finding that, for people born between 1960 and 1989, first exposure occurred at two years old and by 30 y individuals had been cumulatively infected with a median of 72 worms. Trematodes are long-lived and our analysis quantifies the average lifespan of O. viverrini as 13 y (90% credible interval [CrI] 7 to 26 y) within human hosts. The lifetime probability of diagnosis with cholangiocarcinoma is 4.9% (90% CrI 4.7 to 5.0%) given prior exposure to O. viverrini , which is fourteen-fold higher than in populations nonendemic for the parasite. We find strong evidence for a dramatic decline in parasite transmission from 1990 onward in Thailand, suggesting that the incidence of cholangiocarcinoma will decline over the coming decades. Our study demonstrates how pathogen exposure drives patterns of cancer within a population and provides evidence for public health and therapeutic interventions.}, archive = {J_PNAS}, author = {Crellen, Thomas and Vita, Francesca and Braconi, Chiara and Sithithaworn, Paiboon and Hollingsworth, T. Déirdre}, doi = {10.1073/pnas.2423536122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2423536122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Natural history of liver fluke infection underpins epidemiological patterns of biliary cancer}, volume = {122}, year = {2025}, }
• (2025). Species introductions shift seed dispersal potential more than extinctions across 120 island plant–frugivore communities. PNAS, 122(41), e2423438122. (www)

  @article{ , abstract = {Oceanic islands are hotspots of both species extinctions and introductions, which led to marked changes in species composition. This may disrupt key ecological interactions, such as animal-mediated seed dispersal, with potential long-term impacts on ecosystem structure and functioning. While some recent studies on individual taxa and islands report functional shifts, there has been no globally comprehensive study of how these changes vary in intensity and direction across islands. Importantly, it remains unclear how changes in traits of animal communities actually translate to ecologically relevant mismatches with native plant species. We report widespread functional remodeling of frugivore communities based on frugivory-specific traits of all native, extinct, and introduced vertebrate frugivores (birds, mammals, reptiles) from 120 islands in 22 archipelagos. There is a trend for taxonomic and functional substitution, mainly of nonvolant terrestrial mammalian omnivores replacing large-gaped flying frugivores, which caused a mismatch between gape size and seed size. This shift in seed dispersal potential risks underestimation in single-taxon studies. Overall, vertebrate introductions outnumbered extinctions both in terms of species (44 vs. 23%) and islands affected (92 vs. 76%). Moreover, introductions have driven stronger shifts in frugivore trait space compared to extinctions. However, the general patterns are modulated by substantial spatial variation and idiosyncratic functional shifts within frugivore communities on some islands. This, coupled with differences in plant seed size distributions, leads to variability in realized functional mismatches among islands. These results emphasize challenges with predicting functional responses to anthropogenic activities, while highlighting that remodeling of ecosystem interactions is a global concern.}, archive = {J_PNAS}, author = {Heinen, Julia H. and Drake, Donald R. and McConkey, Kim and Hume, Julian P. and Albert, Sébastien and Ando, Haruko and Baider, Cláudia and Bellingham, Peter J. and Case, Samuel B. and Chimera, Charles G. and Florens, F. B. Vincent and Fricke, Evan C. and Gawel, Ann Marie and González-Castro, Aarón and Heleno, Ruben and Hervias-Parejo, Sandra and Hruska, Amy and Imada, Clyde T. and de Lima, Ricardo F. and Nogales, Manuel and Rogers, Haldre S. and Rumeu, Beatriz and Strasberg, Dominique and Traveset, Anna and Valido, Alfredo and Watanabe, Kenta and Wotton, Debra and Yoshikawa, Tetsuro and Rahbek, Carsten and Borregaard, Michael K.}, doi = {10.1073/pnas.2423438122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2423438122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Species introductions shift seed dispersal potential more than extinctions across 120 island plant–frugivore communities}, volume = {122}, year = {2025}, }
• (2025). The locus coeruleus maintains core body temperature and protects against hypothermia during dexmedetomidine-induced sedation. PNAS, 122(41), e2422878122. (www)

  @article{ , abstract = {Activating the adra2a receptors of the brain’s norepinephrine (NE) system produces NREM-like sleep and hypothermia. Dexmedetomidine (DEX), a selective α2 receptor ( adra2a ) agonist, is an important drug used in intensive care for arousable sedation. But for some patients, even slight decreases in body temperature during sedation could pose health risks such as increasing the likelihood of postoperative cognitive dysfunction. Where are the adra2a receptors at which DEX acts to induce hypothermia? A popular theory is that inhibitory adra2a receptors expressed on norepinephrinergic locus coeruleus (LC) neurons are DEX’s prime targets. To examine this, we genetically lesioned galanin ( gal )-expressing norepinephrinergic LC neurons in adult mice. In these ΔLC mice, baseline sleep–wake levels were unchanged, but surprisingly, core body temperatures were lower. Maintaining body temperature depended on NE/ gal projections from the LC to the medial preoptic (MPO) hypothalamus. Furthermore, without these LC neurons, DEX induced hypothermia more strongly. Knockdown with adra2a shRNA revealed that DEX induces hypothermia via adra2a receptors on MPO glutamate cells. When ΔLC mice were kept warm, DEX could induce the same amount of NREM-like sleep as well as it did for mice with an intact LC, and this sleep-like state in ΔLC mice had a higher delta frequency power than in control mice. Our results emphasize that inhibition of the LC by DEX is not required to induce robust sedation. By contrast, the LC likely has a fortuitous background action in protecting against drug-induced hypothermia and speeds recovery from hypothermia.}, archive = {J_PNAS}, author = {Anuncibay Soto, Berta and Ma, Ying and Nollet, Mathieu and Wong, Sara and Miracca, Giulia and Rastinejad, Daniel and Yustos, Raquel and Vyssotski, Alexei L. and Franks, Nicholas P. and Wisden, William}, doi = {10.1073/pnas.2422878122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2422878122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The locus coeruleus maintains core body temperature and protects against hypothermia during dexmedetomidine-induced sedation}, volume = {122}, year = {2025}, }
• (2025). Phycobilisome core architecture influences photoprotective quenching by the orange carotenoid protein. PNAS, 122(41), e2420355122. (www)

  @article{ , abstract = {Photosynthetic organisms rely on sophisticated photoprotective mechanisms to prevent oxidative damage under high or fluctuating solar illumination. Cyanobacteria, which have evolved a unique, water-soluble light-harvesting complex—the phycobilisome—achieve photoprotection through a photoactivatable quencher called the Orange Carotenoid Protein (OCP). Phycobilisomes are highly symmetric and modular, formed by hierarchical assembly of conserved subunits into diverse geometries ranging from simple bundles to elaborate fan- or bouquet-like macromolecular architectures. Although OCP is known to provide photoprotection across species of cyanobacteria with different phycobilisome structures, it is not known whether or how these structural variations relate to changes in the photoprotective function of OCP. For example, OCP was recently discovered to bind as a dimer at two specific instances of an abundant structural motif on the tricylindrical phycobilisome of Synechocystis sp. PCC 6803, yet these sites are sterically inaccessible on a more common pentacylindrical phycobilisome ( Anabaena sp. PCC 7120). To understand how structural modularity and binding specificity contribute to conservation of OCP binding sites and function across different phycobilisome architectures, here we compare experimentally measured photophysical states accessible to these prototypical tricylindrical and pentacylindrical phycobilisomes, with and without OCP, at the single-molecule level. Together with Monte Carlo simulations of exciton transfer in OCP-quenched phycobilisomes, our results suggest that OCP binds at distinct and specific sites in each type of phycobilisome, yet provides nearly identical quenching strength to both phycobilisomes. Our findings highlight the utility of modular phycobilisome structures in balancing robust conservation of photoprotective function with adaptability of site-specific binding across species.}, archive = {J_PNAS}, author = {Ejaz, Ayesha and Sutter, Markus and Lechno-Yossef, Sigal and Kerfeld, Cheryl A. and Squires, Allison H.}, doi = {10.1073/pnas.2420355122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2420355122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phycobilisome core architecture influences photoprotective quenching by the orange carotenoid protein}, volume = {122}, year = {2025}, }
• (2025). Nonuniform water distribution in jupiter’s midlatitudes: Influence of precipitation and planetary rotation. PNAS, 122(41), e2419087122. (www)

  @article{ , abstract = {Knowing the composition of Jupiter’s atmosphere is crucial for constraining Jupiter’s bulk metallicity and formation history. Yet, constraining Jupiter’s atmospheric water abundance is challenging due to its potential nonuniform distribution. Here, we explicitly resolve the water hydrological cycle in Jupiter’s midlatitudes using high-resolution simulations. Falling precipitation leads to a significant large-scale depletion of water vapor beneath the lifting condensation level. A nonuniform water vapor distribution emerges in the midlatitude simulation with a changing Coriolis parameter across latitudes and spatially uniform cooling and heating. Water abundance at the 7-bar level varies by up to a factor of ten across latitudes, from subsolar to supersolar values. We propose that nonlinear large-scale eddies and waves tend to drift air parcels across latitudes along constant potential vorticity (PV) surfaces, thereby sustaining latitudinal dependencies in water vapor and the interplay between water distribution and large-scale dynamics. Therefore, water distribution is influenced by the vertical structure of density stratification and changing Coriolis parameter across Jupiter’s midlatitudes, as quantified by PV. Additionally, the water hydrological cycle amplifies the specific energy of air parcels through the latent heat effect, thereby slowing down vertical mixing with a latent heat flux. The horizontal gradient of water is expected to be more pronounced with a supersolar water abundance. We suggest that similar interplays between precipitating condensates, planetary rotation, and distribution of condensable species generally exist in the weather layer of fast-rotating giant planets. The ongoing Juno mission and future Uranus mission may further reveal the nonuniform distribution of condensed species and their interplay with large-scale dynamics.}, archive = {J_PNAS}, author = {Ge, Huazhi and Li, Cheng and Zhang, Xi and Ingersoll, Andrew P. and Chen, Sihe}, doi = {10.1073/pnas.2419087122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2419087122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nonuniform water distribution in jupiter’s midlatitudes: Influence of precipitation and planetary rotation}, volume = {122}, year = {2025}, }
• (2025). Human MX1 orchestrates the cytoplasmic sequestration of neosynthesized influenza a virus vRNPs. PNAS, 122(41), e2418935122. (www)

  @article{ , abstract = {Interferon-inducible Myxovirus resistance 1 (MX1) proteins are known to restrict influenza A virus (IAV) transcription/replication process. Herein, we show that this early restriction was only partial against human IAVs, with later replication stages more strongly inhibited. Murine (Mm)Mx1 induced an abnormal nuclear accumulation of the viral nucleoprotein (NP) at late time points postinfection. This block was observed to a lower extent with human (Hs)MX1; however, HsMX1 strongly impacted cytoplasmic trafficking of de novo synthesized viral ribonucleoprotein complexes (vRNPs). Indeed, live imaging experiments revealed a transient association of HsMX1 with Rab11a-associated vRNPs, which induced their clustering and their dynein-dependent retrograde transport toward the microtubule organizing center (MTOC). There, vRNPs remained sequestrated together with cellular cofactors YBX1 and Rab11a in large clusters, while MX1 dissociated from them. Dynein inhibition prevented the vRNP clustering and sequestration and significantly rescued infectious IAV production in the presence of HsMX1. In conclusion, this study provides evidence of IAV vRNPs being rerouted and accumulated away from the plasma membrane through the coordinated action of HsMX1 restriction factor, dynein, and the microtubule network.}, archive = {J_PNAS}, author = {McKellar, Joe and Cadènes, Jimmy and García de Gracia, Francisco and Aubé, Corentin and Chaves Valadão, Ana Luiza and Tauziet, Marine and Arnaud-Arnould, Mary and Rebendenne, Antoine and Kociánová, Lenka and Labaronne, Emmanuel and Ricci, Emiliano P. and Delaval, Bénédicte and Gaudin, Raphaël and Naffakh, Nadia and Gallois-Montbrun, Sarah and Moncorgé, Olivier and Goujon, Caroline}, doi = {10.1073/pnas.2418935122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2418935122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Human MX1 orchestrates the cytoplasmic sequestration of neosynthesized influenza a virus vRNPs}, volume = {122}, year = {2025}, }
• (2025). Manifold-constrained nucleus-level denoising diffusion model for structure-based drug design. PNAS, 122(41), e2415666122. (www)

  @article{ , abstract = {AI models have shown great potential in structure-based drug design, generating ligands with high binding affinities. However, existing models have often overlooked a crucial physical prior: Atoms must maintain a minimum pairwise distance to avoid atomic collision, a phenomenon governed by the balance of attractive and repulsive forces. To mitigate such atomic collisions, we propose NucleusDiff. It enforces spatial distance constraints between atomic nuclei and auxiliary mesh points placed on a spherical surface around each atom, approximating van der Waals boundaries to reduce atomic collisions. We quantitatively evaluate NucleusDiff using the CrossDocked2020 dataset and a COVID-19 therapeutic target, demonstrating that NucleusDiff reduces collision rate by up to 100.00% and enhances binding affinity by up to 22.16%, surpassing state-of-the-art models for structure-based drug design. We also provide qualitative analysis through manifold sampling, visually confirming the effectiveness of NucleusDiff in reducing atomic collisions and improving binding affinities.}, archive = {J_PNAS}, author = {Liu, Shengchao and Yan, Liang and Du, Weitao and Liu, Weiyang and Li, Zhuoxinran and Guo, Hongyu and Borgs, Christian and Chayes, Jennifer and Anandkumar, Anima}, doi = {10.1073/pnas.2415666122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2415666122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Manifold-constrained nucleus-level denoising diffusion model for structure-based drug design}, volume = {122}, year = {2025}, }
• (2025). Generative AI for navigating synthesizable chemical space. PNAS, 122(41), e2415665122. (www)

  @article{ , abstract = {We introduce SynFormer, a generative modeling framework designed to efficiently explore and navigate synthesizable chemical space. Unlike traditional molecular generation approaches, we generate synthetic pathways for molecules to ensure that designs are synthetically tractable. By incorporating a scalable transformer architecture and a diffusion module for building block selection, SynFormer surpasses existing models in synthesizable molecular design. We demonstrate SynFormer’s effectiveness in two key applications: 1) local chemical space exploration, where the model generates synthesizable analogs of a query molecule, and 2) global chemical space exploration, where the model aims to identify optimal molecules according to a black-box property prediction oracle. Additionally, we demonstrate the scalability of our approach via the improvement in performance as more computational resources become available. With our code and trained models openly available, we hope that SynFormer will find use across applications in drug discovery and materials science.}, archive = {J_PNAS}, author = {Gao, Wenhao and Luo, Shitong and Coley, Connor W.}, doi = {10.1073/pnas.2415665122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2415665122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Generative AI for navigating synthesizable chemical space}, volume = {122}, year = {2025}, }
• (2025). Lattice distortion leads to glassy thermal transport in crystalline Cs3Bi2I6Cl3. PNAS, 122(41), e2415664122. (www)

  @article{ , abstract = {The glassy thermal conductivities observed in crystalline inorganic perovskites such as Cs 3 Bi 2 I 6 Cl 3 are perplexing and lacking theoretical explanations. Here, we first experimentally measure its thermal transport behavior from 20 to 300 K, after synthesizing Cs 3 Bi 2 I 6 Cl 3 single crystals. Using path-integral molecular dynamics simulations driven by machine learning potentials, we reveal that Cs 3 Bi 2 I 6 Cl 3 has large lattice distortions at low temperatures, which may be related to the large atomic size mismatch. Employing the Wigner formulation of thermal transport, we reproduce the experimental thermal conductivities based on lattice-distorted structures. This study thus provides a framework for predicting and understanding glassy thermal transport in materials with strong lattice disorder.}, archive = {J_PNAS}, author = {Zeng, Zezhu and Fan, Zheyong and Simoncelli, Michele and Chen, Chen and Liang, Ting and Chen, Yue and Thornton, Geoff and Cheng, Bingqing}, doi = {10.1073/pnas.2415664122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2415664122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lattice distortion leads to glassy thermal transport in crystalline Cs3Bi2I6Cl3}, volume = {122}, year = {2025}, }
• (2025). Ab initio machine-learning simulation of calcium carbonate from aqueous solutions to the solid state. PNAS, 122(41), e2415663122. (www)

  @article{ , abstract = {A first-principles machine-learning model has been developed aimed at studying the formation of calcium carbonate from aqueous solution using molecular dynamics simulations. The model, dubbed strongly constrained and appropriately normed-machine learning (SCAN-ML), reproduces accurately the potential energy surface derived from ab initio density-functional theory within the SCAN approximation for the exchange and correlation functional. A broad range of properties have been calculated relevant to ions in solution, solid phases, and the calcite/water interface. Careful comparison with results from experiments and semiempirical force fields shows that SCAN-ML provides an excellent description of this system, surpassing state-of-the-art force fields for many properties, while providing a benchmark for many quantities that are currently beyond the reach of direct ab initio molecular dynamics. A key feature of SCAN-ML is its ability to capture chemical reactions, which reveals that calcium carbonate ion pair formation occurs predominantly via binding of calcium to bicarbonate, with the subsequent loss of a proton to water, rather than by direct association. Our model thus paves the way for the ab initio study of reactive crystallization pathways in biominerals, which are currently poorly understood.}, archive = {J_PNAS}, author = {Piaggi, Pablo M. and Gale, Julian D. and Raiteri, Paolo}, doi = {10.1073/pnas.2415663122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2415663122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ab initio machine-learning simulation of calcium carbonate from aqueous solutions to the solid state}, volume = {122}, year = {2025}, }
• (2025). Generalized convolutional many-body distribution functional representations. PNAS, 122(41), e2415662122. (www)

  @article{ , abstract = {Modern machine learning (ML) models of chemical and materials systems with billions of parameters require vast training datasets and considerable computational efforts. Lightweight kernel or decision tree-based methods, however, can be rapidly trained, leading to a considerably lower carbon footprint. We introduce generalized convolutional many-body distribution functionals (cMBDF) as highly compute and data-efficient atomic representations for accurate kernels that excel in low-data regimes. Generalizing the MBDF framework, cMBDF encodes local chemical environments in a compact fashion using translationally and rotationally invariant functionals of smooth atomic densities weighted by interaction potentials. The functional values can be efficiently evaluated by expressing them in terms of convolutions which are calculated via fast Fourier transforms and stored on predefined grids. In the generalized form, each atomic environment is described using a set of functionals uniformly defined by three integers; many-body, derivative, weighting orders. Irrespective of size/composition, cMBDF atomic vectors remain compact and constant in size for a fixed choice of these orders controlling the structural and compositional resolution. While being up to two orders of magnitude more compact than other popular representations, cMBDF is shown to be more accurate for the learning of various quantum properties such as energies, dipole moments, homo–lumo gaps, heat capacity, polarizability, optimal exact-exchange admixtures, and basis-set scaling factors. Applicability for organic and inorganic chemistry is tested as represented by the QM7b, QM9, and VQM24 datasets. Due to its compactness, model training and testing times are reduced from 23 h to 8 min, implying a corresponding reduction in carbon footprint.}, archive = {J_PNAS}, author = {Khan, Danish and von Lilienfeld, O. Anatole}, doi = {10.1073/pnas.2415662122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2415662122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Generalized convolutional many-body distribution functional representations}, volume = {122}, year = {2025}, }
• (2025). Graph neural networks for predicting metal–ligand coordination of transition metal complexes. PNAS, 122(41), e2415658122. (www)

  @article{ , abstract = {High-throughput virtual screening campaigns are invaluable for surveying the combinatorial space of possible transition metal complexes (TMCs), but they rely on accurate metal–ligand connectivity for meaningful results. Here, we curate a dataset of 70,069 unique ligands of known coordination from experimental structures of TMCs deposited in the Cambridge Structural Database. Using this dataset, we train separate graph neural network models to predict the total number and individual identities of ligand coordinating atoms with high accuracy and precision. Interpreting each model in terms of the learned molecular representations uncovers trends aligned with our understanding of coordination chemistry as well as chemical insights. Next, we integrate the trained models with the high-throughput screening software molSimplify and illustrate their utility by generating 1,175 TMCs and validating their geometries with density functional theory calculations. We anticipate these models will accelerate computational screening of TMCs with de novo combinations of metals and ligands in physically realistic coordination.}, archive = {J_PNAS}, author = {Toney, Jacob W. and St. Michel, Roland G. and Garrison, Aaron G. and Kevlishvili, Ilia and Kulik, Heather J.}, doi = {10.1073/pnas.2415658122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2415658122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Graph neural networks for predicting metal–ligand coordination of transition metal complexes}, volume = {122}, year = {2025}, }
• (2025). The principles behind equivariant neural networks for physics and chemistry. PNAS, 122(41), e2415656122. (www)

  @article{ , abstract = {A distinguishing feature of the neural network models used in Physics and Chemistry is that they must obey basic underlying symmetries, such as symmetry to translations, rotations, and the exchange of identical particles. Over the course of the last several years, the artificial neural networks community has developed a class of networks called group-equivariant neural nets that can efficiently “bake-in” such symmetries into the structure of the network itself. Equivariant neural nets leverage ideas from group representation theory and express all variables in the generalized Fourier space corresponding to the underlying group. In this article, we review this formalism and derive the general form of operations allowable in equivariant neural networks. Specifically, we discuss why the Clebsch–Gordan transform appears in such architectures, and how it can play the role of an equivariant nonlinearity.}, archive = {J_PNAS}, author = {Kondor, Risi}, doi = {10.1073/pnas.2415656122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2415656122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The principles behind equivariant neural networks for physics and chemistry}, volume = {122}, year = {2025}, }
• (2025). Generative AI for computational chemistry: A roadmap to predicting emergent phenomena. PNAS, 122(41), e2415655121. (www)

  @article{ , abstract = {The recent surge in generative AI has introduced exciting possibilities for computational chemistry. Generative AI methods have made significant progress in sampling molecular structures across chemical species, developing force fields, and speeding up simulations. This Perspective offers a structured overview, beginning with the fundamental theoretical concepts in both generative AI and computational chemistry. It then covers widely used generative AI methods, including autoencoders, generative adversarial networks, reinforcement learning, flow models, and language models, and highlights their selected applications in diverse areas including force field development, and protein/RNA structure prediction. A key focus is on the challenges these methods face before they become truly predictive, particularly in predicting emergent chemical phenomena. We believe that the ultimate goal of a simulation method or theory is to predict phenomena not seen before and that generative AI should be subject to these same standards before it is deemed useful for chemistry. We suggest that to overcome these challenges, future AI models need to integrate core chemical principles, especially from statistical mechanics.}, archive = {J_PNAS}, author = {Tiwary, Pratyush and Herron, Lukas and John, Richard and Lee, Suemin and Sanwal, Disha and Wang, Ruiyu}, doi = {10.1073/pnas.2415655121}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2415655121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Generative AI for computational chemistry: A roadmap to predicting emergent phenomena}, volume = {122}, year = {2025}, }
• (2025). Nanomedicines targeting protease-activated receptor 2 in endosomes provide sustained analgesia. PNAS, 122(41), e2412687122. (www)

  @article{ , abstract = {Although many internalized G protein-coupled receptors (GPCRs) continue to signal, the mechanisms and outcomes of intracellular GPCR signaling are uncertain due to the challenges of measuring organelle-specific signals and of selectively antagonizing receptors in intracellular compartments. Herein, genetically encoded biosensors targeted to the plasma membrane and early endosomes were used to analyze compartmentalized signaling of protease-activated receptor 2 (PAR 2 ); the propensity of nanoparticles (NPs) to accumulate in endosomes was leveraged to preferentially antagonize intracellular PAR 2 signaling of pain. PAR 2 agonists evoked sustained activation of PAR 2 , Gαq, and β-arrestin-1 in early endosomes and activated extracellular signal regulated kinase (ERK) in the cytosol and nucleus, measured with targeted biosensors. Fluorescent dendrimer and core-shell polymeric NPs accumulated in endosomes of HEK293T cells, colonic epithelial cells, and nociceptors, detected by confocal microscopy. NPs efficiently encapsulated and slowly released AZ3451, a negative allosteric PAR 2 modulator. NP-encapsulated AZ3451, but not unencapsulated AZ3451, rapidly and completely reversed PAR 2 , Gαq, and β-arrestin-1 activation in early endosomes and ERK activation in the cytosol and nucleus. When administered into the mouse colon lumen, fluorescent dendrimer NPs accumulated in endosomes of colonocytes and polymeric NPs accumulated in neurons, sites of PAR 2 expression. Both NP formulations of AZ3451, but not unencapsulated AZ3451, caused long-lasting analgesia and normalized aberrant behavior in preclinical models of inflammatory bowel disease. These results provide evidence that PAR 2 endosomal signaling mediates pain and that nanomedicines that antagonize PAR 2 in endosomes effectively relieve pain. NP-mediated delivery may improve the efficacy of other GPCR antagonists for treatment of diverse diseases.}, archive = {J_PNAS}, author = {Teng, Shavonne L. and Latorre, Rocco and Bhansali, Divya and Lewis, Parker K. and Pollard, Rachel E. and Peach, Chloe J. and Sokrat, Badr and Thanigai Arasu, Gokul Sriman and Chiu, Tracy and Duran, Paz and Jimenez-Vargas, Nestor N. and Mocherniak, Abby and Bogyo, Matthew and Gaspari, Michael M. and Vanner, Stephen J. and Pinkerton, Nathalie M. and W. Leong, Kam and Schmidt, Brian L. and Jensen, Dane D. and Bunnett, Nigel W.}, doi = {10.1073/pnas.2412687122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2412687122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nanomedicines targeting protease-activated receptor 2 in endosomes provide sustained analgesia}, volume = {122}, year = {2025}, }
• (2025). ProT-VAE: Protein transformer variational AutoEncoder for functional protein design. PNAS, 122(41), e2408737122. (www)

  @article{ , abstract = {Deep generative models have demonstrated success in learning the protein sequence to function relationship and designing synthetic sequences with engineered functionality. We introduce the Protein Transformer Variational AutoEncoder (ProT-VAE) as an accurate, generative, fast, and transferable model for data-driven protein design that blends the merits of variational autoencoders to learn interpretable, low-dimensional latent embeddings for conditional sequence design with the expressive, alignment-free featurization offered by transformer-based protein language models. We implement the model using NVIDIA’s BioNeMo framework and validate its performance in retrospective functional prediction and prospective functional design. The model identifies a phenylalanine hydroxylase enzyme with 2.5× catalytic activity over wild-type, and a γ -carbonic anhydrase enzyme with a melting temperature elevation of ΔT m = +61 ° C relative to the most thermostable sequence reported to date and activity in 23% v/v methyl diethanolamine at pH 11.25 and 93 ° C corresponding to industrially relevant conditions for enzymatic carbon capture technologies. The ProT-VAE model presents a powerful and experimentally validated platform for machine learning-guided directed evolution campaigns to discover synthetic proteins with engineered function.}, archive = {J_PNAS}, author = {Sevgen, Emre and Moller, Joshua and Lange, Adrian and Parker, John and Quigley, Sean and Mayer, Jeff and Srivastava, Poonam and Gayatri, Sitaram and Hosfield, David and Dilks, Clayton and Buchanan, Claire and Speltz, Thomas and Korshunova, Maria and Livne, Micha and Gill, Michelle and Ranganathan, Rama and Costa, Anthony B. and Ferguson, Andrew L.}, doi = {10.1073/pnas.2408737122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {41}, pages = {e2408737122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ProT-VAE: Protein transformer variational AutoEncoder for functional protein design}, volume = {122}, year = {2025}, }
• (2025). Correction for wurman et al., supercell tornadoes are much stronger and wider than damage-based ratings indicate. PNAS, 122(40), e2525962122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2525962122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2525962122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for wurman et al., supercell tornadoes are much stronger and wider than damage-based ratings indicate}, volume = {122}, year = {2025}, }
• (2025). Correction for li et al., comprehensive tissue deconvolution of cell-free DNA by deep learning for disease diagnosis and monitoring. PNAS, 122(40), e2525325122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2525325122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2525325122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for li et al., comprehensive tissue deconvolution of cell-free DNA by deep learning for disease diagnosis and monitoring}, volume = {122}, year = {2025}, }
• (2025). Correction for zhao et al., blood–labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus. PNAS, 122(40), e2525323122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2525323122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2525323122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for zhao et al., blood–labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus}, volume = {122}, year = {2025}, }
• (2025). Correction for sakuma et al., liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis. PNAS, 122(40), e2524902122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2524902122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2524902122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for sakuma et al., liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis}, volume = {122}, year = {2025}, }
• (2025). Correction for hoffmann et al., cancer cells suppress NK cell activity by actin-driven polarization of inhibitory ligands to the immunological synapse. PNAS, 122(40), e2524777122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2524777122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2524777122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for hoffmann et al., cancer cells suppress NK cell activity by actin-driven polarization of inhibitory ligands to the immunological synapse}, volume = {122}, year = {2025}, }
• (2025). Correction for jin et al., autocrine signaling by an aplysia neurotrophin forms a presynaptic positive feedback loop. PNAS, 122(40), e2524028122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2524028122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2524028122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for jin et al., autocrine signaling by an aplysia neurotrophin forms a presynaptic positive feedback loop}, volume = {122}, year = {2025}, }
• (2025). Current progress and research needs to protect children’s environmental health. PNAS, 122(40), e2522786122. (www)

  @article{ , archive = {J_PNAS}, author = {O’Shaughnessy, Katherine L. and Lorenz, Alyson N. and Owens, Elizabeth O. and Miller, Gregory G. and Malashock, Daniel A. and Carlson, Laura M. and Franzosa, Jill A. and Wilson, Michael and Boyle, Elizabeth B.}, doi = {10.1073/pnas.2522786122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2522786122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Current progress and research needs to protect children’s environmental health}, volume = {122}, year = {2025}, }
• (2025). Reply to yu et al.: Datasets, human judges, and future directions for evaluating AI–AI bias. PNAS, 122(40), e2522651122. (www)

  @article{ , archive = {J_PNAS}, author = {Kulveit, Jan and Laurito, Walter and Gavenčiak, Tomáš and Grietzer, Peli and Davis, Benjamin and Böhm, Ada}, doi = {10.1073/pnas.2522651122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2522651122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to yu et al.: Datasets, human judges, and future directions for evaluating AI–AI bias}, volume = {122}, year = {2025}, }
• (2025). Correction for gilboa et al., measurement of α-synuclein as protein cargo in plasma extracellular vesicles. PNAS, 122(40), e2522569122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2522569122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2522569122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for gilboa et al., measurement of α-synuclein as protein cargo in plasma extracellular vesicles}, volume = {122}, year = {2025}, }
• (2025). It’s cool to be green. PNAS, 122(40), e2522472122. (www)

  @article{ , archive = {J_PNAS}, author = {Desai, Ankur R.}, doi = {10.1073/pnas.2522472122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2522472122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {It’s cool to be green}, volume = {122}, year = {2025}, }
• (2025). Rust never sleeps: Climate change, permafrost thaw, and the rapid environmental degradation of wilderness river ecosystems. PNAS, 122(40), e2522469122. (www)

  @article{ , archive = {J_PNAS}, author = {Huryn, Alexander D.}, doi = {10.1073/pnas.2522469122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2522469122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rust never sleeps: Climate change, permafrost thaw, and the rapid environmental degradation of wilderness river ecosystems}, volume = {122}, year = {2025}, }
• (2025). Long-term synchronous changes in body size among domesticated and wild species. PNAS, 122(40), e2521664122. (www)

  @article{ , archive = {J_PNAS}, author = {Stock, Jay T.}, doi = {10.1073/pnas.2521664122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2521664122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Long-term synchronous changes in body size among domesticated and wild species}, volume = {122}, year = {2025}, }
• (2025). Addressing the broader implications of AI–AI bias in decision-making systems. PNAS, 122(40), e2521127122. (www)

  @article{ , archive = {J_PNAS}, author = {Yu, Zekai}, doi = {10.1073/pnas.2521127122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2521127122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Addressing the broader implications of AI–AI bias in decision-making systems}, volume = {122}, year = {2025}, }
• (2025). Curiouser and curiouser: Meningeal lymphoid structures in the aging brain. PNAS, 122(40), e2520203122. (www)

  @article{ , archive = {J_PNAS}, author = {Shaked, Iftach and Frenkel, Dan}, doi = {10.1073/pnas.2520203122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2520203122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Curiouser and curiouser: Meningeal lymphoid structures in the aging brain}, volume = {122}, year = {2025}, }
• (2025). The intrinsic neuronal network of the central nervous system and its modular (subsystem) architecture in a mammal. PNAS, 122(40), e2519768122. (www)

  @article{ , abstract = {The vertebrate central nervous system (CNS) has two great topographic divisions—brain and spinal cord—that together integrate the body’s internal physiology and behavioral interactions with the environment. To clarify the architecture of intra-CNS connectivity supporting this integration in a mammal (rat), network science analyses were applied at the level of gray matter regions (nodes) connected by directed and weighted axonal projections. Neuroanatomical evidence indicates a bilateral, predominantly sexually monomorphic neuronal network of 840 nodes and a projected 81,434 direct interconnections (of the 704,760 possible connections), representing a projected network density of 12%; 32% of identified connections terminate contralaterally, and 41% of identified connections participate in bidirectionally linking a pair of nodes. Local network differentiations examined with unsupervised multiresolution consensus cluster analysis revealed a nested hierarchy of interconnected modules (clusters or subsystems) that were conservatively assigned putative functional roles. This structure–function hierarchy includes only three first-order modules, indicating a tripartite systems architecture (distinct from the bipartite brain-spinal cord topographic division): a bilaterally symmetric module pair centered in the forebrain-midbrain, associated with behavior control, cognition, and affect; and a single bilateral module centered in the rhombicbrain-spinal cord, associated with behavior execution and reflex integration. This modular spatial patterning suggests possible developmental and phylogenetic correlates. Additional analyses of the CNS’s basic structural network plan included global neuronal network features—specifically, measures of centrality, rich club, and small world topology—that transcend modular boundaries.}, archive = {J_PNAS}, author = {Swanson, Larry W. and Hahn, Joel D. and Sporns, Olaf}, doi = {10.1073/pnas.2519768122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2519768122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The intrinsic neuronal network of the central nervous system and its modular (subsystem) architecture in a mammal}, volume = {122}, year = {2025}, }
• (2025). Molecular basis of SARS-CoV-2 proofreading enzyme–mediated resistance to remdesivir. PNAS, 122(40), e2519755122. (www)

  @article{ , abstract = {SARS-CoV-2’s remarkable resistance to nucleotide analog antivirals such as remdesivir, which thwarts RNA synthesis by inhibiting viral polymerase (RdRp), challenges available therapies. We reveal that remdesivir incorporation destabilizes RdRp–RNA complex while enhancing RNA binding to the proofreading exoribonuclease (ExoN), facilitating remdesivir excision. Conserved ExoN determinants for remdesivir recognition and excision underpin ExoN-mediated resistance across all coronaviruses. These findings inform the design of next-generation antivirals and combination therapies capable of overcoming ExoN-mediated resistance.}, archive = {J_PNAS}, author = {Yang, Yang and Li, Yu and Becker, Scott T. and Khan, Ayesha and Luo, Gloria and Liu, Bin and Liu, Chang}, doi = {10.1073/pnas.2519755122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2519755122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular basis of SARS-CoV-2 proofreading enzyme–mediated resistance to remdesivir}, volume = {122}, year = {2025}, }
• (2025). Soluble guanylyl cyclase, the NO receptor, drives vasorelaxation via endothelial S-nitrosation. PNAS, 122(40), e2519105122. (www)

  @article{ , abstract = {We previously demonstrated that the NO-stimulated soluble guanylyl cyclase (GC1), which produces cGMP, also has the ability to transfer S-nitrosothiols (SNO) to other proteins in a reaction involving oxidized Thioredoxin 1 (oTrx1). This transnitrosation cascade was established in vitro and involved Cys 610 (C610) of GC1 as the major SNO-donor. To assay the relevance of GC1 transnitrosation under physiological conditions and in oxidative pathologies, we studied a knock-in mouse in which C610 was replaced with a serine (KI αC 610S ) under basal or angiotensin II (Ang II)-treated conditions. Despite similar GC1 expression and NO responsiveness, the Ang II-treated KI mice displayed exacerbated oxidative pathologies including higher mean arterial pressure and more severe cardiac dysfunctions compared to the Ang II-treated WT. These phenotypes were associated with a drastic decrease in global S-nitrosation and in levels of SNO-Trx1 in the KI mice. To investigate the mechanism underlying the dysregulation of blood pressure, pressure myography and in vivo intravital microscopy were conducted to analyze the vascular tone of resistance vessels. Both approaches indicated that, even in the absence of oxidative stress, the single mutation C610S led to a significant disruption of the endothelium-dependent, acetylcholine-induced vasorelaxation while NO-dependent smooth muscle relaxation remained unchanged. Mechanistically, the vasorelaxation defect was associated with decreased endothelial calcium influx and membrane hyperpolarization, independent of NO bioavailability. These findings indicate that the C610S mutation uncouples two NO signaling vasodilatory pathways (endothelial SNO and smooth muscle NO-cGMP) and suggest that GC1 transnitrosation activity is essential for endothelium-derived hyperpolarization.}, archive = {J_PNAS}, author = {Younis, Waqas and Burboa, Pia C. and Sadeghian, Tanaz and Kuzdowicz, Veronica and Cui, Chuanlong and Shu, Ping and Qin, Yong and Xie, Lai-Hua and Lillo, Mauricio A. and Beuve, Annie}, doi = {10.1073/pnas.2519105122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2519105122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Soluble guanylyl cyclase, the NO receptor, drives vasorelaxation via endothelial S-nitrosation}, volume = {122}, year = {2025}, }
• (2025). Reply to bourguignon et al.: Convergence is a plausible hypothesis for quina technology in east asia. PNAS, 122(40), e2519000122. (www)

  @article{ , archive = {J_PNAS}, author = {Ruan, Qi-Jun and Li, Hao and Marwick, Ben and Peresani, Marco and Moncel, Marie-Hélène and Xiao, Pei-Yuan and Monod, Hélène and Li, Bo and Delpiano, Davide}, doi = {10.1073/pnas.2519000122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2519000122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to bourguignon et al.: Convergence is a plausible hypothesis for quina technology in east asia}, volume = {122}, year = {2025}, }
• (2025). Genetic, phenotypic, and environmental drivers of local adaptation and climate change–induced maladaptation in a migratory songbird. PNAS, 122(40), e2518497122. (www)

  @article{ , abstract = {Understanding processes driving local adaptation in wild species is a key goal in evolutionary biology, but linking genotype to phenotype to environmental drivers of natural selection remains challenging. Even more rare are empirical examples of what happens when genotype and phenotype fail to keep pace with environmental change. Here, we explore these connections by conducting an integrative study on the breeding range of the yellow warbler ( Setophaga petechia ). Using genome-wide association studies (GWAS), we first identify loci associated with variation in bill morphology and individual quality. We then employ gene–environment association (GEA) analyses and find that precipitation is a key environmental driver of putative selection on bill shape. Finally, we test whether contemporary individuals whose bill shapes deviate from the historical relationship with precipitation experience increased stress (measured by telomere length) as a result of maladaptation. We also use historical DNA to test whether local populations have shifted their ranges over the past century, confirming that the observed changes are not due to range shifts. Our results align with predictions from GWAS and GEA analyses, indicating that birds with shallower bills in increasingly arid regions suffer higher stress (i.e., shorter telomeres) because of maladaptation. Overall, this study links genetic, phenotypic, and environmental data with stress biomarkers to improve understanding of the process of local adaptation and the consequence of failing to keep pace with changing climate conditions.}, archive = {J_PNAS}, author = {Rodriguez, Marina D. and Bossu, Christen M. and Anderson, Eric C. and Bay, Rachael A. and Ruegg, Kristen C.}, doi = {10.1073/pnas.2518497122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2518497122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genetic, phenotypic, and environmental drivers of local adaptation and climate change–induced maladaptation in a migratory songbird}, volume = {122}, year = {2025}, }
• (2025). Proof-of-principle demonstration of epithermal neutron resonance spectroscopy utilizing a compact laser–driven electron accelerator. PNAS, 122(40), e2518397122. (www)

  @article{ , abstract = {Epithermal neutron resonance spectroscopy is a key nondestructive approach for discerning material properties. However, the existing spallation and accelerator-based photonuclear neutron sources employed in this spectroscopy are huge and immobile, restricting their application in specialized scenarios. Here, we demonstrate a compact short-pulsed photonuclear neutron source driven by a terawatt femtosecond laser–based electron accelerator. After moderation, this neutron source maintains an outstanding time-resolution of 0.8 μ s at 5 eV, and its energy resolution can be less than 3% at a flight distance 1.72 m. When this compact neutron resonance spectroscopy facility is utilized to examine silver (Ag) and indium (In) metal sheets with a high signal-to-noise ratio, it distinctly reveals the shape of resonance absorption peaks for 115 In at 1.46 eV and 109 Ag at 5.19 eV. This laser-driven electron accelerator offers a solution, overcoming traditional source drawbacks and holding great potential for on-site nuclear material analysis and high-precision nuclear data acquisition.}, archive = {J_PNAS}, author = {Feng, Jie and Ren, Jie and Xu, Hao and Zhu, Mingyang and Shi, Bingzhan and Zhang, Guoqiang and Bao, Jie and Yan, Wenchao and Li, Yifei and Wang, Jinguang and Lu, Xin and Chen, Liming and Zhang, Jie}, doi = {10.1073/pnas.2518397122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2518397122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Proof-of-principle demonstration of epithermal neutron resonance spectroscopy utilizing a compact laser–driven electron accelerator}, volume = {122}, year = {2025}, }
• (2025). The presence of quina lithic technology in china 50 to 60 ka ago remains a hypothesis. PNAS, 122(40), e2518182122. (www)

  @article{ , archive = {J_PNAS}, author = {Bourguignon, Laurence and Soriano, Sylvain and Claud, Émilie and Faivre, Jean-Philippe and Gauvrit-Roux, Eugénie and Jaubert, Jacques and Meignen, Liliane and Vaissié, Erwan and Guérin, Guillaume}, doi = {10.1073/pnas.2518182122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2518182122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The presence of quina lithic technology in china 50 to 60 ka ago remains a hypothesis}, volume = {122}, year = {2025}, }
• (2025). Functional diversity in GII.4 norovirus entry: HBGA binding and capsid clustering dynamics. PNAS, 122(40), e2517493122. (www)

  @article{ , abstract = {Human noroviruses (HuNoVs), especially GII.4 strains, are the leading cause of acute viral gastroenteritis worldwide, yet no approved vaccines or antivirals exist. The pandemic GII.4 Sydney 2012 strain enters cells via membrane wounding and clathrin-independent carrier-mediated endocytosis, but it is unclear whether this entry mechanism is conserved across GII.4 variants. We compared early binding and entry of multiple GII.4 variants using wild-type and mutant GII.4 virus-like particles (VLPs) and modified human intestinal enteroid cultures. Only a subset of GII.4 variants, including GII.4 Sydney, form distinct, histo-blood group antigen (HBGA)-dependent capsid clusters on the cell surface. Clustering strains display significantly enhanced membrane wounding and endocytosis compared to nonclustering strains and outcompete nonclustering strains in replication assays exhibited by complete inhibition of GII.4 Sydney replication. Using mutant VLPs and an HBGA nonbinding mutant (R345A), we identified two residues, V333 and R339, in the VP1 protruding domain as critical mediators of clustering and entry. Mutations of these residues disrupt clustering and endocytosis without affecting HBGA binding, suggesting a role in postattachment processes. While clustering and endocytosis are contingent upon VLP binding to HBGAs, inhibitor studies show they are independent of host protein glycosylation and are driven by lipid raft remodeling regulated by cholesterol and ceramides. Quantitative analyses across multiple GII.4 variants reveal an apparent dichotomy between clustering and nonclustering phenotypes, with clustering variants exhibiting higher entry competence. This distinction offers insight into strain-specific cell entry mechanisms and may aid in identifying the elusive proteinaceous HuNoV cellular receptor(s) supporting targeted therapeutic development.}, archive = {J_PNAS}, author = {Ayyar, B. Vijayalakshmi and Apostol, Carmen V. and Dave, Janam Jitendra and Kaundal, Soni and Kendra, Joseph A. and Neill, Frederick H. and Ettayebi, Khalil and Maher, Sarah and Anish, Ramakrishnan and Parra, Gabriel I. and Larson, Göran and Atmar, Robert L. and Crawford, Sue E. and Prasad, B. V. Venkataram and Estes, Mary K.}, doi = {10.1073/pnas.2517493122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2517493122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Functional diversity in GII.4 norovirus entry: HBGA binding and capsid clustering dynamics}, volume = {122}, year = {2025}, }
• (2025). Exceptionally broad HIV-1 neutralization via bispecific antibody–mediated prepositioning. PNAS, 122(40), e2517311122. (www)

  @article{ , abstract = {Antibodies that recognize the conserved prehairpin intermediate (PHI) of class I viral membrane-fusion proteins typically show limited neutralization and have not been considered promising therapeutic agents. We previously developed a bispecific antibody (bsAb), iMab/D5_AR, directed toward both the gp41 N-heptad repeat (NHR) that is exposed within the HIV-1 PHI and toward CD4, the HIV-1 receptor on T cells. CD4-binding led to prepositioning of the bsAb at the site of viral fusion, enhancing its neutralization potency and achieving 95% breadth (IC80 < 5 μg/mL) against a panel of 119 pseudotyped, multiclade HIV-1 viruses. In the current study, we engineered a bsAb against NHR that also targets CCR5, one of two HIV-1 coreceptors on T cells. This optimized bsAb design further improves neutralization potency and achieves 100% neutralization breadth against the 119-member pseudotyped virus panel, including those resistant to CD4-binding iMab/D5_AR. Considering that nearly all initial HIV-1 infections occur via CCR5-tropic viruses, we expect our redesigned bsAb targeting CCR5 to be an effective prophylactic agent. These findings further support the rationale for pursuing the NHR as a therapeutic target for HIV-1 and lay the groundwork for a new class of engineered broadly neutralizing antibodies.}, archive = {J_PNAS}, author = {Kim, Soohyun and Travisano, Katie A. and Wilder, Bailey and Palomares, Martina and Cao, Zheng and Seaman, Michael S. and Kim, Peter S.}, doi = {10.1073/pnas.2517311122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2517311122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exceptionally broad HIV-1 neutralization via bispecific antibody–mediated prepositioning}, volume = {122}, year = {2025}, }
• (2025). Combined pesticide pollution enhances the dissemination of the phage-encoded antibiotic resistome in the soil under nitrogen deposition. PNAS, 122(40), e2516722122. (www)

  @article{ , abstract = {Phage-mediated dissemination of antibiotic resistance genes (ARGs) intensifies health threat in the environment. Increasing amounts of pesticides are entering the soil ecosystem, yet their potential influence on phage-mediated ARG spread, particularly under conditions of global change, remains poorly understood. In this study, we performed a long-term field experiment simulating pesticide contamination under nitrogen deposition and examined the role of soil phages in ARG spread and host adaptation using metagenomic and viromic sequencing. Combined pesticide markedly elevated the abundance of phage-encoded ARGs under nitrogen deposition. By enhancing phage–host interactions and increasing the co-occurrence of auxiliary metabolic genes with ARGs, phages may further facilitate the transfer of ARGs to bacterial hosts, conferring hosts a competitive edge in intensified microbial competition driven by combined pesticide exposure under nitrogen deposition. The phage-driven mechanism was supported by in vitro cultivation experiments, demonstrating that phages harboring ARGs, shaped by long-term combined pesticide exposure under nitrogen deposition, can infect bacterial hosts and confer resistance. Collectively, our findings underscore the pivotal role of phages in ARG mobilization under environmental stressors, reinforcing the importance of accounting for phage activity in ARG risk assessments under global change.}, archive = {J_PNAS}, author = {Shen, Luo-Qin and Lin, Da and Ye, Yu-Qiu and Liu, Yanjie and Ni, Bang and Wu, Di and Wang, Lu and Zhu, Dong}, doi = {10.1073/pnas.2516722122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2516722122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Combined pesticide pollution enhances the dissemination of the phage-encoded antibiotic resistome in the soil under nitrogen deposition}, volume = {122}, year = {2025}, }
• (2025). Engineering antibody–drug conjugates targeting an adhesion GPCR, CD97. PNAS, 122(40), e2516627122. (www)

  @article{ , abstract = {Adhesion G protein–coupled receptors (aGPCRs) are key cell-adhesion molecules involved in many cellular functions and contribute to human diseases, including cancer. aGPCRs are characterized by large extracellular regions that could serve as readily accessible antigens. However, the potential of aGPCRs as targets for biologic therapeutics has not been extensively explored. CD97, also known as ADGRE5, is an aGPCR that is upregulated in various cancer types, including acute myeloid leukemia (AML) and glioblastoma (GBM), and their respective cancer stem cells. Here, we developed antibody–drug conjugates (ADCs) targeting CD97 and assessed their efficacy against AML and GBM cells. We generated a panel of synthetic human antibodies targeting distinct epitopes of CD97, from which we identified an antibody that was efficiently internalized. This antibody binds to all isoforms of human CD97 but not to its close homolog, EMR2. Structure determination by single-particle cryo-electron microscopy revealed that this antibody targets the CD97 GPCR autoproteolysis-inducing (GAIN) domain, whose presence is conserved in aGPCRs, through an unconventional binding mode where it extensively utilizes the light chain framework for antigen recognition. Screening of conjugation methods and payloads resulted in a stable ADC that effectively killed AML and GBM cell lines, as well as patient-derived GBM stem cells, with minimal cytotoxicity against peripheral blood mononuclear cells from healthy donors. Our study demonstrates the therapeutic potential of targeting CD97, as well as the aGPCR GAIN domain in general, and uncovers a previously unrecognized surface that an antibody can utilize for antigen recognition.}, archive = {J_PNAS}, author = {Hattori, Takamitsu and Wang, Michelle and Corrado, Alexis D. and Gross, Suzanne and Fang, Michelle and Bang, Injin and Roy, Nainita and Berezniuk, Iryna and Donaldson, Hayley and Groff, Karenna and Ravn-Boess, Niklas and Koide, Akiko and Placantonakis, Dimitris G. and Park, Christopher Y. and Koide, Shohei}, doi = {10.1073/pnas.2516627122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2516627122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Engineering antibody–drug conjugates targeting an adhesion GPCR, CD97}, volume = {122}, year = {2025}, }
• (2025). Mesoscale avalanche size underpins the rheology of granular yielding. PNAS, 122(40), e2516426122. (www)

  @article{ , abstract = {Granular materials under loading exhibit intermittent avalanches of varying sizes prior to full yielding, a hallmark of natural failure phenomena such as landslides and earthquakes. While continuum models for postyield plastic flow are well established, a unified framework connecting preyield avalanche dynamics to bulk rheology remains lacking. Here, we introduce a birefringent double-shear experiment that enables sustained probing of avalanche statistics and quasistatic flow behavior near the yielding transition. We find that the avalanche regime exhibits rate-weakening behavior, while the plastic regime is rate-independent, resulting in dual rheology under identical local shear rates and indicating hysteresis and mechanical instability. Within a stress-activated framework, we identify the mean normalized stress drop, a measure for mesoscale avalanche size, as a key field variable that bridges the two regimes. Incorporating this variable, we formulate a unified constitutive model that captures the entire yielding transition. These findings establish mesoscale avalanche evolution as a central mechanism underlying granular yielding rheology.}, archive = {J_PNAS}, author = {Lee, Keng-Lin and Yeh, Ting-Yin}, doi = {10.1073/pnas.2516426122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2516426122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mesoscale avalanche size underpins the rheology of granular yielding}, volume = {122}, year = {2025}, }
• (2025). Global constraint principle for microbial growth laws. PNAS, 122(40), e2515031122. (www)

  @article{ , abstract = {Understanding complex living systems requires identifying universal phenomenological laws that are independent of species and molecular-biological details. The Monod equation is a cornerstone of phenomenological microbial growth laws, depicting the growth rate as a saturating function of a single substrate. Because of its similarity in functional form to the Michaelis–Menten equation, cellular growth is often thought to be limited by a single reaction. However, cellular growth generically results from the coordination of thousands of metabolic reactions and diverse intracellular limited resources. Consequently, the mechanistic origins of the Monod equation remain controversial, and its extension has encountered limitations. Here, we propose the global constraint principle for cellular growth: As one nutrient becomes more available, other intracellular resources become limiting, driving transitions to distinct modes of resource allocation. Based on a general framework of constraint-based modeling and its dual formulations, we mathematically prove that, in general, microbial growth kinetics curves are monotonically increasing and concave with respect to nutrient availability. Numerical simulations using genome-scale Escherichia coli models with proteome allocation, molecular crowding, and membrane capacity constraints reproduce these features in a multiphasic manner. In contrast to the original Monod’s growth law, the global constraint principle also captures the dependence of microbial growth on the availability of multiple nutrients, by generalizing the Liebig’s law of the minimum, another phenomenological growth law for higher organisms, into a terraced landscape of diminishing returns. It thus integrates the classical phenomenological laws proposed by Monod and Liebig into a comprehensive theory of cellular growth.}, archive = {J_PNAS}, author = {Yamagishi, Jumpei F. and Hatakeyama, Tetsuhiro S.}, doi = {10.1073/pnas.2515031122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2515031122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global constraint principle for microbial growth laws}, volume = {122}, year = {2025}, }
• (2025). Fiber recruitment drives a phase transition of cell polarization at a critical cell spacing in matrix-mediated tissue remodeling. PNAS, 122(40), e2514995122. (www)

  @article{ , abstract = {Biological tissues exhibit sharp phase transitions where cells collectively transition from disordered to ordered states at critical densities. We demonstrate through bio-chemo-mechanical modeling that this emergent behavior arises from a nonmonotonic dependence on nonlinear extracellular matrix (ECM) mechanics: mechanical communication between cells is optimized at intermediate stiffness values where cells can both generate sufficient forces and create strain-stiffened tension bands in the ECM. This balance establishes a critical cell spacing threshold for cell–cell communication ( ∼ 100 to 200 μ m) that is conserved across experimental observations for a broad range of cell types and collagen densities. Our model reveals that the critical stretch ratio at which fibrous networks transition from compliant to strain-stiffening governs this threshold through the formation of tension bands between neighboring cells. These mechanical communication networks drive collective phase transition in tissue condensation when cell density exceeds an effective percolation threshold. Our model explains how microscale cell–ECM interactions control emergent mechanical properties in biological systems and offers insight both into the physics of inhomogeneous materials under active stress, and into potential mechanical interventions for wound healing and fibrotic disorders.}, archive = {J_PNAS}, author = {Peng, Xiangjun and Huang, Yuxuan and Kong, Wenyu and Du, Yanan and Elson, Elliot L. and Feng, Xi-Qiao and Genin, Guy M.}, doi = {10.1073/pnas.2514995122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2514995122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fiber recruitment drives a phase transition of cell polarization at a critical cell spacing in matrix-mediated tissue remodeling}, volume = {122}, year = {2025}, }
• (2025). Enhanced PIEZO1 function contributes to the pathogenesis of sickle cell disease. PNAS, 122(40), e2514863122. (www)

  @article{ , abstract = {Sickle cell disease (SCD), an inherited blood disorder caused by a mutation in the β-globin gene, is characterized by sickle erythrocytes that are prone to hemolysis, leading to anemia and vaso-occlusion crises. In sickle erythrocytes, hemoglobin aggregation is followed by altered cation permeability and subsequent dehydration. Interventions that restore cation permeability can decrease hemolysis and ameliorate the symptoms associated with SCD. PIEZO1 is a nonselective mechanosensitive cation channel that regulates erythrocyte volume. Gain-of-function (GOF) mutations in PIEZO1 cause hemolytic anemia by increasing cation permeability, leading to erythrocyte dehydration in humans and mice. Although PIEZO1 plays a key role in erythrocyte homeostasis, its role in SCD remains unknown. Here, we demonstrate that the function of the PIEZO1 channel is upregulated in sickle erythrocytes of humans and mice, and this enhancement can be restored through a dietary intervention. We found that PIEZO1 activity in sickle erythrocytes resembles that of the GOF mutation causing hemolytic anemia. A diet enriched in the ω -3 fatty acid eicosapentaenoic (EPA) acid decreases PIEZO1 activity in sickle erythrocytes, attenuates hemolysis, and reduces hypoxia-induced sickling. Furthermore, EPA reduces inflammatory markers. We propose that PIEZO1 contributes to the increase in nonselective cationic conductance (i.e., Psickle), which leads to dehydration downstream of hemoglobin polymerization. Our results suggest that reducing PIEZO1 function represents a promising therapeutic strategy to reestablishing normal cation permeability in SCD.}, archive = {J_PNAS}, author = {Romero, Luis O. and Bade, Manisha and Elsherif, Laila and Williams, Jada D. and Kong, Xiangmei and Adebiyi, Adebowale and Ataga, Kenneth I. and Ma, Shang and Cordero-Morales, Julio F. and Vásquez, Valeria}, doi = {10.1073/pnas.2514863122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2514863122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Enhanced PIEZO1 function contributes to the pathogenesis of sickle cell disease}, volume = {122}, year = {2025}, }
• (2025). How to upgrade stolen organelles into permanent plastids: A comparative transcriptomic perspective. PNAS, 122(40), e2514821122. (www)

  @article{ , abstract = {Tertiary plastids derived from diatoms in “dinotom” dinoflagellates offer a rare view of organellogenesis in action, while the genomic and metabolic processes underlying their conversion remain poorly understood. Here, we present a comparative transcriptomic analysis of two dinotoms at different plastidial levels: Durinskia capensis at the kleptoplastidy state, alongside its kleptoplastid-source diatom Nitzschia captiva , and its close relative Durinskia kwazulunatalensis at an early permanent state. We show that in both dinotoms, the diatom nucleus retains high transcriptional autonomy, but its expression profile is plastid biased, signaling early host influence. In contrast, only D. kwazulunatalensis exhibits striking signs of genomic reconfiguration in the diatom nucleus: intron insertions, increased guanine (G) and cytosine (C) content, and growing nucleotide similarity to host transcripts. These shifts suggest an incipient nucleomorph-like transformation. Metabolically, only D. kwazulunatalensis expresses a complete hexose phosphate export pathway, suggesting deeper metabolic integration, while both species retain simpler carbohydrate transport routes. Additionally, we propose that diatom karyokinesis might be controlled by a dual mechanism via suppression of key transcription factors at the G1-S checkpoint and nitrate availability. Together, our findings reveal a continuum of plastid integration degrees, from temporary organelle theft to genomic accommodation and metabolic codependence. Dinotoms thus serve not only as evolutionary artifacts but as living laboratories, illuminating how kleptoplastids inch toward permanence.}, archive = {J_PNAS}, author = {Yamada, Norico and Dorrell, Richard G. and Cenci, Ugo and Kroth, Peter G. and Lombard, Vincent and Sprecher, Brittany N.}, doi = {10.1073/pnas.2514821122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2514821122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How to upgrade stolen organelles into permanent plastids: A comparative transcriptomic perspective}, volume = {122}, year = {2025}, }
• (2025). Tyrosine phosphorylation coupling of one-carbon metabolism and virulence in an endogenous pathogen. PNAS, 122(40), e2514754122. (www)

  @article{ , abstract = {Endogenous pathogens can constrain virulence to ensure survival in the host. Pathogenic state can be controlled by metabolic responses to the prevailing microenvironment; however, the coupling and effector mechanisms are not well understood. Flux through the one-carbon metabolism (OCM) pathway can modulate virulence of the oral pathobiont Porphyromonas gingivalis , and here we show that this is controlled by tyrosine phosphorylation-dependent differential partitioning of gingipain proteases. The OCM essential precursor pABA inhibits the low molecular weight tyrosine phosphatase Ltp1, and consequently relieves inhibition of its cognate kinase, Ptk1. We found that in the absence of pABA, reduced Ptk1 kinase activity blocks extracellular release of gingipains. Surface retention of gingipains confers resistance to neutrophil mobilization and killing, and virulence in animal models of disease is elevated. Reciprocally, Ptk1 and gingipains are required for maximal flux through OCM, and Ptk1 can phosphorylate the OCM pathway enzymes GlyA and GcvT. Further, ALP, an alkaline phosphatase involved in synthesis of DHPPP, which combines with pABA to make DHP, is phosphorylated and activated by Ptk1. We propose, therefore, that although the primary function of Ptk1 is to maintain OCM balance, it mechanistically couples metabolism with tunable pathogenic potential through directing the location of proteolytic virulence factors.}, archive = {J_PNAS}, author = {Stocke, Kendall S. and Pandey, Satya D. and Jin, Shunying and Perpich, John D. and Yakoumatos, Lan and Kosaki, Hirotaka and Wilkey, Daniel W. and Fitzsimonds, Zackary R. and Vashishta, Aruna and Snider, Ian and Sriwastva, Mukesh K. and Li, Hong and Jin, Jiu-Zhen and Miller, Daniel P. and Merchant, Michael L. and Bagaitkar, Juhi and Uriarte, Silvia M. and Potempa, Jan and Lamont, Richard J.}, doi = {10.1073/pnas.2514754122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2514754122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tyrosine phosphorylation coupling of one-carbon metabolism and virulence in an endogenous pathogen}, volume = {122}, year = {2025}, }
• (2025). Parallel reactions on a single t cell receptor offer a robust kinetic proofreading mechanism. PNAS, 122(40), e2514057122. (www)

  @article{ , abstract = {T cells can recognize a few molecules of cognate antigen among vastly outnumbering noncognate ligands. The T cell receptor (TCR) differentiates antigens based on antigen–TCR binding dwell time through a kinetic proofreading process. Historically, this has been modeled as the ligated receptor undergoing a series of reactions before producing a signal. In such a sequential mechanism, the number of steps is a key determinant of discrimination fidelity. Here, we consider two features of the molecular mechanism of TCR activation that diverge from a sequential process and suggest that an alternative kinetic proofreading mechanism may be at play. First, activation processes of multiple ITAM domains of the TCR represent parallel reaction sequences taking place on a single TCR molecule. Second, the states of the parallel proofreading reactions are integrated to produce a binary output from each TCR in the form of a discrete LAT condensation event, which may or may not occur. We examine a revised kinetic proofreading scheme based on parallel reactions followed by an integration step (multithread scheme) and compare its performance with the sequential scheme in a stochastic setting. A distinct difference in a multithread scheme is that multiplicity of the parallel reaction threads provides an additional means to increase discrimination fidelity. This relieves the need for fine-tuned kinetics among chemically distinct reaction steps, which is a major hurdle for physical implementation of a sequential mechanism. Lastly, we reinterpret previously reported experimental observations and find that various proofreading behaviors are well described as proofreading through parallel reaction threads.}, archive = {J_PNAS}, author = {Morita, Shumpei and Groves, Jay T.}, doi = {10.1073/pnas.2514057122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2514057122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Parallel reactions on a single t cell receptor offer a robust kinetic proofreading mechanism}, volume = {122}, year = {2025}, }
• (2025). Spectroscopic supermassive dark star candidates. PNAS, 122(40), e2513193122. (www)

  @article{ , abstract = {Dark Stars (DSs), i.e., early stars composed almost entirely of hydrogen and helium but powered by Dark Matter (DM), could form in zero metallicity clouds located close to the center of high redshift DM halos. In 2023, three of us identified (in a PNAS work) the first three photometric DS candidates: JADES-GS-z11-0, JADES-GS-z12-0, and JADES-GS-z13-0. We report here our results of a follow-up analysis based on available NIRSpec JWST data. We find that JADES-GS-z11-0 and JADES-GS-z13-0 are spectroscopically consistent with a DS interpretation. Moreover, we find two additional spectroscopic DS candidates: JADES-GS-z14-0 and JADES-GS-z14-1, with the former being the second most distant luminous object ever observed. We furthermore identify, in the spectrum of JADES-GS-z14-0, a tentative feature ( S / N ∼ 2 ) indicative of the smoking gun signature of DSs: the He II λ 1640 absorption line. In view of ALMA’s recent identification of a probable O III nebular emission line in the spectrum of JADES-GS-z14-0, the simple interpretation of this object as an isolated DS is unlikely. If both spectral features survive follow-up observations, it would imply a DS embedded in a metal rich environment, requiring theoretical refinements of the formation of evolution of DSs, which in previous studies were assumed to form in isolation, without any companions.}, archive = {J_PNAS}, author = {Ilie, Cosmin and Mahmud, Sayed Shafaat and Paulin, Jillian and Freese, Katherine}, doi = {10.1073/pnas.2513193122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2513193122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spectroscopic supermassive dark star candidates}, volume = {122}, year = {2025}, }
• (2025). Biliverdin reductase a is a major determinant of protective NRF2 signaling. PNAS, 122(40), e2513120122. (www)

  @article{ , abstract = {Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a nonenzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical nonenzymatic antioxidant activity. Transcriptomic analyses further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived factor-like 2 (NRF2), a major transcriptional regulator of cellular redox signaling. ChIP-seq and RNA-seq analyses reveal that BVRA and NRF2 coordinate the expression of antioxidant genes, many of which are typically dysregulated in neurodegenerative conditions such as Alzheimer’s disease. Thus, this noncanonical BVRA–NRF2 axis controls an essential pathway of redox signaling in neuroprotection. Our findings position BVRA as a dual-function integrator of antioxidant defense across both lipophilic and hydrophilic compartments, bridging these two distinct modes of redox protection in the brain.}, archive = {J_PNAS}, author = {Vasavda, Chirag and Kothari, Ruchita and Ammal Kaidery, Navneet and Chakraborty, Suwarna and Jamuna Tripathi, Sunil and Dhindsa, Ryan S. and Ricco, Cristina and Shanmukha, Shruthi and Saberi, Samaneh and Lefler, Julia E. and Kothari, Priyanka and Chaubey, Kalyani and Snowman, Adele M. and Ostrowski, Michael C. and Barone, Eugenio and Iyer, Lakshminarayan M. and Aravind, L. and Sharma, Sudarshana M. and Pieper, Andrew A. and Thomas, Bobby and Snyder, Solomon H. and Paul, Bindu D.}, doi = {10.1073/pnas.2513120122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2513120122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biliverdin reductase a is a major determinant of protective NRF2 signaling}, volume = {122}, year = {2025}, }
• (2025). Geometrical compartmentalization of trigger waves. PNAS, 122(40), e2512872122. (www)

  @article{ , abstract = {Trigger waves, self-regenerating fronts of biochemical activity that spread without losing speed or amplitude, are widespread in cell signaling. Apoptosis is one example of a process that propagates through the cytoplasm via trigger waves. Curiously, in some contexts, like synaptic pruning, apoptotic caspase activation is confined to specific subcellular regions. We hypothesized that at junctions between a thin cytoplasmic extension, like a dendritic spine, and a thicker one, like a dendrite, trigger wave propagation may be blocked even though diffusion is not, as a result of the general properties of trigger waves and bistable systems. This hypothesis was explored theoretically through modeling studies and dimensional arguments, which confirmed that trigger wave compartmentalization was possible and that the critical channel width required for compartmentalization was likely to be biologically relevant. These predictions were then tested experimentally with undiluted Xenopus egg extracts that were induced to undergo apoptosis. We found that channels that are less than a few microns in diameter are small enough to compartmentalize apoptosis, and that the critical width is inversely proportional to trigger wave speed. Thus, cellular projections and tubules can allow for the compartmentalization of biochemical states within a spatially continuous cytoplasm, a fundamental yet previously overlooked mechanism for controlling biochemical signaling and cellular functions.}, archive = {J_PNAS}, author = {Li, Zhengda and Zhang, Kevin S. and Chen, Yuping and Tang, Sindy K. Y. and Ferrell, James E.}, doi = {10.1073/pnas.2512872122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2512872122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Geometrical compartmentalization of trigger waves}, volume = {122}, year = {2025}, }
• (2025). Mapping macaque to human cortex with natural scene responses. PNAS, 122(40), e2512619122. (www)

  @article{ , abstract = {Neuroscience has long relied on macaque studies to infer human brain function, yet identifying functionally corresponding brain regions across species and measurement modalities remains a fundamental challenge. This is especially true for the higher-order cortex, where functional interpretations are constrained by narrow hypotheses and anatomical landmarks are often nonhomologous. We present a data-driven approach for mapping functional correspondence across species using rich, naturalistic stimuli. By directly comparing macaque electrophysiology with human fMRI responses to 700 natural scenes, we identify fine-grained alignment based on response pattern similarity, without relying on predefined tuning concepts or hand-picked stimuli. As a test case, we examine the ventral face patch system, a well-studied but contested domain in cross-species alignment. Our approach resolves a long-standing ambiguity by supporting a correspondence between macaque ML and human FFA and between AL and more anterior temporal cortex in humans. This result is consistent with full-brain anatomical warping but inconsistent with prior studies limited by narrow functional hypotheses. These findings show that natural image-evoked response patterns provide a robust foundation for cross-species functional alignment, supporting scalable comparisons as large-scale primate recordings become more widespread.}, archive = {J_PNAS}, author = {Vinken, Kasper and Sharma, Saloni and Livingstone, Margaret S.}, doi = {10.1073/pnas.2512619122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2512619122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mapping macaque to human cortex with natural scene responses}, volume = {122}, year = {2025}, }
• (2025). Overcoming the space clamp effect: Reliable recovery of local and effective synaptic conductances of neurons. PNAS, 122(40), e2512294122. (www)

  @article{ , abstract = {Neurons process information by integrating thousands of synaptic inputs along their dendrites. Understanding the computational principles underlying neuronal information processing requires a reliable measure of synaptic conductance dynamics that accurately represents the input sources before signal integration and processing. Prevailing approaches to measuring synaptic conductances typically employ a voltage clamp at the soma of a neuron and assume the neuron as an isopotential point when processing electrical signals. However, owing to the presence of the well-known space clamp effect, the measurement of synaptic conductances through these methods often leads to significant errors, impeding the elucidation of dendritic signal features and subsequent signal integration processes. To address this issue, here we first develop a two-step clamp method at the soma that separately recovers the mean and time constant information of local synaptic conductance on the dendrite with high accuracy when a neuron receives a single synaptic input. Furthermore, under in vivo conditions of multiple synaptic inputs, we propose an intercept method to extract effective net excitatory and inhibitory synaptic conductances from measurements of synaptic currents at the soma. Both methods are grounded in mathematical perturbation analyses of a conductance-based passive cable model and are validated across multiple biologically detailed multicompartment neuron models with active channels, including Purkinje neuron, pyramidal neuron, and fast-spiking interneuron. Results demonstrate that our methods effectively circumvent the space clamp effect, offering reliable means to assess the role of measured conductances and synaptic activity in neuronal information processing.}, archive = {J_PNAS}, author = {Wang, Ziling and McLaughlin, David W. and Zhou, Douglas and Li, Songting}, doi = {10.1073/pnas.2512294122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2512294122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Overcoming the space clamp effect: Reliable recovery of local and effective synaptic conductances of neurons}, volume = {122}, year = {2025}, }
• (2025). Hidden order in active nematic defects. PNAS, 122(40), e2512147122. (www)

  @article{ , abstract = {Hyperuniformity and giant number fluctuations represent opposite ends in a spectrum of statistical correlations found in physical systems outside of thermal equilibrium. Dynamic phase transitions exhibit critical points that are hyperuniform, while anomalously large fluctuations are often quoted as a hallmark of active matter. Here, we show that the apparently disordered state of active nematic defects exhibits suppression of fluctuations on scales as large as the system size, reminiscent of what is seen for ordered lattices. Modeling the nematic defects in terms of continuum densities, we show that their distribution becomes asymptotically hyperuniform in the limit where their proliferation is solely driven by activity, rather than by thermal fluctuations. When both effects are at play, the resultant hyperuniform structure is limited to a finite range of length scales, ℓ < ℓ × , with ℓ × → ∞ as thermal unbinding is suppressed. The system of active nematic defects can therefore be said to possess hidden order across scales provided ℓ is comparable to the system size. This organization is most pronounced when considering the subpopulation of either the positive or the negative defects, illustrating lack of multihyperuniformity. Our experimental findings are supported by hydrodynamic theory and agent-based simulations, which further allow elucidating the role of both creation/annihilation of defect pairs and of their mutual repulsion and attraction in achieving hyperuniformity.}, archive = {J_PNAS}, author = {de la Cotte, Alexis and Pearce, Daniel J. G. and Nambisan, Jyothishraj and Puggioni, Leonardo and Levy, Aviv and Giomi, Luca and Fernandez-Nieves, Alberto}, doi = {10.1073/pnas.2512147122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2512147122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hidden order in active nematic defects}, volume = {122}, year = {2025}, }
• (2025). High energy density carbon–cement supercapacitors for architectural energy storage. PNAS, 122(40), e2511912122. (www)

  @article{ , abstract = {Electron-conducting carbon concrete (ecˆ3) is a multifunctional cement-based composite material that combines mechanical robustness with electrochemical energy storage. To further expand our understanding of structure–function relationships in this complex multiphase material system and provide a roadmap for transitioning this technology from a simple proof-of-concept to a viable large-scale energy storage alternative, we report insights into the nanoscale connectivity of the electrode’s conductive carbon network, explore different electrolyte compositions and material integration strategies, and highlight opportunities for device scaling. Through the use of FIB-SEM tomography, the electrode’s percolating fractal-like nano-carbon black network has been visualized at the nanoscale, providing insights into the theoretical energy storage capacity of this material. To reduce the required times for the production of functional electrodes, we also present a cast-in electrolyte approach, where centimeter-thick electrodes could be produced without the need for postcuring steps. In these prototypes, device performance scales linearly with electrode thickness and cell count, and a simple analytical model was developed to explain these scaling phenomena. Furthermore, the exploration of alternative ionic and organic electrolytes further contribute to improved electrochemical behavior, with the fabricated designs ultimately achieving a 10-fold increase in supercapacitor energy density compared to previous designs. Finally, we were able to fabricate a 12 V, 50 F supercapacitor module and a 9 V arch prototype that integrate energy storage into load-bearing architectural elements. These functional prototypes highlight the potential for real-time structural health monitoring, while demonstrating the potential of our ecˆ3 technology for the production of a scalable, high-voltage concrete energy-storing infrastructure.}, archive = {J_PNAS}, author = {Stefaniuk, Damian and Weaver, James C. and Ulm, Franz-Josef and Masic, Admir}, doi = {10.1073/pnas.2511912122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2511912122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High energy density carbon–cement supercapacitors for architectural energy storage}, volume = {122}, year = {2025}, }
• (2025). Emerging hemispheric asymmetry of earth’s radiation. PNAS, 122(40), e2511595122. (www)

  @article{ , abstract = {Twenty-four years of satellite observations from the Clouds and the Earth’s Radiant Energy System show a northern hemisphere (NH) minus southern hemisphere (SH) trend difference of 0.34 ± 0.23 Wm −2 dec −1 (5 to 95% CI) in absorbed solar radiation (ASR) and a weaker trend difference of 0.21 ± 0.21 Wm −2 dec −1 in outgoing longwave radiation. The emerging darkening of the NH relative to the SH is associated with changes in hemispheric differences in aerosol–radiation interactions, surface albedo, and water vapor changes. Cloud changes also contribute to a greater ASR hemispheric contrast, but the magnitude is small due to opposing trend differences in the tropics and extratropics. The break in hemispheric symmetry in ASR challenges the notion that clouds naturally compensate for forced hemispheric asymmetries in noncloud properties. Hemispheric (a)symmetry in radiation is linked with the atmosphere–ocean general circulation. How clouds respond to this hemispheric imbalance has important implications for future climate.}, archive = {J_PNAS}, author = {Loeb, Norman G. and Thorsen, Tyler J. and Kato, Seiji and Rose, Fred G. and Hodnebrog, Øivind and Myhre, Gunnar}, doi = {10.1073/pnas.2511595122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2511595122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Emerging hemispheric asymmetry of earth’s radiation}, volume = {122}, year = {2025}, }
• (2025). Molecular divergence and convergence of mammalian antibody responses to the influenza virus hemagglutinin stem. PNAS, 122(40), e2510927122. (www)

  @article{ , abstract = {Antibody responses to the influenza virus hemagglutinin (HA) stem, a major target for broadly protective vaccine development, have been extensively characterized in humans. However, they remain largely elusive in other natural influenza hosts, including pigs, which are considered intermediate hosts for the emergence of pandemic strains. By leveraging single-cell variable, diversity, and joining (VDJ) sequencing, this study identified 25 porcine antibodies to the HA stem, including two cross-group bnAbs, 14-8 and 15-1, from vaccinated specific-pathogen-free pigs and unvaccinated domestic pigs. Cryogenic electron microscopy analysis showed that 14-8 targeted the well-characterized central stem epitope, whereas 15-1 bound to a linear epitope spanning the HA1/HA2 junction. Additionally, while some porcine and human bnAbs targeted the central stem epitope via convergent molecular signatures, our results revealed a pig-specific recurring binding motif. Overall, our findings provide important insights into the commonalities and uniqueness of antibody responses between different species, which have significant implications for vaccine development for nonhuman animals.}, archive = {J_PNAS}, author = {Lv, Huibin and Teo, Qi Wen and Pholcharee, Tossapol and Liu, Wenkan and Roy, Sawrab and Shi, Lei and Gopal, Akshita B. and Ardagh, Madison R. and Chen, Chunke and Sun, Yuanxin and Huan, Yang Wei and Harrington, Walter N. and Mehta, Arjun and Szlembarski, Mateusz and Choi, Danbi and Gao, Qihong and Fung, Fiona S. L. and Xu, Fangxiu and Webby, Richard J. and Mok, Chris K. P. and Ma, Wenjun and Wu, Nicholas C.}, doi = {10.1073/pnas.2510927122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2510927122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular divergence and convergence of mammalian antibody responses to the influenza virus hemagglutinin stem}, volume = {122}, year = {2025}, }
• (2025). Mouse X-linked microRNA cluster regulates the meiotic checkpoint and prdm9-driven hybrid sterility in a copy number–dependent manner. PNAS, 122(40), e2510229122. (www)

  @article{ , abstract = {One of the reproductive barriers between diverging populations during formation of a new species is the sterility of their hybrids. The Prdm9- driven hybrid male sterility of Mus musculus musculus × Mus musculus domesticus hybrids depends on the interaction between PRDM9, a histone methyltransferase that determines the positions of meiotic recombination hotspots, and an as yet unknown X-linked genetic factor within the Hybrid sterility X2 ( Hstx2 ) locus. Here, we report that the Mir465 microRNA (miRNA) gene cluster is the predicted Hstx2 hybrid sterility factor. We show that removal of the Mir465 genes restores the fertility of sterile hybrids and improves meiotic synapsis of homologous chromosomes. Mir465 knockout also restores spermatogenesis in sterile chromosomal translocation carriers, demonstrating that Mir465 acts as a meiotic checkpoint that can be activated independently of Prdm9 intersubspecific incompatibility. Furthermore, the Mir465 knockout increases the global recombination rate in hybrids and in parental Mus m. domesticus mice. This demonstrates that Mir465 is responsible for the phenotypes of the two overlapping genetic loci, the Hstx2 engaged in fertility of hybrids and the Meiotic recombination 1 ( Meir1 ) controlling the recombination rate. The finding of enlarged Mir465 clusters in all European Mus m. musculus samples tested and the identification of differentially expressed targets suggest that the reproductive barrier between the two subspecies is sensitive to copy number variation of Mir465 genes. Together, the underdominant interaction between Prdm9 and Mir465 provides a rare example of Dobzhansky–Muller incompatibility in hybrids of closely related species, making it accessible for further analysis at the molecular level.}, archive = {J_PNAS}, author = {Jansa, Petr and Tanieli, Giordano and Vucinic, Kim and Lustyk, Diana and Fusek, Karel and Valiskova, Barbora and Morimoto, Kento and Mizuno, Seiya and Ullrich, Kristian and Odenthal-Hesse, Linda and Provaznik, Jan and Benes, Vladimir and Pfeiferova, Lucie and Kolar, Michal and Gergelits, Václav and Pialek, Jaroslav and Forejt, Jiri}, doi = {10.1073/pnas.2510229122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2510229122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mouse X-linked microRNA cluster regulates the meiotic checkpoint and prdm9-driven hybrid sterility in a copy number–dependent manner}, volume = {122}, year = {2025}, }
• (2025). Electronic origin of the anomalous melting of sodium under pressure. PNAS, 122(40), e2510213122. (www)

  @article{ , abstract = {Despite extensive experimental and theoretical investigations, the fundamental electronic origin of compressed sodium’s melting temperature reversal under pressure, characterized by a maximum and a minimum in its melting curve, remains unclear. A recent two-state model proposed for high-pressure potassium, which exhibits a similar melting anomaly, attributes this behavior to changes in the distribution of non-nuclear localized electrons (electrides), resulting in distinct liquid phases. To test this hypothesis for sodium, we conducted ab initio molecular dynamics simulations to examine its atomic dynamics and electronic properties under high pressure. Our results reveal no discontinuities in atomic or electronic transport properties, nor any evidence of multiple inherent structural forms. Furthermore, the electronic screening potential governing liquid structure remains largely unchanged above 50 GPa. Instead, we find that the key parameter responsible for the melting anomaly arises from differences in the average number of electrons per non-nuclear maximum, which affects the relative packing densities of the liquid and solid phases.}, archive = {J_PNAS}, author = {Liu, Yuan and Liu, Hanyu and Tse, John S.}, doi = {10.1073/pnas.2510213122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2510213122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electronic origin of the anomalous melting of sodium under pressure}, volume = {122}, year = {2025}, }
• (2025). Living/controlled supramolecular protein polymerization. PNAS, 122(40), e2510077122. (www)

  @article{ , abstract = {With the learning from living protein polymerization in nature, achieving living/controlled supramolecular assembly of biopolymers such as proteins in vitro is a longstanding challenge for material design. Herein, we provide a thiol-regulated interfacial protein aggregation (TRIPA) for unfolded protein systems with typical living polymerization features. By triggering globule proteins into the unfolded state through a reversible exchange reaction of disulfide bonds and sulfhydryl agents (R-SH), protein monomers are partially unfolded and assembled at the air–water/solid–water interface (AWI/SWI) through the entropy-driven adsorption and conformation transition. The process could be well repeated over time to form a two-dimensional (2D) nanofilm at the interface by following a pathway of monomer-oligomer-2D assembly. Similar to living polymerization, the film thickness exhibited a linear increase with the assembly conversion ratio of the monomers. With the stepwise addition of native protein into the reaction system, the thickness periodically increased in a linear manner. Such living/controlled supramolecular polymerization (LCSP) of protein at the interface leads to the synthesis of a nanofilm with well-defined flat morphology, ultrahigh modulus, and nano- to macroscale controlled thickness. The resultant protein nanofilm could then attach onto a variety of flexible and rigid material surfaces to produce a stable structural color coating. Compelling evidence in the present work thus underlines a demonstration of LCSP of biopolymers in vitro. It may hold a solid impact by opening a window for living/controlled polymerization of versatile biospecies such as proteins, saccharides, nucleic acids, and cells.}, archive = {J_PNAS}, author = {Ren, Hao and Zhang, Qianhui and Wang, Kai and Xu, Siqi and Liu, Wei and Tao, Fei and Han, Qian and Miao, Shuting and Zhang, Yingying and Liu, Yonggang and Yang, Peng}, doi = {10.1073/pnas.2510077122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2510077122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Living/controlled supramolecular protein polymerization}, volume = {122}, year = {2025}, }
• (2025). Chemobiological synthesis of benzene, toluene, ethylbenzene, and xylene from glucose or glycerol. PNAS, 122(40), e2509568122. (www)

  @article{ , abstract = {Benzene, toluene, ethylbenzene, and p -xylene (BTEX) are key aromatic hydrocarbons widely used in fuels, polymers, and industrial chemicals, yet their production remains heavily dependent on fossil resources, raising environmental and public health concerns. To promote de novo production of BTEX from renewable feedstocks, we developed a chemobiological platform that integrates microbial biosynthesis with chemical deoxygenation. Four metabolically engineered Escherichia coli strains were constructed to produce one of four oxygenated precursors of BTEX—phenol, benzyl alcohol, 2-phenylethanol, or 2,5-xylenol—from glucose or glycerol. After in situ two-phase extractive fermentation of the individual engineered strains using isopropyl myristate (IPM) as the organic solvent, the organic phase containing one of the oxygenated precursors was separated from the aqueous phase and subjected to distinct chemical deoxygenation reactions to reduce the precursor to the corresponding BTEX compound. This modular approach, based on the compatible organic solvent, streamlines biotransformation and consecutive chemical derivatization, providing a practical and viable route to sustainable BTEX production. The platform is extensible and provides a generalizable framework for integrating biosynthesis with chemical deoxygenation in hybrid bioprocessing.}, archive = {J_PNAS}, author = {Zou, Xuan and Kim, Taewan and Luo, Zi Wei and Choi, Kyeong Rok and Han, Sunkyu and Lee, Sang Yup}, doi = {10.1073/pnas.2509568122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2509568122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chemobiological synthesis of benzene, toluene, ethylbenzene, and xylene from glucose or glycerol}, volume = {122}, year = {2025}, }
• (2025). Density-dependent recruitment but not survival drives cyclic dynamics in a field vole population. PNAS, 122(40), e2509516122. (www)

  @article{ , abstract = {Arguably, the most fundamental question in population ecology is what drives patterns in the abundance of populations? Small rodents exhibiting regular multiannual cycles in abundance have long been a test bed for addressing this question. The prevailing orthodoxy, the predation hypothesis, contends that nonmigratory, specialist predators are necessary, and specialist and generalist predators, combined, are both necessary and sufficient, for causing population cycles. Thus, variations in survival, from predation, are the key drivers of the cycles. However, this, and other competing theories, have hitherto lacked supportive demographic evidence and hence a solid evidential foundation. Here, we provide such evidence, analyzing 10 y of monthly data from a cyclic field vole population. We find, contrary to the prevailing orthodoxy, that recruitment, not survival, varied substantially from phase to phase in the cycles, made the major contribution to variations in population growth rate, and had cycle-phase-specific negative delayed density dependence. These results, their consistency with what is known from other systems, and the weak demographic foundations of the predation hypothesis, together suggest recruitment, specifically breeding-season length, not predation, as the cycles’ driving force. They therefore suggest that re-evaluation of the importance of the various determinants of population abundances, more generally, may be necessary.}, archive = {J_PNAS}, author = {Lambin, Xavier and Begon, Mike and Burthe, Sarah J. and Graham, Isla M. and MacKinnon, James L. and Telfer, Sandra and Oli, Madan K.}, doi = {10.1073/pnas.2509516122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2509516122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Density-dependent recruitment but not survival drives cyclic dynamics in a field vole population}, volume = {122}, year = {2025}, }
• (2025). Activation of epigenetic reprogramming via crotonylation overcomes resistance to EGFR-TKI therapy in lung cancer. PNAS, 122(40), e2509255122. (www)

  @article{ , abstract = {Posttranslational modifications (PTMs) on histones play critical roles in cellular processes, including gene expression and tumorigenesis. However, the regulatory mechanisms and functional consequences of newly identified lysine acylation modifications in cancer therapy remain to be elucidated. Here, we established diverse preclinical tumor models resistant to epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and focused on histone lysine crotonylation (Kcr), as it exhibited more pronounced alterations compared to other acylations. Next, we identified acyl-CoA synthetase short-chain family member 2 as a key regulator responsible for the resistance-associated decrease in crotonylation levels. Furthermore, integrated crotonylomic, transcriptomic, and epigenomic profiling, supplemented by gene manipulation studies, revealed that EGFR-TKI resistance resulted from transcriptional suppression of HNF1A and activation of the PI3K/AKT signaling pathway, which were regulated by reduced histone H3 lysine 56 crotonylation. Importantly, through pharmacological screening, we identified a histone decrotonylase inhibitor that enhanced EGFR-TKI sensitivity by activating epigenetic reprogramming through the selective upregulation of histone Kcr levels across multiple models in vitro and in vivo. Collectively, our findings uncover a previously unrecognized epigenetic mechanism driven by crotonylation that contributes to EGFR-TKI resistance, highlighting the potential of modulating crotonylation as a novel therapeutic strategy to enhance the efficacy of EGFR-TKIs in lung cancer.}, archive = {J_PNAS}, author = {Chen, Sihong and Zhong, Mengyan and Wang, Xiaoyuan and Su, Youwei and Zhao, Yingxi and Wang, Simeng and Liu, Shougeng and Zhao, Yongshan and Zhang, Yang and Fan, Xinyu and Liu, Zongang and Jia, Lina and Bao, Xuefei and Cui, Wei and Yang, Jingyu and Wu, Chunfu and Chen, Guoliang and Wang, Lihui}, doi = {10.1073/pnas.2509255122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2509255122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Activation of epigenetic reprogramming via crotonylation overcomes resistance to EGFR-TKI therapy in lung cancer}, volume = {122}, year = {2025}, }
• (2025). A chemical epigenetic tool to probe site-specific DNA-binding protein complexes. PNAS, 122(40), e2509021122. (www)

  @article{ , abstract = {Site-specific DNA binding by proteins is critical for regulating transcriptional activity and cell fate decision. However, identifying proteins bound to specific genomic regions (e.g., promoter or enhancer regions) remains challenging. To address this, we developed a chemical epigenetic tool, named Site-specific noncanonical amino acid-mediated capture of protein (SCOPE), incorporating a photo-crosslinking amino acid into a nuclease-deficient dCas9 mutant. Human pluripotent stem cells (hPSCs) carrying SCOPE enable the capture of proteins bound to, in theory, any genomic location, facilitating the study of the cell context–dependent DNA–protein interactions. Using SCOPE, we identified the OCT4/SOX2/CARHSP1 complex binding to the NANOG promoter to maintain pluripotency in hPSCs. During ectoderm differentiation, ZIC2 acts as a competitive inhibitor, binding the same promoter region to downregulate NANOG expression and promote differentiation. Additionally, SCOPE identified that ZNF8 binds to the distal regulatory region of OCT4 to maintain naïve pluripotency. In summary, SCOPE provides a robust system for uncovering cell context–dependent, site-specific genome regulators, offering valuable insights into gene regulation networks driving cell fate transitions.}, archive = {J_PNAS}, author = {Zhu, Jiajun and Li, Zhucui and Xue, Dongxiang and Meng, Zihe and Shao, Sida and Pulecio, Julian and Zhang, Guoan and Huangfu, Danwei and Evans, Todd and Chen, Shuibing and Schultz, Peter G.}, doi = {10.1073/pnas.2509021122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2509021122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A chemical epigenetic tool to probe site-specific DNA-binding protein complexes}, volume = {122}, year = {2025}, }
• (2025). Meta-analysis finds large variation but no general patterns in the relationship between climate and parasitism in terrestrial animals. PNAS, 122(40), e2508970122. (www)

  @article{ , abstract = {Climate can vary spatially and temporally and is becoming increasingly unpredictable due to climate change. It can have a large impact on host–parasite interactions and investigating this effect is vital both for understanding current parasite distribution and epidemiology, and predicting how this will change in the future. Here, we conducted a meta-analysis to determine whether temperature and precipitation have an overall effect on parasite prevalence and infection intensity in terrestrial animals. This is a phylogenetically controlled quantitative synthesis to assess parasite prevalence and infection intensity in terrestrial animals across contrasting temperatures and precipitation. We found large variation in the effect of temperature on parasite prevalence, precipitation on parasite prevalence, and temperature on infection intensity. This provides robust quantitative evidence against the controversial “warmer sicker world” hypothesis. There was no effect of climate on parasitism, irrespective of whether the parasite was an endoparasite or ectoparasite, or across different parasite lifecycles. Although some host and parasite taxa were understudied, we found no consistent taxonomic patterns. Importantly, we revealed large gaps in the literature, including the relationship between humidity, prevalence, and infection intensity. Ectoparasites and reptile hosts were also very underrepresented, and deserve further study. Focusing future research on these gaps will help to confirm whether certain types of host–parasite interactions are more or less sensitive to changes in climate, with implications for conservation.}, archive = {J_PNAS}, author = {Wolmuth-Gordon, Hannah S. and Koricheva, Julia and Brown, Mark J. F.}, doi = {10.1073/pnas.2508970122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2508970122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Meta-analysis finds large variation but no general patterns in the relationship between climate and parasitism in terrestrial animals}, volume = {122}, year = {2025}, }
• (2025). Uncovering cargo clients and accessory factors of AP-1 and AP-4 through vesicle proteomics. PNAS, 122(40), e2508961122. (www)

  @article{ , abstract = {The trans -Golgi network (TGN) is a crucial sorting station in the secretory pathway, where adaptor protein (AP) complexes ensure selective cargo packaging into transport vesicles. However, the complete repertoire of cargoes and regulators associated with individual AP complexes remains poorly defined. Intriguingly, AP-4-mediated TGN export operates independently of clathrin, suggesting the involvement of uncharacterized accessory factors in vesicle biogenesis. To address these gaps, we developed an in vitro vesicle formation assay using wild-type HeLa cells or cells deficient in AP1γ1 or AP4ε, reconstituting their roles in packaging their known clients, Vangl2 and ATG9A, respectively. Coupling this assay with label-free quantitative mass spectrometry, we mapped distinct cargo profiles for AP-1 (which buds from the TGN and ARF1-positive endosomes) and AP-4, identifying the 45 kDa calcium-binding protein (CAB45) as an AP-1-dependent cargo and the Type-1 angiotensin II receptor-associated protein (ATRAP) as an AP-4-dependent cargo. Additionally, we uncovered PRRC1 and WDR44 as cytosolic regulators essential for AP-4-mediated TGN export. Our study advances the mechanistic understanding of AP-1 and AP-4 in secretory trafficking and provides a robust strategy to systematically identify cargo clients and accessory factors for specific adaptor complexes.}, archive = {J_PNAS}, author = {Peng, Ziqing and Fan, Jingran and Liu, Yang and Jia, Qinyu and An, Junkun and Wang, Jianying and Huang, Yan and Yao, Zhong-Ping and Guo, Yusong}, doi = {10.1073/pnas.2508961122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2508961122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Uncovering cargo clients and accessory factors of AP-1 and AP-4 through vesicle proteomics}, volume = {122}, year = {2025}, }
• (2025). Identification of claudin-3 as an entry factor for rat hepacivirus. PNAS, 122(40), e2508736122. (www)

  @article{ , abstract = {Approximately 58 million people worldwide are believed to be infected with hepatitis C virus (HCV), a major causative agent of chronic liver diseases. Hepacivirus ratti strain rn-1, which was discovered from Rattus norvegicus (Norway rat) and designated Norway rat hepacivirus 1 (NRHV1), shares similar properties with HCV in terms of genetic homology, target cell tropism, pathogenicity, and the immune response. In vivo infection systems for NRHV1 will help overcome the challenges in HCV research for vaccine development. However, the virological characteristics of NRHV1, such as the mechanisms of cell entry, remain largely unexplored, in part owing to a paucity of cell culture systems for NRHV1. Here, we identified the host factors that facilitate NRHV1 entry by profiling the gene expression of two cell lines with different susceptibilities to NRHV1 infection. NRHV1 employs rodent orthologues of HCV entry factors, including scavenger receptor class BI, CD81, and occludin, and utilizes claudin-3 (CLDN3) but not claudin-1. The expression of rat and mouse, but not human, CLDN3 facilitates the entry of NRHV1 into murine cell lines that are nonsusceptible to NRHV1 infection. The host-specific cell entry of CLDN3 is determined by two amino acid residues, Ile 44 and Trp 46 , in extracellular loop 1. These findings suggest that CLDN3 serves as an entry factor for rat hepacivirus.}, archive = {J_PNAS}, author = {Tanaka, Tomohisa and Akaike, Yasunori and Kasai, Hirotake and Yamashita, Atsuya and Matsuura, Yoshiharu and Moriishi, Kohji}, doi = {10.1073/pnas.2508736122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2508736122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identification of claudin-3 as an entry factor for rat hepacivirus}, volume = {122}, year = {2025}, }
• (2025). Reaction-induced departures from continuum Navier–Stokes turbulence. PNAS, 122(40), e2508608122. (www)

  @article{ , abstract = {Reactive hydrodynamic turbulence is an inherently multiscale phenomenon, characterized by the separation between energy-containing, viscous, and molecular length and time scales. The separation between the viscous scale (the Kolmogorov scale) and the molecular mean free path ostensibly justifies a macroscopic description of reactive turbulence via the Navier–Stokes (NS) equations. However, here we use molecular-level simulations to demonstrate that exothermic bimolecular reactions can cause the NS description of turbulence to break down in the near-continuum regime. Sufficiently energetic heat-releasing reactive collisions strongly distort the Maxwell–Boltzmann velocity distribution function, modifying not only the macroscopic chemical rate law but the kinetic-energy-transfer processes as well. This translational nonequilibrium ultimately introduces significant departures from the NS description in the kinetic energy spectra at scales orders of magnitude larger than both the molecular mean free path and the Kolmogorov length scale. These departures prove substantial enough to meaningfully alter integrated quantities, including the overall turbulence kinetic energy itself.}, archive = {J_PNAS}, author = {Williams, Christopher T. and McMullen, Ryan M. and Gallis, Michael A.}, doi = {10.1073/pnas.2508608122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2508608122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reaction-induced departures from continuum Navier–Stokes turbulence}, volume = {122}, year = {2025}, }
• (2025). An extended network for regulation of heme homeostasis in cells. PNAS, 122(40), e2508237122. (www)

  @article{ , abstract = {Iron-bound tetrapyrroles (hemes) are essential for the regulation of cellular functions and bioenergetics. The processes of heme biosynthesis, transport, and degradation are responsible for the supply of heme in mitochondria and its insertion into other downstream proteins. What remains unresolved is how these processes interconnect and the wider implications for the cell in the restoration of homeostasis when heme concentrations change. We demonstrate a wide-ranging and coordinated response to changes in intracellular heme in HEK293 cells through a network of complementary mechanisms that extend well beyond the direct regulation of heme biosynthesis and degradation. These responses connect changes in heme homeostasis to mitochondrial function, including core metabolic processes such as the tricarboxylic acid cycle and oxidative phosphorylation, as well as to enzymes involved in the control and storage of iron. Our findings demonstrate far-reaching consequences to perturbations of heme homeostasis and provide insights into the complexity of the cellular hemome.}, archive = {J_PNAS}, author = {Gallio, Andrea E. and Marson, Noa A. and Heesom, Kate J. and Lewis, Philip A. and Alibhai, Dominic and Dugdale, Celyn A. and Herman, Andrew and Basran, Jaswir and Hudson, Andrew J. and Raven, Emma L.}, doi = {10.1073/pnas.2508237122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2508237122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An extended network for regulation of heme homeostasis in cells}, volume = {122}, year = {2025}, }
• (2025). High rates of polygyny do not lock large proportions of men out of the marriage market. PNAS, 122(40), e2508091122. (www)

  @article{ , abstract = {There is a widespread belief, in both the scholarly literature and the popular press, that polygyny prevents large numbers of men from marrying by skewing the sex ratio of the marriage market. In turn, the exclusion of men from marriage is thought to lead to negative outcomes, e.g., by fueling crime and armed conflict. In this paper, we investigate systematically the relationship between polygyny and men’s marriage prospects. First, using a demographic model, we show that marriage markets are skewed sufficiently feminine, under a range of realistic demographic scenarios, to sustain some level of polygyny without locking any men out of marriage. Second, through analysis of 84.1 million census records from 30 countries across Africa, Asia, and Oceania between 1969 and 2016, we show that the subnational association between the prevalence of polygyny and the prevalence of unmarried men is negative or null, rather than positive, for almost all countries in the sample. Third, through analysis of the full-count 1880 US federal census, we show that the average prevalence of unmarried men is lower, not higher, across counties of the West with Mormon polygyny, compared to other counties of the West, and to counties of the Midwest and the Northeast; it is higher only compared to counties of the South. Overall, these findings challenge a dominant narrative linking polygyny to negative social outcomes. Drawing on existing evidence, we suggest that the observed patterns may be explained by an underlying association between the prevalence of polygyny and the strength of promarriage norms.}, archive = {J_PNAS}, author = {Gaddy, Hampton and Sear, Rebecca and Fortunato, Laura}, doi = {10.1073/pnas.2508091122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2508091122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High rates of polygyny do not lock large proportions of men out of the marriage market}, volume = {122}, year = {2025}, }
• (2025). Influence of the protein corona on hematopoietic stem and progenitor cell uptake and macrophage clearance of membrane-wrapped nanoparticles. PNAS, 122(40), e2507922122. (www)

  @article{ , abstract = {The ideal delivery of therapeutic nanoparticles (NPs) to specific sites requires evading immune clearance and selectively binding target cells. Wrapping NPs in cell-derived membranes has shown promise in improving targeted delivery, but the mechanisms underlying this phenomenon are not fully understood. Protein corona (PC) formation on NPs can significantly alter their biological identity to influence biodistribution, making its characterization on membrane-wrapped NPs (MWNPs) and unwrapped NPs crucial. In this study, we compared MWNPs incorporating membranes derived from megakaryoblastic CHRF-288-11 cells, which can accumulate in bone marrow (BM) and preferentially bind hematopoietic stem and progenitor cells (HSPCs), with unwrapped NPs. We investigated differences in PC composition, macrophage uptake, target cell uptake, and biodistribution in wild type (WT) mice and knockout mice that have low or absent expression of different opsonin proteins. In vitro, MWNPs with a PC exhibited increased target cell uptake and decreased macrophage uptake compared to unwrapped NPs with a PC. Proteomics revealed apolipoprotein B as the dominant opsonin on both NP types after incubation in mouse, bovine, or human serum, with other proteins like complement, immunoglobulins, and apolipoproteins also being present. Biodistribution studies indicated a complex interplay between the PC and targeting/clearance, where complement component 3 and immunoglobulin G adsorption on MWNPs led to macrophage clearance but also enabled HSPC targeting. Meanwhile, apolipoprotein E adsorption facilitated hepatocyte clearance but reduced immune cell uptake in the liver. Future research on PCs could determine whether these mechanisms are generalizable to other types of MWNPs, potentially revealing strategies to enhance their effectiveness as delivery systems.}, archive = {J_PNAS}, author = {Sterin, Eric H. and Weinstein, Laura A. and Tiwari, Ashish and Kramarenko, George C. and Chowdhury, Chitran Roy and Li, Kejian and Day, Emily S.}, doi = {10.1073/pnas.2507922122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2507922122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Influence of the protein corona on hematopoietic stem and progenitor cell uptake and macrophage clearance of membrane-wrapped nanoparticles}, volume = {122}, year = {2025}, }
• (2025). The role of innate immunity, antibiotics, and bacteriophages in the course of bacterial infections and their treatment. PNAS, 122(40), e2507914122. (www)

  @article{ , abstract = {Critical to our understanding of infections and their treatment is the role the innate immune system plays in controlling bacterial pathogens. Nevertheless, many in vivo systems are made or modified such that they do not have an innate immune response. Use of these systems denies the opportunity to examine the synergy between the immune system and antimicrobial agents. In this study, we demonstrate that the larva of Galleria mellonella is an effective in vivo model for the study of the population and evolutionary biology of bacterial infections and their treatment. To do this, we test three hypotheses concerning the role of the innate immune system during infection. We show that i) sufficiently high densities of bacteria are capable of saturating the innate immune system, ii) bacteriostatic drugs and bacteriophages are as effective as bactericidal antibiotics in preventing mortality and controlling bacterial densities, and iii) minority populations of bacteria resistant to a treating antibiotic will not ascend. Using a highly virulent strain of Staphylococcus aureus and a mathematical computer-simulation model, we further explore how the dynamics of the infection within the short term determine the ultimate infection outcome. We find that immune activation in response to high densities of bacteria leads to a strong but short-lived immune response which ultimately results in a high degree of mortality. Overall, our findings illustrate the utility of the G. mellonella model system in conjunction with established in vivo models in studying infectious disease progression and treatment.}, archive = {J_PNAS}, author = {Berryhill, Brandon A. and Gil-Gil, Teresa and Witzany, Christopher and Goldberg, David A. and Vega, Nic M. and Regoes, Roland R. and Levin, Bruce R.}, doi = {10.1073/pnas.2507914122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2507914122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The role of innate immunity, antibiotics, and bacteriophages in the course of bacterial infections and their treatment}, volume = {122}, year = {2025}, }
• (2025). Sustainable separation of rare earth elements from wastes. PNAS, 122(40), e2507819122. (www)

  @article{ , abstract = {Rare earth elements (REEs) are indispensable in modern technologies, but their supply chain faces challenges due to limited geographical availability and political difficulties. Recycling REEs from industrial waste provides a sustainable alternative to mining, promoting a circular economy and reducing environmental impacts. The mainstay approaches for REE recovery, hydrometallurgical and pyrometallurgical methods, can be inefficient, consuming high energy and generating large aqueous and acid waste streams. Here, we introduce flash Joule heating (FJH) combined with chlorination (FJH-Cl 2 ) as an efficient method for REE separation and recovery by capitalizing on the free energies of formation (ΔG form ) of the metal chlorides and the boiling points of those metal chlorides. FJH-Cl 2 enables high-purity (>90%) and high-yield (>90%) REE recovery from waste magnets in a single step. Life cycle assessment and techno-economic analysis show that this process reduces the number of steps by 3× while reducing energy consumption by 87%, greenhouse gas emissions by 84%, and operating costs by 54% while eliminating water and acid use by 100% compared to traditional methods. This offers an environmentally friendly and economically viable pathway for sustainable REE recycling and recovery.}, archive = {J_PNAS}, author = {Xu, Shichen and Sharp, Justin and Deng, Bing and Liu, Qiming and Eddy, Lucas and Chen, Weiqiang and Shin, Jaeho and Chen, Shihui and Ye, Haoxin and JeBailey, Khalil and Li, Bowen and Si, Tengda and Gong, Kai and Tour, James M.}, doi = {10.1073/pnas.2507819122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2507819122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sustainable separation of rare earth elements from wastes}, volume = {122}, year = {2025}, }
• (2025). Aluminum speciation identification reveals water interactions in silicoaluminophosphate zeolites. PNAS, 122(40), e2507802122. (www)

  @article{ , abstract = {Water plays a crucial role in material development. As it is ubiquitous throughout zeolite generation and application, host–guest interaction between zeolite and water attracts broad interest, but mechanistic understanding remains fragmented. Here, advanced solid-state NMR techniques (2D 17 O SPAM-MQ, 27 Al{ 31 P} J -HMQC, 27 Al{ 29 Si} REDOR, and 1 H TQ-SQ NMR) combined with isotopic tracing and theoretical calculations determine water-induced octahedrally coordinated aluminum in silicoaluminophosphate molecular sieves (SAPOs) as an exclusive product of Al(OP) 4 units coordinated with two water molecules—a structure distinct from that in aluminosilicates. Based on the knowledge of aluminum speciation, we elucidate four water interaction mechanisms in SAPOs, including Brønsted-acid interaction, coordination, reversible/irreversible hydrolysis, and capillary condensation. Contrary to conventional wisdom attributing SAPO degradation to Al-O-P hydrolysis, we clarify that desilication dominates structural collapse, establishing Si environments as catalyst durability descriptors. These mechanistic insights decipher the nature of SAPO interacting with water and its fundamental differences from aluminosilicate zeolite.}, archive = {J_PNAS}, author = {Lou, Caiyi and Zhang, Wenna and Gao, Pan and Zhou, Yida and Zhi, Yuchun and Ye, Fangxiu and Yan, Wenfu and Xu, Shutao and Wei, Yingxu and Liu, Zhongmin}, doi = {10.1073/pnas.2507802122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2507802122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Aluminum speciation identification reveals water interactions in silicoaluminophosphate zeolites}, volume = {122}, year = {2025}, }
• (2025). Hierarchical woven fibrillar structures in developing single gyroids in butterflies. PNAS, 122(40), e2507297122. (www)

  @article{ , abstract = {Nature offers a remarkable diversity of nanomaterials that have extraordinary functional and structural properties. Intrinsic to nature is the impressive ability to form complex ordered nanomaterials via self-organization. One particularly intriguing nanostructure is the gyroid, a network-like structure exhibiting high symmetry and complex topology. Although its existence in cells and tissues across many biological kingdoms is well documented, how and why it forms remains elusive and uncovering these formation mechanisms will undoubtedly inform bioinspired designs. A beautiful example is the smooth single gyroid that is found in the wing scales of several butterflies, where it behaves as a photonic crystal generating a vibrant green color. Here, we report that the gyroid structures of the Emerald-patched Cattleheart, Parides sesostris , develop as woven fibrillar structures, in contrast to the commonly held assumption that they form as smooth constructs. Ultramicroscopy of pupal tissue reveals that the gyroid geometry consists of helical weavings of fibers, akin to hyperbolic line patterns decorating the gyroid. Interestingly, despite their fibrillar nature, electron diffraction reveals the absence of crystalline order within this material. Similar fibrillar structures are also observed in the mature wing scales of P. sesostris specimens with surgically altered pupal development, leading to a blue coloration. Our findings not only introduce a variation of the gyroid in biology but also have significant implications for our understanding of its formation in nature.}, archive = {J_PNAS}, author = {Jessop, Anna-Lee and Clode, Peta L. and Saunders, Martin and Evans, Myfanwy E. and Hyde, Stephen T. and McPherson, James N. and Pedersen, Kasper S. and Kirkensgaard, Jacob J. K. and Patel, Nipam H. and DeMarr, Kyle A. and McMillan, W. Owen and Wilts, Bodo D. and Schröder-Turk, Gerd E.}, doi = {10.1073/pnas.2507297122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2507297122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hierarchical woven fibrillar structures in developing single gyroids in butterflies}, volume = {122}, year = {2025}, }
• (2025). A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron–sulfur cluster and supercomplex formation. PNAS, 122(40), e2506761122. (www)

  @article{ , abstract = {MEPAN ( M itochondrial E noyl CoA Reductase P rotein- A ssociated N eurodegeneration) is an early-onset movement disorder characterized by ataxia, dysarthria, and optic atrophy. Here, we report the creation of a mouse model of MEPAN with patient-similar compound heterozygous mutations in the Mecr gene. The MEPAN mouse recapitulates the major hallmarks of MEPAN, including a movement disorder, optic neuropathy, defects in protein lipoylation, and reduced mitochondrial oxidative phosphorylation in the brain. MECR catalyzes the last step in mitochondrial fatty acid synthesis (mtFASII), and the mechanism by which loss of mtFASII leads to neurological disease is unknown. LC–MS/MS-based proteomic analysis of Mecr mutant cerebella identified loss of subunits of complex I of oxidative phosphorylation (OXPHOS) and subunits of the iron–sulfur cluster assembly (ISC) complex. Native gels revealed altered OXPHOS complex and supercomplex formation and changes in binding of the acyl carrier protein (ACP) to mitochondrial complexes. These results demonstrate that MECR plays a key role in the acylation of ACP which is necessary for ACP-LYRM-mediated supercomplex modulation and ISC biogenesis and suggest unique pathways for therapeutics.}, archive = {J_PNAS}, author = {Murdock, Deborah G. and Janssen, Kevin A. and Keller, Kierstin and Mitchell, Katherine L. and Beauplan, Maina and O’Brien, William T. and D’Alessandro, Lia and Haltom, Jeffrey A. and Wallace, Douglas C.}, doi = {10.1073/pnas.2506761122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2506761122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron–sulfur cluster and supercomplex formation}, volume = {122}, year = {2025}, }
• (2025). Forest biodiversity increases productivity via complementarity from greater canopy structural complexity. PNAS, 122(40), e2506750122. (www)

  @article{ , abstract = {The horizontal distribution and vertical stratification of tree crowns can affect light interception and tree growth, thus driving forest productivity and carbon storage. However, how canopy structure is affected by tree diversity and thus can mediate its effects on productivity remains unclear. Using 4-y consecutive unmanned aerial vehicle-borne light detection and ranging and ground-based growth measurements from 482 plots and 38,088 trees, 11 to 15 y after planting, within a large-scale forest biodiversity experiment in southeast China, we found that increased canopy structural complexity consistently explains the positive effects of tree diversity on productivity. Species complementarity was the main mediator of diversity-enhanced productivity, with the positive complementarity effects strengthening over time. Our study underscores the importance of establishing multispecies forest communities with complex canopy structure to maximize productivity and carbon sequestration in forest ecosystems.}, archive = {J_PNAS}, author = {Deng, Xianglu and Schmid, Bernhard and Bruelheide, Helge and Chen, Chen and Li, Yi and Li, Shan and Morsdorf, Felix and Ray, Tama and Schuman, Meredith C. and Tang, Ting and von Oheimb, Goddert and Ma, Keping and Liu, Xiaojuan}, doi = {10.1073/pnas.2506750122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2506750122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Forest biodiversity increases productivity via complementarity from greater canopy structural complexity}, volume = {122}, year = {2025}, }
• (2025). Climate change intensifies plant–pollinator mismatch and increases secondary extinction risk for plants in northern latitudes. PNAS, 122(40), e2506265122. (www)

  @article{ , abstract = {Climate change is altering the timing of species’ life-cycle events (i.e., phenology), but the rates of phenological shifts vary across taxa. These mismatches in phenological response may disrupt interactions between interdependent species, such as plants and their pollinators, which may lead to reduced plant reproduction via pollen limitation and thus contribute to secondary extinction risks for plants. However, secondary extinction risk is rarely assessed under future climate-change scenarios. Here, we used ca. 15,000 crowdsourced specimen records of Viola species and their solitary bee pollinators, spanning 120 y across the eastern United States, and integrated climate data, phenological information, and species distribution models to quantify the risk of secondary plant extinction associated with phenological mismatch with their bee pollinators. We further examined geographical patterns in secondary extinction risk for plants and explored how their interactions between plants and generalist versus specialist pollinators influence such risk. Secondary local extinction risk of Viola spp. increases with latitude, indicating that future climate change will pose a greater threat to plant–bee pollinator networks at northern latitudes. Additionally, the sensitivity of secondary local extinction risk to phenological mismatch with both generalist and specialist bee pollinators varies by latitude, with specialist bees showing a sharper decline at higher latitudes. Our findings demonstrate that existing conservation priorities based solely on primary extinction risk directly caused by climate change may be insufficient to support self-sustaining populations of plants. Thus, incorporating secondary extinction risk resulting from ecological mismatches between plants and pollinators into future global conservation frameworks should be carefully considered.}, archive = {J_PNAS}, author = {Peng, Shijia and Ellison, Aaron M. and Davis, Charles C.}, doi = {10.1073/pnas.2506265122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2506265122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Climate change intensifies plant–pollinator mismatch and increases secondary extinction risk for plants in northern latitudes}, volume = {122}, year = {2025}, }
• (2025). Hippocampal CA2 to CA1: A metaplastic switch for memory encoding. PNAS, 122(40), e2505936122. (www)

  @article{ , abstract = {The hippocampus is essential for spatial and episodic memory, subserved by CA1 neurons. Hippocampal area CA2, which processes social memory, also makes direct connections to CA1. However, the function of these connections is unknown. To test whether CA2-CA1 connections might facilitate the interaction of social and episodic memories, we used models of behaving mice and in vitro electrophysiology that allow prior activation of CA2 by either novel social interaction or electrical stimulation before inhibitory avoidance training or induction of activity-dependent synaptic plasticity in CA1. We show that social novelty promotes consolidation of CA1-associated memory, which was blocked by the selective chemogenetic silencing of CA1-projecting CA2 neurons. In both cases, CA2 priming was time-dependent, involved direct CA2-CA1 connections, increased expression of plasticity protein protein kinase M zeta (PKMζ), and promoted associativity via synaptic tagging and capture. Taken together, CA2-CA1 connections can significantly impact CA1 plasticity and memory consolidation. The inclusion of CA2 into hippocampal circuitry and function broadens the role of the hippocampus as an integrative memory hub.}, archive = {J_PNAS}, author = {Bin Ibrahim, Mohammad Zaki and Goh, Louise Zi Ning and Koh, Nicholas Wee Kiat and Polepalli, Jai S. and Behnisch, Thomas and Sajikumar, Sreedharan}, doi = {10.1073/pnas.2505936122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2505936122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hippocampal CA2 to CA1: A metaplastic switch for memory encoding}, volume = {122}, year = {2025}, }
• (2025). The impact of air pollution on petcare utilization. PNAS, 122(40), e2504553122. (www)

  @article{ , abstract = {Air pollution is one of the leading causes of morbidity and premature mortality globally. A large literature documents the adverse impacts of ambient air pollution on human health. In contrast, there is a lack of comparable research studying the effects of air pollution on animal health. We fill this gap, utilizing 5 y of data on over seven million visits to veterinary practices across the United Kingdom. Leveraging within-city variation in daily monitor-measured air pollution levels, we find that increases in fine particulate matter (i.e., PM 2.5 ) are associated with significant increases in the number of vet visits for both cats and dogs. In aggregate, these estimates suggest that reducing ambient PM 2.5 levels to a maximum of 5 mg per cubic meter as recommended by the World Health Organization would result in a 0.7 to 2.5% reduction in vet visits.}, archive = {J_PNAS}, author = {Jarvis, Stephen and Deschenes, Olivier and Jha, Akshaya and Radford, Alan D.}, doi = {10.1073/pnas.2504553122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2504553122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The impact of air pollution on petcare utilization}, volume = {122}, year = {2025}, }
• (2025). A fixed mutation in the respiratory complex i impairs mitochondrial bioenergetics in the endangered apennine brown bear. PNAS, 122(40), e2504409122. (www)

  @article{ , abstract = {Effective conservation genomics of endangered species requires realistic understanding of the fitness consequences caused by the accumulation of deleterious mutations in declining populations. We experimentally investigated three mutations which have been bioinformatically predicted to be deleterious in the mitochondrial ND5 subunit of respiratory complex I and are fixed in the Apennine brown bear, an inbred population of about 50 individuals isolated in Central Italy. Functional assays in transfected cell models and fibroblasts demonstrated that the G527E substitution significantly reduces mitochondrial transmembrane potential and calcium uptake by ca. 40 and 25% of the control level, respectively, while increasing reactive oxygen species production by ca. 45%. While further confirming these findings, experiments with bear fibroblasts highlighted lower oxygen consumption and impaired mitochondrial turnover in the Apennine bear. Molecular dynamics simulations uncovered structural effects of the G527E substitution, including increased rigidity of the ND5 and associated NDUFB8 subunits and altered hydration dynamics in key aqueous channels of the complex I which are essential for proton pumping. These findings validate previous bioinformatic predictions of the negative fitness effects for one out of three mtDNA mutations, and elucidate the molecular mechanisms behind compromised bioenergetics in this endangered bear population produced by the G527E substitution. By linking genotype to phenotype via advanced molecular biology tools in a non-model species of conservation concern, this study highlights the need to fully integrate genomics and molecular experimental approaches in modern conservation biology.}, archive = {J_PNAS}, author = {Trucchi, Emiliano and Fuselli, Silvia and Perta, Nunzio and Patergnani, Simone and Danese, Alberto and Balestra, Dario and Capriotti, Emidio and Di Muccio, Giovanni and Di Marino, Daniele and Pinton, Paolo and Bertorelle, Giorgio}, doi = {10.1073/pnas.2504409122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2504409122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A fixed mutation in the respiratory complex i impairs mitochondrial bioenergetics in the endangered apennine brown bear}, volume = {122}, year = {2025}, }
• (2025). From propulsion to suction: Unraveling thrust reversal in propellers at intermediate reynolds numbers. PNAS, 122(40), e2504153122. (www)

  @article{ , abstract = {This study investigates propeller hydrodynamics at intermediate Reynolds numbers ( Re ), crucial for small-scale robotic systems but still uncharted. Experiments on a propeller-driven underwater vehicle and numerical simulations reveal thrust reversal—a phenomenon where clockwise propeller rotation leads to backward motion—in the approximate range 1.3 ≲ Re ≲ 150 under specific conditions. Notably, counterclockwise rotation consistently results in backward motion. Simulations reveal that this behavior arises when centrifugal suction, an inward force along the axis caused by radial outward flow from the propeller’s rotation, dominates over fluid backward acceleration, the primary thrust mechanism at high Re . These findings provide critical insights into the unique dynamics of the intermediate Re regime and inform the design of efficient propulsion systems for miniature aquatic robots.}, archive = {J_PNAS}, author = {Fu, Rong and Li, Siyu and Ding, Yang}, doi = {10.1073/pnas.2504153122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2504153122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {From propulsion to suction: Unraveling thrust reversal in propellers at intermediate reynolds numbers}, volume = {122}, year = {2025}, }
• (2025). CAR-SPLASH identifies nascent pre-mRNA structures implicated in kinetic coupling and alternative splicing. PNAS, 122(40), e2504034122. (www)

  @article{ , abstract = {Pre-mRNA splicing is kinetically coupled to transcription as shown by the widespread effects of transcription speed on alternative splicing (AS) outcomes. The molecular basis for such kinetic coupling is incompletely understood, but one potential mechanism is through elongation rate–dependent alternative folding pathways of the nascent pre-messenger RNA (pre-mRNA). To search for RNA structures in nascent pre-mRNA, we modified Sequencing of Psoralen Crosslinked, Ligated And Selected Hybrids (SPLASH) [J. G. Ashley Aw et al. , Mol. Cell 62 , 603–617 (2016)] for use with C hromatin A ssociated R NA. We applied this method called Chromatin Associated RNA (CAR)-SPLASH to cells expressing wild-type and slow mutant RNA polymerase II and identified >3,000 intramolecular RNA duplexes of which >400 are proximal to splice sites. Antisense oligonucleotide (ASO) disruption of several such duplexes that sequester splice sites has a major impact on AS outcomes, even though the ASOs do not directly disrupt splice sites. ASO disruption of these regulatory elements that we designate “RNA kinetic switches” modified AS of NISCH Exon 18, GAK Exon 7, and MEGF8 Exon 14 in a way that depends on the rate of transcription elongation. We propose that these switches mediate kinetic coupling via the effects of transcription speed on folding of nascent RNA structures that modulate AS and that many nascent RNA structures can thereby serve as targets for splice-modifying ASOs.}, archive = {J_PNAS}, author = {Shenasa, Hossein and Fong, Nova and Erickson, Benjamin and Iosub, Ira A. and Ule, Jernej and Bentley, David L.}, doi = {10.1073/pnas.2504034122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2504034122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CAR-SPLASH identifies nascent pre-mRNA structures implicated in kinetic coupling and alternative splicing}, volume = {122}, year = {2025}, }
• (2025). HISTONE DEACETYLASE-1 is required for epigenome stability in neurospora crassa. PNAS, 122(40), e2503876122. (www)

  @article{ , abstract = {Polycomb group (PcG) proteins form chromatin modifying complexes that stably repress lineage- or context-specific genes in animals, plants, and some fungi. Polycomb Repressive Complex 2 (PRC2) catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3) to assemble repressive chromatin. In the model fungus Neurospora crassa, H3K27me3 deposition is regulated by the H3K36 methyltransferase ASH1 and components of constitutive heterochromatin including the H3K9me3-binding protein HETEROCHROMATIN PROTEIN 1 (HP1). Hypoacetylated histones are a defining feature of both constitutive heterochromatin and PcG-repressed chromatin, but how histone deacetylases (HDACs) contribute to normal H3K27me3 and transcriptional repression within PcG-repressed chromatin is poorly understood. We performed a genetic screen to identify HDACs required for repression of PRC2-methylated genes. In the absence of HISTONE DEACETYLASE-1 (HDA-1), PRC2-methylated genes were activated and H3K27me3 was depleted from typical PRC2-targeted regions. At constitutive heterochromatin, HDA-1 deficient cells displayed reduced H3K9me3, hyperacetylation, and aberrant enrichment of H3K27me3 and H3K36me3. CHROMODOMAIN PROTEIN-2 (CDP-2) is required to target HDA-1 to constitutive heterochromatin and is also required for normal H3K27me3 patterns. Patterns of aberrant H3K27me3 were distinct in isogenic ∆ hda-1 strains, suggesting that loss of HDA-1 causes stochastic or progressive epigenome dysfunction. To test this, we constructed a new Δhda-1 strain and performed a laboratory “aging” experiment. Deletion of hda-1 led to progressive epigenome decay over hundreds of nuclear divisions. Together, our data indicate that HDA-1 is a critical regulator of epigenome stability in N. crassa.}, archive = {J_PNAS}, author = {Ebot-Ojong, Felicia and Ferraro, Aileen R. and Yap, Rochelle E. and Kaddar, Farh and Hull-Crew, Clayton and Scadden, Ashley W. and Deaven, Abigail M. and Klocko, Andrew D. and Lewis, Zachary A.}, doi = {10.1073/pnas.2503876122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2503876122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {HISTONE DEACETYLASE-1 is required for epigenome stability in neurospora crassa}, volume = {122}, year = {2025}, }
• (2025). Ultrasmall inorganic nanoparticles repair damaged meningeal lymphatic vessels to boost parkinson’s disease therapy. PNAS, 122(40), e2503434122. (www)

  @article{ , abstract = {Meningeal lymphatic vessels (MLVs) have been identified to associate with various neurological diseases, such as traumatic brain injury (TBI), Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, and brain tumors. Damage to MLVs can exacerbate the pathological progression of these diseases and significantly impede therapeutic efficacy. Therefore, targeted repair of the damaged MLVs has emerged as an innovative strategy for treating these central nervous system (CNS) diseases. In this study, we find that inorganic Cu 2− x Se nanoparticles, rather than conventional endogenous vascular endothelial growth factor-C (VEGF-C), can repair the damaged MLVs to restore their structure and functions. These nanoparticles not only promote the growth and development of lymphatic vessels but also enhance the drainage capacity of impaired MLVs, thereby facilitating the transport of immune cells and macromolecules through these vessels. Unlike the conventional repair of damaged MLVs, this is an instance where inorganic nanoparticles have been explored to stimulate the expression of VEGF-C and its receptor VEGFR3, thereby promoting the structural and functional recovery of these vessels. The enhanced drainage function of MLVs mediated by Cu 2− x Se nanoparticles significantly alleviates the symptoms of pre-formed fibrils (PFFs)-induced Parkinson’s disease in mice. Collectively, our findings demonstrate that inorganic nanoparticles can promote the growth and development of meningeal lymphatics like VEGF-C, providing a cost-effective and innovative strategy for repairing damaged MLVs to boost the therapeutic efficacy of CNS diseases.}, archive = {J_PNAS}, author = {Han, Mengxiao and Han, Yaobao and Jiang, Zhilin and Gao, Yifan and Cao, Guozhi and Zhang, Hao and Wang, Tingting and Li, Zhen}, doi = {10.1073/pnas.2503434122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2503434122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ultrasmall inorganic nanoparticles repair damaged meningeal lymphatic vessels to boost parkinson’s disease therapy}, volume = {122}, year = {2025}, }
• (2025). Cranial modularity drives phenotypic diversification and adaptive radiation of antarctic icefishes. PNAS, 122(40), e2503283122. (www)

  @article{ , abstract = {Modularity among traits is thought to drive morphological evolution and diversification, with more modular species often showing greater morphological disparity and faster evolutionary rates. However, recent studies suggest this pattern is not universal, as higher integration can sometimes be linked to faster rates of evolution. In adaptive radiation, modularity likely facilitates morphological divergence, but its specific role in trait diversification within these events remains uncertain. Antarctic icefishes (Perciformes: Notothenioidei) have undergone adaptive radiation in the frigid Southern Ocean, yet the role of modularity in their craniofacial evolution remains poorly understood. Emerging from a common ancestor 22 Mya, these fishes developed unique morpho-physiological adaptations, such as antifreeze glycoproteins, that contributed to their evolutionary success, but the contribution of cranial modularity to their diversification is still unexplored. Here, we analyze skull shape across 172 perciform species using micro-CT scanning and geometric morphometrics to investigate the tempo and mode of skull evolution in 80 notothenioids versus 92 perciform relatives. Notothenioids exhibit considerable cranial shape diversity, with skull shapes ranging from short to long faces. Fast rates of skull shape evolution occurred in smaller subclades following the emergence of cranial elongation, a derived trait within notothenioids. They also exhibit elevated evolutionary modularity relative to their perciform relatives, with reduced covariation among skeletal elements over time, likely corresponding with Miocene cooling events and the formation of the Antarctic Circumpolar Current. We propose that greater phenotypic modularity in notothenioid skulls represents a pivotal innovation, facilitating their evolutionary response to new ecological opportunities in the Antarctic.}, archive = {J_PNAS}, author = {Neves, Mayara P. and Chan, HoWan and M. Santos, Elizabeth C. and Evans, Kory M.}, doi = {10.1073/pnas.2503283122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2503283122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cranial modularity drives phenotypic diversification and adaptive radiation of antarctic icefishes}, volume = {122}, year = {2025}, }
• (2025). Operation warp speed offers a roadmap for improving the efficiency of bench to bedside medical advances. PNAS, 122(40), e2502975122. (www)

  @article{ , archive = {J_PNAS}, author = {Corey, Lawrence}, doi = {10.1073/pnas.2502975122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2502975122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Operation warp speed offers a roadmap for improving the efficiency of bench to bedside medical advances}, volume = {122}, year = {2025}, }
• (2025). Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway. PNAS, 122(40), e2502841122. (www)

  @article{ , abstract = {The homeostatic link between the production of mitochondrial ROS (mtROS) and mitophagy plays a significant role in how cells respond to various physiological and pathological conditions. However, it remains unclear how cells translate oxidative stress signals into adaptive mitophagy responses. Here, we show that mtROS act as signaling molecules that activate the ataxia-telangiectasia mutated (ATM)-cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway. When activated, CHK2 regulates three critical steps in mitophagy. First, CHK2 phosphorylates mitochondrial membrane protein ATAD3A at Ser371, which inhibits the transport of PINK1 to the inner mitochondrial membrane and leads to the accumulation of PINK1 and the commencement of mitophagy. Second, activated CHK2 targets the autophagy adaptor OPTN at Ser177 and Ser473, thereby enhancing the targeting of ubiquitinated mitochondria to autophagosomes. Finally, CHK2 phosphorylates Beclin 1 at Ser90 and Ser93, hence promoting the formation of autophagosomal membranes. Consistent with these effects, Chk2 −/− mice show impaired mitophagic induction and impaired recovery in a ROS-dependent model of renal ischemia–reperfusion. Our study reveals a mtROS-triggered adaptive pathway that coordinates mitophagic induction, in order to protect cells and tissues exposed to pathophysiological stress-induced damage.}, archive = {J_PNAS}, author = {Guo, Qi-Qiang and Wang, Shan-Shan and Jiang, Xiao-You and Xie, Xiao-Chen and Zou, Yu and Liu, Jing-Wei and Guo, Yang and Li, Yu-Han and Liu, Xi-Yan and Hao, Shuang and Zhang, Xin-Yue and Wu, Xiao-Xu and Lu, Song-Ming and Xu, Hong-De and Guo, Wen-Dong and Feng, Yan-Ling and Wang, Chuan-Gui and Zhang, Sheng-Ping and Li, Jia-Bin and Liu, Chen and Song, Xiao-Yu and Finkel, Toren and Cao, Liu}, doi = {10.1073/pnas.2502841122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2502841122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway}, volume = {122}, year = {2025}, }
• (2025). The role of colony morphotype in shaping gene essentiality in mycobacteroides abscessus. PNAS, 122(40), e2500719122. (www)

  @article{ , abstract = {Changes in bacterial colony morphology are common during chronic human infections and are thought to provide a survival advantage. In the human pathogen Mycobacteroides abscessus (MAB), a unidirectional transition from a smooth (MAB S ) to rough (MAB R ) morphotype frequently occurs during chronic infection. This transition has profound clinical implications, as MAB R induces a heightened proinflammatory response, contributing to increased morbidity. To better understand this phenomenon, we used transposon insertion site sequencing (Tn-seq) to identify genes essential for the survival of MAB S and MAB R . Our analysis revealed distinct genetic requirements for growth in vitro, including several genes involved in responding to environmental stresses. Notably, some of these uniquely essential genes are therapeutic targets in mycobacteria. In a murine infection model, the divergence in essential gene profiles between MAB S and MAB R was even more pronounced, driven partly by the differing host immune responses elicited by each morphotype. These findings demonstrate that the transition from a smooth to rough morphotype not only impacts MAB’s survival strategies but also highlights the importance of considering morphotype-specific genetic and functional adaptations when developing therapeutic approaches. Our work underscores the critical need to incorporate morphotype conversion into the prioritization of drug targets, as targeting morphotype-specific vulnerabilities could improve treatment outcomes for infections caused by this pathogen.}, archive = {J_PNAS}, author = {Ross, Brittany N. and Evans, Emma and Diggle, Frances and Briaud, Paul and Whiteley, Marvin}, doi = {10.1073/pnas.2500719122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2500719122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The role of colony morphotype in shaping gene essentiality in mycobacteroides abscessus}, volume = {122}, year = {2025}, }
• (2025). Targeting the 3D genome by anthracyclines for chemotherapeutic effects. PNAS, 122(40), e2500704122. (www)

  @article{ , abstract = {The chromatin is folded into three-dimensional (3D) structures, and aberrant 3D chromatin folding has been implicated in cancer. We performed ATAC-seq and TOP2A ChIP-seq to assess the potential effects of various anthracycline drugs on the chromatin architecture. We found that specific anthracycline variants selectively disrupt chromatin looping anchors by interfering with CTCF binding, suggesting an additional therapeutic mechanism of anthracycline drugs targeting the 3D genome. Hi-C experiments in K562 cells treated with anthracycline drugs revealed widespread disruption of 3D chromatin organization, including altered long-range regulation at the Myc locus. Furthermore, AML patients treated with anthracycline drugs exhibited changes in chromatin structures near possible looping anchors, which were associated with distinct clinical outcomes. Together, our findings indicate that anthracycline drugs function as potent and selective epigenomic modulators, with the capacity to further target the 3D genome to exert anticancer effects, highlighting their potential for personalized therapy in tumors with aberrant 3D chromatin architecture.}, archive = {J_PNAS}, author = {Tan, Minkang and Sun, Shengnan and Liu, Yuchen and Perreault, Andrea A. and Phanstiel, Douglas H. and Dou, Liping and Pang, Baoxu}, doi = {10.1073/pnas.2500704122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2500704122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Targeting the 3D genome by anthracyclines for chemotherapeutic effects}, volume = {122}, year = {2025}, }
• (2025). Protopeptide backbone affects assembly in aqueous solutions. PNAS, 122(40), e2500503122. (www)

  @article{ , abstract = {One of the most fascinating mysteries in the field of origins of life concerns the driving force that led to the selection of today’s 20 universal L -alpha amino acids in biology. An essential aspect of life’s emergence involves the formation of compartments, which offer encapsulation for target molecules and provide protection from hydrolysis in aqueous environments. Thus, polymers capable of assembly may have had a chemical evolutionary advantage over polymers that lacked this ability. We postulated that primordial peptide assembly could be one of the driving forces that led to the chemical selection of alpha amino acids in life today. To test this hypothesis, we generated depsipeptides, oligomers composed of ester bonds and peptide bonds that form readily under mild drying conditions, as model prebiotic peptides. However, it is unknown whether depsipeptides form assemblies in an aqueous environment similarly to peptides and proteins. To test the hypothesis that depsipeptides with alpha backbones will form assemblies more readily than beta backbones, we synthesized depsipeptides using a matrix of eight alpha- and beta-hydroxy acids and six alpha-, beta-, and gamma-amino acids. The reaction products were analyzed by microscopy and a physical stability analyzer to study assembly formation as well as various analytical techniques for chemical analysis. Our results demonstrate assembly formation in depsipeptide systems containing hydrophobic hydroxy acids and indicate that depsipeptide assemblies containing alpha hydroxy acid backbones are significantly more stable than beta analogs. Overall, our results offer an assembly-driven mode of selection for the alpha backbone in present-day biology.}, archive = {J_PNAS}, author = {Fisher, Sarah and Ezerzer, Yishi and Edri, Rotem and Akulenko, Daniil and Marland, Eliav and Frenkel-Pinter, Moran}, doi = {10.1073/pnas.2500503122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2500503122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Protopeptide backbone affects assembly in aqueous solutions}, volume = {122}, year = {2025}, }
• (2025). Higher-order interactions in neuronal function: From genes to ionic currents in biophysical models. PNAS, 122(40), e2500048122. (www)

  @article{ , abstract = {Neuronal firing patterns are the consequence of precise variations in neuronal membrane potential, which are themselves shaped by multiple ionic currents. In this study, we use biophysical models, statistical methods, and information theory to explore the interaction between these ionic currents and neuron electrophysiological phenotype. We created numerous electrical models with diverse firing patterns. By analyzing these models, we identified intricate relationships between model parameters and electrical features. Our findings show that neuronal activity is often influenced by multiple biophysical model parameters, in a nonadditive (i.e. synergistic) fashion. When comparing this with single-cell RNAseq data, we found a contrasting structure: gene expression profiles were dominated by redundancy, reflecting differences in regulatory constraints and sampling diversity. This research sheds light on the complex links between biophysical parameters and neuronal phenotypes.}, archive = {J_PNAS}, author = {Reva, Maria and Arnaudon, Alexis and Zbili, Mickael and Makkeh, Abdullah and Markram, Henry and Goaillard, Jean-Marc and Van Geit, Werner}, doi = {10.1073/pnas.2500048122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2500048122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Higher-order interactions in neuronal function: From genes to ionic currents in biophysical models}, volume = {122}, year = {2025}, }
• (2025). When crops fail, forests follow: Agricultural shocks and deforestation in zambia. PNAS, 122(40), e2427156122. (www)

  @article{ , abstract = {As climate change makes agricultural production shocks more frequent and severe, it is vital to understand their effect on farmer welfare, land use, and deforestation. Theoretically, a change in agricultural productivity could increase or decrease deforestation by changing demand for agricultural land and/or through the consumption of forests as a coping strategy. This paper uses the introduction of a crop pest to sub-Saharan Africa to estimate the effect of a negative agricultural productivity shock on deforestation. Using primary household data, we first find that farmers who were exposed to higher levels of fall armyworm saw substantial decreases in yield and food security. Using estimates of fall armyworm suitability in conjunction with machine-learning models of maize yields and deforestation, we find that the introduction of the fall armyworm induced a doubling of the deforestation rate in Zambia in the 3 y following the outbreak. This increase was driven both by increased agricultural land expansion and increased charcoal production as a coping strategy. These responses vary substantially over space. More remote areas experienced 23% lower FAW-induced deforestation compared with the sample average, suggesting that farmers with access to maize and charcoal markets may have increased deforestation as a response. Wealthier areas were also less likely to deforest in response to FAW pressure. In sum, our results suggest that negative agricultural productivity shocks may lead to a negative climate feedback, with farmers engaging in emissions-increasing strategies in response.}, archive = {J_PNAS}, author = {Ordóñez, Pablo J. and Hadunka, Protensia and Del Rossi, Gemma and Baylis, Kathy}, doi = {10.1073/pnas.2427156122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2427156122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {When crops fail, forests follow: Agricultural shocks and deforestation in zambia}, volume = {122}, year = {2025}, }
• (2025). Autoimmunity-associated DIORA1 binds the MRCK family of serine/threonine kinases and controls cell motility. PNAS, 122(40), e2426917122. (www)

  @article{ , abstract = {Genetic association links disordered autoimmunity 1 (DIORA1) to numerous autoimmune rheumatic diseases, including systemic lupus erythematosus, Sjögren’s disease, rheumatoid arthritis, polymyositis, and systemic sclerosis. However, its cellular function has remained unknown. Here, we identify the Myotonic Dystrophy Kinase-Related Cdc42-Binding Kinases (MRCK kinases) family of serine/threonine kinases—key regulators of actomyosin contractility and cell motility—as direct interactors of DIORA1. Through interaction mapping, we show that DIORA1 binds three distinct modules of MRCK kinases, including the conserved kinase inhibitory motif, C1-PH, and citron homology domains. DIORA1 knockdown in human cells altered cellular phosphorylation patterns and reduced phosphorylation of known MRCK targets. RNA-sequencing and proteomic analyses revealed upregulation of epithelial–mesenchymal transition genes and proteins, and functional analyses confirmed increased cell invasion, following knockdown of DIORA1. Together, these findings identify the autoimmunity-associated DIORA1 protein as an interactor of MRCK kinases and a regulator of cell motility.}, archive = {J_PNAS}, author = {Tršelič, Tilen and Pelo, Nathalie and Martin de Fremont, Gregoire and Iyer, Vaishnavi S. and Richardsdotter Andersson, Elina and Ottosson, Vijole and Frei, David Alexander and Baas, Elisa and Nyberg, William A. and Thorlacius, Guðný Ella and Mentlein, Lara and Boddul, Sanjaykumar V. and Sandu, Ioana and Velasquez Pulgarin, Diego and Végvári, Ákos and Gerlach, Carmen and Wermeling, Fredrik and Sunnerhagen, Maria and Wallner, Björn and Espinosa, Alexander and Wahren-Herlenius, Marie}, doi = {10.1073/pnas.2426917122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2426917122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Autoimmunity-associated DIORA1 binds the MRCK family of serine/threonine kinases and controls cell motility}, volume = {122}, year = {2025}, }
• (2025). Electrostatics and viscosity are strongly linked in concentrated antibody solutions. PNAS, 122(40), e2425974122. (www)

  @article{ , abstract = {Monoclonal antibodies are among the most promising therapeutic agents in modern medicine, yet their formulation into high-concentration solutions for subcutaneous self-administration poses a major challenge. A key obstacle is the marked increase in viscosity often observed under these conditions. To gain deeper insights into this phenomenon, coarse-grained models derived from soft matter physics have been widely employed. However, these models have yet to be fully leveraged for analyzing the rheological collective properties of such systems. In this study, using molecular dynamics simulations, we directly compute the antibody solution viscosity by starting from commonly used models in which electrostatic interactions are treated through effective screened Coulomb potentials. We demonstrate that this approach fails to reproduce experimental evidence and we show, by analyzing stress correlations in the system, that it is necessary to treat the heterogeneously charged domains with explicit Coulomb interactions, also including counterions and salt ions. By thoroughly analyzing the microscopic structure of the system, we further reveal the presence of transient strongly correlated antibodies which would not be present if charges were treated implicitly, thus pointing to a prominent role of electrostatics in determining the increase in viscosity at high concentrations. By taking advantage of our realistic treatment, new approaches can be devised to ensure that antibody solutions exhibit the desired characteristics for their intended broad use and effective deployment.}, archive = {J_PNAS}, author = {Camerin, Fabrizio and Polimeni, Marco and Stradner, Anna and Zaccarelli, Emanuela and Schurtenberger, Peter}, doi = {10.1073/pnas.2425974122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2425974122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electrostatics and viscosity are strongly linked in concentrated antibody solutions}, volume = {122}, year = {2025}, }
• (2025). Recent drying of the ganga river is unprecedented in the last 1,300 years. PNAS, 122(40), e2424613122. (www)

  @article{ , abstract = {The Ganga River basin, critical to over 600 million people, is experiencing a severe and unprecedented drying trend, threatening water and food security. Using streamflow reconstructions spanning 1,300 y (700–2012 C.E.) from instrumental data, paleohydrological records, and hydrological modeling, we show that drying from 1991 to 2020 is unmatched in the past millennium. Streamflow decline since the 1990s, driven by frequent and prolonged droughts, is 76% more intense than the 16th-century drought—the closest historical analogue. This drying exceeds natural variability, highlighting the dominant role of anthropogenic factors. Despite CMIP6 models projecting increased streamflow under warming scenarios, the recent decline indicates complexities associated with future water availability projections. Our findings underscore the urgent need to examine the interactions among the factors that control summer monsoon precipitation, including large−scale climate variability and anthropogenic forcings. Better constraints on these processes in climate models will be essential for improving future monsoon projections and implementing adaptive water management strategies to secure the Ganga basin’s freshwater availability under a changing climate.}, archive = {J_PNAS}, author = {Singh Chuphal, Dipesh and Thirumalai, Kaustubh and Mishra, Vimal}, doi = {10.1073/pnas.2424613122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2424613122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Recent drying of the ganga river is unprecedented in the last 1,300 years}, volume = {122}, year = {2025}, }
• (2025). Late cenozoic river reorganization related to tectonic extrusion formed the modern drainage system in southeastern tibet. PNAS, 122(40), e2424554122. (www)

  @article{ , abstract = {The formation and organization of southeastern Tibetan river systems reflect feedbacks between tectonics, climate, and landscape evolution. However, our understanding of these interactions remains unclear. We approach this issue from the view that the river incision histories and their bedload provenance provide complementary evidence for reconstructing the evolution of the ancient river system. Zircon and apatite (U-Th)/He data from the middle Jinsha (upper Yangtze) River gorge reveal two episodes of accelerated river incision at 18-17 Ma and 8-7 Ma. The onset of the former incision event, coeval with other incision events along the upper-middle Jinsha and Lancang Rivers, implies their hydrological connection and formation of a south-flowing river system. Additionally, detrital geochronology and thermochronology data of late Oligocene–Miocene fluvial-alluvial sediments along the Red River valley provide constraints on their ages and provenance, suggesting emergence of a throughgoing paleo-Red River in the early-middle Miocene. This ancient Red River was disconnected from the upper Jinsha River but connected with Yalong River (upper Yangtze tributary), forming another south-flowing river system. Landscape evolution modelling supports the view that these south-flowing rivers were successively captured by the westward-propagating Yangtze River in the middle-late Miocene, giving birth to the modern drainages of southeastern Tibet. The resultant integration of the upper-middle and lower Jinsha River is manifested by the progressively upstream-propagating acceleration in river incision from 13-9 Ma to 6-5 Ma along the gorges. Our findings from southeastern Tibet suggest that orogen-scale topographic change, river reorganization, and a coeval increase in biodiversity were driven by extrusion tectonics.}, archive = {J_PNAS}, author = {Cao, Kai and Wang, Guocan and Harrison, T. Mark and Yuan, Xiaoping and Leloup, Philippe Hervé and Kusky, Timothy M. and Cao, Licheng and Shen, Xiaoming and Cheng, Yizhuang and Yao, Junzhe and He, Xiang and Zhu, Zongmin and Xie, Shucheng}, doi = {10.1073/pnas.2424554122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2424554122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Late cenozoic river reorganization related to tectonic extrusion formed the modern drainage system in southeastern tibet}, volume = {122}, year = {2025}, }
• (2025). The distinctive innovation patterns and network embeddedness of scientific prizewinners. PNAS, 122(40), e2424143122. (www)

  @article{ , abstract = {Science prizes purportedly reward innovation and explorations of new phenomena. Yet in practice, prizes may inadvertently divert resources from similarly impactful but less celebrated scholars. Despite this paradox, and even as prizes proliferate, knowledge of how prizewinning relates to innovation is nascent. Analyzing 2,460 worldwide prizes, we compared the innovativeness of over 23,000 prizewinners and matched nonprizewinners whose performance records were statistically equivalent up to the prize year. First, we find that prizewinners are more innovative. Their research is more likely to combine existing ideas in new ways, integrate a topic’s historical and contemporary thinking, and incorporate interdisciplinary perspectives. Second, although prizewinners and matched nonprizewinners have statistically equivalent impact and productivity records up to the prize year, at about five years before the prize, prizewinners’ papers become more innovative than their matched peers. This difference widens each year, peaks during the prize year, and then persists for the remainder of their careers. Third, network embeddedness predicts unusual innovativeness. Compared to nonprizewinners, prizewinners’ collaborations are shorter in duration, encompass wider exposure to unfamiliar topics, and involve coauthors whose networks minimally overlap with each other. The findings’ implications for innovation in science and the efficacy of reward systems and innovation in science are discussed.}, archive = {J_PNAS}, author = {Tian, Chaolin and Huang, Yurui and Jin, Ching and Ma, Yifang and Uzzi, Brian}, doi = {10.1073/pnas.2424143122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2424143122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The distinctive innovation patterns and network embeddedness of scientific prizewinners}, volume = {122}, year = {2025}, }
• (2025). Wild canids and felids differ in their reliance on reused travel routeways. PNAS, 122(40), e2401042122. (www)

  @article{ , abstract = {Diverse factors, including environmental features and cognitive processes, can drive animals’ movements and space use, with far-reaching implications. For example, repeated use of individual-level travel routeways (directionally constrained but imperfectly aligned routes), which results in spatial concentration of activity, can shape encounter-based processes including predation, mate finding, and disease transmission. However, how much variation in routeway usage exists across species remains unknown. By analyzing GPS movement tracks for 1,239 range-resident mammalian carnivores—representing 16 canid and 18 felid species from six continents—we found strong evidence of a clade-level difference in species’ reliance on repeatedly used travel routeways. Across the global dataset, tracked canids had a 15% (±7 CI) greater density of routeways within their home ranges than did felids, rising to 33% (±16 CI) greater in landscapes shared with tracked felids. Moreover, comparisons within species across landscapes revealed broadly similar home range routeway densities despite habitat differences. On average, canids also reused their travel routeways more intensively than did felids, with hunting strategies and spatial contexts also contributing to the intensity of routeway usage. Collectively, our results suggest that key aspects of carnivore routeway-usage have an evolutionary component. Striking interspecific and clade-level differences in carnivores’ reliance on reused travel routeways within home ranges identify important ways in which the movement patterns of real-world predators depart from classical assumptions of predator-prey theory. Because such departures can drive key aspects of human-wildlife interactions and other encounter-based processes, continued investigations of the relationships between movement mechanisms and space use are critical.}, archive = {J_PNAS}, author = {Fagan, William F. and Krishnan, Ananke G. and Fleming, Christen H. and Ferreira, Elizabeth and Chia, Stephanie and Swain, Anshuman and Abrahms, Briana and Bracis, Chloe and Gurarie, Eliezer and Mueller, Thomas and Noonan, Michael J. and Oliveira-Santos, Luiz Gustavo R. and Tucker, Marlee A. and Anand, Gayatri and Liao, Qianru and Na, Sarah and Su, Steven and Liao, Daisy and Chilukuri, Varun and Ramulu, Shreyas and Diele-Viegas, Luisa Maria and Dougherty, Michael and Illingworth, David and Alexandrov, Dmitry Y. and Antunes, Pamela Castro and Azevedo, Fernanda C. and Barrett, Christina and Barroso, Matías Taborda and Behr, Dominik M. and Belant, Jerrold L. and Bellan, Steven and Berteaux, Dominique and Beyer, Dean E. and Bidner, Laura R. and Bishop, Jacqueline and Blount, J. David and Butler, Andrew and Carter, Andrew and Carvalho, Marina Motta and Chamberlain, Michael and Chistopolova, Maria D. and Clark, Darren and Conner, L. Mike and Cotterill, Alayne and Cozzi, Gabriele and Cristescu, Bogdan and Cunningham, Calum X. and Çoban, Emrah and Darlington, Siobhan and Candeias, Ísis Zanini das and DePerno, Christopher S. and Dekker, Jasja J. A. and Downs, Colleen T. and Dronova, Natalia and Drouilly, Marine and Eblate, Ernest and Ekwanga, Steve and Swingen, Morgan and Farhadinia, Mohammad and Ford, Adam T. and Frair, Jacqueline and Frank, Laurence and Fryxell, John M. and Fuller, Todd K. and Fyumagwa, Robert and Garthe, Stefan and Getz, Wayne M. and Palacios Gonzalez, Maria Jesus and Gooliaff, TJ and Götz, Malte and Hamer, Rowena and Haberfeld, Mario and Hebblewhite, Mark and Hernandez-Blanco, Jose A. and Herrmann, Mathias and Heurich, Marco and Hodges, Karen E. and Houser, AnnMarie and Humphries, Bruce and López Iglesias, Miguel Ángel López and Isbell, Lynne A. and Jachowski, David and Jackson, Craig and Janssen, René and Jenks, Kate E. and Jiménez, Jaime E. and Jorge, Maria Luisa S. P. and Jorge, Rodrigo and Jubete, Fernando and Katna, Anjan and Kays, Roland and Kittle, Andrew M. and Klein, Rebecca and Kont, Raido and Kral, Michelle J. C. and Kusak, Josip and Lang, Johannes and Latham, Andrew David M. and Leimgruber, Peter and Lemos, Frederico G. and Levi, Taal and Lima, Caio F. M. and Lima, Edson and Lima, Fernando and Linnell, John D. C. and Macdonald, David W. and Mahoney, Peter and Männil, Peep and Masenga, Emmanuel and Mattisson, Jenny and May, Roel F. and McBride, Roy T. and McDonald, Robbie A. and McNutt, J. Weldon and Miller, Karl and Minaev, Alexander and Miquelle, Dale G. and Moorman, Christopher E. and Morato, Ronaldo G. and Moreno, Ricardo and Mourão, Guilherme and Munkhtsog, Bariushaa and Munkhtsog, Bayaraa and Naidenko, Sergey V. and Nava, Teresa and Odden, John and Odden, Morten and Palomares, Francisco and Patterson, Brent R. and Patterson, Bruce D. and de Paula, Rogerio Cunha and Paviolo, Agustin and Petrunenko, Yury K. and Pkhitikov, Alim B. and Poyarkov, Andrey D. and Prugh, Laura R. and Rafiq, Kasim and Ramalho, Emiliano Esterci and Ramesh, Tharmalingam and Ranc, Nathan and Ranglack, Dustin H. and Ratnayaka, Anya and Roshier, David and Røskaft, Eivin and Rozhnov, Viatcheslav V. and Ruiz-Villar, Hector and Ruprecht, Joel and Samelius, Gustaf and Schwemmer, Philipp and Şekercioğlu, Çağan H. and Serieys, Laurel E. K. and Seryodkin, Ivan V. and Simon, Olaf and Songsasen, Nucharin and Sorokin, Pavel A. and Soutryina, Svetlana and Stent, Patrick and Stoner, David and Streicher, Jarryd and Tatler, Jack and Teichman, Kristine and Thaker, Maria and Thompson, Katerina V. and Thompson, Jeffrey J. and Tortato, Marcos Adriano and Trinzen, Manfred and Van Der Weyde, Leanne and Vanak, Abi Tamim and Velilla, Marianela and Walton, Zea and Wheeldon, Tyler J. and Willebrand, Tomas and Williams, Terrie M. and Wilmers, Christopher C. and Wilson-Aggarwal, Jared and Wysong, Michael L. and Yachmennikova, Anna A. and Young, Julie K. and Calabrese, Justin M.}, doi = {10.1073/pnas.2401042122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2401042122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Wild canids and felids differ in their reliance on reused travel routeways}, volume = {122}, year = {2025}, }
• (2025). Toward a relational biodiversity economics: Embedding plural values for sustainability transformation. PNAS, 122(40), e2314586122. (www)

  @article{ , abstract = {The prioritization of market over nonmarket values of nature is a key driver of the global biodiversity crisis. Recognizing nature’s diverse values in decisions is a fundamental lever for sustainability transformation. While economic valuation of nature has a long history, it has struggled to recognize the full suite of nature’s values, particularly the broad, relational, intrinsic, and shared values reflecting the complexity of human–nature relationships. We explore opportunities to expand the consideration of values within the economics of biodiversity by reviewing conventional and heterodox economic approaches. We argue that integrating pluralistic values requires a relational biodiversity economics that transcends people–nature dualism and seeks the flourishing of life. We synthesize foundations for such a paradigm in relation to worldviews, values, value indicators, and life frames. Our perspective transcends the dominant economic framing of nature as a passive, largely substitutable asset, to also consider nature as place, self, and harboring agency. This helps to overcome the limitations of conventional economic assumptions, better reflects peoples’ lived experiences, and supports transformations toward more just and sustainable futures.}, archive = {J_PNAS}, author = {Kenter, Jasper O. and Carmenta, Rachel and Christie, Michael and Griffiths, Hywel and Ihemezie, Eberechukwu and Martin, Adrian and Gomez-Osorio, M. Teresa and Pascual, Unai and Raymond, Christopher M. and Remoundou, Kyriaki and Waters, Ruth}, doi = {10.1073/pnas.2314586122}, journal = {Proceedings of the National Academy of Sciences}, month = {10}, number = {40}, pages = {e2314586122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Toward a relational biodiversity economics: Embedding plural values for sustainability transformation}, volume = {122}, year = {2025}, }
• (2025). Correction for nehemy et al., embolism resistance supports the contribution of dry-season precipitation to transpiration in eastern amazon forests. PNAS, 122(39), e2524503122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2524503122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2524503122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for nehemy et al., embolism resistance supports the contribution of dry-season precipitation to transpiration in eastern amazon forests}, volume = {122}, year = {2025}, }
• (2025). Could dark energy be changing over time?. PNAS, 122(39), e2524499122. (www)

  @article{ , archive = {J_PNAS}, author = {Mann, Adam}, doi = {10.1073/pnas.2524499122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2524499122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Could dark energy be changing over time?}, volume = {122}, year = {2025}, }
• (2025). Correction for yeh et al., three things we can do now to reduce the risk of avian influenza spillovers. PNAS, 122(39), e2524485122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2524485122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2524485122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for yeh et al., three things we can do now to reduce the risk of avian influenza spillovers}, volume = {122}, year = {2025}, }
• (2025). Correction for pederson, Étienne-Émile baulieu (1929–2025): Scientist of steroids and champion of women’s reproductive rights. PNAS, 122(39), e2524134122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2524134122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2524134122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for pederson, Étienne-Émile baulieu (1929–2025): Scientist of steroids and champion of women’s reproductive rights}, volume = {122}, year = {2025}, }
• (2025). Reply to lakhan and wicks: Placement of drug–software combinations within VISTA’s platform taxonomy. PNAS, 122(39), e2522921122. (www)

  @article{ , archive = {J_PNAS}, author = {Jones, Charles H.}, doi = {10.1073/pnas.2522921122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2522921122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to lakhan and wicks: Placement of drug–software combinations within VISTA’s platform taxonomy}, volume = {122}, year = {2025}, }
• (2025). Software-enhanced drugs™: The third platform reshaping drug development. PNAS, 122(39), e2522286122. (www)

  @article{ , archive = {J_PNAS}, author = {Lakhan, Shaheen E. and Wicks, Paul}, doi = {10.1073/pnas.2522286122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2522286122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Software-enhanced drugs™: The third platform reshaping drug development}, volume = {122}, year = {2025}, }
• (2025). FGF21 acting on the noradrenergic nervous system protects against influenza virus infection. PNAS, 122(39), e2522045122. (www)

  @article{ , abstract = {The hormone fibroblast growth factor 21 (FGF21) is induced in murine liver in response to both bacterial and viral infection. In this report, we show that FGF21 is induced by infection with influenza virus in both humans and mice. Mice lacking FGF21 had decreased food intake, body weight, and body temperature compared to wild-type mice following influenza virus inoculation, indicating reduced tolerance to the infection. Conversely, pharmacologic administration of FGF21 after viral infection protected mice against these pathologic changes. Pair feeding studies showed that neither the induction of FGF21 nor the hypothermia was secondary to decreased food intake. Notably, mice selectively lacking FGF21’s coreceptor protein, βKlotho, in noradrenergic neurons were also more susceptible to influenza virus infection, including hypothermia. We show that FGF21 acting on noradrenergic neurons, including those in the locus coeruleus region, stimulates energy expenditure and thermogenic gene expression in brown adipose tissue. Our findings reveal an FGF21-regulated neuronal pathway that protects mice against influenza infection and suggest the potential utility of using FGF21 pharmacologically to improve outcomes after influenza infection.}, archive = {J_PNAS}, author = {Fan, Wei and Zhang, Yuan and Gautron, Laurent and Thomas, David G. and Stout-Delgado, Heather W. and Schenck, Edward J. and Gwatiringa, Tadiwanashe and Rajagopalan, Kartik N. and Mangelsdorf, David J. and Kliewer, Steven A.}, doi = {10.1073/pnas.2522045122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2522045122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {FGF21 acting on the noradrenergic nervous system protects against influenza virus infection}, volume = {122}, year = {2025}, }
• (2025). Reply to fleming: Not a gossamer web. PNAS, 122(39), e2521259122. (www)

  @article{ , archive = {J_PNAS}, author = {Santer, Benjamin D. and Solomon, Susan and Thompson, David W. J. and Fu, Qiang and Li, Yaowei}, doi = {10.1073/pnas.2521259122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2521259122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to fleming: Not a gossamer web}, volume = {122}, year = {2025}, }
• (2025). Oxytocin and vasopressin enhance social pain empathy via common and distinct of neural expressions, genetic pathways, and networks. PNAS, 122(39), e2520651122. (www)

  @article{ , abstract = {Witnessing social distress of others evokes social pain empathy, a complex process engaging cognitive, affective, and motivational dimensions. Although hypothalamic neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are known to modulate social function, their respective contributions to the process of social pain empathy have not been systematically characterized. To address this, we employed a multimethod approach, combining naturalistic fMRI, functional decoding, gene expression analysis, and pharmacological modulation using intranasal administration of OXT (24 IU) or AVP (20 IU) in a cohort of 163 participants. Our findings indicated that both OXT and AVP significantly enhanced pain empathy compared to placebo, with overlapping yet distinct neurofunctional and genetic modulation patterns. Specially, both neuropeptides engaged a shared perception-cognition-emotion network, including frontal regions, the insula, superior temporal sulcus, and parahippocampal gyrus. Crucially, they exhibited divergent mechanistic profiles: OXT preferentially influenced resting-state connectivity and perceptional-visual processing areas, while AVP exerted stronger modulation on perceptional-execution circuits. These differential effects aligned with their unique receptor expression patterns and interactions with distinct genetic systems. By delineating how OXT and AVP shape the multidimensional nature of social pain empathy, our findings provide a neurobiological framework for understanding these processes and offer potential pathways for targeted interventions in social cognition disorders.}, archive = {J_PNAS}, author = {Zhang, Xiaodong and Liu, Qi and Liu, Can and Wang, Ziheng and Fu, Kun and Lan, Chunmei and Xu, Ting and Zhou, Xinqi and Kendrick, Keith M. and Yao, Dezhong and Becker, Benjamin and Zhao, Weihua}, doi = {10.1073/pnas.2520651122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2520651122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Oxytocin and vasopressin enhance social pain empathy via common and distinct of neural expressions, genetic pathways, and networks}, volume = {122}, year = {2025}, }
• (2025). Coding of tool use independent of body part. PNAS, 122(39), e2520437122. (www)

  @article{ , archive = {J_PNAS}, author = {Cooke, Dylan F.}, doi = {10.1073/pnas.2520437122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2520437122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Coding of tool use independent of body part}, volume = {122}, year = {2025}, }
• (2025). CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma. PNAS, 122(39), e2519568122. (www)

  @article{ , abstract = {Cholangiocarcinoma (CCA) remains a lethal malignancy with limited therapeutic options. Through genome-wide CRISPR-Cas9 screening, we identified the adenosine triphosphatase (ATPase) valosin-containing protein (VCP) as a critical dependency in CCA. Compound screens revealed that the VCP inhibitor CB-5339 potently suppresses CCA proliferation in a panel of patient-derived organoids by inducing cellular senescence. It is known that senescent cells persist, and this can contribute to therapy resistance. To address this, we combined CB-5339 with senolytic agents (ABT-263 and conatumumab), which selectively eliminate senescent CCA cells, resulting in enhanced tumor suppression both in vitro and in vivo. Clinical analysis showed that VCP overexpression in CCA patients correlates with poor prognosis. Our study unveils a “one-two punch” strategy, targeting VCP-mediated senescence followed by senolytic clearance, offering a promising therapeutic approach for CCA.}, archive = {J_PNAS}, author = {Yang, Wu and Wang, Siying and Ji, Shuyi and Wang, Jian and Lian, Shuo and Li, Zhe and Jansen, Robin A. and Wu, Wei and Niu, Kongyan and Sun, Zhen and Jia, Qi and Zheng, Jiaojiao and Zhu, Huijue and Deng, Xuan and Wang, Liqin and Fan, Zhoulong and Shi, Yaoping and Lieftink, Cor and Guan, Ming and Beijersbergen, Roderick L. and Qin, Wenxin and Gao, Qiang and Bernards, René and Jin, Haojie}, doi = {10.1073/pnas.2519568122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2519568122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma}, volume = {122}, year = {2025}, }
• (2025). Counterfactual history. PNAS, 122(39), e2519485122. (www)

  @article{ , archive = {J_PNAS}, author = {Fleming, James Rodger}, doi = {10.1073/pnas.2519485122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2519485122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Counterfactual history}, volume = {122}, year = {2025}, }
• (2025). Fast calculation of small-angle scattering profiles of dense protein solutions modeled at the all-atom level. PNAS, 122(39), e2519265122. (www)

  @article{ , abstract = {The small-angle scattering (SAS) profile of a dense protein solution contains rich information about interprotein interactions, but extracting this information has been extremely challenging. In previous studies, we developed a fast Fourier transform-based method, FMAPB2, to compute protein pair interactions at the all-atom level. Here, we use FMAPB2 to precompute pair interaction energies and then use the latter to drive simulations of dense protein solutions. The resulting MAEPPI (many-protein atomistic energy from precomputed pair interaction) enables simulations of atomistic proteins at the speed of Lennard-Jones particles. On snapshots sampled from the simulations, we directly calculate the SAS profile. The results reveal artifacts generated by widely used spherical models and support a significant dimer population of bovine serum albumin at high concentrations. Our approach promises to modernize the prediction and interpretation of SAS profiles of dense protein solutions.}, archive = {J_PNAS}, author = {Qin, Sanbo and Zhou, Huan-Xiang}, doi = {10.1073/pnas.2519265122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2519265122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fast calculation of small-angle scattering profiles of dense protein solutions modeled at the all-atom level}, volume = {122}, year = {2025}, }
• (2025). Bacillus subtilis in defense mode: Switch-like adaptations to protistan predation. PNAS, 122(39), e2518989122. (www)

  @article{ , abstract = {Single-cell eukaryotic predators in the soil are a primary cause of bacterial cell death. Yet, most functional genomic studies on soil bacteria have been performed without predation, thereby selecting for phenotypes impacting growth rather than survival and biasing our view on the ecological factors driving genomic evolution. Here, we study how predation by the ubiquitous amoebal predator Dictyostelium discoideum affects Bacillus subtilis ’ growth and survival using both a genome-scale mutant screen and de novo evolution of resistance. We show that predation-related genes (many not previously identified) promote survival by enabling filament or aggregate formation, thereby outsizing D. discoideum and slowing or preventing ingestion. Importantly, we find that predation resistance is costly, causing a trade-off between growth and survival. B. subtilis navigates this trade-off through switch-like adaptations, where cells switch back-and-forth between a slow-growing resistant state and a fast-growing susceptible state. These behaviors are controlled through both genotypic and phenotypic switches, with a central role for the Spo0A phosphorylation cascade, whose ancestral function may have been to evade or slow predation. Taken together, we uncover how the antagonist selection pressure imposed by predation is an important ecological driver of phenotypic heterogeneity in B. subtilis .}, archive = {J_PNAS}, author = {van Gestel, Jordi and Koo, Byoung-Mo and Stürmer, Vanessa S. and Garriga-Canut, Mireia and Wagner, Jonas and Zanon, Andrea and Gross, Carol A.}, doi = {10.1073/pnas.2518989122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2518989122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bacillus subtilis in defense mode: Switch-like adaptations to protistan predation}, volume = {122}, year = {2025}, }
• (2025). Correction for wang et al., interplay of mevalonate and hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. PNAS, 122(39), e2518601122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2518601122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2518601122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for wang et al., interplay of mevalonate and hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility}, volume = {122}, year = {2025}, }
• (2025). In vitro maturation of fully active [FeFe]-hydrogenase in a defined system including the iron carrier NfuA. PNAS, 122(39), e2517347122. (www)

  @article{ , abstract = {The [FeFe]-hydrogenase employs an active-site 6Fe H-cluster to catalyze the reversible reduction of protons to H 2 . A [4Fe-4S] subcluster of the H-cluster is synthesized by housekeeping iron-sulfur cluster assembly machinery, and then dedicated hydrogenase maturation enzymes, together with components of the glycine cleavage system, build and deliver a [2Fe] subcluster to generate the full H-cluster. Here, we report that the Escherichia coli iron-sulfur carrier protein NfuA supports in vitro maturation of fully active [FeFe]-hydrogenase, with H 2 production rates comparable to that of the in vivo - matured Chlamydomonas reinhardtii [FeFe]-hydrogenase ( Cr HydA). Inclusion of NfuA in the in vitro maturation process improves its efficacy by delivering the iron essential for formation of the [Fe II (cys)(CN)(CO) 2 ] – synthon at the dangler iron site of the HydG auxiliary cluster. NfuA serves an additional role in reconstituting and maintaining the catalytically essential iron-sulfur clusters on the maturase enzymes HydE, HydF, and HydG. Further inclusion of a high CO affinity myoglobin variant (Mb H64L ) sequesters free CO generated during the maturation process, minimizing formation of the CO-inhibited H ox -CO enzyme state, significantly increasing hydrogenase activity. The addition of NfuA and Mb H64L to the fully defined maturation system thus results in an in vitro [FeFe]-hydrogenase maturation system that generates highly active enzyme while providing insights into factors important to in vivo maturation.}, archive = {J_PNAS}, author = {Marlott, Alexander and Pagnier, Adrien and Shepard, Eric M. and Balci, Batuhan and Teye, Abraham and Warui, Douglas M. and Yang, Hao and Drena, Alex and Booker, Squire J. and Hoffman, Brian M. and Broderick, William E. and Broderick, Joan B.}, doi = {10.1073/pnas.2517347122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2517347122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In vitro maturation of fully active [FeFe]-hydrogenase in a defined system including the iron carrier NfuA}, volume = {122}, year = {2025}, }
• (2025). A TGF-βR/IL-2R immunomodulatory fusion protein transforms immunosuppression into t cell activation to enhance adoptive t cell therapy. PNAS, 122(39), e2516951122. (www)

  @article{ , abstract = {Adoptive T cell therapies have shown limited efficacy against solid tumors due in part to immunosuppressive cues such as from TGF-β and insufficient survival/proliferative signals within the tumor microenvironment (TME). We engineered chimeric immunomodulatory fusion proteins (IFPs) that convert immunosuppressive TGF-β signals into proliferative/survival Interleukin 2 (IL-2) signals in T cells. Chimeric TGF-βR/IL-2R IFPs were constructed by fusing extracellular domains of the TGF-β receptor chains with intracellular domains of IL-2Rβ and IL-2Rγ to enable TGF-β binding to trigger STAT5 phosphorylation and activate the downstream IL-2 pathway. In human primary CD8 + T cells, select IFP designs robustly induced p-STAT5 upon exposure to TGF-β1, and simultaneously reduced canonical SMAD2/3 signaling. IFP-expressing T cells proliferated and displayed enhanced viability in response to TGF-β1, effectively leveraging TGF-β-rich conditions to outcompete nontransduced cells. Transcriptomic analyses revealed that IFP signaling promoted T cell activation and allowed maintenance of stemness during culture with TGF-β. Functionally, coexpressing IFPs with a mesothelin-specific T cell receptor improved tumor killing and promoted T cell expansion in the presence of TGF-β1, highlighting both neutralization of TGF-β–mediated suppression and enhanced proliferation. TGF-βR/IL-2R IFPs appear promising for reprogramming the signals T cells receive in the TME and improving efficacy of adoptive T cell therapy in solid tumors.}, archive = {J_PNAS}, author = {Su, Yapeng and Thelen, Ashley and Wirth, Lena V. and Jenkins, Cody M. and Mak, Sam R. and Chen, Daniel G. and Gottardo, Raphael and Greenberg, Philip D.}, doi = {10.1073/pnas.2516951122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2516951122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A TGF-βR/IL-2R immunomodulatory fusion protein transforms immunosuppression into t cell activation to enhance adoptive t cell therapy}, volume = {122}, year = {2025}, }
• (2025). Structural and functional analysis of the mycobacterium tuberculosis MmpS5L5 efflux pump presages increased bedaquiline resistance. PNAS, 122(39), e2516660122. (www)

  @article{ , abstract = {Bedaquiline, an antitubercular drug that targets ATP-synthase, is a key component of a new oral drug regimen that has revolutionized the treatment of multidrug-resistant tuberculosis. Clinical bedaquiline resistance in Mycobacterium tuberculosis has rapidly emerged, primarily due to mutations in the transcriptional repressor Rv0678 that result in upregulation of the resistance-nodulation-division (RND) efflux pump MmpS5/MmpL5 (MmpS5L5). Here, to understand how MmpS5L5 effluxes bedaquiline, we determined the structure of the MmpS5L5 complex using cryo-electron microscopy, revealing a trimeric architecture distinct from the canonical tripartite RND efflux pumps of gram-negative bacteria. Structure prediction modeling in conjunction with functional genetic analysis indicates that it uses a periplasmic coiled-coil tube to transport molecules across the cell wall. Structure-guided genetic approaches identify MmpL5 mutations that alter bedaquiline transport; these mutations converge on a region in MmpL5 located in the lower portion of the periplasmic cavity, proximal to the outer leaflet of the inner membrane, suggesting a route for bedaquiline entry into the pump. While currently known clinical resistance to bedaquiline is due to pump upregulation, our findings that several MmpL5 variants increase bedaquiline efflux may presage the emergence of additional modes of clinical resistance.}, archive = {J_PNAS}, author = {Fountain, Adam J. and Böhning, Jan and McLaughlin, Stephen H. and Morgan, Tomos E. and Edelstein, Paul H. and Troll, Mark and Lamers, Meindert H. and Bharat, Tanmay A. M. and Luisi, Ben F. and Ramakrishnan, Lalita}, doi = {10.1073/pnas.2516660122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2516660122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural and functional analysis of the mycobacterium tuberculosis MmpS5L5 efflux pump presages increased bedaquiline resistance}, volume = {122}, year = {2025}, }
• (2025). SARS-CoV-2-derived RNA replicons as safe and effective vaccines. PNAS, 122(39), e2516587122. (www)

  @article{ , abstract = {A collection of RNA replicons (RRs) derived from severe acute respiratory syndrome 2 (SARS-CoV-2) for use in vaccine design was constructed by genetic engineering using bacterial artificial chromosomes. A replicon, which was deleted in six genes (3a, 3c, E, 6, 7a, and 7b) was selected. Cells infected with the RR vaccine candidate led to the formation of virus-like particles that, due to the failure of being secreted, increase vaccine safety, in contrast to the wild type virions. The replicon maintained the production of RNAs encoding at least proteins S, M, and N for several days. Intranasal immunization with the RR of transgenic mice, expressing human ACE2, elicited respiratory mucosal immunity. Immunization protected against challenge with SARS-CoV-2, inducing IgG, IgM, and IgA antibodies to the spike (S) protein, the receptor binding domain, N and M proteins, and cellular immune responses (CD4 + , CD8 + , and long-term memory T cells). Coinfection of cells with the RR vaccine and a full-length SARS-CoV-2 led to a significant inhibition of replication of full-length virus, increasing the safety of the RR vaccine. The RR vaccine induced a minor inflammatory reaction in the absence of major side effects and was stable at different temperatures. An updated RR expressing XBB.1.5 S protein elicited neutralizing antibodies against the homologous virus and provided full protection against recent SARS-CoV-2 variants.}, archive = {J_PNAS}, author = {Villarejo-Torres, Marta and Nombela-Diaz, Iván and Muñóz-Santos, Diego and Ruiz-Yuste, Mercedes and Marchena-Pasero, Ana and Rueda-Huélamo, María A. and Ripoll-Gómez, Jorge and Sánchez-Cordón, Pedro J. and Fernandez del Ama, Laura and Honrubia, José M. and Gutiérrez-Álvarez, Javier and Hurtado-Tamayo, Jesús and Requena-Platek, Ricardo and Guzmán, María and Casasnovas, Jose M. and García-Arriaza, Juan F. and Perez, Patricia and Martin-Jouve, Beatriz and Matamoros, Tania and Pintado, Belén and Perlman, Stanley and Sola, Isabel and Zuñiga, Sonia and Enjuanes, Luis}, doi = {10.1073/pnas.2516587122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2516587122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SARS-CoV-2-derived RNA replicons as safe and effective vaccines}, volume = {122}, year = {2025}, }
• (2025). IFN-inducible human phospholipid scramblase 1 (PLSCR1) protein restricts HIV-1 infection by inhibiting membrane fusion. PNAS, 122(39), e2516527122. (www)

  @article{ , abstract = {Human phospholipid scramblase 1 (PLSCR1) is an interferon-stimulated gene (ISG) that inhibits viral infections through various mechanisms. Here, we identify PLSCR1 as a host restriction factor that inhibits HIV-1 entry by impairing membrane fusion mediated by the envelope glycoprotein (Env). Using multiple cell types including the human SupT1 T cell line and purified CD4 + T cells, we demonstrate that PLSCR1 inhibits the replication of HIV-1 with diverse tropisms and subtypes, as well as HIV-2 and SIV. Mechanistically, we find that PLSCR1 blocks viral entry and cell-to-cell transmission, in part by restricting HIV-1 virion–cell and cell–cell fusion without affecting CD4 or CXCR4 expression or virus binding to the cell surface. Collectively, these findings establish PLSCR1 as a broad-spectrum lentiviral restriction factor that acts at the membrane fusion stage, thereby expanding our understanding of ISG-mediated antiviral defense.}, archive = {J_PNAS}, author = {Liu, Yajie and Li, Pei and Zheng, Yi-Min and Hikichi, Yuta and Ablan, Sherimay D. and Freed, Eric O. and Liu, Shan-Lu}, doi = {10.1073/pnas.2516527122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2516527122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {IFN-inducible human phospholipid scramblase 1 (PLSCR1) protein restricts HIV-1 infection by inhibiting membrane fusion}, volume = {122}, year = {2025}, }
• (2025). In situ structures of the legionella Dot/Icm T4SS identify the DotA–IcmX complex as the gatekeeper for effector translocation. PNAS, 122(39), e2516300122. (www)

  @article{ , abstract = {The Dot/Icm machine of Legionella pneumophila is among the most versatile type IV secretion systems (T4SSs), capable of translocating more than 330 distinct effector proteins across the bacterial envelope into host cells. Assembly and function of the system require at least 27 Dot and Icm proteins, yet its architecture and activation mechanism remain poorly understood at the molecular level. Here, we deploy in situ single-particle cryoelectron microscopy to determine near-atomic structures of the Dot/Icm machine and its intimate association with three distinct outer membrane porins in intact bacteria. Notably, two essential yet enigmatic components, DotA and IcmX, form a pentameric protochannel in an inactive state at the central axis of the Dot/Icm machine. Upon Dot/Icm activation with host lysate, this protochannel undergoes extensive rearrangements to generate an extended transenvelope conduit, as visualized by cryoelectron tomography (cryo-ET) and subtomogram averaging. Furthermore, a combination of cryo-ET and cryo-FIB milling of macrophages infected with L. pneumophila reveals tethering of the Dot/Icm machine to the host membrane, suggesting direct translocation of effector proteins from the bacterial cytoplasm into the host. Together, our studies identify the DotA–IcmX complex as a gatekeeper for effector translocation and provide a molecular framework for understanding the assembly and activation of the elaborate Dot/Icm T4SS.}, archive = {J_PNAS}, author = {Yue, Jian and Heydari, Samira and Park, Donghyun and Chetrit, David and Tachiyama, Shoichi and Guo, Wangbiao and Botting, Jack M. and Wu, Shenping and Roy, Craig R. and Liu, Jun}, doi = {10.1073/pnas.2516300122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2516300122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In situ structures of the legionella Dot/Icm T4SS identify the DotA–IcmX complex as the gatekeeper for effector translocation}, volume = {122}, year = {2025}, }
• (2025). SARS-CoV-2 mutant spectrum complexity is an epidemiologically evolvable trait. PNAS, 122(39), e2515706122. (www)

  @article{ , abstract = {RNA virus populations consist of complex and dynamic mutant spectra in which most individual genomes differ in one or more positions from the other genomes of the same population. This behavior, known as quasispecies dynamics, applies to SARS-CoV-2 which exhibits intrahost genetic and functional heterogeneity while evolving at a high rate in the human population. In the present study, we describe a remarkable reduction in mutant spectrum complexity (intrahost viral genome heterogeneity) in SARS-CoV-2 isolates of late relative to early COVID-19 waves, as they reached Madrid (Spain) from 2020 until 2022. In contrast, the consensus (average) sequence of the corresponding isolates displayed a continuing divergence from the initial Wuhan-Hu-1 virus as the pandemic advanced. The mutant spectrum complexity developed upon replication in Vero E6 cells of the isolates from the first and sixth COVID-19 waves, as well as of biological clones retrieved from them, was similar. Therefore, the mutant spectrum complexity reduction observed in vivo was not due to an increased accuracy of the viral replicative machinery, but rather to other factors related to viral epidemiology or pathogenesis. Such possible factors and their implications for viral trait modifications in the course of a viral pandemic are discussed. The results establish that mutant spectrum complexity of genetically variable viruses can be an epidemiologically evolvable trait.}, archive = {J_PNAS}, author = {Martínez-González, Brenda and Soria, María Eugenia and de Ávila, Ana Isabel and Somovilla, Pilar and Aguilar-Sabido, Claudia and Mínguez, Pablo and Ferrer-Orta, Cristina and Salar-Vidal, Llanos and Lorenzo-Redondo, Ramón and Delgado, Soledad and Morán, Federico and Verdaguer, Nuria and Gadea, Ignacio and Domingo, Esteban and Perales, Celia}, doi = {10.1073/pnas.2515706122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2515706122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SARS-CoV-2 mutant spectrum complexity is an epidemiologically evolvable trait}, volume = {122}, year = {2025}, }
• (2025). Glycosylated cannabinoids in cannabis sativa and enzyme design to modulate their synthesis. PNAS, 122(39), e2515688122. (www)

  @article{ , abstract = {Despite extensive study of its chemical composition and long history of medicinal use, the occurrence of glycosylated cannabinoid derivatives in Cannabis sativa has not been documented to date. Here, we identified glycosylated cannabinoids and their common intermediate olivetolic acid (OA) in various C. sativa tissues and cultivars. We moreover identified four UDP-glycosyltransferases (UGTs) from C. sativa with OA glycosylating activity. Enhancing the water solubility of cannabinoids through glycosylation holds potential for pharmaceutical development and cosmetic applications. However, glycosylation of pathway intermediates such as OA may divert metabolic flux away from cannabinoid production, complicating efforts to engineer glycosylated forms. To resolve this, we applied FuncLib design to an AlphaFold-predicted structure of one of the identified enzymes CsUGT14, generating active-site variants. Through functional screening, we identified mutants that display increased specificity toward cannabinoid end products over the OA intermediate. Moreover, we recognized a single point mutation that dictates OA positioning within the active site, thereby altering isomer formation. These findings expand the known repertoire of natural cannabinoids and provide a rare example of crystallography-free enzyme design to improve stability, substrate selectivity, and isomer specificity. Furthermore, this work lays the foundation for the tailored biosynthesis of soluble glycosylated cannabinoids in heterologous systems.}, archive = {J_PNAS}, author = {Pinkas, Zoe and Khersonsky, Olga and Berman, Paula and Kuzmich, Nikolay and Rogachev, Ilana and Fleishman, Sarel J. and Aharoni, Asaph}, doi = {10.1073/pnas.2515688122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2515688122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Glycosylated cannabinoids in cannabis sativa and enzyme design to modulate their synthesis}, volume = {122}, year = {2025}, }
• (2025). Motor expertise modulates cortical activation during imagery of simple and complex actions. PNAS, 122(39), e2515027122. (www)

  @article{ , abstract = {Motor imagery (MI) engages neural systems that overlap with actual movement and is widely used in sport and rehabilitation. Yet conflicting findings suggest that experts show either reduced (neural efficiency) or increased (vivid simulation) brain activation during MI. We hypothesized that task complexity moderates this effect. Using fNIRS, we compared experts and novices during MI of simple versus complex soccer actions. Experts showed lower activation for simple tasks but higher activation for complex ones, while novices showed the opposite pattern. These findings unify opposing accounts of expertise, revealing that expert brains adaptively scale simulation to task demands. This has practical implications for optimizing MI-based training across skill levels.}, archive = {J_PNAS}, author = {Yin, Jie and Yang, Ke and Zhou, Chendi and Dang, Junhua}, doi = {10.1073/pnas.2515027122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2515027122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Motor expertise modulates cortical activation during imagery of simple and complex actions}, volume = {122}, year = {2025}, }
• (2025). PPT1 is a negative regulator of STING signaling in cancer cells and its inhibition reactivates immune surveillance in cold tumors. PNAS, 122(39), e2514948122. (www)

  @article{ , abstract = {Immunotherapy modalities have revolutionized cancer treatment for a number of metastatic and treatment-refractory tumor types. Still, many malignancies that lack T cell infiltration and are termed immunologically “cold” fail to respond to these modalities. One approach to increase tumor immunogenicity has been to induce stimulator of interferon gene (STING) and downstream interferon signaling that is often dysregulated in cold tumors. Despite some early success of STING agonists in preclinical cancer models, these approaches have not been successful in the clinic due to poor tumor penetrance and systemic toxicities. Here, we performed a genome-wide CRISPR screen to uncover therapeutic targets to activate STING expression in human tumors. We identified the lysosomal hydrolase Palmitoyl Protein Thioesterase1 (PPT1) as a negative regulator of STING highly expressed in cold ovarian and prostate tumors. Genetic or pharmacological PPT1 suppression increased STING protein stability and its downstream activation of interferon and inflammatory cytokine signaling to enhance T cell migration. Treatment of preclinical prostate and ovarian cancer models expressing low levels of STING with the small molecule PPT1 inhibitor GNS561 enhanced STING expression and activation, leading to infiltration and activation of cytotoxic T cells that turned these tumors “hot” and reduced tumor growth, fibrosis, and dissemination without toxicity. Further analysis demonstrated that PPT1 is associated with reduced STING expression, CD8 + T cell numbers, overall survival, and immunotherapy outcomes in ovarian and prostate cancer patients. Thus, PPT1 inhibition may be a promising approach to activate STING and potentiate the effects of immunotherapy in cold tumors.}, archive = {J_PNAS}, author = {Chowdhury, Shreya R. and Parikh, Chaitanya N. and Kaur, Arshia N. and DeMarco, Kelly D. and Giwa, Hadiya K. and Mishra, Alok K. and Murphy, Katherine C. and Zhou, Lin and Ma, Boyang and Ye, Tianyi and Li, Junhui and Liu, Haibo and Bai, Shi and Johnson, Calvin and Simin, Karl and Pitarresi, Jason R. and Zhu, Lihua Julie and Watson, Emma V. and Kelliher, Michelle A. and Green, Michael R. and Fitzgerald, Katherine A. and Ruscetti, Marcus}, doi = {10.1073/pnas.2514948122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2514948122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PPT1 is a negative regulator of STING signaling in cancer cells and its inhibition reactivates immune surveillance in cold tumors}, volume = {122}, year = {2025}, }
• (2025). A supporting-electrolyte-free four-compartment electrochemical reactor for aqueous and organic phase electrosynthesis. PNAS, 122(39), e2514240122. (www)

  @article{ , abstract = {Electrosynthesis offers a promising method to make valuable chemicals under mild conditions; however, its application has been greatly hampered by issues including the requirement of a supporting electrolyte, the limited solubility of reactant(s) in electrochemical compartments, the complex product(s) separation processes, etc. Herein, we innovatively present a four-compartment electrochemical reactor equipped with delicately designed active species diffusion membrane electrodes. Four compartments include two chemical (reduction and oxidation) compartments and two electrochemical (cathode and anode) compartments. The unique membrane electrodes physically separate the chemical compartments (containing organic reactants in pure solvent) from the electrochemical compartments (containing supporting electrolytes), while allowing electrosynthesis of high-value-added chemicals in both nonconducting aqueous and organic environments without the need of a supporting electrolyte. The reactor is able to drive both the anodic electrosynthesis (e.g., oxidation with a halogenation yield > 93%) and the cathodic electrosynthesis (e.g., reduction with a hydrogenation yield > 95% and a deuteration incorporation > 85%). The batch four-compartment electrochemical reactor can be engineered into a continuous type, where substrates in pure solvent can be converted into products with a conversion > 90% as they travel from the inlet to the outlet of the continuous reactor.}, archive = {J_PNAS}, author = {Wu, Huan and Liu, Baoquan and Su, Chenliang and Chen, Deyin and Jiao, Longhao and Zheng, Huajun and Wang, Lianbang and Teng, Zhenyuan and Shao, Lianchong and Xu, Yinghua and Liu, Bin}, doi = {10.1073/pnas.2514240122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2514240122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A supporting-electrolyte-free four-compartment electrochemical reactor for aqueous and organic phase electrosynthesis}, volume = {122}, year = {2025}, }
• (2025). A diverse family of bacterial deubiquitinases is defined by the coxiella burnetii effector EmcB. PNAS, 122(39), e2513714122. (www)

  @article{ , abstract = {The obligate intracellular pathogen Coxiella burnetii encodes a deubiquitinase called EmcB that prevents signaling by the host immune sensor Retinoic acid Inducible Gene I (RIG-I). The evolutionary relationship between EmcB and other deubiquitinases is currently unknown. Here, we show that EmcB defines a broad family of bacterial deubiquitinases divergently evolved from the eukaryotic Ovarian Tumor (OTU) family of deubiquitinases. Our data indicate that the emcB gene has an internal gene rearrangement that resulted in a circular permutation of the OTU fold. Proteins with a region homologous to the deubiquitinase domain of EmcB were identified in numerous members of the bacterial order Legionellales. Proteins with an EmcB-related deubiquitinase domain demonstrated cysteine protease activity that cleaved ubiquitin and ubiquitin-related modifiers. Most of the bacteria encoding EmcB-related proteins had components of the Dot/Icm Type IVB secretion system that delivers EmcB into host cells. Indeed, many of these EmcB-related proteins were translocated into eukaryotic cells by the Dot/Icm system of Legionella pneumophila , consistent with their predicted roles as bacterial effector proteins that target host pathways. Comparison of EmcB family deubiquitinases revealed a two-domain architecture of EmcB comprising a deubiquitinase domain and a ubiquitin binding module that confers enzyme specificity for certain polyubiquitin chains. This ubiquitin binding region in EmcB was found to be necessary for efficient inhibition of RIG-I signaling. Thus, these EmcB-related proteins represent a large family of deubiquitinating enzymes that arose by divergent evolution in Legionellales , likely enabling these bacteria to infect different host cells by targeting signaling pathways regulated by ubiquitin.}, archive = {J_PNAS}, author = {Duncan-Lowey, Jeffrey K. and Roy, Craig R.}, doi = {10.1073/pnas.2513714122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2513714122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A diverse family of bacterial deubiquitinases is defined by the coxiella burnetii effector EmcB}, volume = {122}, year = {2025}, }
• (2025). Action painting under spectroscopic light: Excited-state exchange interactions behind the vibrant blue in jackson pollock’s number 1A, 1948. PNAS, 122(39), e2513166122. (www)

  @article{ , abstract = {Number 1A, 1948 by Jackson Pollock is a quintessential example of his action painting technique where ropes of color, drips of black, and pools of white coalesce into the layered dynamism that defines his style. While past work has identified the red and yellow pigments that form part of his core palette, the vibrant blue in the painting has remained unassigned. In this study resonance Raman spectroscopy is used to assign the blue in the painting as manganese blue. This assignment offers critical context for the conservation of his works. Importantly, assignment of this pigment enables spectroscopic investigation of the electronic structure origin of the pure hue of manganese blue and the chemical phenomena that produce its color. To probe these phenomena, resonance Raman data are coupled to magnetic circular dichroism spectroscopy and density functional theory calculations to assign and analyze the two electronic transitions that create the blue color. This study reveals these bands are split by excited-state exchange interactions; the gap between them contains the reflected light that gives manganese blue its appearance. This sheds light on distinct advantages of molecular inorganic pigments: their ability to leverage ligand field effects in charge transfer states to create multiple intense visible absorption features and the ability to fine-tune pigment color through host lattice electrostatics.}, archive = {J_PNAS}, author = {Heyer, Alexander J. and Haddad, Abed and Scott, Racquel and Kowach, Glen and Solomon, Edward I.}, doi = {10.1073/pnas.2513166122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2513166122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Action painting under spectroscopic light: Excited-state exchange interactions behind the vibrant blue in jackson pollock’s number 1A, 1948}, volume = {122}, year = {2025}, }
• (2025). Ectopic transcription due to inherited histone methylation may interfere with the ongoing function of differentiated neurons. PNAS, 122(39), e2513137122. (www)

  @article{ , abstract = {How mutations in histone modifying enzymes lead to neurodevelopmental defects is unknown. To address this question, we took advantage of the invariant embryonic lineage and adult nervous system in Caenorhabditis elegans to investigate a double mutant between spr-5/Lsd1/Kdm1a (H3K4me1/2 demethylase) and met-2/Setdb1/Kmt1e (H3K9 methyltransferase). We demonstrate that spr-5; met-2 double mutant worms have a severe chemotaxis defect caused by the ectopic expression of germline genes in somatic tissues. Despite this behavioral defect, we observe few embryonic lineage alterations and the normal complement of neurons. This raised the possibility that the abnormal chemotaxis behavior may be due to ongoing defects in terminally differentiated cells rather than alterations in development. Consistent with this possibility, we find that shutting off the ectopic expression of germline genes specifically in neurons rescues chemotaxis in spr-5; met-2 mutants. Remarkably, shutting off the ectopic germline expression in spr-5; met-2 adult worms, that had a chemotaxis defect earlier in development, is also sufficient to rescue chemotaxis behavior. These results suggest that ongoing inappropriate transcription in neurons can block normal behavior despite the chemotaxis neurons being intact.}, archive = {J_PNAS}, author = {Rodriguez, Juan D. and Reeves, Monica N. and Chavez, Sindy R. and Wang, Hsiao-Lin V. and Chavez, Jaely Z. and Rastogi, Rhea and Sun, Liyang I. and Roberson, Mackenzie S. and Preston, Elicia A. and Massenburg, Zaynab and Cruz, Kiani N. and Chadha, Madhav S. and Hill, Emily J. and Soares, Miguel L. and Corces, Victor G. and Carpenter, Brandon S. and Schmeichel, Karen L. and Murray, John I. and Katz, David J.}, doi = {10.1073/pnas.2513137122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2513137122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ectopic transcription due to inherited histone methylation may interfere with the ongoing function of differentiated neurons}, volume = {122}, year = {2025}, }
• (2025). Duplication of a conserved mitochondrial enzyme gene arms parasitoid wasps with venom cytotoxicity and oogenesis regulation. PNAS, 122(39), e2512820122. (www)

  @article{ , abstract = {Gene duplication, followed by neofunctionalization, is a key mechanism driving the emergence of evolutionary novelties. Despite its significance, the molecular and functional processes underlying this phenomenon remain incompletely understood. By tracing the evolutionary history of cysteine-S-conjugate beta-lyase genes within the kynurenine aminotransferase family, we identified a gene duplication event in parasitoid wasps of the Chalcidoidea superfamily. Notably, a single-copy, highly conserved mitochondria-localized physiological gene underwent a significant duplication, resulting in one copy being recruited into the venom system and acquired cytotoxicity against wasps' hosts. Through this neofunctionalization process, we observed several key evolutionary changes, including loss of ancestral mitochondrial localization and enzyme activity, acquisition of a secretory signal peptide, shift in expression pattern, positive selection, and the establishment of evolutionary acquired protein–protein interactions. Additionally, we found that another duplicate copy was specialized in wasps' ovary and repurposed for oogenesis regulation. Our study offers a detailed insight into the genetic and molecular mechanisms that drive functional diversification during the evolution of gene families.}, archive = {J_PNAS}, author = {Song, Jiqiang and Qi, Zihan and He, Chun and Luo, Guilin and Yuan, Bo and Xiao, Shan and Yang, Yi and Wang, Fang and Ye, Gongyin and Fang, Qi and Yan, Zhichao}, doi = {10.1073/pnas.2512820122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2512820122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Duplication of a conserved mitochondrial enzyme gene arms parasitoid wasps with venom cytotoxicity and oogenesis regulation}, volume = {122}, year = {2025}, }
• (2025). Sustainable forest planning: Assessing biodiversity effects of triad zoning based on empirical data and virtual landscapes. PNAS, 122(39), e2512683122. (www)

  @article{ , abstract = {The Triad framework seeks to balance the economic and ecological functions in forested landscapes by combining intensively, extensively, and unmanaged areas, assuming a higher support to biodiversity in extensively rather than in intensively managed forests. We quantified the effects of Triad zoning on biodiversity in (sub)montane eutrophic European beech forests. Using a European-wide multitaxon database and a “virtual” landscape approach (i.e., by resampling empirical data), we evaluated how the proportion of Triad management categories affected the landscape-level species diversity of birds, saproxylic beetles, vascular plants, epiphytic bryophytes, lichens, and wood-inhabiting fungi, as well as multitaxonomic diversity. The results varied greatly among taxonomic groups. Multitaxonomic diversity peaked in landscapes composed of 60% unmanaged and 40% intensively managed forests. While intensive management can benefit some taxa through the creation of open habitats, unmanaged forests are the backbone of biodiversity conservation, underlining the need to safeguard the remaining old-growth forests under natural dynamics, and to extend the current area of unmanaged forests in Europe. Extensive forest management, however, did not contribute to biodiversity conservation as expected. As withdrawing such a high proportion of European forest landscapes from management is unfeasible given the increasing demand for timber, efforts are needed to increase the presence of structural features supporting biodiversity into extensively managed forests.}, archive = {J_PNAS}, author = {Duflot, Rémi and Heinrichs, Steffi and Balducci, Lorenzo and Chianucci, Francesco and Hofmeister, Jeňýk and Paillet, Yoan and Trentanovi, Giovanni and Archaux, Frédéric and Boch, Steffen and Bouget, Christophe and Dvořák, Daniel and Fischer, Markus and Gosselin, Frédéric and Gosselin, Marion and Gossner, Martin M. and Holá, Eva and Hošek, Jan and Jung, Kirsten and Palice, Zdeněk and Renner, Swen C. and Weisser, Wolfgang W. and Nagel, Thomas A. and Burrascano, Sabina and Schall, Peter}, doi = {10.1073/pnas.2512683122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2512683122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sustainable forest planning: Assessing biodiversity effects of triad zoning based on empirical data and virtual landscapes}, volume = {122}, year = {2025}, }
• (2025). A campylobacter jejuni sensor phosphatase–driven two-component system integrates metabolic phosphodonors as cues in signal transduction. PNAS, 122(39), e2512446122. (www)

  @article{ , abstract = {Canonical bacterial two-component signal transduction systems (TCSs) detect cues by sensors with opposing kinase and phosphatase activities to alter the level of phosphorylation of cognate response regulators to mediate responses. We previously identified the Campylobacter jejuni BumSR TCS as the founding member of a bacterial TCS family in which the sensor solely functions as a phosphatase. Sensing specific intestinal metabolites inhibits BumS dephosphorylation of phospho-BumR (P-BumR) to impact BumR as a transcriptional regulator of genes influencing host colonization. Since BumS lacks kinase activity, BumR must depend upon a noncognate phosphodonor in the bacterium to form P-BumR. Through a genetic screen and selection, physiological assays, and biochemical analysis, we identified acetyl phosphate (AcP) and carbamoyl phosphate (CP) as natural in vivo phosphodonors for BumR. In C. jejuni , AcP and CP are products of metabolic pathways fueled by amino acids favored by the bacterium as carbon sources for growth. Producing and utilizing AcP and CP as bona fide BumR phosphodonors allows BumSR to integrate different types of inputs for signal transduction. Microbiota-generated gut metabolites are cues for BumS to control its phosphatase activity for P-BumR and inform about the spatial location of C. jejuni in host intestines. In contrast, AcP and CP are cues for BumR that directly influence P-BumR levels and activity and inform about the richness of favored carbon sources in intestinal niches for optimal energy generation and metabolism. Our study reveals how a bacterial TCS strategically integrates information from multiple cues through both essential components for optimal signal transduction.}, archive = {J_PNAS}, author = {Ruiz, Nestor and Hendrixson, David R.}, doi = {10.1073/pnas.2512446122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2512446122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A campylobacter jejuni sensor phosphatase–driven two-component system integrates metabolic phosphodonors as cues in signal transduction}, volume = {122}, year = {2025}, }
• (2025). Antagonistic SnRK2 and PID kinases' action on auxin transport–mediated root gravitropism. PNAS, 122(39), e2512274122. (www)

  @article{ , abstract = {Plants have evolved sophisticated mechanisms to adapt to environmental changes, with root gravitropism playing a pivotal role in nutrient and water acquisition. Our study reveals that SnRK2 kinases (SnRK2.2 and SnRK2.3) are critical regulators of root gravitropism through their direct phosphorylation of the auxin transporter PIN2 at S259. We demonstrate that SnRK2s-mediated phosphorylation modulates both the polar localization and transport activity of PIN2. Importantly, SnRK2s function antagonistically to the AGCVIII kinase PID, which phosphorylates PIN2 at a distinct site (S258), establishing a regulatory balance essential for adaptive root growth. Structural modeling and phosphorylation assays further suggest that SnRK2s-mediated phosphorylation at S259 sterically hinders access of PID to S258, providing a mechanistic basis for their antagonistic relationship. These findings uncover a novel regulatory mechanism, by which plants fine-tune root developmental programs to adapt to environmental stimuli, highlighting the evolutionary significance of multilayered kinase-mediated regulation in plant adaptation.}, archive = {J_PNAS}, author = {Sheng, Fang and Gao, Yu and Wang, Yaping and Li, Yang and Zhang, Ji-Ao and Zhang, Zhaoheng and Qin, Xinyan and Zhang, Shujuan and Song, Wen and Li, Jigang and Guo, Yan and Friml, Jiří and Gong, Zhizhong and Zhang, Qun and Zhang, Jing}, doi = {10.1073/pnas.2512274122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2512274122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Antagonistic SnRK2 and PID kinases' action on auxin transport–mediated root gravitropism}, volume = {122}, year = {2025}, }
• (2025). Nonmuscle myosin 2 turnover in cells is synergistically controlled by the tail and the motor domain. PNAS, 122(39), e2511046122. (www)

  @article{ , abstract = {Myosin 2, an actin-dependent motor, is universally responsible for cell contractility due to its ability to form bipolar filaments. Fast turnover of nonmuscle myosin 2 (NM2) filaments is necessary to keep up with cell motility and shape changes. The turnover mechanisms are not fully understood and differ for two main mammalian paralogs—NM2A and NM2B—whereas paralog copolymerization adds complexity to this process by enabling the intrinsically fast NM2A to dynamize the intrinsically slow NM2B. Here, we show that the nonhelical tail, the C-terminal phosphorylation sites, and surprisingly, the motor domain of the NM2A heavy chain synergistically accelerate the turnover of NM2B in trans and cell motility, suggesting that these three mechanisms collectively control NM2A’s own dynamics. Conversely, the phosphomimetic NM2B tail facilitates only local turnover of endogenous wild type NM2B but not its global redistribution unless the NM2A motor is combined with the phosphomimetic NM2B tail. Collectively, we reveal the cooperation between the motor activity and the NM2 tail-targeting turnover mechanisms in regulating the NM2 filament turnover in trans and cell motility.}, archive = {J_PNAS}, author = {Chougule, Anil and Svitkina, Tatyana M.}, doi = {10.1073/pnas.2511046122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2511046122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nonmuscle myosin 2 turnover in cells is synergistically controlled by the tail and the motor domain}, volume = {122}, year = {2025}, }
• (2025). Dynamics of longitudinal hawaiian hotspot motion and the formation of the hawaiian-emperor bend. PNAS, 122(39), e2510972122. (www)

  @article{ , abstract = {Formation of the Hawaiian-Emperor Bend has been a key geological puzzle that involves both plate tectonics and plume dynamics. Constrained by paleomagnetic data, southward hotspot motion has been considered a major contributor to the formation of the bend, but the role of longitudinal hotspot motion remains largely overlooked. Here, we analyze the Hawaiian hotspot motion using plate kinematics and geographical distances between hotspot tracks. Both analyses indicate a substantial longitudinal Hawaiian hotspot motion. Further application of global mantle convection models reveals a westward (by ~6°) and then an eastward (by ~2°) hotspot drift in addition to the southward motion before and after the bend, with the westward motion primarily controlled by the intraoceanic subduction in Northeast Pacific. We find that both the westward and southward motion are required to fit the seamount chain, with the former contributing a substantial amount of ~20 degrees to the bend angle, no less than the latter, challenging traditional views. Combined with a geodynamically predicted Pacific Plate motion change at 47 Ma, our model provides a nearly perfect fit to the seamount chain. This result suggests that the Hawaiian plume conduit is tilted toward the southwest, providing a strong indication for the source of the Hawaiian plume that has long been debated among seismological studies.}, archive = {J_PNAS}, author = {Zhang, Jie and Hu, Jiashun}, doi = {10.1073/pnas.2510972122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2510972122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamics of longitudinal hawaiian hotspot motion and the formation of the hawaiian-emperor bend}, volume = {122}, year = {2025}, }
• (2025). Favorable epistasis in ancestral diterpene synthases promoted convergent evolution of a resin acid precursor in conifers. PNAS, 122(39), e2510962122. (www)

  @article{ , abstract = {A long-standing question in biology is what makes evolution more or less repeatable. Although evolution seems repeatable when observing convergent phenotypic outcomes, each episode of convergence could have been contingent on an idiosyncratic history that is not expected to repeat. Overlooking events that preceded convergent episodes therefore risks overestimating repeatability. Here, we demonstrate using resurrected ancestral proteins that the evolution of a characteristic diterpene resin acid precursor, isopimaradiene, became especially repeatable in conifers following genetic divergence that simultaneously changed the effects of phenotype-altering substitutions in diterpene synthase enzymes. We found that millions of years of epistatic change prior to three genus-level episodes of convergent isopimaradiene formation led to ancestral diterpene synthases in the family Pinaceae that served as suitable starting points for evolving identical products. However, enzymes predating the Pinaceae formed different diterpenes when the same substitutions were introduced as mutations, indicating that critical alterations in the effects of substitution occurred after the origin of this plant family. Because these alterations occurred prior to the evolution of isopimaradiene, the convergence appears dependent on a history that is less likely to repeat. Our work shows how contingency can lead to repeatable evolution of a trait in related present-day plant lineages.}, archive = {J_PNAS}, author = {O’Donnell, Andrew J. and Pellatz, Preston J. and Nichols, Caroline S. and Gershenzon, Jonathan and Peters, Reuben J. and Schmidt, Axel}, doi = {10.1073/pnas.2510962122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2510962122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Favorable epistasis in ancestral diterpene synthases promoted convergent evolution of a resin acid precursor in conifers}, volume = {122}, year = {2025}, }
• (2025). The discovery of adzuki bean (Vigna angularis) in eastern china during the 9th millennium BP and its domestication in east asia. PNAS, 122(39), e2510835122. (www)

  @article{ , abstract = {Adzuki bean ( Vigna angularis ) is a key legume widely cultivated in East Asia, prized for both its nutritional value and nitrogen-fixing properties. This paper presents one of the oldest directly dated archaeological finds of adzuki bean, recovered from the Xiaogao site in Shandong, China, and dated to 8985-8645 and 8032-7939 cal. BP—predating previously known Chinese records by at least 4,000 y (approximately 6,000 y considering published directly dated evidence alone). The evidence suggests that adzuki beans formed part of an Early Neolithic multicropping system alongside millet, rice, and soybean in a well-established agricultural tradition in the Lower Yellow River region. Morphometric analysis of adzuki beans from 41 archaeological sites across East Asia reveals a gradual increase in seed size over time when regional data are aggregated, yet highlights distinct regional trajectories. These patterns reflect complex, multiregional domestication processes shaped by both cultural practices and ecological conditions. Notably, the marked differences in bean sizes observed between the Neolithic Yellow River and Jomon-period Japan could be contingent on the distinctions in dietary regimes and associated selective pressures.}, archive = {J_PNAS}, author = {Chen, Xuexiang and Sun, Zejuan and Zhang, Shuhan and Lee, Gyoung-Ah and Nasu, Hiroo and Zhang, Fei and Cai, Haohong and Liu, Xu and Gao, Jixi and Zhu, Chao and Lang, Jianfeng and Zhao, Zhijun and Liu, Xinyi}, doi = {10.1073/pnas.2510835122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2510835122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The discovery of adzuki bean (Vigna angularis) in eastern china during the 9th millennium BP and its domestication in east asia}, volume = {122}, year = {2025}, }
• (2025). Transcriptional regulation of thorn tip sclerification in plants. PNAS, 122(39), e2510775122. (www)

  @article{ , abstract = {A common characteristic of thorns, prickles, and spines is a hardened and sharp tip. This feature complicates cultivation and postharvest processing for many crops, yet the molecular mechanisms governing this specific sclerification process remain unclear. By genome editing screening, we identified a MYB family gene named S HORT and S OFT T HORN 1 ( SST1 ) that specifically promotes the development of sclerenchyma cells at Citrus thorn tips. CRISPR-Cas9 editing of SST1 results in the formation of short and soft thorns with significantly reduced secondary wall thickening at the tips, while leaving stem growth unaffected. SST1 directly activates NST1 and SND1 , driving a hierarchical transcriptional regulatory network for secondary wall biosynthesis. Moreover, SST1 homologs in various species are specifically expressed in thorns, suggesting a potential conserved role. Our results uncover the molecular basis for hard plant protective structures, and modulation of this pathway could be an effective strategy for optimizing cultivation practices.}, archive = {J_PNAS}, author = {Ren, Jie and Duan, Yaoyuan and Li, Ruoqi and Zhang, Xin and Shi, Yanfei and Zhou, Shiyun and Xie, Kaidong and Wu, Xiaomeng and Irish, Vivian F. and Deng, Xiuxin and Zhang, Fei and Guo, Wenwu}, doi = {10.1073/pnas.2510775122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2510775122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transcriptional regulation of thorn tip sclerification in plants}, volume = {122}, year = {2025}, }
• (2025). RNA triple helix assembled by the poly(A) tail enhances retrotransposon mobilization by preventing RNA deadenylation. PNAS, 122(39), e2510774122. (www)

  @article{ , abstract = {Transposable elements (TEs), ubiquitous mobile DNAs, are largely repressed by cellular mechanisms such as epigenetic silencing and RNA decay, yet some retain the ability to transpose. The Arabidopsis long terminal repeat retrotransposon Copia93 , also known as Evade , exhibits exceptionally high transpositional activity, but the mechanism underlying its extraordinary mobility remains unclear. Here, we identify an Element for Nuclear Expression (ENE) motif within the 3′ UTR of Evade that forms a triple helical RNA structure with the poly(A) tail, shielding the transcript from deadenylation and degradation. Deletion of the ENE motif significantly reduces Evade transcript stability, extrachromosomal DNA levels, and de novo insertions. Furthermore, we show that the mRNA deadenylase CCR4a directly binds Evade RNA to shorten its poly(A) tail, thereby suppressing transposition. Loss of CCR4a leads to Evade upregulation, while additional deadenylases contribute to its repression in the absence of CCR4a. Our findings uncover an RNA-based strategy that enhances transposon stability and mobility, illustrating a coevolutionary arms race between host silencing pathways and TE-encoded structural elements.}, archive = {J_PNAS}, author = {Li, Hui and Wang, Ling and Lei, Zhen and Biacsi, Anna-Sara and Jeong, Dong-Hoon and Cho, Jungnam}, doi = {10.1073/pnas.2510774122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2510774122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RNA triple helix assembled by the poly(A) tail enhances retrotransposon mobilization by preventing RNA deadenylation}, volume = {122}, year = {2025}, }
• (2025). Functional spectrum of USP7 pathogenic variants in Hao–Fountain syndrome: Insights into the enzyme’s activity, stability, and allosteric modulation. PNAS, 122(39), e2510252122. (www)

  @article{ , abstract = {Hao–Fountain syndrome is a rare neurodevelopmental disorder caused by mutations in the deubiquitinating enzyme Ubiquitin-Specific Protease 7 (USP7). Due to the novelty of the disease and its poorly understood molecular mechanisms, treatments for the syndrome are currently lacking. This study examines the effects of 11 patient-derived variants located within the catalytic domain of USP7, focusing on their impact on the enzyme’s activity, thermodynamic stability, and substrate recognition. Our findings reveal a spectrum of functional consequences, ranging from complete inactivation to hyperactivation of USP7. Notably, we identify a specific subset of pathogenic variants whose catalytic activity can be significantly boosted using an allosteric activator, MS-8. These results provide insight into USP7 malfunction in Hao–Fountain syndrome–linked variants and pave the way for improved prognostic approaches and targeted treatments in the future.}, archive = {J_PNAS}, author = {Korchak, Emilie J. and Sharafi, Mona and Jaen Maisonet, Isabella and Salazar-Chaparro, Andres and Semenova, Irina V. and Khan, Hamza and O’Neil, Alison L. and Caro, Pilar and Schaaf, Christian P. and Buhrlage, Sara J. and Bezsonova, Irina}, doi = {10.1073/pnas.2510252122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2510252122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Functional spectrum of USP7 pathogenic variants in Hao–Fountain syndrome: Insights into the enzyme’s activity, stability, and allosteric modulation}, volume = {122}, year = {2025}, }
• (2025). Incentivizing teamwork to promote sustainability. PNAS, 122(39), e2510162122. (www)

  @article{ , abstract = {There are a variety of contexts in which “pitching in” to address environmental or resource management problems could benefit from individuals or firms working not just on their own but also working together collaboratively as a group. Examples include working together on promoting conservation or habitat protection, the sharing of information, or the development of less polluting products or production processes. However, to date, the literature on environmental policy has considered only the incentives for individual parties (e.g., firms, landowners, or individuals) to take steps (i.e., exert “effort”) to reduce pollution or meet resource management goals where those steps impact that party’s own environmental footprint or performance. Missing from the literature is any consideration of the ability of one party to undertake activities that instead help another improve the latter’s performance. Such help could be either a substitute for or a complement to one’s own effort. This paper presents an analysis showing that traditional policy approaches based on individual performance cannot generally efficiently incentivize both effort and help, but a (properly designed) collective approach where rewards or punishments are based on group performance can. This suggests an additional rationale for the use of collective approaches as a potentially important tool for promoting sustainability that has not been recognized in the literature.}, archive = {J_PNAS}, author = {Segerson, Kathleen}, doi = {10.1073/pnas.2510162122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2510162122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Incentivizing teamwork to promote sustainability}, volume = {122}, year = {2025}, }
• (2025). Genetic dissection of nonconventional introns reveals codominant noncanonical splicing code in euglena. PNAS, 122(39), e2509937122. (www)

  @article{ , abstract = {Pre-mRNA splicing is essential for eukaryotic gene expression and is achieved through the accurate recognition of exon–intron boundaries. Although nonconventional introns, which do not follow the conventional GT-AG splicing rule, have been identified in several species, these introns are typically rare in any given genome. Here, we demonstrate the widespread occurrence of nonconventional introns (71.8% of all introns) in the Euglena agilis genome and identify consensus motifs at these nonconventional exon–intron boundaries. We assessed the splicing efficiency of nonconventional introns and variants with point mutations via genomic knock-in within the second exon of Glucan synthase-like 2 in Euglena gracilis and genetically defined the sequence signature (5′-N 3 CDG-/-CH′GN 5–6 |R exon -3′) required for their proper splicing. This signature is present in 61.2% of all nonconventional introns detected in the E. agilis genome. Accordingly, we present a noncanonical splicing code for Euglena introns, highlighting the global coexistence of dual splicing rules for conventional and nonconventional introns.}, archive = {J_PNAS}, author = {Nomura, Toshihisa and Kim, June-Sik and Iwata, Osamu and Yamada, Koji and Atsuji, Kohei and Uehara-Yamaguchi, Yukiko and Yoshida, Takuhiro and Inoue, Komaki and Takahagi, Kotaro and Sakurai, Tetsuya and Shinozaki, Kazuo and Ito, Takuro and Suzuki, Kengo and Goda, Keisuke and Mochida, Keiichi}, doi = {10.1073/pnas.2509937122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2509937122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genetic dissection of nonconventional introns reveals codominant noncanonical splicing code in euglena}, volume = {122}, year = {2025}, }
• (2025). Distinguishing direct interactions from global epistasis using rank statistics. PNAS, 122(39), e2509444122. (www)

  @article{ , abstract = {The phenotypic effect of a mutation may depend on the genetic background in which it occurs, a phenomenon referred to as epistasis. One source of epistasis in proteins is direct interactions between residues in close physical proximity to one another. However, epistasis may also occur in the absence of specific interactions between amino acids if the genotype-to-phenotype map is nonlinear. Disentangling the contributions of these two phenomena—specific and global epistasis—from noisy, high-throughput mutagenesis experiments is highly nontrivial: The form of the nonlinearity is generally not known and model misspecification may lead to over- or underestimation of specific epistasis. In contrast to previous approaches, we do not attempt to model the fitness measurements directly. Rather, we begin with the observation that global epistasis, under the assumption of monotonicity, imposes strong constraints on the rank statistics of a combinatorial mutagenesis experiment. Namely, the rank-order of mutant phenotypes should be preserved across genetic backgrounds. We exploit this constraint to devise a simple semiparametric method to detect specific epistasis in the presence of global epistasis and measurement noise. We apply this method to three high-throughput mutagenesis experiments, uncovering known protein contacts with similar accuracy to existing, more complicated procedures. Our method immediately generalizes beyond proteins, providing a simple, yet powerful framework for interpreting the epistasis observed in combinatorial datasets.}, archive = {J_PNAS}, author = {Carlson, Maryn O. and Andrews, Bryan L. and Simons, Yuval B.}, doi = {10.1073/pnas.2509444122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2509444122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Distinguishing direct interactions from global epistasis using rank statistics}, volume = {122}, year = {2025}, }
• (2025). De novo design of potent inhibitors of clostridial family toxins. PNAS, 122(39), e2509329122. (www)

  @article{ , abstract = {Clostridioides difficile remains a leading cause of hospital-acquired infections, with its primary virulence factor, toxin B (TcdB), responsible for severe colitis and recurrent disease. The closely related toxin, TcsL, from Paeniclostridium sordellii , causes a rarer but often fatal toxic shock syndrome, particularly in gynecological and obstetric contexts. We report the de novo design of small protein minibinders that directly neutralize TcdB and TcsL by preventing their entry into host cells. Using deep learning and Rosetta-based approaches, we generated high-affinity minibinders that protect cells from intoxication with picomolar potency and, in the case of TcsL, prolonged survival following lethal toxin challenge in mice. The designed proteins against TcdB demonstrate exceptional stability in proteolytic and acidic environments, making them well-suited for oral delivery—a valuable feature for treating C. difficile infections localized to the gastrointestinal tract. For TcsL, potent inhibitors were identified from 48 initial designs and 48 optimized designs, highlighting the potential of computational design for rapidly developing countermeasures against life-threatening bacterial toxins.}, archive = {J_PNAS}, author = {Ragotte, Robert J. and Liang, Huazhu and Tam, John and Miletic, Sean and Berman, Jacob M. and Palou, Roger and Weidle, Connor and Li, Zhijie and Glögl, Matthias and Beilhartz, Greg L. and Carr, Kenneth D. and Borst, Andrew J. and Coventry, Brian and Wang, Xinru and Rubinstein, John L. and Tyers, Mike and Schramek, Daniel and Melnyk, Roman A. and Baker, David}, doi = {10.1073/pnas.2509329122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2509329122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {De novo design of potent inhibitors of clostridial family toxins}, volume = {122}, year = {2025}, }
• (2025). Why depolarization is hard: Evaluating attempts to decrease partisan animosity in america. PNAS, 122(39), e2508827122. (www)

  @article{ , abstract = {Affective polarization is a corrosive force in American politics. While numerous studies have developed interventions to reduce it, their capacity for creating lasting, large-scale change is unclear. This study comprehensively evaluates existing interventions through a meta-analysis of 77 treatments from 25 published studies and two large-scale experiments. Our meta-analysis reveals that the average effect of treatments on animosity is modest (a 5.4-point shift on a 101-point scale), and decays within two weeks. We experimentally test whether stacking multiple treatments in one sitting or repeating them over time as “booster shots” enhances their impact. We find no evidence that multiple or repeated exposures produce substantially larger or more durable reductions in partisan animosity. This reveals the uneven utility of these interventions. They serve as valuable tools for testing the psychological mechanisms of polarization, but our findings indicate they are not, on their own, a scalable solution for reducing societal-level conflict. We conclude that achieving lasting depolarization will likely require a shift in focus, moving beyond individual-level treatments to address the elite behaviors and structural incentives that fuel partisan conflict.}, archive = {J_PNAS}, author = {Holliday, Derek E. and Lelkes, Yphtach and Westwood, Sean J.}, doi = {10.1073/pnas.2508827122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2508827122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Why depolarization is hard: Evaluating attempts to decrease partisan animosity in america}, volume = {122}, year = {2025}, }
• (2025). Anion–π interaction–induced phase separation as a prebiotic pathway to oxygenation. PNAS, 122(39), e2508804122. (www)

  @article{ , abstract = {Compartmentalization and chemical reactivity serve as the key elements driving prebiotic chemistry for evolution and selection. However, the potential coupling of compartmentalization chemistry with the intrinsic chemical activity of prebiotic compartments remains largely unexplored. Here, we demonstrate that anion–π interactions, which are largely overlooked in the chemistry of phase transition, can drive the formation of micron-sized assemblies. These structures further recruit cations to form anion–π–cation triads. Such assemblies mediate spontaneous oxygenation reactions through their electrochemical environments. This process provides a plausible prebiotic pathway for bioenergetics and molecular oxygen generation on early Earth, leading to the formation of primitive pigments via the oxidation of small molecules and the nontemplated selection of protocells through oxidation-dependent lipid degradation. Our findings highlight a simple yet functionally significant noncovalent interaction that introduces chemical functions into self-assembly and phase transition chemistry, delivering generalizable principles for engineering electrochemically active supramolecular assemblies and a conceptual framework in understanding abiotic evolution and selection.}, archive = {J_PNAS}, author = {Ren, Xiaokang and Song, Xiaowei and Lyu, Lecheng and Chen, Michael W. and Zare, Richard N. and Dai, Yifan}, doi = {10.1073/pnas.2508804122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2508804122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Anion–π interaction–induced phase separation as a prebiotic pathway to oxygenation}, volume = {122}, year = {2025}, }
• (2025). Childhood allostatic load predicts cardiometabolic health in adulthood. PNAS, 122(39), e2508549122. (www)

  @article{ , abstract = {Allostatic load (AL) measures multisystem physiological functioning to reflect the cumulative burden of chronic stress. Incurring AL during sensitive developmental periods such as childhood may affect health outcomes later in life, but longitudinal measures to test these life course effects are lacking. This study tested associations between childhood AL and adult cardiometabolic health in a large sample of youth repeatedly measured across ages 9 to 16, and their adult cardiometabolic health at age 30. AL scores were calculated at each age by summing across sex- and age-standardized values for biomarkers representing immune (C-Reactive Protein, Epstein–Barr Virus antibodies), neuroendocrine (cortisol, DHEA-s), and cardiometabolic indicators (body mass index; BMI). Adult cardiometabolic health was measured using a composite sum score of sex-standardized systolic and diastolic blood pressure, BMI, and waist-to-hip ratio. Multiple approaches aggregating repeated AL scores were tested, including mean, maximum, oldest available AL score across childhood, and a version omitting BMI from the index. Childhood AL was significantly associated with adult cardiometabolic health ( P < 0.001), with higher AL predicting worse cardiometabolic outcomes at age 30 in all models, regardless of how AL was defined. Sensitivity analyses to address potential bias from missing observations using 20 imputed datasets were consistent with unimputed models. Follow-up analyses suggested risk for adult cardiometabolic outcomes was primarily associated with C-reactive protein, DHEA-s, and childhood BMI. In this cohort study, physiological dysregulation experienced in early life had lasting consequences. These results underscore the importance of childhood as a sensitive period during which cumulative stress exposure can shape long-term health trajectories.}, archive = {J_PNAS}, author = {Hinz, Elena and Vitali, Alexander J. and Tong, Guangyu and Pontzer, Herman and Copeland, William E.}, doi = {10.1073/pnas.2508549122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2508549122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Childhood allostatic load predicts cardiometabolic health in adulthood}, volume = {122}, year = {2025}, }
• (2025). Investigating the effects of single-dose intranasal testosterone on economic preferences in a large randomized trial of men. PNAS, 122(39), e2508519122. (www)

  @article{ , abstract = {There is conflicting evidence on whether testosterone affects economic preferences such as risk taking, fairness, and altruism, with most evidence coming from correlational studies or small testosterone administration studies. To credibly test this hypothesis, we conducted a large-scale, preregistered, double-blind randomized controlled trial with 1,000 male participants—10 to 20 times larger than typical prior studies. Participants were randomly allocated to receive a single dose of either placebo or intranasal testosterone, and carried out a series of economic tasks capturing social preferences, competitiveness, and risk preferences. We find no evidence of a treatment effect for any of our nine primary outcome measures, and no strong evidence of an association between basal salivary testosterone and economic preferences within men. These results fail to conceptually replicate previous high-impact publications reporting positive findings in smaller samples, calling into question the idea that short-term testosterone fluctuations are important drivers of men’s economic preferences. Our results do not rule out the possibility that different effects might emerge under alternative dosages, administration protocols, or task timings, or that behavioral effects differ between men and women. The potential for developmental or long-term effects of testosterone also remains an open question for future research, though such effects are ethically challenging to investigate experimentally in humans.}, archive = {J_PNAS}, author = {Dreber, Anna and Johannesson, Magnus and Nave, Gideon and L. Apicella, Coren and Geniole, Shawn N. and Imai, Taisuke and L. Knight, Erik and Manfredi, Dylan and Mehta, Pranjal H. and Proietti, Valentina and Stanton, Steven J. and Zeltikova, Alina and R. Luberti, Francesca and Ortiz, Triana and Carré, Justin M.}, doi = {10.1073/pnas.2508519122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2508519122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Investigating the effects of single-dose intranasal testosterone on economic preferences in a large randomized trial of men}, volume = {122}, year = {2025}, }
• (2025). Nanotechnology-driven coordination of shoot–root systems enhances rice nitrogen use efficiency. PNAS, 122(39), e2508456122. (www)

  @article{ , abstract = {Enhancing nitrogen use efficiency (NUE) in agricultural production can reduce fertilizer input, mitigate greenhouse gas emissions and decrease water pollution incidence. However, improving NUE in farming systems without compromising food security remains challenging. Herein, we have successfully developed and applied selenium-based nanotechnology, which capitalizes on above- and belowground synergies to enhance field-scale NUE. Specifically, when N fertilizer application was reduced by 30%, foliar application of selenium nanomaterials significantly enhanced rice photosynthesis by 40.3% compared with reduced N fertilizer treatment (189 kg N/ha). This enhancement promoted carbohydrate synthesis and translocation, providing abundant carbon sources for rhizosphere processes. These abundant carbon sources modulated rhizosphere N transformation processes, stimulating ammonification and nitrification while suppressing denitrification, thereby reducing methane, ammonia, and nitrous oxide emissions by 18.8 to 45.6%. In addition, compared with controls (270 kg N/ha), our approach improved rice root growth and upregulated gene expression associated with N uptake and translocation, increasing rice NUE (48.3%). While maintaining comparable yields to conventional practice, we observed significant improvements in rice quality parameters including crude protein, amino acids, and Se content. Furthermore, the application of this above- and belowground synergistic nano-regulation technology reduced environmental negative impacts by 41.0% and increased economic benefits by 38.2% per ton of rice produced, relative to conventional practices. This work elucidates how nano-enabled agricultural regulation achieves reduced input, enhanced efficiency, and increased income, emphasizing the high potential of nanotechnology in agricultural applications, particularly in improving the utilization efficiency of N fertilizers.}, archive = {J_PNAS}, author = {Wang, Chuanxi and Cheng, Bingxu and Xiao, Zhenggao and Ji, Yahui and Zhang, Jiangshan and Zhou, Rongxin and Yuan, Xian-Zheng and Kah, Melanie and Wang, Zhenyu and Xing, Baoshan}, doi = {10.1073/pnas.2508456122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2508456122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nanotechnology-driven coordination of shoot–root systems enhances rice nitrogen use efficiency}, volume = {122}, year = {2025}, }
• (2025). Severe water crisis in southern spain under expanding irrigated agriculture: A multidimensional drought analysis. PNAS, 122(39), e2508055122. (www)

  @article{ , abstract = {The Axarquía region in southern Spain, a hotspot of avocado and mango production in Europe, underwent an extreme water crisis in 2019–2024. Reservoir levels dropped below the 8% outlet threshold and groundwater in the main aquifer dropped to sea level in several locations, risking seawater intrusion. Socioeconomic impacts ranged from substantial crop losses to a potential long-term decline in regional economic viability. We examine the main drivers of this crisis using a coupled human and natural systems approach, combining an examination of water and land governance with analysis of time series (dam inflows and outflows, meteorological variables, reservoir, and groundwater levels) and spatial data (irrigated land use, groundwater bodies, water entitlement location, and volume). Our results show two severe meteorological droughts in close succession immediately preceding rapid declines in reservoir and groundwater reserves. Emergency measures delayed dam depletion but likely exacerbated groundwater extraction. Reservoir data disaggregating inflows, outflows, and uses (irrigation and urban) show an increasing trend in dam water use for irrigation in 2000–2022 associated with increasing irrigated area. Water management planning since 1998 reveals important inconsistencies within and between plans pointing to large uncertainties in freshwater availability and extraction and aquifer overdraft even during nondrought periods. The Axarquía case exhibits many symptoms of water crises faced by agriculturally significant regions globally. It highlights the necessity for integrated basin-scale land–water management, caps on irrigated area, flexible extraction quotas, real-time metering at all extraction points, and effective enforcement mechanisms, substantiating management lessons derived from major drought-affected regions worldwide.}, archive = {J_PNAS}, author = {Junquera, Victoria and Hormaza, José I. and Rubenstein, Daniel I. and Levin, Simon A. and Vadillo Pérez, Iñaki and Gavilán, Pablo Jiménez}, doi = {10.1073/pnas.2508055122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2508055122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Severe water crisis in southern spain under expanding irrigated agriculture: A multidimensional drought analysis}, volume = {122}, year = {2025}, }
• (2025). Châtelperronian cultural diversity at its western limits: Shell beads and pigments from la roche-à-pierrot, saint-césaire. PNAS, 122(39), e2508014122. (www)

  @article{ , abstract = {The timing and mechanisms underlying the gradual replacement of Neanderthal populations by Homo sapiens groups have elicited heated debate for decades. The Châtelperronian of France and northern Spain has figured prominently in these discussions. While the Neanderthal authorship of this techno-complex is far less certain than previously thought, the Châtelperronian is now generally accepted as being among the first genuine Upper Paleolithic industries in Eurasia rather than a “transitional” stone tool technology. Here, we report the first association of shell beads with Châtelperronian artifacts from new excavations at the site of La-Roche-à-Pierrot, Saint-Césaire (France), supported by a multiproxy spatial analysis that incorporates site formation processes. Similar types of personal ornaments are unknown from Middle Paleolithic contexts. Comparable examples have, however, been recovered from contexts penecontemporaneous with the Châtelperronian in south-eastern Europe and around the Mediterranean. This hitherto undocumented combination of an early Upper Paleolithic industry and shell beads provides insights into cultural variability in western Europe and raises the question as to whether the makers of the Châtelperronian were influenced by or formed part of the earliest dispersals of H. sapiens into the region.}, archive = {J_PNAS}, author = {Bachellerie, François and Gravina, Brad and Rigaud, Solange and Dayet, Laure and Thomas, Marc and Lebreton, Loïc and Morin, Eugène and Lesage, Camille and Falguères, Christophe and Bard, Edouard and Bahain, Jean-Jacques and Baillet, Mickaël and Beauval, Cédric and Bordes, Jean-Guillaume and Culioli, Gérald and Devièse, Thibaut and Flas, Damien and Garbé, Lisa and Guérin, Guillaume and Lacrampe-Cuyaubère, François and Lahaye, Christelle and Mallol, Carolina and Marot, Josserand and Maureille, Bruno and Michel, Alexandre and Muth, Xavier and Regniers, Olivier and Tartar, Elise and Teyssandier, Nicolas and Thibeault, Adrien and Todisco, Dominique and Tombret, Olivier and Rougier, Hélène and Crevecoeur, Isabelle}, doi = {10.1073/pnas.2508014122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2508014122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Châtelperronian cultural diversity at its western limits: Shell beads and pigments from la roche-à-pierrot, saint-césaire}, volume = {122}, year = {2025}, }
• (2025). Evolution under vancomycin selection drives divergent collateral sensitivity patterns in staphylococcus aureus. PNAS, 122(39), e2507962122. (www)

  @article{ , abstract = {Staphylococcus aureus bacteremia is typically treated empirically with vancomycin, with therapy later tailored based on susceptibility results. However, these tests occur before vancomycin exposure and do not account for adaptation during empiric treatment that can alter S. aureus ’ susceptibility to first-line drugs. To investigate these collateral drug responses, we experimentally evolved 18 methicillin-susceptible S. aureus (MSSA) populations under increasing vancomycin concentrations until they achieved intermediate resistance. Genomic sequencing revealed two distinct adaptive pathways characterized by mutations in the WalKR regulon, affecting cell wall metabolism, or rpsU , impacting translational stress responses. These pathways correlated with divergent collateral sensitivity profiles to first-line antibiotics. By developing a Collateral Response Score (CRS), we quantified the probability and magnitude of these responses, demonstrating that evolutionary dynamics critically influence resistance outcomes. Our findings suggest a probabilistic approach to antimicrobial therapy, advocating for rapid genomic diagnostics alongside susceptibility testing to better anticipate and respond to evolutionary changes.}, archive = {J_PNAS}, author = {Card, Kyle J. and Crozier, Dena and Durmaz, Arda and Gray, Jason and Creary, Justin and Stocks, Amira and Maltas, Jeff and Bonomo, Robert A. and Burke, Zachary D. C. and Scott, Jacob G.}, doi = {10.1073/pnas.2507962122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2507962122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolution under vancomycin selection drives divergent collateral sensitivity patterns in staphylococcus aureus}, volume = {122}, year = {2025}, }
• (2025). An unusual Co–S bond links b12 chaperones in an interprotein complex. PNAS, 122(39), e2507700122. (www)

  @article{ , abstract = {Chaperones in trafficking pathways ensure specificity of transition metal loading and protection against adventitious side reactions. In B 12 , an essential cofactor for humans, a cobalt ion is coordinated to a >1.3 kDa tetrapyrrolic scaffold, posing logistical challenges for its translocation. In this study, we report the 3.4 Å crystal structure of the human MMACHC and MMADHC B 12 chaperones, tethered via a rarely seen covalent cobalt–sulfur bond. B 12 is bound in the base-off state to MMACHC, with Cys-261 on MMADHC serving as the upper axial ligand; the lower-axial position is vacant. The propensity of thiolato-cobalamin derivatives bound to MMACHC to undergo spontaneous decomposition via general acid catalysis or reduction/oxidation chemistry is averted in the interprotein complex with MMADHC. An exposed face in the complex suggests an exit route for B 12 . No known clinical variants localize to the interprotein interface, consistent with the cobalt–sulfur bond being key to forming the high-affinity complex.}, archive = {J_PNAS}, author = {Mascarenhas, Romila and Ruetz, Markus and Heitman, Natalie and Hall, Ryan L. and Brunold, Thomas C. and Banerjee, Ruma}, doi = {10.1073/pnas.2507700122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2507700122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An unusual Co–S bond links b12 chaperones in an interprotein complex}, volume = {122}, year = {2025}, }
• (2025). Nav1.8: Intrinsic limits on the functional effect of abrogation in DRG neurons. PNAS, 122(39), e2507342122. (www)

  @article{ , abstract = {Voltage-gated sodium channel Nav1.8 plays a crucial role in regulating excitability of small dorsal root ganglion (DRG) neurons and is an emerging target for pain therapeutics. Using dynamic clamp, we systematically manipulated Nav1.8 conductance to assess its impact on action potential (AP) electrogenesis, rheobase, and repetitive firing in native rat DRG neurons and those expressing the gain-of-function Nav1.7L858H mutation which underlies inherited erythromelalgia, a human genetic pain disorder. Our findings reveal that the Nav1.8 contribution to net sodium current is highly correlated with AP voltage threshold. Nav1.8 conductance regulated AP overshoot and voltage threshold without significantly affecting undershoot or resting membrane potential. We identified two populations of wild-type DRG neurons: strong responders (50% of cells), which exhibited substantial rheobase modulation with alterations in Nav1.8 conductance, and weak responders (50% of cells), which remained largely unaffected. In hyperexcitable Nav1.7L858H-expressing neurons, partial Nav1.8 subtraction (50%) restored rheobase above control levels in 63% of cells. However, weak responders (37%) remained hyperexcitable. The effect of Nav1.8 subtraction in responsive neurons supports the conclusion that Nav1.8 inhibition can reduce neuropathic pain. However, the presence of weakly responsive DRG neurons suggests that other channels might need to be targeted for full pain relief.}, archive = {J_PNAS}, author = {Vasylyev, Dmytro V. and Zhao, Peng and Schulman, Betsy R. and Waxman, Stephen G.}, doi = {10.1073/pnas.2507342122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2507342122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nav1.8: Intrinsic limits on the functional effect of abrogation in DRG neurons}, volume = {122}, year = {2025}, }
• (2025). Strategic planning of prevention and surveillance for emerging diseases and invasive species. PNAS, 122(39), e2507202122. (www)

  @article{ , abstract = {Emerging infectious diseases and biological invasions pose increasing threats to public and ecosystems health. Proactive measures—such as prevention and surveillance taken before initial detection of the pathogen or species—are essential to ensure minimal spread prior to first detection. We developed an optimization model to determine where, when, and how much effort should be allocated to prevention versus surveillance. The model accounts for imperfect detection, system dynamics, spatial heterogeneity in risk and costs and is scalable to large landscapes. We found that the most cost-effective strategy is to maintain the prevention and surveillance efforts at stable equilibrium for the majority of the time, with deviations occurring only initially to steer the system toward the equilibrium. The equilibrium effort is jointly determined by the introduction risk, management costs, and total budget. Application of this model to chronic wasting disease in New York State suggests that the optimal strategy could reduce the cumulative disease cases before initial detection by an average of 22% compared to current practice. The optimal surveillance strategy could detect the disease on average over 8 mo earlier than the current strategy.}, archive = {J_PNAS}, author = {Wang, Jue and Hanley, Brenda J. and Thompson, Noelle E. and Gong, Yu and Walsh, Daniel P. and Gonzalez-Crespo, Carlos and Huang, Yitong and Booth, James G. and Caudell, Joe N. and Miller, Landon A. and Schuler, Krysten L.}, doi = {10.1073/pnas.2507202122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2507202122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Strategic planning of prevention and surveillance for emerging diseases and invasive species}, volume = {122}, year = {2025}, }
• (2025). Targeting endothelial ERG to mitigate vascular regression in retinopathies. PNAS, 122(39), e2507194122. (www)

  @article{ , abstract = {Retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are ocular disorders in which an initial loss of retinal capillaries leads to damaging tissue ischemia followed by a compensatory neovascularization response that generates pathological capillaries in the eye. Using a mouse model of ROP and samples from DR patients, we found that the highly homologous and homeostatic erythroblast transformation-specific (ETS) family transcription factors ETS-related gene (ERG) and Friend leukemia integration 1 (FLI1) are downregulated in endothelial cells (ECs) of retinal capillaries prior to their regression in early stages of these diseases. We developed a mouse model of inducible EC-specific overexpression of Erg and found it mitigates capillary regression, retinal neuron death, neovascularization, and visual defects in the ROP model. Erg overexpression also reduces capillary regression in early stages of a murine DR model. We next found that simultaneous deletion of endothelial Erg and Fli1 is sufficient to promote regression of the pathological retinal capillaries that arise in late stages of the ROP model. Altogether, our data demonstrate that deletion of homeostatic endothelial ETS factors promotes capillary regression, while maintenance of even one of these factors prevents regression. These findings offer insights into approaches for preventing and treating retinopathies at different stages of these diseases.}, archive = {J_PNAS}, author = {Ma, Eric and Schafer, Christopher M. and Xie, Jun and Rudenko, Yelyzaveta and Knapp, John T. H. and Randi, Anna M. and Birdsey, Graeme M. and Griffin, Courtney T.}, doi = {10.1073/pnas.2507194122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2507194122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Targeting endothelial ERG to mitigate vascular regression in retinopathies}, volume = {122}, year = {2025}, }
• (2025). Characterization of exoplanets in the james webb space telescope era. PNAS, 122(39), e2507109122. (www)

  @article{ , archive = {J_PNAS}, author = {Lunine, Jonathan I. and Bahcall, Neta}, doi = {10.1073/pnas.2507109122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2507109122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Characterization of exoplanets in the james webb space telescope era}, volume = {122}, year = {2025}, }
• (2025). Biomarkers of immune dysregulation and posttreatment inflammation in spinal muscular atrophy. PNAS, 122(39), e2506976122. (www)

  @article{ , abstract = {Spinal Muscular Atrophy (SMA) is a neurodegenerative disorder primarily affecting motor neurons, but immune dysfunction may contribute to disease progression and treatment response. While AAV9-delivered SMN1 gene therapy (e.g., Zolgensma) improves survival, long-term motor outcomes remain variable. This study integrates bulk and single-cell RNA sequencing (scRNA-seq) to define immune dysregulation in SMA. We analyzed peripheral blood from infants with SMA (n = 7 for bulk RNA-seq; n = 4 for scRNA-seq, <25 mo of age) along with age-matched healthy controls (n = 4 for bulk RNA-seq; n = 6 for scRNA-seq). We profiled differentially expressed genes, immune pathways, cell–cell interactions, and gene regulatory networks. SMA samples showed distinct transcriptomic signatures and elevated immune activation compared to controls. NECTIN1 was identified as a transcriptomic biomarker of disease progression, while HSPA7 was validated from prior reports. A 6- to 7-mo inflection point marked a transition from metabolic regulation to immune activation in SMA infants. NF-κB–related inflammatory gene expression was significantly elevated post–gene therapy relative to both pretreatment and healthy controls, with IL1B and RNF19B emerging as key transcriptomic mediators. scRNA-seq revealed early dysfunction and G1-phase arrest in CD4+ T-cells, along with a switch to RELB -mediated noncanonical NF-κB signaling. In symptomatic infants, CD8+ T-cells showed higher proliferation and exhaustion, with co-upregulation of TBX21 and EOMES , genes consistent with chronic stimulation and a trajectory toward terminal differentiation. Immune dysregulation is a central feature of SMA and may influence treatment response. These findings support future development of adjunct immunomodulatory strategies to enhance gene therapy efficacy and suggest that immune signatures may correlate with motor function outcomes.}, archive = {J_PNAS}, author = {Jordan, Sean C. and Bakhtiari, Mojtaba and Bhasin, Swati S. and Verma, Sumit and Bhasin, Manoj K.}, doi = {10.1073/pnas.2506976122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2506976122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biomarkers of immune dysregulation and posttreatment inflammation in spinal muscular atrophy}, volume = {122}, year = {2025}, }
• (2025). Disentangling metabolic and neurovascular timescales supporting cognitive processes. PNAS, 122(39), e2506513122. (www)

  @article{ , abstract = {The balance between neural excitation and inhibition (EIB), governed by glutamatergic and GABAergic neurotransmission, is an essential mechanism supporting cognitive processes. Yet, little is understood about how EIB shifts with engaging cognitive load and its impact on functional connectivity dynamics. Here, we combined time-resolved functional magnetic resonance spectroscopy and magnetic resonance imaging to investigate temporal profiles of the reciprocal modulation between EIB and functional network dynamics during working memory tasks in healthy subjects. We quantified EIB kinetics by measuring excitatory (Glx) and inhibitory (GABA+) levels and assessed their temporal coupling with dynamic functional connectivity states, revealing a dependence that scales with cognitive load. Notably, we found that as cognitive challenges intensify, brain networks transition toward more specialized and enduring connectivity configurations, accompanied by imbalances that favor excitation, changes that may impact cognitive adaptability. Fluctuations in EIB and functional connectivity occurred on comparable timescales and were both associated with individual differences in cognitive performance. Importantly, this experimental approach demonstrates a close synergy between EIB kinetics, brain network dynamics, and cognitive performance, defining the groundwork for exploring healthy and aberrant cognitive states.}, archive = {J_PNAS}, author = {Saviola, Francesca and Tambalo, Stefano and Beghini, Laura and Ferrari, Asia and Cassone, Barbara and Van De Ville, Dimitri and Jovicich, Jorge}, doi = {10.1073/pnas.2506513122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2506513122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Disentangling metabolic and neurovascular timescales supporting cognitive processes}, volume = {122}, year = {2025}, }
• (2025). Muscle-specific increased expression of JAG1 improves the skeletal muscle phenotype in dystrophin-deficient mice. PNAS, 122(39), e2506437122. (www)

  @article{ , abstract = {Therapeutic strategies for Duchenne muscular dystrophy (DMD) will likely require complementary approaches. One possibility is to explore genetic modifiers that improve muscle regeneration and function. The beneficial effects of the overexpression of Jagged-1 were described in escaper golden retriever muscular dystrophy (GRMD) dogs that had a near-normal life and validated in dystrophin-deficient zebrafish. To clarify the underlying biology of JAG1 overexpression in dystrophic muscles, we generated a transgenic mouse (mdx 5cv - JAG1 ) model that lacks dystrophin and overexpresses human JAG1 in striated muscles. Skeletal muscles from mdx 5cv - JAG1 and mdx 5cv mice were studied at 1-, 4-, and 12-mo time points. JAG1 expression in mdx 5cv - JAG1 increased by 3 to 5 times compared to mdx 5cv . Consequently, mdx 5cv - JAG1 muscles were significantly bigger and stronger than dystrophic controls, along with an increased number of myofibers. Proteomics data show increased dysferlin in mdx 5cv - JAG1 muscles and an association of the histone methyltransferase Nsd1 with the phenotype. Our data support the positive effect of JAG1 overexpression in dystrophic muscles.}, archive = {J_PNAS}, author = {de Souza Leite, Felipe and Lambert, Matthias R. and Zhang, Tracy Yuanfan and Conner, James R. and Paulo, Joao A. and Oliveira, Sheldon Furtado and Guha Thakurta, Sanjukta and Bowles, Jennifer and Gussoni, Emanuela and Gygi, Steven P. and Widrick, Jeffrey J. and Kunkel, Louis M.}, doi = {10.1073/pnas.2506437122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2506437122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Muscle-specific increased expression of JAG1 improves the skeletal muscle phenotype in dystrophin-deficient mice}, volume = {122}, year = {2025}, }
• (2025). Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase. PNAS, 122(39), e2506417122. (www)

  @article{ , abstract = {Prior to ejaculation, mammalian sperm are stored in the epididymis in a “resting” metabolic state. Upon ejaculation, sperm must alter their metabolism to generate the energy needed to support the motility and maturation process known as capacitation to reach and fertilize the oocyte. How sperm regulate the capacitation-induced increase in carbon flux is unknown. Here, we use 13 C stable isotope labeling in mouse sperm isolated from the cauda epididymis to follow glucose metabolism through central carbon metabolic network before and after sperm activation. As sperm transition from resting to highly activated states, they boost energy yield by increasing flux through glycolysis at the expense of the pentose phosphate pathway. Increased glycolytic activity seems to be achieved via capacitation-induced stimulation of flux through aldolase. In the mitochondria-containing midpiece, glycolytically generated pyruvate feeds the tricarboxylic acid (TCA) cycle to further maximize energy yield via oxidative phosphorylation. In the mitochondria-free principal piece of the flagellum, pyruvate produced from glycolysis is reduced to lactate by lactate dehydrogenase, which also serves to regenerate oxidized nicotinamide adenine dinucleotide (NAD + ) ensuring a sufficient supply to support glycolysis. The resultant lactate is at least partially secreted. Finally, we find evidence that there is an as yet unknown endogenous source of energy in sperm, feeding the upregulation of TCA cycle intermediates. These studies provide the most complete picture of the metabolic shift which occurs in capacitating mouse sperm in glucose.}, archive = {J_PNAS}, author = {Violante, Sara and Kyaw, Aye and Kouatli, Lana and Paladugu, Kaushik and Apostolakis, Lauren and Jenks, Macy and Johnson, Amy and Sheldon, Ryan D. and Whitten, Douglas and Schilmiller, Anthony L. and Visconti, Pablo E. and Cross, Justin R. and Levin, Lonny R. and Buck, Jochen and Balbach, Melanie}, doi = {10.1073/pnas.2506417122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2506417122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase}, volume = {122}, year = {2025}, }
• (2025). Glycan microarray analysis of candida-related antibodies in human and mice sera guides biomarker discovery and vaccine development. PNAS, 122(39), e2505340122. (www)

  @article{ , abstract = {Invasive, high-mortality yeast infections caused by pathogenic Candida species are the most common fungal nosocomial bloodstream infections. The World Health Organization (WHO) has called for improved prevention and diagnostic strategies for fungal pathogens. Here, we demonstrate that Candida -related antibodies can be detected using glycan microarrays containing synthetic glycans to guide the discovery of oligosaccharide epitopes for diagnostics and vaccine design. Pure, synthetic mannans and β -glucans, resembling carbohydrates found on the surface of Candida spp., were employed to screen and compare sera from infected humans and mice with noninfected individuals. IgM antibodies directed toward β -glucans were observed shortly after infection, and after a longer time of infection, IgM and IgG antibodies that preferentially recognize mannans. Phosphodiester-linked mannosides and the β -(1,2)-mannose monomer help to distinguish different Candida spp. The tetrasaccharide antigen β -(1,2)Man- α -(1,2)Man- α -(1,2)Man- α -(1,2)Man, and the pentasaccharide antigens α -(1,2)Man- α -(1,3)Man- α -(1,2)Man- α -(1,2)Man- α -(1,2)Man and β -(1,3)Glc- β -(1,3)Glc- β -(1,3)Glc-[ β -(1,6)Glc]- β -(1,3)Glc were identified as potential epitopes for detection, e.g., through monoclonal antibody lateral flow tests, and the development of glycoconjugate or monoclonal antibody vaccines against Candida.}, archive = {J_PNAS}, author = {Reuber, Emelie E. and Hickey, Emer and Pradhan, Arnab and Sprute, Rosanne and Lingscheid, Tilman and Tober-Lau, Pinkus and Leaves, Ian and Stappers, Mark H. T. and Kurth, Florian and Bruno, Mariolina and Netea, Mihai G. and Sander, Leif E. and Cornely, Oliver A. and Gow, Neil A. R. and Brown, Alistair J. P. and Singh, Rajat K. and Omoregbee-Leichnitz, Sabrina and Sletten, Eric T. and Danglad-Flores, José and Seeberger, Peter H.}, doi = {10.1073/pnas.2505340122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2505340122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Glycan microarray analysis of candida-related antibodies in human and mice sera guides biomarker discovery and vaccine development}, volume = {122}, year = {2025}, }
• (2025). Within-country inequality and the shaping of a just global climate policy. PNAS, 122(39), e2505239122. (www)

  @article{ , abstract = {Climate policy design must balance emissions mitigation with concerns for fairness, particularly as climate change disproportionately affects the poorest households within and across countries. Integrated Assessment Models used for global climate policy evaluation have so far typically not considered inequality effects within countries. To fill this gap, we develop a global Integrated Assessment Model representing national economies and subnational income, mitigation cost, and climate damage distribution and assess a range of climate policy schemes with varying levels of effort sharing across countries and households. The schemes are consistent with limiting temperature increases to 2 °C and account for the possibility to use carbon tax revenues to address distributional effects within and between countries. We find that carbon taxation with redistribution improves global welfare and reduces inequality, with the most substantial gains achieved under uniform taxation paired with global per capita transfers. A Loss and Damage mechanism offers significant welfare improvements in vulnerable countries while requiring only a modest share of global carbon revenues in the medium term. The poorest households within all countries may benefit from the transfer scheme, in particular when some redistribution is made at the country level. Our findings underscore the potential for climate policy to advance both environmental and social goals, provided revenue recycling mechanisms are effectively implemented. In particular, they demonstrate the feasibility of a welfare improving global climate policy involving limited international redistribution.}, archive = {J_PNAS}, author = {Young-Brun, Marie and Dennig, Francis and Errickson, Frank and Feindt, Simon and Méjean, Aurélie and Zuber, Stéphane}, doi = {10.1073/pnas.2505239122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2505239122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Within-country inequality and the shaping of a just global climate policy}, volume = {122}, year = {2025}, }
• (2025). Structural insights into the dynamic mechanism of bornavirus polymerase. PNAS, 122(39), e2504779122. (www)

  @article{ , abstract = {Borna disease virus 1 (BoDV-1), an emerging zoonotic pathogen from the Bornaviridae family, is neurotropic and can infect a variety of mammalian hosts, including humans. Linked to severe encephalitis and high mortality, BoDV-1 currently lacks licensed treatments or vaccines. The BoDV-1 polymerase complex, comprising the large (L) and phosphoprotein (P) subunits, is crucial for viral replication and transcription, making it a promising target for antiviral intervention. Here, we present the cryoelectron microscopy structure of the apo BoDV-1 L-P complex, revealing a unique “mitten-shaped” architecture. The structure characterizes key domains involved in RNA synthesis, including RNA-dependent RNA polymerase, polyribonucleotidyltransferase, and an inactive methyltransferase domain. While no RNA or NTPs were visible, we observed distinct conformational states, showing large-scale rearrangements of the P tetramer and L domains, as well as remodeling of the RNA template, nucleoside triphosphates, and nascent RNA entrances and/or exits, upon introducing RNA and NTPs. These findings highlight the dynamic structural changes probably associated with polymerase activity and advance the understanding of the BoDV-1 polymerase mechanisms, offering a basis for developing targeted antiviral strategies against this deadly pathogen.}, archive = {J_PNAS}, author = {Yang, Ge and Wang, Dong and Liu, Bin}, doi = {10.1073/pnas.2504779122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2504779122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural insights into the dynamic mechanism of bornavirus polymerase}, volume = {122}, year = {2025}, }
• (2025). The genome of the vining fern lygodium microphyllum highlights genomic and functional differences between life phases of an invasive plant. PNAS, 122(39), e2504773122. (www)

  @article{ , abstract = {Functional and genomic studies on the differences between the gametophyte and sporophyte life phases of plants remain scarce, yet unraveling these dynamics is crucial to understanding the biology of plants and the success of each phase under different conditions. Here, we provide a reference genome for the highly invasive fern Lygodium microphyllum and compare the transcriptomic and epigenomic landscapes of its gametophyte and sporophyte life phases. Under ambient conditions, we found differential regulation and splicing of developmental genes (homeobox and MADS-box clades) may play a role in the genomic determination of the haploid and diploid life stages. We generated a base pair-resolution methylome of a fern gametophyte, and determined that methylation patterns are remarkably similar between vegetative tissues despite their morphological and functional differences. We further explored the physiological and transcriptomic responses of gametophytes and sporophytes to freezing stress, the most likely abiotic factor limiting further range expansion of this invasive species. While controlled by the same genome, we show that life phases and tissues use alternative molecular pathways in response to freezing and greater physiological resilience in the gametophyte life stage to this stressor. Our results underscore the need to incorporate both life phases when developing effective mitigation strategies, as differential responses to environmental stressors between phases reveal opportunities for management approaches (e.g., targeting gametophytes in addition to sporophytes). These genomic resources fill a gap in our understanding of fundamental plant biology and inform invasive species research.}, archive = {J_PNAS}, author = {Pelosi, Jessie A. and Davenport, Ruth and Kuo, Li-Yaung and Gray, Levi N. and Dant, Anthony J. and Kim, Emily H. and Li, Fay-Wei and Dlugosch, Katrina M. and Krabbenhoft, Trevor J. and Barbazuk, William Bradley and Sessa, Emily B.}, doi = {10.1073/pnas.2504773122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2504773122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The genome of the vining fern lygodium microphyllum highlights genomic and functional differences between life phases of an invasive plant}, volume = {122}, year = {2025}, }
• (2025). ALKBH5 demethylates the m6A modification of SOCS3 in microglia/macrophages and alleviates neuroinflammation after brain injury. PNAS, 122(39), e2504697122. (www)

  @article{ , abstract = {Microglia/macrophage-induced neuroinflammation plays a crucial role in the progression of traumatic brain injury (TBI). However, the involvement of N6-methyladenosine (m 6 A) RNA modifications in this process remains elusive. Single-cell RNA sequencing (scRNA-seq) and m 6 A RNA immunoprecipitation sequencing (MeRIP-seq) across multiple time points postinjury revealed a strong correlation between m 6 A modifications and genes enriched in microglia/macrophages. Furthermore, the m 6 A demethylase ALKBH5 was identified as a key regulator of dynamic m 6 A patterns at the injury site. ALKBH5 suppression in microglia/macrophages exacerbated neuroinflammation in vitro and worsened neurological deficits in controlled cortical impact (CCI) models. MeRIP-qPCR and RNA pull-down assays revealed SOCS3 was a downstream target of ALKBH5-mediated m 6 A demethylation. This demethylation stabilized Socs3 mRNA and enhanced its protein expression, which in turn suppressed neuroinflammation via inhibiting the JAK2-STAT3 pathway. Conversely, SOCS3 depletion impaired functional recovery after injury. These findings unveiled a critical ALKBH5–m 6 A–SOCS3 regulatory axis that mitigated microglia/macrophage-driven neuroinflammation after TBI, underscoring its potential as a therapeutic intervention target for TBI progression.}, archive = {J_PNAS}, author = {Cai, Lin and Liang, Yuqing and Li, Xiaoyu and Fu, Runxi and Niu, Xingyu and Jin, Yuxiao and Li, Yuxin and Zhang, Yuheng and Ouyang, Pei and Wang, Chen and Gong, Qiuyuan and Yang, Yang and Wei, Lai and Jing, Yao and Yang, Dianxu and Xu, Zhiming and Yuan, Fang and Ding, Jun and Chen, Hao and Peng, Bo and Rao, Yanxia and Tian, Hengli}, doi = {10.1073/pnas.2504697122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2504697122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ALKBH5 demethylates the m6A modification of SOCS3 in microglia/macrophages and alleviates neuroinflammation after brain injury}, volume = {122}, year = {2025}, }
• (2025). The potential impacts of human genetics on virus emergence. PNAS, 122(39), e2504318122. (www)

  @article{ , abstract = {Human monogenic traits can confer resistance to viral infection in exposed individuals or predisposition to severe disease in infected individuals. Enhanced susceptibility can be driven directly by mutations in genes essential for control of the virus or indirectly via the production of autoantibodies against components of host defense. While the impact of viruses on individuals carrying these genotypes permitted their identification and has been amply studied, little is known about the impact of these human genotypes on the natural history of viruses, including not only persisting but also emerging viruses. We envisage several scenarios, including the possibility that genetically susceptible individuals serve as patient zeros, superspreaders, or mutation incubators, or that genetically resistant individuals even permit the selection of new viral mutants. Viruses are continually shared between individuals and even host species, where they can benefit from adaption to new environments. Current human viruses, as well as novel viruses from animal reservoirs, will continue to threaten the human population. Improvements in the scale of human genomic sequencing and analysis will permit testing hypotheses about the impact of human genetics on the origin and trajectory of viral infections, including future pandemics, which may ultimately help to prevent or curtail impending outbreaks.}, archive = {J_PNAS}, author = {Langlois, Ryan A. and Casanova, Jean-Laurent}, doi = {10.1073/pnas.2504318122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2504318122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The potential impacts of human genetics on virus emergence}, volume = {122}, year = {2025}, }
• (2025). Inorganic sulfate is critical for mycobacterium tuberculosis lung tissue colonization and redox balance. PNAS, 122(39), e2503966122. (www)

  @article{ , abstract = {Tuberculosis remains the deadliest infectious disease caused by a single pathogen, highlighting the urgent need for novel therapies. A deeper understanding of Mycobacterium tuberculosis metabolism could uncover specific vulnerabilities and inform the development of new treatments. Sulfur, essential for bacterial growth and survival, fuels key pathways including redox buffering and coenzyme production. Although previous studies suggest that M. tuberculosis utilizes various substrates to meet its sulfur requirements, the primary sources of sulfur exploited during in vivo infection remain unclear. Here, we reveal that M. tuberculosis acquires inorganic sulfate through the SubI-CysTWA transporter during macrophage infection. Using nanoSIMS (high spatial resolution Secondary Ion Mass Spectrometry) analysis, we observed significant sulfate-derived 33 S enrichment in intracellular bacteria, correlating with metabolic activity. Deletion of subI abolished sulfate uptake, impairing bacterial growth in vitro and reducing M. tuberculosis survival in murine macrophages and lungs of infected mice. Finally, our data demonstrate that sulfate acquisition is essential for maintaining mycobacterial redox balance and resisting nitrosative stress in vitro and in vivo. Thus, unlike many intracellular pathogens, M. tuberculosis depends on an energetically costly inorganic sulfate assimilation pathway to survive in the nutrient-limited host environment. These findings challenge prior assumptions that organic reduced sulfur sources, such as methionine, fuel M. tuberculosis sulfur metabolism during infection. Since animal cells lack a sulfate assimilation pathway, uncovering the critical role of SubI-CysTWA-mediated sulfate import in M. tuberculosis pathogenesis highlights this pathway as a promising pathogen-specific therapeutic target. Targeting this system could either directly impair M. tuberculosis survival during infection or sensitize bacilli to antibiotic-induced oxidative stress by disrupting redox homeostasis.}, archive = {J_PNAS}, author = {Le Mouëllic, Wendy and Levillain, Florence and Wu, Ting-Di and Caouaille, Maxime and Bousso, Philippe and Poquet, Yannick and Neyrolles, Olivier}, doi = {10.1073/pnas.2503966122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2503966122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inorganic sulfate is critical for mycobacterium tuberculosis lung tissue colonization and redox balance}, volume = {122}, year = {2025}, }
• (2025). VOC injection into a house reveals large surface reservoir sizes in an indoor environment. PNAS, 122(39), e2503399122. (www)

  @article{ , abstract = {The total partitioning capacity of indoor surface reservoirs determines the mechanism by which humans receive nondietary exposure to organic contaminants, via inhalation, dermal uptake, and dust ingestion. And yet, this capacity is largely unknown. Surface organic films are ubiquitously present but have very low partitioning volume being only 10’s of nanometer thick, whereas other surface reservoirs such as building materials and furnishings can be permeable or porous with large surface areas at the molecular level. Here, we assess the total partitioning capacity of volatile organic compounds (VOCs) in an indoor environment from the measured kinetics of VOC surface uptake after injection of compounds with variable volatility into a well-characterized, unoccupied test house. We show that the size of the indoor surface reservoirs is very large with an octanol-equivalent average thickness on the order of micrometers, indicating that permeable/porous materials such as painted surfaces and wood are likely the major surface reservoirs in the house rather than organic surface films. Large surface reservoirs result in compounds with octanol-air partition coefficients ( K OA ) larger than 10 5 being predominantly partitioned to indoor surface reservoirs, making them hard to be removed via ventilation. This result significantly impacts our understanding of VOC fate and human exposure in indoor environments. With such a large partitioning capacity, organic contaminants will have much longer indoor residence times than previously predicted.}, archive = {J_PNAS}, author = {Yu, Jie and Lakey, Pascale S. J. and Ditto, Jenna C. and Huynh, Han N. and Link, Michael F. and Poppendieck, Dustin and Zimmerman, Stephen M. and Wang, Xing and Farmer, Delphine K. and Vance, Marina E. and Abbatt, Jonathan P. D. and Shiraiwa, Manabu}, doi = {10.1073/pnas.2503399122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2503399122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {VOC injection into a house reveals large surface reservoir sizes in an indoor environment}, volume = {122}, year = {2025}, }
• (2025). Riverine heat waves on the rise, outpacing air heat waves. PNAS, 122(39), e2503160122. (www)

  @article{ , abstract = {While air heat waves often grab headlines, riverine heat waves have gone quietly unnoticed because rivers are commonly perceived as cool refuges. Analysis of riverine heat waves has been hindered by fragmented datasets, despite a proliferation in water-temperature monitoring with sensors and satellites. Here, we analyze riverine heat wave events by training one single deep learning (long short-term memory) model and reconstructing consistent and continuous daily water temperatures (WT) in 1471 sites in the Contiguous United States (1980–2022). We show that riverine heat waves occur at about half the frequency (2.3 versus 4.6 events/year), a third intensity (2.6 versus 7.7 °C/event), but almost double the duration (7.2 versus 4.0 d/event) of air heat waves. Riverine heat wave events have increased at double to quadruple rates of air heat wave events, amounting to an additional 1.8 events/year in frequency, 0.43 °C/event in intensity, 3.4 d/event in duration, and 7 to 15 additional thermal stress days for aquatic ecosystems in 2022 compared to 1980. Rising riverine heat waves have outpaced those of air heat waves in 65 to 76% of the sites, particularly in regions experiencing accelerated warming (e.g., the Rockies). Riverine heat wave trends are driven predominantly by climate-induced changes such as warming and dwindling snowpacks and water flow. Human activities do play important roles: large dams elongate, whereas agriculture reduces heat waves. These results highlight anthropogenic climate change as the primary external driver, whereas human-induced structural changes as the secondary internal modulators of river response to heat disturbance. The widespread rise of riverine heat waves threatens aquatic ecosystems and water-energy-food security, underscoring the need for their global characterization and risk assessment.}, archive = {J_PNAS}, author = {Sadayappan, Kayalvizhi and Li, Li}, doi = {10.1073/pnas.2503160122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2503160122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Riverine heat waves on the rise, outpacing air heat waves}, volume = {122}, year = {2025}, }
• (2025). Preferential apical infection and spread of human metapneumovirus highlights the importance of inhaled delivery of neutralizing monoclonal antibody to treat established infections. PNAS, 122(39), e2502897122. (www)

  @article{ , abstract = {Human metapneumovirus (hMPV) is a frequent cause of acute respiratory infections in infants, the elderly, and the immunocompromised. No vaccines or treatments are currently available beyond supportive care. Building on our previous work with parainfluenza viruses and respiratory syncytial virus, we investigate the pattern of hMPV infection and spread in polarized and well-differentiated cultures of human airway epithelium (WD-HAE). We found productive infection of WD-HAE requires apical inoculation of hMPV, with infectious spread dependent on progeny viruses shedding into mucus secretions overlaying the apical surface of WD-HAE. A potent neutralizing monoclonal antibodies (mAb) against hMPV fusion protein—mAb364 (also termed MPV364)—prevented initial infection by hMPV and halted spread of established hMPV infection when dosed directly to the apical surface of WD-HAE. Conversely, mAb364 delivered to the basal compartment was unable to curb established infections, even at 100-fold greater concentrations. Intranasal delivery of mAb364 to hamsters with established hMPV infections reduced viral titers by ~four logs within 2 d and alleviated key pathological outcomes of hMPV infection. These results are consistent with hMPV infection and continued spread occurring via the apical surface of the respiratory epithelium, and underscore delivery of neutralizing mAbs to the respiratory tract as an effective intervention against established hMPV infections.}, archive = {J_PNAS}, author = {Tiruthani, Karthik and Card, Madison P. and Wolf, Whitney and Shen, Limei and Schaefer, Alison and Fritz, Marshall and Okuda, Kenichi and Harkema, Jack R. and Mousa, Jarrod J. and J. Pickles, Raymond and Lai, Samuel K.}, doi = {10.1073/pnas.2502897122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2502897122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Preferential apical infection and spread of human metapneumovirus highlights the importance of inhaled delivery of neutralizing monoclonal antibody to treat established infections}, volume = {122}, year = {2025}, }
• (2025). Novelty as a drive of human exploration in complex stochastic environments. PNAS, 122(39), e2502193122. (www)

  @article{ , abstract = {In order to find extrinsic rewards, humans explore their environment even if exploration requires several intermediate, reward-free decisions. It has been hypothesized that intrinsic rewards, such as novelty, surprise, or information gain, guide this reward-free exploration. However, in artificial agents, different intrinsic reward signals induce exploration strategies that respond differently to stochasticity. In particular, some strategies are vulnerable to the “noisy TV problem,” i.e., an attraction to irrelevant stochastic stimuli. Here, we ask whether humans exhibit a similar attraction to reward-free stochasticity. We design a multistep decision-making paradigm in which participants search for rewarding states in a complex environment containing a highly stochastic but reward-free subregion. We show that i) participants persistently explore the stochastic subregion, and ii) their decisions are best explained by a novelty-driven exploration strategy, compared to alternatives driven by information gain or surprise. Our findings suggest that novelty and extrinsic rewards jointly control human exploration in complex environments.}, archive = {J_PNAS}, author = {Modirshanechi, Alireza and Lin, Wei-Hsiang and Xu, He A. and Herzog, Michael H. and Gerstner, Wulfram}, doi = {10.1073/pnas.2502193122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2502193122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Novelty as a drive of human exploration in complex stochastic environments}, volume = {122}, year = {2025}, }
• (2025). When neighbors play a role: A systems-level analysis of protein interactions conditioning cancer driver mutation effects. PNAS, 122(39), e2501925122. (www)

  @article{ , abstract = {Cancer is driven by the accumulation of somatic mutations, including driver mutations that confer a selective advantage to cancer cells. Driver proteins operate within complex interaction networks, and their activity is conditioned by neighbor proteins. Understanding the interplay between driver mutations and the expression of their neighbor proteins can provide insights into cancer biology and potential therapeutic targets. We assessed associations between expression of neighbor proteins and driver mutation status, comparing both between and within cancer types. We further evaluated if neighbors were enriched in significant associations with multiple drivers and characterized the impact of neighbor expression on overall survival for all cancer types. We found a significant correlation between the number of driver associations (DA) a neighbor gene has and the number of sign-coherent survival associations, particularly for neighbors enriched in positive associations, where high neighbor expression correlated with increased driver mutations and poorer survival. We identified 119 neighbors enriched in positive DA with at least two unfavorable survival associations and 25 neighbors enriched in negative DA with at least two favorable survival associations. Our study systematically identified neighbors associated with driver mutation status. Complementary evidence from survival analysis and the literature suggests that neighbors enriched in DA can be further explored as drug target candidates.}, archive = {J_PNAS}, author = {Miranda, João A. I. and Vital, Márcia F. S. and Carrolo, Margarida and Quintela, António and Pinto, Francisco R.}, doi = {10.1073/pnas.2501925122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2501925122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {When neighbors play a role: A systems-level analysis of protein interactions conditioning cancer driver mutation effects}, volume = {122}, year = {2025}, }
• (2025). Dual bmp-negative feedback loops modulate function of both AER and ZPA to buffer and constrain postaxial digit number. PNAS, 122(39), e2427249122. (www)

  @article{ , abstract = {Several lines of evidence indicate that posterior (postaxial) digit number in tetrapod vertebrates is constrained to the pentadactyl state by interactions between the two major signaling centers that organize digit pattern and growth, the Sonic hedgehog (Shh)-expressing Zone of Polarizing Activity (ZPA) and the Fgf-expressing Apical Ectodermal Ridge (AER) ectoderm. Negative short-range effects of Shh on the immediately overlying AER limit its posterior extent and function, either by direct Shh signaling or with Bmps playing a key role. How this strong inhibitory effect is counterbalanced to maintain pentadactyly in many vertebrate species remains less clear. In this study, we used genetic approaches in mice to reevaluate the mechanism by which Shh signaling modulates AER function and demonstrate that this occurs via Shh-target Bmps that act as a relay signal, rather than by direct Shh action. Furthermore, we show that Shh-induced Bmps also act directly on the ZPA, in a negative feedback loop, to down-regulate Shh expression and ZPA extent. We provide evidence that these dual Bmp-driven negative feedback loops robustly balance total Bmp levels to constrain postaxial digit number.}, archive = {J_PNAS}, author = {Patel, Rashmi and Mackem, Susan}, doi = {10.1073/pnas.2427249122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2427249122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dual bmp-negative feedback loops modulate function of both AER and ZPA to buffer and constrain postaxial digit number}, volume = {122}, year = {2025}, }
• (2025). Versatile xenopus tropicalis model with targeted integration of human BRAFV600E. PNAS, 122(39), e2426981122. (www)

  @article{ , abstract = {Targeting exogenous gene integrations in animals often exhibits low efficiency, limiting the development of gene knock-in models. Theoretically, by screening founder generation individuals based on the cell phenotypes resulting from gene knock-ins and leveraging the high fecundity of animals, heritable descendants with targeted knock-ins can be efficiently generated. Therefore, we utilized the high fecundity of Xenopus tropicalis and easily observable pigment phenotypes to construct a BRAF V600E -targeted mitf locus knock-in model. Results indicated that this approach enabled efficient generation of BRAF V600E knock-in X. tropicalis and produced a versatile frog model. The BRAF V600E knock-in induced the transdifferentiation of RPE cells into retinal cells, resulting in a symmetric retinal structure in the eyes of these frogs. The transformation of RPE cells ultimately leads to these frogs becoming eyeless frogs, which serve as a tool for retinal regeneration research. Additionally, in eyeless frogs the BRAF V600E knock-in led to the abnormal proliferation of both melanocytes and xanthophores into melanocytic and xanthocytic nevi respectively. Consequently, eyeless frogs provide a model for studying abnormal pigment cell proliferation, offering a platform for investigating pigment cell nevus formation. Furthermore, the cdkn2b -knockout eyeless frogs serve as a valuable xanthophoroma model for tumor biology research. Overall, the BRAF V600E -targeted knock-in X. tropicalis not only represents a strategy for constructing gene knock-in animal models but also serves as a versatile tool for research in retinal regeneration and tumor biology.}, archive = {J_PNAS}, author = {Ran, Rensen and Li, Lanxin and Chen, Peng and Li, Shuai and Wang, Peng and Zhu, Zhenpeng and Wang, Xiran and Chen, Yonglong and Hang, Jing and Liang, Weizheng}, doi = {10.1073/pnas.2426981122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2426981122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Versatile xenopus tropicalis model with targeted integration of human BRAFV600E}, volume = {122}, year = {2025}, }
• (2025). Dried fish provide widespread access to critical nutrients across africa. PNAS, 122(39), e2426844122. (www)

  @article{ , abstract = {Aquatic foods are essential in supporting food security and nutrition across the tropics, with “dried” fish particularly affordable, available, and nutritious. However, dried fish food systems are often hidden and overlooked due to data scarcity, limiting understanding of how dried fish contribute to nutrient intakes. Here, we combine nutrient analysis of fish samples with national household surveys from across East and West Africa to understand the importance of dried fish in diets. We find that small portions of dried fish contribute over 15% of recommended intakes for multiple essential dietary nutrients (calcium, iodine, iron, selenium, zinc, and vitamins B12 and D), with low heavy metal concentrations, and are consumed weekly by ~one-third of households in six countries (Côte d’Ivoire, Ghana, Nigeria, Malawi, Tanzania, and Uganda) (~144 million people). Dried fish consumption was more prevalent than fresh fish, reaching 54% more people, particularly those in poor households and near to marine coastlines or urban centers. The widespread prevalence of nutritious dried fish suggests that these foods and their distribution networks play critical roles in food security and nutrition, even in households distant from fisheries or urban centers. Dried fish can fill nutrient gaps across the tropics but will require policies that mitigate negative effects of overfishing, environmental changes, and competition with international markets, while providing postharvest support to fish processors.}, archive = {J_PNAS}, author = {Robinson, James P. W. and O’Meara, Lydia and Fiorella, Kathryn J. and Byrd, Kendra A. and Kjellevold, Marian and Ansong, Richard S. and Aura, Christopher Mulanda and Mwirigi, Naftaly and Allegretti, Antonio and Karkarey, Rucha and Lamont, Tim A. C. and Maire, Eva and Martin, Sarah M. and Omukoto, Johnstone O. and Standen, Sophie and Gephart, Jessica A. and Graham, Nicholas A. J. and Thilsted, Shakuntala H. and Hicks, Christina C.}, doi = {10.1073/pnas.2426844122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2426844122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dried fish provide widespread access to critical nutrients across africa}, volume = {122}, year = {2025}, }
• (2025). Motor origins of timbre in piano performance. PNAS, 122(39), e2425073122. (www)

  @article{ , abstract = {Creativity in the arts, such as painting and musical performance, hinges on the ability to produce a wide spectrogram of perceptual experiences. In music, it has long been believed that the timbre of tones can be altered by nuanced movements of performers. Previous studies have described relationships between fundamental elements of auditory perceptions (e.g., loudness, tempo) and physical movements (e.g., force, speed), but it remains unknown whether and how delicate features of perceptual experiences such as tone timbre are manipulated through dexterous motor skills. Here, we bridge this gap using a twofold experimental approach. First, our listening test revealed that the timbral qualities pianists intended to express in piano playing were perceived as intended by both pianists and musically untrained individuals, with pianists showing a greater perceptual sensitivity to different timbres. Second, through a motor behavioral experiment using a noncontact, high-resolution sensing system, we identified five specific movement features in piano touch that were intricately linked to three categories of perceived timbre; weight, clarity, and brightness. Furthermore, the direct manipulation of a specific key movement feature resulted in systematic changes in perceived timbre, providing evidence for a causal relationship. The result indicates that pianists share common motor skills to modify perceived tone timbre by manipulating specific movement features. Our findings underscore the pivotal roles of subtle physical gestures in creating the rich timbral palette of piano tones, advancing our understanding of the intersection between motor control and artistic expression.}, archive = {J_PNAS}, author = {Kuromiya, Kaori and Kobayashi, Yuya and Hirano, Masato and Furuya, Shinichi}, doi = {10.1073/pnas.2425073122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2425073122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Motor origins of timbre in piano performance}, volume = {122}, year = {2025}, }
• (2025). The multimodal transcriptional response of denervated skeletal muscle involves regulation of gramd1 genes impacting muscle size. PNAS, 122(39), e2424246122. (www)

  @article{ , abstract = {The development and maintenance of the neuromuscular junction (NMJ) requires reciprocal signals between the nerve terminals and multinucleated skeletal muscle fibers (myofibers). This interaction drives highly specialized transcription in the subsynaptic or NMJ myonuclei within mature myofibers leading to clustering of acetylcholine receptors (AChRs). Here, we utilized single-nucleus RNA sequencing (snRNA-seq) to delineate the transcriptional response of myonuclei to denervation. Through snRNA-seq on skeletal muscle from two independent mouse models of denervation, sciatic nerve transection and amyotrophic lateral sclerosis, we identify a multimodal transcriptional response of NMJ-enriched genes and an alteration in cholesterol homeostasis in myofibers. Gramd1 , a family of genes involved in nonvesicular cholesterol transport, are enriched at the NMJ in innervated muscle and upregulated in both models of denervation by the NMJ and extrasynaptic myonuclei. In vivo gain and loss of function studies indicate that Gramd1 genes regulate myofiber sizes. Mechanistically, we did not detect obvious changes in AChR clustering due to Gramd1 knockdown but revealed a role in autophagy after denervation. We uncovered a dynamic transcriptional response of myonuclei to denervation and highlight a critical role for Gramd1 to maintain myofiber sizes.}, archive = {J_PNAS}, author = {Calvo, Cristofer and Swoboda, Casey O. and Montecino-Morales, Fabian and Nagar, Siddhant and Petrany, Michael J. and Sun, Chengyi and Bindu Durumutla, Hima and Quattrocelli, Mattia and Millay, Douglas P.}, doi = {10.1073/pnas.2424246122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2424246122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The multimodal transcriptional response of denervated skeletal muscle involves regulation of gramd1 genes impacting muscle size}, volume = {122}, year = {2025}, }
• (2025). Toward a unified taxonomy of information dynamics via integrated information decomposition. PNAS, 122(39), e2423297122. (www)

  @article{ , abstract = {Our ability to understand and control complex systems of many interacting parts remains limited. A key challenge is that we still do not know how best to describe—and quantify—the many-to-many dynamical interactions that characterize their complexity. To address this limitation, we introduce the mathematical framework of Integrated Information Decomposition, or Φ ID. Φ ID provides a comprehensive framework to disentangle and characterize the information dynamics of complex multivariate systems. On the theoretical side, Φ ID reveals the existence of previously unreported modes of collective information flow, providing tools to express well-known measures of information transfer, information storage, and dynamical complexity as aggregates of these modes, thereby overcoming some of their known theoretical shortcomings. On the empirical side, we validate our theoretical results with computational models and examples from over 1,000 biological, social, physical, and synthetic dynamical systems. Altogether, Φ ID improves our understanding of the behavior of widely used measures for characterizing complex systems across disciplines and leads to new more refined analyses of dynamical complexity.}, archive = {J_PNAS}, author = {Mediano, Pedro A. M. and Rosas, Fernando E. and Luppi, Andrea I. and Carhart-Harris, Robin L. and Bor, Daniel and Seth, Anil K. and Barrett, Adam B.}, doi = {10.1073/pnas.2423297122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2423297122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Toward a unified taxonomy of information dynamics via integrated information decomposition}, volume = {122}, year = {2025}, }
• (2025). Spin-resolved imaging of atomic-scale helimagnetism in mono- and bilayer NiI2. PNAS, 122(39), e2422868122. (www)

  @article{ , abstract = {Noncollinear magnetic orders in monolayer van der Waals magnets are crucial for probing delicate magnetic interactions under minimal spatial constraints and advancing miniaturized spintronic devices. Despite their significance, achieving atomic-scale identification remains challenging. In this study, we utilized spin-polarized scanning tunneling microscopy and density functional theory calculations to identify spin-spiral orders in mono- and bilayer NiI 2 , grown on graphene-covered SiC(0001) substrates. We found two distinct spin-spiral states with Q vectors aligning and deviating by 7° from the lattice direction, exhibiting periodicities of 4.54 and 5.01 times the lattice constant, respectively. These findings contrast with bulk properties and align closely with our theoretical calculations. Surprisingly, the nonmultiples of spin spirals within finite-sized magnetic domains induce net magnetic moments, facilitating collective spin switching behavior under magnetic fields. Our research reveals intrinsic noncollinear magnetism at the monolayer limit with atomic-scale resolution, paving the way for exploring spin phenomena.}, archive = {J_PNAS}, author = {Miao, Mao-Peng and Liu, Nanshu and Zhang, Wen-Hao and Zhou, Jian-Wang and Wang, Dao-Bo and Wang, Cong and Ji, Wei and Fu, Ying-Shuang}, doi = {10.1073/pnas.2422868122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2422868122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spin-resolved imaging of atomic-scale helimagnetism in mono- and bilayer NiI2}, volume = {122}, year = {2025}, }
• (2025). Intranasal hemagglutinin protein boosters induce protective mucosal immunity against influenza a viruses in mice. PNAS, 122(39), e2422171122. (www)

  @article{ , abstract = {Licensed parenteral influenza vaccines induce systemic antibody responses and alleviate disease severity but do not efficiently induce local mucosal immune responses. Here, we describe an intranasal booster strategy with unadjuvanted recombinant hemagglutinin (HA) following initial messenger RNA-lipid nanoparticle (mRNA-LNP) vaccination, Prime and HA. This regimen establishes highly protective HA-specific mucosal immune memory responses in the respiratory tract. Intranasal HA boosters resulted in significantly reduced viral replication compared to parenteral mRNA-LNP boosters in both young and old mice. Correlation analysis revealed that slightly increased levels of nasal Immunoglobulin A (IgA) are significantly associated with a reduced viral burden in the upper respiratory tract. Intranasal boosting with bivalent H1 HA induced mucosal immunity against vaccine-matched and mismatched heterologous influenza viruses. Additionally, a heterosubtypic intranasal H5 HA booster elicited H5-reactive mucosal humoral responses in H1-surviving mice. Our work illustrates the potential of a nasal HA protein booster as an adjuvant-free strategy to prevent infection and disease from influenza A viruses.}, archive = {J_PNAS}, author = {Moriyama, Miyu and Rodrigues, Gisele and Wang, Jiping and Jayewickreme, Radeesha and Hudak, Andrew and Dong, Huiping and Homer, Robert J. and Ma, Shuangge and Iwasaki, Akiko}, doi = {10.1073/pnas.2422171122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2422171122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intranasal hemagglutinin protein boosters induce protective mucosal immunity against influenza a viruses in mice}, volume = {122}, year = {2025}, }
• (2025). Developing new technologies to protect ecosystems: Planning with adaptive management. PNAS, 122(39), e2422002122. (www)

  @article{ , abstract = {Technology development is an essential investment for policymakers to address contemporary global crises, including climate change, biodiversity loss, the energy transition, and emergent infectious diseases. However, investing limited resources in the development of new technologies is risky. The research and development process is unpredictable, with unknown timelines and outcomes. In addition, even after successful development, the effects of deploying a new technology remain uncertain. When confronted with these uncertainties, policymakers must determine how long they should allocate resources to developing new technologies. Informed decisions require anticipating possible successes and failures of both technology development and deployment, which is a challenging optimization task when managing dynamic systems, such as threatened ecological systems. Using an adaptive management approach from AI, we find a time limit new technologies should be developed for, which balances costs, benefits, and uncertainties during development and deployment. We extract clear and transparent general rules for investing in new technologies, building on an analytical approximation. Using Australia’s Great Barrier Reef as a case study, we demonstrate that the development time limit ranges between 0 to 45 y before surrendering. We also show how characteristics of an ecological system influence the optimal investment strategy. Our approach can inform the development of new technologies in multiple domains including biodiversity conservation, public health, energy production, and the technology industry more broadly.}, archive = {J_PNAS}, author = {Pascal, Luz Valerie and Chadès, Iadine and Adams, Matthew P. and Helmstedt, Kate J.}, doi = {10.1073/pnas.2422002122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2422002122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Developing new technologies to protect ecosystems: Planning with adaptive management}, volume = {122}, year = {2025}, }
• (2025). A spatially differentiated water pollution policy leads to economic and health inequity. PNAS, 122(39), e2421404122. (www)

  @article{ , abstract = {Disparities in air pollution exposure by socioeconomic status (SES) are well documented. However, there is much less evidence on the inequitable consequences of water pollution and policies affecting water pollution gaps. This study uncovers the distributional impact of China’s 11th Five-Year Plan (2006–2010), which triggered spatially differentiated water pollution abatement for a population of almost 1.3 billion. We document that the policy reduced water pollution overall, targeting areas based on pollution level. Since high pollution areas tend to be wealthier, this policy concentrated firm water pollution abatement and reductions in polluting firm entry in higher-SES areas. While pollution fell, the policy further widened the gap in health and economic outcomes, particularly for those without tap water access: Disparities in risks of tumor, cardiovascular disease, labor supply, and wages increased. Our findings demonstrate that policy-induced changes in water pollution can interact with unequal access to defensive infrastructure to exacerbate SES gaps in outcomes. The analysis also suggests that consideration of heterogeneous pollution vulnerability across the population may affect the overall benefits of a policy.}, archive = {J_PNAS}, author = {Luo, Zhonghui and Ma, Lala and Xie, Rui and Song, Ran}, doi = {10.1073/pnas.2421404122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2421404122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A spatially differentiated water pollution policy leads to economic and health inequity}, volume = {122}, year = {2025}, }
• (2025). Triple checkpoint blockade of PD-1, tim-3, and lag-3 enhances adoptive t cell immunotherapy in a mouse model of ovarian cancer. PNAS, 122(39), e2419888122. (www)

  @article{ , abstract = {The five-year survival rate for ovarian cancer patients remains below 50%, underscoring the need for innovative therapies. One promising approach involves engineering T cells to specifically target proteins uniquely overexpressed in tumors, thereby controlling tumor growth without toxicity to healthy tissues. Mesothelin (MSLN) contributes to the malignant and invasive phenotype in ovarian cancer and has limited expression in healthy cells, making it a candidate immunotherapy target. Our previous results in a mouse model of ovarian cancer demonstrated that T cells engineered to express a T cell receptor (TCR) targeting MSLN (TCR MSLN ) mediated therapeutic activity, delaying tumor growth and prolonging mouse survival. However, inhibitory ligands expressed in the tumor microenvironment (TME) interacted with inhibitory receptors on activated T cells, suppressing antitumor function. We hypothesized combining engineered T cells with checkpoint blockade would enhance T cell function and improve therapeutic efficacy, but administration of monospecific antibodies targeting individual inhibitory pathways had no significant impact on T cell efficacy. By contrast, the combination of PD-1, Tim-3, and Lag-3 blockade with engineered T cells significantly improved T cell function and overall animal survival relative to treatment with antibody alone or TCR MSLN with singlet or doublet antibody combinations. Single-cell RNA sequencing revealed TCR MSLN T cells treated with the triplet antibody combination increased expression of genes involved in interferon responses and metabolic function, and reduced expression of genes associated with exhaustion. These results suggest that strategies to disrupt multiple inhibitory pathways simultaneously may be necessary for improved adoptive T cell therapy efficacy in patients.}, archive = {J_PNAS}, author = {Alencar, Gabriel F. and Mohamed, Asmaa O. and Burnett, Madison G. and Jean, Samantha St. and Nelson, Anders R. and Su, Yapeng and Voillet, Valentin and Bates, Breanna M. and Rodgers Suarez, Magdalia and Ruskin, Susan L. and Trieu, Lam and Lam, Jennifer L. and Bekiranov, Stefan and Gottardo, Raphael and Greenberg, Philip D. and Anderson, Kristin G.}, doi = {10.1073/pnas.2419888122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2419888122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Triple checkpoint blockade of PD-1, tim-3, and lag-3 enhances adoptive t cell immunotherapy in a mouse model of ovarian cancer}, volume = {122}, year = {2025}, }
• (2025). Language models reveal a complex sequence basis for adaptive convergent evolution of protein functions. PNAS, 122(39), e2418254122. (www)

  @article{ , abstract = {Convergent evolution, or convergence, refers to repeated, independent emergences of the same trait in two or more lineages of species during evolution, often indicating functional adaptation to specific environmental factors. Many computational methods have been proposed to investigate the genetic basis for organismal functional convergence, as an important way to decode the complex sequence–function map of proteins. These methods mostly focus on the convergence of amino acid states at the level of individual sites in functionally related proteins. However, even without site-level sequence similarity, protein function similarity may also stem from convergence of high-order protein features, which cannot be captured by the conventional methods. To fill this gap, we first derived numerical embeddings from protein sequences by pretrained protein language models (PLM). In four previously reported cases, we found that functionally convergent proteins have similar embeddings despite no site-level convergence, indicating that PLM embeddings can reflect convergence of high-order protein features. We then designed a pipeline to detect Adaptive Convergence by Embedding of Protein (ACEP). ACEP tests were significant on known and additional candidate genes with putative adaptive convergence like echolocation and crassulacean acid metabolism. Genome-wide application showed that the ACEP framework can effectively enrich such candidates. Relations between convergences of PLM embeddings and specific protein physicochemical features were further examined. In conclusion, PLM embeddings can indicate adaptive convergence of high-order protein features beyond site identities, demonstrating the power of deep learning tools for investigating the complex mapping between molecular sequences and functions.}, archive = {J_PNAS}, author = {Cao, Zhenqiu and Zhang, Hongjiu and Zou, Zhengting}, doi = {10.1073/pnas.2418254122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2418254122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Language models reveal a complex sequence basis for adaptive convergent evolution of protein functions}, volume = {122}, year = {2025}, }
• (2025). Exploring the sub-neptune frontier with JWST. PNAS, 122(39), e2416194122. (www)

  @article{ , abstract = {Sub-Neptune planets, with sizes and masses between those of Earth and Neptune, dominate the exoplanet population. Sub-Neptunes are expected to be the most diverse family of the exoplanet population, potentially including rocky gas dwarfs, water worlds, and mini-Neptunes, with a wide range of atmospheric, surface, and interior conditions. With no analogue in the solar system, these planets open fundamental questions in planetary processes, origins, and habitability, and present avenues in the search for life elsewhere. Atmospheric observations with the James Webb Space Telescope (JWST) are enabling unprecedented characterization of sub-Neptunes, starting with the first detections of carbon-bearing molecules in the habitable zone sub-Neptune K2-18 b. We survey the present landscape of JWST observations and atmospheric inferences of sub-Neptunes, which in turn provide key insights into their atmospheric processes, internal structures, surface conditions, formation pathways, and potential habitability. The atmospheric abundance constraints reveal evidence of chemical disequilibria, and insights into the planetary mass–metallicity relation in the sub-Neptune regime. Similarly, for sub-Neptunes with H 2 O-rich interiors, increasing atmospheric H 2 O abundances with the equilibrium temperature may indicate the existence of a critical temperature for transition from H 2 dominated atmospheres with tropospheric cold traps to those with steamy atmospheres. The chemical abundances also provide initial evidence for diverse planet types, from potentially habitable hycean worlds to steam worlds with supercritical water layers. These planet types serve as benchmarks for an emerging taxonomy of volatile-rich sub-Neptunes as a function of their equilibrium temperature and atmospheric extent, heralding a new era of chemical classification of low-mass exoplanets with JWST.}, archive = {J_PNAS}, author = {Madhusudhan, Nikku and Holmberg, Måns and Constantinou, Savvas and Cooke, Gregory J.}, doi = {10.1073/pnas.2416194122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2416194122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exploring the sub-neptune frontier with JWST}, volume = {122}, year = {2025}, }
• (2025). A precise metallicity and carbon-to-oxygen ratio for a warm giant exoplanet from its panchromatic JWST emission spectrum. PNAS, 122(39), e2416193122. (www)

  @article{ , abstract = {WASP-80 b, a warm sub-Jovian (equilibrium temperature ∼ 820 K, 0.5 Jupiter masses), presents an opportunity to characterize a rare gas giant exoplanet around a low-mass star. In addition, its moderate temperature enables its atmosphere to host a range of carbon and oxygen species (H 2 O, CH 4 , CO, CO 2 , NH 3 ). In this paper, we present a panchromatic emission spectrum of WASP-80 b, the first gas giant around a late K/early M-dwarf star and the coolest planet for which the James Webb Space Telescope has obtained a complete emission spectrum spanning 2.4 to 12 μ m, including NIRCam F322W2 (2.4 to 4 μ m) and F444W (4 to 5 μ m), and MIRI LRS (5 to 12 μ m). We report confident detections of H 2 O, CH 4 , CO, and CO 2 , and a tentative detection of NH 3 . We estimate WASP-80 b’s atmospheric metallicity and carbon-to-oxygen ratio and compare them with estimates for other gas giants. Despite the relative rarity of giant planets around low-mass stars, we find that WASP-80 b’s composition is consistent with other hot gas giants, suggesting that the formation pathway of WASP-80 b may not be dissimilar from hot gas giants around higher-mass stars.}, archive = {J_PNAS}, author = {Wiser, Lindsey S. and Bell, Taylor J. and Line, Michael R. and Schlawin, Everett and Beatty, Thomas G. and Welbanks, Luis and Greene, Thomas P. and Parmentier, Vivien and Murphy, Matthew M. and Fortney, Jonathan J. and Arnold, Kenny and Mehta, Nishil and Ohno, Kazumasa and Mukherjee, Sagnick}, doi = {10.1073/pnas.2416193122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2416193122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A precise metallicity and carbon-to-oxygen ratio for a warm giant exoplanet from its panchromatic JWST emission spectrum}, volume = {122}, year = {2025}, }
• (2025). A first look at rocky exoplanets with JWST. PNAS, 122(39), e2416190122. (www)

  @article{ , abstract = {Rocky exoplanet characterization has been a top priority for early James Webb Space Telescope (JWST) science operations. Several milestones have been achieved, including the most precise rocky planet transmission spectra measured to date, and the first detection of thermal emission for rocky worlds below 800 K. Despite these advances, no atmospheres have been definitively detected. Several transmission spectra show tentative evidence for molecular absorption features, but these hints are marginally significant and the spectra may be affected by stellar contamination. Features from many plausible atmospheres, including those dominated by oxygen, nitrogen, and carbon dioxide, are below the current noise level. Meanwhile, the emerging picture from thermal emission spectra is that the planets have hot daysides, consistent with either a bare rock composition or low surface pressure atmospheres ( < 10 bar). Higher surface pressures and high carbon dioxide abundances are generally ruled out, assuming cloud-free atmosphere models. The absence of strong CO 2 features hints at a limited initial volatile inventory or rapid atmospheric escape during the planets’ early lifetimes. Taken together, these results motivate a push toward higher precision data, as well as observations of cooler planets that may be more likely to retain atmospheres. As a goal for future transmission spectroscopy, we suggest a “five scale height challenge,” to achieve the precision necessary to detect CO 2 features in nitrogen-rich atmospheres. Detecting rocky planet atmospheres remains challenging, but with JWST’s excellent performance and a continuing investment of telescope time, we are optimistic these uncharted atmospheres will be detected in coming years.}, archive = {J_PNAS}, author = {Kreidberg, Laura and Stevenson, Kevin B.}, doi = {10.1073/pnas.2416190122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2416190122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A first look at rocky exoplanets with JWST}, volume = {122}, year = {2025}, }
• (2025). Exploring exoplanet dynamics with JWST: Tides, rotation, rings, and moons. PNAS, 122(39), e2416189122. (www)

  @article{ , abstract = {Although nearly 6,000 exoplanets are currently known, in most cases, our knowledge is limited to a handful of the planet’s orbital characteristics and bulk properties such as radius and mass. The James Webb Space Telescope (JWST) can expand our knowledge not only by probing exoplanet atmospheres but also by measuring additional orbital and physical properties of exoplanets, thanks to its superior light-gathering power and measurement precision. Here, we describe the potential of JWST to unveil dynamical phenomena that were previously beyond our reach, such as tidal distortion and inflation, rotational flattening, planetary rings, and moons.}, archive = {J_PNAS}, author = {Millholland, Sarah C. and Winn, Joshua N.}, doi = {10.1073/pnas.2416189122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2416189122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exploring exoplanet dynamics with JWST: Tides, rotation, rings, and moons}, volume = {122}, year = {2025}, }
• (2025). Prospects for detecting signs of life on exoplanets in the JWST era. PNAS, 122(39), e2416188122. (www)

  @article{ , abstract = {The search for signs of life in the Universe has entered a new phase with the advent of the James Webb Space Telescope (JWST). Detecting biosignature gases via exoplanet atmosphere transmission spectroscopy is in principle within JWST’s reach. We reflect on JWST’s early results in the context of the potential search for biological activity on exoplanets. The results confront us with a complex reality. Established inverse methods to interpret observed spectra—already known to be highly averaged representations of intricate three dimensional (3D) atmospheric processes—can lead to disparate interpretations even with JWST’s quality of data. Characterizing rocky or sub-Neptune-size exoplanets with JWST is an intricate task, and moves us away from the notion of finding a definitive “silver bullet” biosignature gas. Indeed, JWST results necessitate us to allow “parallel interpretations” that will perhaps not be resolved until the next generation of observatories. Nonetheless, with a handful of habitable-zone planet atmospheres accessible given the anticipated noise floor, JWST may continue to contribute to this journey by designating a planet as biosignature gas candidate. To do this we will need to sufficiently refine our inverse methods and physical models for confidently quantifying specific gas abundances and constraining the atmosphere context. Looking ahead, future telescopes and innovative observational strategies will be essential for the reliable detection of biosignature gases.}, archive = {J_PNAS}, author = {Seager, Sara and Welbanks, Luis and Ellerbroek, Lucas and Bains, William and Petkowski, Janusz J.}, doi = {10.1073/pnas.2416188122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2416188122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prospects for detecting signs of life on exoplanets in the JWST era}, volume = {122}, year = {2025}, }
• (2025). Inseparable/IER3IP1 are essential for cytokinesis in drosophila neuroblasts and human cells. PNAS, 122(39), e2415361122. (www)

  @article{ , abstract = {To unveil the molecular players that maintain neural stem cell (NSC) homeostasis, we conducted a genetic screen in Drosophila and isolated an uncharacterized gene that we named Inseparable ( Insep ). Insep is the Drosophila homologue of human IER3IP1 , a gene associated with Microcephaly, Epilepsy, and Neonatal Diabetes Syndrome-1 (MEDS-1). We show that Insep loss leads to early larval lethality with small brains and these phenotypes can be rescued by expressing IER3IP1 indicating that their biological function is conserved through evolution. The Insep deficient neuroblasts fail to complete cytokinesis and show excessive accumulation of Rab11 vesicles in the cytoplasm. Similarly, IER3IP1 depletion in human cells leads to cytokinesis failure and accumulation of Rab11 vesicles. Insep and IER3IP1 localize to Rab11 vesicles and interact with Rab11. The pathogenic mutations in IER3IP1 perturb its localization to Rab11 vesicles. These results suggest that Insep and IER3IP1 work along with Rab11 and may regulate fusion of Rab11 vesicles to the advancing furrow during cytokinesis.}, archive = {J_PNAS}, author = {Kakade, Aishwarya Arun and Gupta, Sachin and Johnson, Andrea and Varghese, Reshmi and Adicherla, Harikrishna and Nagarkar-Jaiswal, Sonal}, doi = {10.1073/pnas.2415361122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2415361122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inseparable/IER3IP1 are essential for cytokinesis in drosophila neuroblasts and human cells}, volume = {122}, year = {2025}, }
• (2025). Emergence of activation or repression in transcriptional control under a fixed molecular context. PNAS, 122(39), e2413715122. (www)

  @article{ , abstract = {Transcription factors (TFs) can be both activators and repressors of gene transcription. This can manifest as “duality,” where the transcriptional response increases (activation) with TF concentration in one context but decreases (repression) in another context, or as “nonmonotonicity,” where, in the same context, the response increases in part of the concentration range and decreases outside that range. Here we use biophysical models of gene regulation to investigate how duality and nonmonotonicity relate to the interactions between a TF, Polymerase and the regulatory DNA. We distinguish two modes of TF action on Polymerase: “coherent,” with interactions either positive or negative, and “incoherent,” where interactions are a mix of both. For TFs that act incoherently from a single TF–DNA binding site, nonmonotonicity can arise, but only under nonequilibrium models. For single-site models, we show that nonmonotonicity can never happen under the common thermodynamic models of gene regulation, which consider equilibrium conditions and ignore the dissipative nature of the transcription process. Moreover, we show that merely changing the TF–DNA binding affinity, while keeping other features fixed, can tune the response between activation and repression, with responses either evaluated as a function of TF concentration or site number. Using the mammalian Sp1 as a case study and synthetically designed target sequences, we find experimental evidence for nonmonotonicity, and activation or repression tuned by affinity, which we interpret as evidence of incoherent action. Our work highlights the importance of moving from a TF-centric view to a systems view when reasoning about transcriptional control.}, archive = {J_PNAS}, author = {Martinez-Corral, Rosa and Friedrich, Dhana and Frömel, Robert and Velten, Lars and Gunawardena, Jeremy and DePace, Angela H.}, doi = {10.1073/pnas.2413715122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2413715122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Emergence of activation or repression in transcriptional control under a fixed molecular context}, volume = {122}, year = {2025}, }
• (2025). Ebola virus VP35 NNLNS motif modulates viral RNA synthesis and MIB2-mediated signaling. PNAS, 122(39), e2411961122. (www)

  @article{ , abstract = {Ebola virus (EBOV) is a nonsegmented, negative-sense virus (NNSV) with a single-stranded RNA genome. EBOV encodes for a limited number of proteins and thus depends on host factors to facilitate viral replication and pathogenesis. Of the virus-encoded proteins, multifunctional EBOV VP35 (eVP35) is necessary for host immune evasion and viral RNA synthesis. Previous proteomics studies identified an interaction between eVP35 and the host E3 ubiquitin ligase Mindbomb 2 (MIB2). Here, we show how an NNLNS (Asn-Asn-Leu-Asn-Ser) motif (residues 201 to 205) within eVP35 serves as a binding site for MIB2. This motif is critical for eVP35-dependent inhibition of MIB2-mediated interferon induction. It is also important for EBOV RNA synthesis as MIB2 binding to eVP35 inhibited EBOV minigenome activity. Altogether, these findings highlight the importance of the eVP35 protein and the role of host factors in EBOV infection.}, archive = {J_PNAS}, author = {Uwase, Grace and Luthra, Priya and Vogel, Olivia A. and Batra, Jyoti and La Rosa, Bruno A. and Sheehan, Kathleen C. F. and Khatavkar, Oam and Payton, Jacqueline E. and Davey, Robert A. and Krogan, Nevan J. and Basler, Christopher F. and Leung, Daisy W. and Amarasinghe, Gaya K.}, doi = {10.1073/pnas.2411961122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {39}, pages = {e2411961122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ebola virus VP35 NNLNS motif modulates viral RNA synthesis and MIB2-mediated signaling}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(38), eiti3825122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti3825122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {eiti3825122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Correction for bender et al., differential representations of spatial location by aperiodic and alpha oscillatory activity in working memory. PNAS, 122(38), e2524377122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2524377122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2524377122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for bender et al., differential representations of spatial location by aperiodic and alpha oscillatory activity in working memory}, volume = {122}, year = {2025}, }
• (2025). Correction for tobias et al., biodiversity conservation requires integration of species-centric and process-based strategies. PNAS, 122(38), e2524376122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2524376122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2524376122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for tobias et al., biodiversity conservation requires integration of species-centric and process-based strategies}, volume = {122}, year = {2025}, }
• (2025). Correction for loop yao et al., synergistic action of specialized metabolites from divergent biosynthesis in the human oral microbiome. PNAS, 122(38), e2523373122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2523373122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2523373122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for loop yao et al., synergistic action of specialized metabolites from divergent biosynthesis in the human oral microbiome}, volume = {122}, year = {2025}, }
• (2025). Correction for mitani et al., microscopic and structural observations of actin filament capping and severing by cytochalasin d. PNAS, 122(38), e2523366122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2523366122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2523366122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for mitani et al., microscopic and structural observations of actin filament capping and severing by cytochalasin d}, volume = {122}, year = {2025}, }
• (2025). Correction for berenbaum, political and biological reality checks. PNAS, 122(38), e2523336122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2523336122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2523336122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for berenbaum, political and biological reality checks}, volume = {122}, year = {2025}, }
• (2025). Correction for agip et al., structures of chaetomium thermophilum TOM complexes with bound preproteins. PNAS, 122(38), e2523199122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2523199122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2523199122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for agip et al., structures of chaetomium thermophilum TOM complexes with bound preproteins}, volume = {122}, year = {2025}, }
• (2025). Reply to possenriede et al.: LDLR as a targetable HlyA receptor in escherichia coli pyelonephritis. PNAS, 122(38), e2522220122. (www)

  @article{ , archive = {J_PNAS}, author = {Kuhn, Hunter W. and Smither, Madeleine R. and Collins, Christina A. and Gaut, Joseph P. and Diamond, Michael S. and Hunstad, David A.}, doi = {10.1073/pnas.2522220122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2522220122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to possenriede et al.: LDLR as a targetable HlyA receptor in escherichia coli pyelonephritis}, volume = {122}, year = {2025}, }
• (2025). Correction for leprevost et al., a widespread family of ribosomal peptide metallophores involved in bacterial adaptation to metal stress. PNAS, 122(38), e2522214122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2522214122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2522214122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for leprevost et al., a widespread family of ribosomal peptide metallophores involved in bacterial adaptation to metal stress}, volume = {122}, year = {2025}, }
• (2025). Designers join scientists to make living architecture a reality. PNAS, 122(38), e2522200122. (www)

  @article{ , archive = {J_PNAS}, author = {Beans, Carolyn}, doi = {10.1073/pnas.2522200122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2522200122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Designers join scientists to make living architecture a reality}, volume = {122}, year = {2025}, }
• (2025). Did the vilca/tobacco snuff combination at chavín aim for an “ayahuasca effect”?. PNAS, 122(38), e2521671122. (www)

  @article{ , archive = {J_PNAS}, author = {Whitridge, Peter}, doi = {10.1073/pnas.2521671122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2521671122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Did the vilca/tobacco snuff combination at chavín aim for an “ayahuasca effect”?}, volume = {122}, year = {2025}, }
• (2025). An uphill struggle for tropical forest trees. PNAS, 122(38), e2520436122. (www)

  @article{ , archive = {J_PNAS}, author = {Collins, Scott L.}, doi = {10.1073/pnas.2520436122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2520436122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An uphill struggle for tropical forest trees}, volume = {122}, year = {2025}, }
• (2025). LDL receptor promotes urinary tract infection by α-hemolysin-producing escherichia coli and long-term histopathologic sequelae in the kidney. PNAS, 122(38), e2520130122. (www)

  @article{ , archive = {J_PNAS}, author = {Possenriede, Lena and Sendtner, Georg W. and Falahat, Peyman and Miranda, Julia and Schmidt, Axel and Ludwig, Kerstin U. and von Vietinghoff, Sibylle}, doi = {10.1073/pnas.2520130122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2520130122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {LDL receptor promotes urinary tract infection by α-hemolysin-producing escherichia coli and long-term histopathologic sequelae in the kidney}, volume = {122}, year = {2025}, }
• (2025). Probing the connection between chirality and spin through time-resolved EPR spectroscopy. PNAS, 122(38), e2519806122. (www)

  @article{ , archive = {J_PNAS}, author = {Saxena, Sunil and Waldeck, David H.}, doi = {10.1073/pnas.2519806122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2519806122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Probing the connection between chirality and spin through time-resolved EPR spectroscopy}, volume = {122}, year = {2025}, }
• (2025). Intron 1 of the c9orf72 gene: The RNA that RAN. PNAS, 122(38), e2519800122. (www)

  @article{ , archive = {J_PNAS}, author = {Hagerman, Paul J.}, doi = {10.1073/pnas.2519800122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2519800122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intron 1 of the c9orf72 gene: The RNA that RAN}, volume = {122}, year = {2025}, }
• (2025). Dimerization propensity of the β1-adrenergic receptor in lipid nanodiscs probed by DEER and single-molecule spectroscopies. PNAS, 122(38), e2519609122. (www)

  @article{ , abstract = {G protein–coupled receptors (GPCRs) comprise a large class of membrane proteins that mediate cellular responses to a wide range of external signals and as such constitute major drug targets. While oligomerization has been shown to play a well-established role in modulating signaling for class C GPCRs (e.g., the glutamate and GABA receptors), the functional relevance of oligomerization for class A receptors, such as the β 1 -adrenergic receptor (β 1 AR), remains unclear. Here, we have examined the influence of the membrane mimetic environment on the dimerization propensity of β 1 AR using a combination of pulsed Q-band double electron–electron resonance spectroscopy and single-molecule fluorescence brightness measurements in an Anti-Brownian Elektrokinetic trap. While β 1 AR is predominantly monomeric in docecyl-β-D-maltoside (DDM) micelles, reconstitution of β 1 AR in lipid nanodiscs preferentially favors symmetric parallel dimers. Using nanodiscs of different diameters we observed a clear size-dependent increase in the dimer fraction, reaching over 50% of the β 1 AR molecules in large (~12.5 nm diameter) nanodiscs. Addition of cholesteryl hemisuccinate, an analog of cholesterol, suppresses β 1 AR dimerization in lipid nanodiscs, recapitulating the behavior in DDM micelles. This work provides quantitative evidence that β 1 AR possesses an intrinsic, membrane sensitive predisposition for dimerization, and highlights the importance of spatial membrane constraints in the modulation of class A GPCR dimerization.}, archive = {J_PNAS}, author = {Kubatova, Nina and Schmidt, Thomas and Wang, Quan and Clore, G. Marius}, doi = {10.1073/pnas.2519609122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2519609122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dimerization propensity of the β1-adrenergic receptor in lipid nanodiscs probed by DEER and single-molecule spectroscopies}, volume = {122}, year = {2025}, }
• (2025). C4d, a high-affinity LilrB2 ligand, is elevated in alzheimer’s disease and mediates synapse pruning. PNAS, 122(38), e2519253122. (www)

  @article{ , abstract = {Synapse pruning sculpts neural circuits throughout life. The human Leukocyte immunoglobulin-like receptor type B2 (LilrB2)/murine Paired immunoglobulin receptor B (PirB) receptors expressed in neurons and complement protein C4 have been separately implicated in pruning. Here, we report that C4d, a C4 cleavage product with unknown function, binds LilrB2/PirB with nanomolar affinity. C4d and LilrB2 colocalize at excitatory synapses in the human cerebral cortex as well as with beta amyloid in Alzheimer’s disease (AD). C4d, as well as C4, increase with age and more so in AD. To examine whether C4d-PirB interactions can drive pruning, dendritic spines—the postsynaptic structure of excitatory synapses—were monitored on L5 pyramidal neurons in the mouse cerebral cortex: A significant decrease in dendritic spine density occurred in WT with C4d exposure, but KO of PirB completely prevented this loss. Together, our findings reveal an unexpected physiological role for C4d in pruning and imply that different complement cascade components may collaborate to engage both neuronal and glial-specific effectors of synaptic pruning.}, archive = {J_PNAS}, author = {Brott, Barbara K. and Raissi, Aram J. and Micheva, Kristina D. and Vielmetter, Jost and Mendes, Monique S. and Baccus, Caroline J. and Huang, Jolie and Shatz, Carla J.}, doi = {10.1073/pnas.2519253122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2519253122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {C4d, a high-affinity LilrB2 ligand, is elevated in alzheimer’s disease and mediates synapse pruning}, volume = {122}, year = {2025}, }
• (2025). Remembering ecologist margaret bryan davis (1931–2024). PNAS, 122(38), e2519126122. (www)

  @article{ , abstract = {Margaret Bryan Davis, a prominent ecologist, died on May 22, 2024. She was a Regents Professor at the University of Minnesota and a member of the National Academy of Sciences. Her students remember her as a creative and clear-thinking scientist who combined the tools and perspectives of paleoecology with ideas and problems of ecology in order to understand long-term forest dynamics. She was a champion of diversity and equity in science.}, archive = {J_PNAS}, author = {Lynch, Elizabeth A. and Calcote, Randy and Zabinski, Catherine A. and Hotchkiss, Sara C.}, doi = {10.1073/pnas.2519126122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2519126122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Remembering ecologist margaret bryan davis (1931–2024)}, volume = {122}, year = {2025}, }
• (2025). Rootworm resistance to bt associated with increased injury to corn pyramids combining bt proteins and RNA interference. PNAS, 122(38), e2518683122. (www)

  @article{ , abstract = {Crops genetically engineered to produce insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) have revolutionized pest management, but their benefits have been reduced by evolution of practical resistance in at least 31 cases. To delay evolution of resistance, farmers have shifted from crops producing one Bt protein to crops called pyramids that produce two or more Bt proteins or other traits targeting each pest. Here, we focus on resistance to transgenic corn pyramids in the western corn rootworm ( Diabrotica virgifera virgifera ) and northern corn rootworm ( Diabrotica barberi ), which cost farmers in the United States $2 billion yearly in yield losses. We analyzed 998 relevant data values for 2005 to 2023 from 12 published field studies. The results support the hypothesis that rootworm resistance to Bt proteins Cry3Bb and Gpp34/Tpp35Ab reduces the efficacy of pyramids that produce one or both of these proteins and an RNA interference trait (DvSnf7) targeting rootworms, despite no apparent strong cross-resistance between the Bt proteins and DvSnf7. The reduced efficacy of pyramids producing Bt proteins and DvSnf7 entails increased root injury and emergence of adult beetles. Efficacy of DvSnf7 was substantially lower for reducing root injury than emergence. Because root injury decreases yield, the increased root injury has immediate practical consequences. More sustainable control may be achieved by deploying pyramids with traits that are each highly effective against rootworms, increasing the abundance of host plants that do not target rootworms, and combining transgenic corn with crop rotation and other control tactics in integrated pest management programs.}, archive = {J_PNAS}, author = {Tabashnik, Bruce E. and Carrière, Yves}, doi = {10.1073/pnas.2518683122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2518683122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rootworm resistance to bt associated with increased injury to corn pyramids combining bt proteins and RNA interference}, volume = {122}, year = {2025}, }
• (2025). Reply to quillien: Intuitive preferences and interpretive humility in intentionality judgments. PNAS, 122(38), e2518353122. (www)

  @article{ , archive = {J_PNAS}, author = {Gervais, Will M. and McKay, Ryan T. and Brown-Iannuzzi, Jazmin L. and Ross, Robert M. and Pennycook, Gordon and Jong, Jonathan and Lanman, Jonathan A.}, doi = {10.1073/pnas.2518353122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2518353122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to quillien: Intuitive preferences and interpretive humility in intentionality judgments}, volume = {122}, year = {2025}, }
• (2025). Improving the efficacy of anti-SSEA4 antibody in pancreatic cancer immunotherapy with glyco-optimization and immune checkpoint blockade. PNAS, 122(38), e2517415122. (www)

  @article{ , abstract = {Pancreatic cancer remains one of the most lethal malignancies with limited therapeutic options. Among the alternative targets explored for pancreatic cancer, the glycolipid stage-specific embryonic antigen-4 (SSEA4) has been extensively studied. We have previously demonstrated that the chimeric anti-SSEA4 antibody with alpha-2,6-sialylated complex type biantennary glycan (SCT) or its 3-fluorosialyl derivative (FSCT) attached to the Fc-Asn297 residue exhibited enhanced binding to the Fc-receptors FcγRIIIA and FcγRIIA which are responsible for antibody-dependent cellular cytotoxicity and phagocytosis as well as vaccinal effect. Here, we found that high-SSEA4 expression correlates with increasing tumor proliferation and sensitivity to the glyco-optimized antibodies (anti-SSEA4-SCT and anti-SSEA4-FSCT) which preferentially recruit NKG2D-expressing natural killer cells and FcγRIIA-bearing macrophages with enhanced target killing activity. We also uncovered an immune evasion mechanism involving the interaction of sialoglycans on the cancer cell with Siglec-9 on NK cells or Siglec-10 on macrophages to block the antibody-mediated effector functions, and this immune checkpoint inhibition can be suppressed with the removal of sialic acid on cancer cells or blockade of Siglec recognition. In xenograft models, the glyco-optimized antibodies exhibited superior inhibition of tumor growth with high-SSEA4 expression compared to the wild-type antibody and persistent antitumor activity without additional antibody administration. These findings support anti-SSEA4 antibodies with enhanced effector functions and blockade of Siglec-mediated immune checkpoint as a promising therapeutic strategy for pancreatic cancer.}, archive = {J_PNAS}, author = {Chuang, Po-Kai and Chung, Cinya and Liao, Kuo-Shiang and Wong, Chi-Huey}, doi = {10.1073/pnas.2517415122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2517415122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Improving the efficacy of anti-SSEA4 antibody in pancreatic cancer immunotherapy with glyco-optimization and immune checkpoint blockade}, volume = {122}, year = {2025}, }
• (2025). Kupffer cells are essential for platelet-mediated thrombopoietin generation in the liver. PNAS, 122(38), e2517319122. (www)

  @article{ , abstract = {Thrombopoietin (TPO), predominantly produced by the liver, is the key regulator for platelet production and the hematopoietic stem cell niche. Our earlier report demonstrated that platelet GPIbα is required for hepatocellular TPO generation, which is the major resource of TPO in the blood circulation. However, how hepatocytes physically contact circulating sinusoidal platelets across the liver endothelium for this process is unknown. Kupffer cells reside in contact with both sinusoidal blood and underlying hepatocytes, and mediate senescent platelet clearance, but their role in TPO regulation has never been explored. Here, we found Kupffer cell depletion via either clodronate liposomes or specific transgenic models abrogated circulating TPO. Kupffer cell depletion also prevented TPO level increase in GPIbα-deficient mice following wild-type (GPIbα + ) platelet transfusion, signifying an interdependent mechanism for TPO regulation. Mice treated with arsenite had significantly decreased liver endothelial fenestrations and hepatocyte sinusoidal protrusions as well as TPO levels. This effect was exacerbated by Kupffer cell depletion, and Kupffer cells were identified to enhance liver endothelial fenestrations. Electron microscopy and immunofluorescence analysis of the liver revealed platelets arrested on Kupffer cell surface were in contact with hepatocyte protrusions. Thus, we elucidated that Kupffer cells promote endothelial fenestrae and hepatocyte protrusions, accumulate circulating platelets, and facilitate cellular interactions between hepatocytes and platelets, which drive TPO generation. This connection between platelet clearance and thrombopoiesis should have broad implications for hematology and pathologies such as Bernard–Soulier syndrome, thrombocytopenias, as well as liver diseases.}, archive = {J_PNAS}, author = {Karakas, Danielle and Li, June and Ma, Wenjing and Wu, Xun Grace and Khoury, Christopher J. and Masoud, Mina and Hoard, Brock and Liu, Yuning Jay and Zhu, Guangheng and Chen, Junmei and Sim, Martha and Shen, Chuanbin and López, José A. and MacParland, Sonya A. and Kahr, Walter H. A. and Ni, Heyu}, doi = {10.1073/pnas.2517319122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2517319122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Kupffer cells are essential for platelet-mediated thrombopoietin generation in the liver}, volume = {122}, year = {2025}, }
• (2025). Structurally diverse viral inhibitors converge on a shared mechanism to stall the antigen transporter TAP. PNAS, 122(38), e2516676122. (www)

  @article{ , abstract = {In the host–pathogen arms race, herpesviruses and poxviruses encode proteins that sabotage the transporter associated with antigen processing (TAP), thereby suppressing MHC-I antigen presentation and enabling lifelong infection. Of the five known viral TAP inhibitors, only the herpes simplex virus (HSV) protein ICP47 has been structurally resolved. We now report cryoelectron microscopy structures of TAP in complex with the remaining four: BNLF2a (Epstein–Barr virus), hUS6 (human cytomegalovirus), bUL49.5 (bovine herpesvirus 1), and CPXV012 (cowpox virus), assembling a structural atlas of viral TAP evasion. Despite employing divergent sequences, folds, and conformational targets, these viral inhibitors converge on a common strategy: they stall TAP from the alternating access cycle, precluding peptide entry into the ER and shielding infected cells from cytotoxic T cell surveillance. These findings reveal striking functional convergence and provide a structural framework for rational antiviral design.}, archive = {J_PNAS}, author = {Lee, James and Manon, Victor and Chen, Jue}, doi = {10.1073/pnas.2516676122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2516676122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structurally diverse viral inhibitors converge on a shared mechanism to stall the antigen transporter TAP}, volume = {122}, year = {2025}, }
• (2025). Intention judgments are not a reliable measure of intuitive preferences. PNAS, 122(38), e2516523122. (www)

  @article{ , archive = {J_PNAS}, author = {Quillien, Tadeg}, doi = {10.1073/pnas.2516523122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2516523122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intention judgments are not a reliable measure of intuitive preferences}, volume = {122}, year = {2025}, }
• (2025). Employing deep mutational scanning in the escherichia coli periplasm to decode the thermodynamic landscape for amyloid formation. PNAS, 122(38), e2516165122. (www)

  @article{ , abstract = {Deep mutational scanning (DMS) assays provide a powerful method to generate large-scale datasets essential for advancing AI-driven predictions in biology. The tripartite β-lactamase assay (TPBLA), in which a protein of interest is inserted between two domains of β-lactamase, has previously been reported as capable of detecting and quantitating the aggregation of proteins and biologics in the oxidizing periplasm of Escherichia coli and used as a platform for identifying small molecule inhibitors of aggregation. Here, we repurpose the TPBLA into a high-throughput DMS platform. We validate this format using a single-site saturation library of the intrinsically disordered peptide Aβ 42 , linked to Alzheimer’s disease, demonstrating strong agreement between observed variant fitness scores and variant behavior using our previously reported low-throughput TPBLA. The results of DMS revealed variant fitness scores that correlate with known amyloid-promoting regions. An in silico approach using FoldX-derived per-residue thermodynamic stability confirmed that the TPBLA reports on amyloid fibril stability. In vitro experiments support this finding, showing a strong correlation between variant fitness scores and the critical concentration of amyloid formation. Machine learning using the DMS dataset identified β‐sheet propensity and polarity as primary drivers of variant fitness scores. The derived model is also able to predict thermodynamically stabilizing regions in other amyloid systems, underscoring its generalizability. Collectively, our results demonstrate the TPBLA as a versatile platform for generating robust datasets to advance predictive modeling and to inform the design of aggregation‐resistant proteins.}, archive = {J_PNAS}, author = {McKay, Conor E. and Deans, Miles and Connor, Jack and Saunders, Janet C. and Lloyd, Christopher and Radford, Sheena E. and Brockwell, David J.}, doi = {10.1073/pnas.2516165122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2516165122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Employing deep mutational scanning in the escherichia coli periplasm to decode the thermodynamic landscape for amyloid formation}, volume = {122}, year = {2025}, }
• (2025). Phonons in electron crystals with berry curvature. PNAS, 122(38), e2515532122. (www)

  @article{ , abstract = {Recent advances in 2D materials featuring nonzero Berry curvature have inspired extensions of the Wigner crystallization paradigm. This paper derives a low-energy effective theory for such quantum crystals, including the anomalous Hall crystal (AHC) with nonzero Chern number. First, we show that the low frequency dispersion of phonons in AHC, despite the presence of Berry curvature, resembles that of the zero field (rather than finite magnetic field) Wigner crystal due to the commutation of translation generators. We explain how key parameters of the phonon theory such as elastic constants and effective mass can be extracted from microscopic models, and apply them to two families of models: the recently introduced λ -jellium model and a model of rhombohedral multilayer graphene (RMG). In the λ -jellium model, we explore the energy landscape as crystal geometry shifts, revealing that AHC can become “soft” under certain conditions. This causes transitions in lattice geometry, although the quantized Hall response remains unchanged. Surprisingly, the Berry curvature seems to enhance the effective mass, leading to a reduction in phonon speed. For the AHC in RMG, we obtain estimates of phonon speed and shear stiffness. We also identify a previously overlooked “kineo-elastic” term in the phonon effective action that is present in the symmetry setting of RMG, and leads to dramatic differences in phonon speeds in opposite directions. We numerically confirm these predictions of the effective actions by time-dependent Hartree–Fock calculations.}, archive = {J_PNAS}, author = {Dong, Junkai and Sommer, Ophelia Evelyn and Soejima, Tomohiro and Parker, Daniel E. and Vishwanath, Ashvin}, doi = {10.1073/pnas.2515532122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2515532122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phonons in electron crystals with berry curvature}, volume = {122}, year = {2025}, }
• (2025). Earliest evidence of smoke-dried mummification: More than 10,000 years ago in southern china and southeast asia. PNAS, 122(38), e2515103122. (www)

  @article{ , abstract = {In southern China and Southeast Asia (collectively, Southeastern Asia), Terminal Pleistocene and Early to Middle Holocene (ca. 12,000 to 4,000 cal. BP) hunter-gatherer burials feature tightly crouched or squatting postures, sometimes with indications of post-mortem dismemberment. Such burials contrast strongly with the extended supine burial postures typical of subsequent Neolithic inhumations in these regions. Their contorted postures, often with traces of burning, present interpretive challenges. This study uses multiple techniques, including X-ray diffraction and Fourier-transform infrared spectroscopy, to investigate 54 pre-Neolithic burials from 11 archaeological sites located across Southeastern Asia. The findings confirm that many of these pre-Neolithic flexed and squatting burials were treated by an extended period of smoke-drying over fire, a process of mummification similar to that recorded ethnographically in some Australian and Highland New Guinea societies. Some of the analyzed archaeological samples represent the oldest known instances of such artificial mummification in the world.}, archive = {J_PNAS}, author = {Hung, Hsiao-chun and Deng, Zhenhua and Liu, Yiheng and Ran, Zhiyu and Zhang, Yue and Li, Zhen and Kaifu, Yousuke and Huang, Qiang and Nguyen, Khanh Trung Kien and Le, Hai Dang and Xie, Guangmao and Nguyen, Anh Tuan and Yamagata, Mariko and Simanjuntak, Truman and Noerwidi, Sofwan and Fauzi, Mohammad Ruly and Tolla, Marlin and Wetipo, Alpius and He, Gang and Sawada, Junmei and Zhang, Chi and Bellwood, Peter and Matsumura, Hirofumi}, doi = {10.1073/pnas.2515103122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2515103122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Earliest evidence of smoke-dried mummification: More than 10,000 years ago in southern china and southeast asia}, volume = {122}, year = {2025}, }
• (2025). Engineering a serum response factor superactivator of smooth muscle gene expression with a condensate-forming domain. PNAS, 122(38), e2514363122. (www)

  @article{ , abstract = {Differentiation of smooth muscle cells (SMCs) is driven by the activation of a set of genes controlled by serum response factor (SRF), a ubiquitous transcription factor with limited intrinsic transcriptional activity. Myocardin (MYOCD) is a strong transcriptional coactivator that orchestrates smooth muscle differentiation through its association with SRF. MYOCD forms nuclear condensates via its intrinsically disordered transcription activation domain (TAD), whereas SRF is diffusely distributed in the nucleus. MYOCD recruits SRF into these condensates, thereby activating the smooth muscle gene program. We engineered a “superactivator” of smooth muscle genes by replacing SRF’s weak TAD with that of MYOCD, thereby enabling SRF to form nuclear condensates and reprogram fibroblasts into SMCs. Using protein proximity labeling, quantitative proteomics and superresolution confocal microscopy, we show that condensates formed by the MYOCD TAD aggregate chromatin remodelers, RNA polymerases, and mRNA processing factors to drive smooth muscle gene expression. These findings provide insights into the mechanisms whereby nuclear condensates facilitate tissue-specific gene expression and highlight a strategy for engineering cell fate determinants by coupling condensate-forming domains to heterologous DNA-binding proteins.}, archive = {J_PNAS}, author = {Gan, Peiheng and Zhou, Xinyi and Shah, Akansha M. and Bezprozvannaya, Svetlana and Chen, Kenian and Ding, Qianqian and Li, Hui and Xu, Lin and Liu, Ning and Olson, Eric N.}, doi = {10.1073/pnas.2514363122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2514363122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Engineering a serum response factor superactivator of smooth muscle gene expression with a condensate-forming domain}, volume = {122}, year = {2025}, }
• (2025). Weighted active space protocol for multireference machine-learned potentials. PNAS, 122(38), e2513693122. (www)

  @article{ , abstract = {Multireference methods such as multiconfiguration pair-density functional theory accurately capture electronic correlation in systems with strong multiconfigurational character, but their cost precludes direct use in molecular dynamics. Combining these methods with machine-learned interatomic potentials (MLPs) can extend their reach. However, the sensitivity of multireference calculations to the choice of the active space complicates the consistent evaluation of energies and gradients across structurally diverse nuclear configurations. To overcome this limitation, we introduce the weighted active space protocol (WASP), a systematic approach to assign a consistent active space for a given system across uncorrelated configurations. By integrating WASP with MLPs and enhanced sampling techniques, we propose a data-efficient active learning cycle that enables the training of an MLP on multireference data. We demonstrated the approach on the TiC + -catalyzed C–H activation of methane, a reaction that poses challenges for Kohn–Sham density functional theory due to its significant multireference character. This framework enables accurate and efficient modeling of catalytic dynamics, establishing a paradigm for simulating complex reactive processes beyond the limits of conventional electronic-structure methods.}, archive = {J_PNAS}, author = {Seal, Aniruddha and Perego, Simone and Hennefarth, Matthew R. and Raucci, Umberto and Bonati, Luigi and Ferguson, Andrew L. and Parrinello, Michele and Gagliardi, Laura}, doi = {10.1073/pnas.2513693122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2513693122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Weighted active space protocol for multireference machine-learned potentials}, volume = {122}, year = {2025}, }
• (2025). Sizing the largest ocean waves using the SWOT mission. PNAS, 122(38), e2513381122. (www)

  @article{ , abstract = {Winds generate waves over the oceans with a wide range of properties. The largest wave heights and periods are important parameters in the design of marine structures. Extreme waves also play an outsize role in air–sea fluxes and coastal dynamics, and leave imprints on seismic and sediment records. Rare events have so far escaped measurements, with few wave heights from satellite altimeters exceeding 16 m, and no associated measurement of wave periods. Here, we use swells radiated from storms to reveal long wave periods within the storms, and their generation mechanism. Swells are resolved in the Surface Water and Ocean Topography (SWOT) satellite sea level measurements. Patterns of increasing swell wavelength and decreasing swell height away from storms are consistent with a nonlinear transfer of energy from short to long period waves. We propose an updated parametric shape for wave spectra in storms that aligns with SWOT swell measurements. It reduces energy levels by a factor of 20 at 1.2 to 1.4 times the peak period compared to commonly used spectral shapes and allows estimation of storm wave periods from swell heights. Consistent with less extreme conditions, the peak period generally increases with wave height. This was particularly verified for the largest storm peak period of 20.2 ± 0.6 s, obtained for the event with the largest significant wave height 19.7 ± 0.3 m measured by altimeters. These observations of long period swells should have a wide range of applications from coastal dynamics to seismology.}, archive = {J_PNAS}, author = {Ardhuin, Fabrice and Postec, Taina and Accensi, Mickael and Piolle, Jean-François and Dodet, Guillaume and Passaro, Marcello and De Carlo, Marine and Husson, Romain and Guitton, Gilles and Collard, Fabrice}, doi = {10.1073/pnas.2513381122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2513381122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sizing the largest ocean waves using the SWOT mission}, volume = {122}, year = {2025}, }
• (2025). Spatiotemporal mapping of alloy mesostructure dynamics via multimodal coherent X-ray diffraction imaging. PNAS, 122(38), e2513369122. (www)

  @article{ , abstract = {Understanding mesoscale structural dynamics of precipitation-strengthened alloys is essential for optimizing the mechanical performances of these alloys. Herein, we establish a multimodal coherent X-ray diffraction imaging framework for spatiotemporal mapping of mesoscale structural dynamics in precipitation-strengthened alloys. As a demonstrative application, we visualized the structural evolution in Mg 97 Zn 1 Gd 2 during isothermal annealing at 700 K, revealing real-time dynamics of nucleation, growth, and coarsening. Ptychographic reconstruction enabled imaging of microstructural transformations across a wide field of view (~100 μm 2 ) with temporal resolution spanning several hours. We observed decomposition of (Mg, Zn) 3 Gd and concurrent precipitation and coarsening of long-period stacking ordered phases. To resolve local dynamics at finer spatiotemporal scales, we combined dynamic coherent diffraction imaging with X-ray photon correlation spectroscopy, targeting selected regions (~10 μm 2 ) with time resolution down to tens of seconds. This approach revealed the rapid formation of nanoscale precipitates within 10 s after heating, followed by coarsening over several hundred seconds. Additionally, we applied optical flow analysis—a computational method to track motion patterns—to visualize and quantify the nucleation, growth, and coarsening kinetics. The abovementioned findings demonstrate the capability of in situ coherent X-ray techniques to acquire the real-time evolutions of mesoscale structures in complex materials. Our methodology offers a robust framework for investigating dynamic phenomena in diverse material systems, including metals, polymers, and functional nanomaterials, under realistic thermal or mechanical conditions.}, archive = {J_PNAS}, author = {Takazawa, Shuntaro and Ninomiya, Kakeru and Ha, Minh-Quyet and Vu, Tien-Sinh and Sasaki, Yuhei and Abe, Masaki and Uematsu, Hideshi and Okawa, Naru and Ishiguro, Nozomu and Ozaki, Kyosuke and Hatsui, Takaki and Hoshino, Taiki and Nishibori, Maiko and Dam, Hieu-Chi and Takahashi, Yukio}, doi = {10.1073/pnas.2513369122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2513369122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatiotemporal mapping of alloy mesostructure dynamics via multimodal coherent X-ray diffraction imaging}, volume = {122}, year = {2025}, }
• (2025). ComFB, a widespread family of c-di-NMP receptor proteins. PNAS, 122(38), e2513041122. (www)

  @article{ , abstract = {Cyclic dimeric-GMP (c-di-GMP) is a ubiquitous bacterial second messenger that regulates a variety of cellular processes, including motility, biofilm formation, secretion, cell cycle progression, and development, and also contributes to the virulence of many bacterial pathogens. While the genes encoding c-di-GMP cyclases and hydrolases are readily identifiable in microbial genomes, known c-di-GMP receptor domains are quite few, with only PilZ and MshEN broadly distributed across bacterial phyla. Recently, a new c-di-GMP receptor, named CdgR or ComFB, has been identified in cyanobacteria and shown to regulate cell size and natural competence. We demonstrated that CdgR proteins exhibit sequence and structural similarity to the Bacillus subtilis late competence development protein ComFB, a conserved protein of unknown function associated with bacterial competence. This prompted us to hypothesize that ComFB and ComFB-like proteins could also serve as c-di-GMP receptors. Here, we comprehensively investigated the ComFB protein family and demonstrated that ComFB proteins are evolutionarily widespread among bacteria and function as a novel family of c-di-GMP receptors. We showed that ComFB proteins from Gram-positive bacteria ( B. subtilis , Thermoanaerobacter brockii ) and Gram-negative pathogens ( Vibrio cholerae , Treponema denticola ) bind c-di-GMP with high affinity. Several ComFB proteins also bind cyclic di-adenosine monophosphate (c-di-AMP), suggesting that ComFB represents a widely distributed bacterial protein family with dual specificity for c-di-GMP and c-di-AMP. Our physiological studies further showed that ComFB plays vital roles in controlling motility in a c-di-GMP-dependent manner in two phylogenetically distant bacteria, B. subtilis and the gram-negative Shewanella oneidensis , attesting to the biological relevance of ComFB as a c-di-GMP binding protein.}, archive = {J_PNAS}, author = {Samir, Sherihan and Elshereef, Abdalla A. and Alva, Vikram and Hahn, Jeanette and Eck, Frederik and Celma, Louisa and Lopes, Eduardo S. and Thormann, Kai and Dubnau, David and Galperin, Michael Y. and Selim, Khaled A.}, doi = {10.1073/pnas.2513041122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2513041122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ComFB, a widespread family of c-di-NMP receptor proteins}, volume = {122}, year = {2025}, }
• (2025). Stress-induced preference for antioxidants by drosophila. PNAS, 122(38), e2512852122. (www)

  @article{ , abstract = {In an ever-changing environment, animals make optimal decisions to ensure their well-being. Faced with limited food sources, they often seek foods that provide the nutrients they require to maintain homeostasis. Under extreme circumstances (e.g., infection), they may exhibit ingestive behaviors, such as seeking out substances (e.g., toxins) that suggest self-medication. Few studies, however, have investigated the mechanisms that ensue self-medication. Here, we report the selective intake of antioxidants by Drosophila melanogaster during a period of heat stress or sleep deprivation. This preference was alleviated by prefeeding them vitamin C or dehydroascorbic acid (DHA) before exposure to stress. Heat stress led to an increase in reactive oxygen species (ROS) levels in the gut, which was alleviated by the intake of vitamin C. Heat stress reduced vitamin C in hemolymph, whereas the consumption of vitamin C or DHA increased it. Furthermore, the intake of vitamin C ameliorated the intestinal barrier dysfunction and extended the survival of flies that had been exposed to chronic heat stress. The heat-induced preference for vitamin C appears to develop independently of the known peripheral chemosensory receptors for this micronutrient. We propose that fruit flies possess an interoceptive mechanism that mediates the detection of vitamin C to overcome environmental challenges.}, archive = {J_PNAS}, author = {Hwang, Gayoung and Yang, Dae-Wook and Klaudia Geisseova, Terezia and Kim, Hae A. and Oh, Yangkyun and Suh, Greg S. B.}, doi = {10.1073/pnas.2512852122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2512852122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stress-induced preference for antioxidants by drosophila}, volume = {122}, year = {2025}, }
• (2025). Cryo-EM structure of the prohibitin complex in open conformation. PNAS, 122(38), e2512430122. (www)

  @article{ , abstract = {Prohibitin 1 (PHB1) and Prohibitin 2 (PHB2), two conserved prohibitin members, are primarily localized to the mitochondrial inner membrane (MIM) to form a nanoscale macromolecular prohibitin complex. This prohibitin complex can facilitate the spatial organization of proteins and lipids, thus maintaining cellular metabolism and homeostasis, but its architecture remains largely unknown. Here, we report the cryo-EM structure of a prohibitin complex at 2.8 Å resolution, which contains 11 PHB1–PHB2 heterodimers. This complex displays a bell-like cage, consisting of a lid and a wall, which creates an intermembrane space-facing compartment for the MIM. The lid of the cage is stably assembled, and it is responsible for the prohibitin complex formation. In contrast, the wall of the cage is flexible and exhibits lateral openings, providing a channel for intramembrane exchange of proteins and lipids. These findings provide a structural basis for understanding the scaffold role of the prohibitin complex in organizing intramembrane proteins and lipids.}, archive = {J_PNAS}, author = {Hong, Sixing and Guan, Zeyuan and Zhang, Liying and Zhuang, Jinjin and Yan, Ling and Liu, Yanjun and Liu, Zhu and Wang, Qiang and Yin, Ping}, doi = {10.1073/pnas.2512430122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2512430122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryo-EM structure of the prohibitin complex in open conformation}, volume = {122}, year = {2025}, }
• (2025). Φ value analysis underscores strong functional and structural compactness of the GABAA receptor. PNAS, 122(38), e2512278122. (www)

  @article{ , abstract = {γ-aminobutyric acid type A receptor (GABA A R) is a pentameric ligand-gated ion channel that plays a crucial role in inhibition in the adult brain. Structural and electrophysiological studies have provided numerous insights into the receptor’s functioning but the complete molecular mechanism of GABA A R action remains elusive. Herein, we used high-resolution single-channel recording to analyze point-mutated α 1 β 2 γ 2 receptors and applied so called Φ value (REFER, rate-equilibrium free energy relationship) analysis which allows to infer the order of domains engagement during activation, offering a complementary “dynamic” insight into the receptor’s function. As anticipated, point mutations at the orthosteric binding sites reduced GABA binding affinity, with the magnitude of this effect diminishing progressively with increasing distance from the binding site. On the contrary, mutations located all over the macromolecule’s structure, e.g., in “peripheral top position,” extracellular/transmembrane interface, and channel pore, affected the receptor with a clear tendency to influence entire gating including opening/closing, preactivation, and desensitization with no clear correlation with the distance to the channel gate. Interestingly, the calculated Φ values for the GABA A R showed a relatively narrow range (0.42 to 0.81), suggesting that the conformational transitions are highly synchronized and coordinated by a global network of interactions. This prediction is also in agreement with observation that, typically, single GABA A R residue mutation alters the kinetics of not just one but many (often all) conformational transitions. We thus propose a dictum reflecting modus operandi of the GABA A R: Binding is local and gating is global. In conclusion, our analysis indicates that GABA A R shows particularly strong functional compactness manifested as global gating mechanisms and high allostery.}, archive = {J_PNAS}, author = {Michałowski, Michał A. and Terejko, Katarzyna and Gos, Michalina and Iżykowska, Ilona and Czyżewska, Marta M. and Kłopotowski, Karol and Kaczor, Przemysław T. and Brzóstowicz, Aleksandra and Płużek, Estera and Migdałek, Monika and Mozrzymas, Jerzy W.}, doi = {10.1073/pnas.2512278122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2512278122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Φ value analysis underscores strong functional and structural compactness of the GABAA receptor}, volume = {122}, year = {2025}, }
• (2025). The cost of banning TikTok: Implications for the digital advertising market. PNAS, 122(38), e2512043122. (www)

  @article{ , abstract = {Social media platforms have become vital channels for businesses to reach consumers through advertising. But in the United States, the digital advertising market in which these platforms operate is dominated by a few major players, raising concerns for antitrust regulators. In such a concentrated market, the entry or exit of a single platform can reallocate billions in ad spending, affecting businesses and users. TikTok’s temporary suspension in the United States in January 2025 provides a unique natural experiment to examine how the removal of a major player would shift advertising demand and supply on competitors, specifically Facebook and Instagram, revealing the degree of substitutability across platforms and the intensity of competition. Using a difference-in-differences approach comparing advertising activity in the United States to other countries, we find that Meta ad volume and spend rose by 6.3% and 22.4%, as a result of the outage, without a corresponding increase in ad impressions. Consequently, Meta ad prices, as measured by cost per thousand impressions, jumped by 12.1%. Shifts in demand were three times greater for larger advertisers relative to smaller ones, suggesting that Meta platforms and TikTok are closer substitutes for larger firms and that a TikTok ban would therefore impose greater challenges on smaller businesses.}, archive = {J_PNAS}, author = {Donati, Dante and Fong, Hortense}, doi = {10.1073/pnas.2512043122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2512043122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The cost of banning TikTok: Implications for the digital advertising market}, volume = {122}, year = {2025}, }
• (2025). Designing for cooperative grain boundary segregation in multicomponent alloys. PNAS, 122(38), e2511930122. (www)

  @article{ , abstract = {Tailoring the nanoscale distribution of chemical species at grain boundaries is a powerful method to dramatically influence the properties of polycrystalline materials. However, classical approaches to the problem have tacitly assumed that only competition is possible between solute species. In this paper, we show that solute elements can cooperate in the way they segregate to grain boundaries: In properly targeted alloys, the different chemical species cooperate to each fill complementary grain boundary sites disfavored by the other. By developing a theoretical “spectral” approach to this problem based on quantum-accurate grain boundary site distributions, we show how grain boundaries can be cooperatively alloyed, whether by depletion or enrichment. We provide machine-learned cosegregation information for over 700 ternary aluminum-based alloys and experimentally validate the concept in one ternary alloy where cosegregation is not expected by prior models but is expected based on the cooperative model.}, archive = {J_PNAS}, author = {Wagih, Malik and Naunheim, Yannick and Lei, Tianjiao and Schuh, Christopher A.}, doi = {10.1073/pnas.2511930122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2511930122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Designing for cooperative grain boundary segregation in multicomponent alloys}, volume = {122}, year = {2025}, }
• (2025). PI31 expression is neuroprotective in a mouse model of early-onset parkinsonism. PNAS, 122(38), e2511899122. (www)

  @article{ , abstract = {Neurodegenerative diseases present one of the most significant global health challenges. These disorders are defined by the accumulation of abnormal protein aggregates that impair synaptic function and cause progressive neuronal degeneration. Therefore, stimulating protein clearance mechanisms may be neuro-protective. Variants in FBXO7/PARK15 cause Parkinsonian Pyramidal Syndrome, an early-onset parkinsonian neurodegenerative disorder in humans, and inactivation of this gene in mice recapitulates many phenotypes seen in patients. The proteasome regulator PI31 is a direct binding partner of Fbxo7 and promotes local protein degradation at synapses by mediating fast proteasome transport in neurites. PI31 protein levels are reduced when the function of Fbxo7 is impaired. Here we show that restoring PI31 levels in Fbxo7 mutant fly and mouse strains prevents neuronal degeneration and significantly improves neuronal function, health, and lifespan. Notably, Fbxo7 inactivation in mouse neurons causes hyperphosphorylation of tau, and this was suppressed by transgenic expression of PI31. Our results demonstrate that PI31 is a crucial biological target through which Fbxo7 deficiency drives pathology. Therefore, targeting the PI31-pathway may represent a promising therapeutic approach for treating neurodegenerative disorders.}, archive = {J_PNAS}, author = {Rodriguez, Jose A. and Minis, Adi and Aref, Rasha and Nguyen, Hieu Hoang Minh and Sun, Fiona and Steller, Hermann}, doi = {10.1073/pnas.2511899122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2511899122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PI31 expression is neuroprotective in a mouse model of early-onset parkinsonism}, volume = {122}, year = {2025}, }
• (2025). Drosophila ahcy is a redox sensor that modulates gene expression to protect against light stress–induced retinal degeneration. PNAS, 122(38), e2511388122. (www)

  @article{ , abstract = {One-carbon metabolism influences gene expression by providing methyl units for DNA, RNA, and histone methylation. Robust methylation requires rapid hydrolysis of the methylation by-product S -adenosylhomocysteine (SAH) by S -adenosylhomocysteinase (Ahcy). Ahcy is essential for maintaining methylation potential; however, the mechanisms governing its enzymatic activity, particularly in response to cellular stress, remain largely uncharacterized. Here, we show Ahcy is a redox-sensitive enzyme that is inhibited by oxidation of a conserved cysteine, C195, in vitro resulting in elevated SAH levels upon oxidative stress in vivo. We leveraged High-Throughput Desorption Electrospray Ionization Mass Spectrometry to directly quantify Ahcy enzymatic activity and observed that H 2 O 2 -induced oxidation significantly reduced its catalytic efficiency. Notably, while C195 is essential for enzymatic activity in Drosophila melanogaster and humans, this residue is not conserved in Caenorhabditis elegans Ahcy that is also insensitive to H 2 O 2 . Structural analysis revealed that C195 is positioned near NAD + in the active site, close to a second cysteine residue that is also lacking in C. elegans Ahcy. Ahcy oxidation is neuroprotective in a Drosophila light stress model that increases oxidative stress. Moreover, Ahcy knockdown suppresses light stress–induced gene expression changes in photoreceptors, although this response is uncoupled from changes in H3K4me3 and H3K27me3 levels, which were previously reported to alter in response to Ahcy knockdown in cultured cells. Thus, the one-carbon metabolism enzyme Ahcy senses changes in cellular redox homeostasis through a conserved cysteine residue that alters its activity, enabling rapid changes in gene expression that enable a neuroprotective response.}, archive = {J_PNAS}, author = {Stanhope, Sarah C. and Singhal, Kratika and Morato, Nicolás M. and Feng, Yunfei and Meng, Gaoya and Marlin, Makayla N. and Kotanko, Claudia C. and Jarrett, Madolyn M. and Mesecar, Andrew D. and Cooks, R. Graham and Weake, Vikki M.}, doi = {10.1073/pnas.2511388122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2511388122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Drosophila ahcy is a redox sensor that modulates gene expression to protect against light stress–induced retinal degeneration}, volume = {122}, year = {2025}, }
• (2025). A solid-state battery capable of 180 c superfast charging and 100% energy retention at –30 °C. PNAS, 122(38), e2511121122. (www)

  @article{ , abstract = {Solid-state electrolytes (SSEs) are being extensively researched as replacements for liquid electrolytes in future batteries. Despite significant advancements, there are still challenges in using SSEs, particularly in extreme conditions. This study presents a hydrated metal-organic ionic cocrystal (HMIC) solid-state ion conductor with a solvent-assisted ion transport mechanism suitable for extreme operating conditions. Through crystal engineering strategies, the adsorption capacity of HMIC for anions and water molecules can be regulated, thereby facilitating cation hopping transport and enhancing electrochemical stability. As a result, optimized HMIC shows exceptional properties, including an extraordinarily high Zn 2+ transference number (t Zn2+ = 0.81), an expanded electrochemical stability window (~2.6 V), and an exceptionally high Zn 2+ ion conductivity (8.6 mS cm –1 , 25 °C). Interface dynamics analysis indicates that this strong binding to water molecules can significantly reduce the desolvation energy barrier and enhance the ionic diffusion coefficient. (10 to 100 times higher than that in aqueous electrolytes). This allows Zn|| Prussian blue analog batteries to exhibit impressive fast-charging performance (180 C, 20 s, over 1,000 charge/discharge cycles) and maintain 100% discharge capacity retention and discharge plateau from –30 to 30 °C. The development of HMICs with a solvent-assisted hopping mechanism provides a promising path for solid-state zinc-ion batteries in extreme conditions, including fast charging, low temperature, and high loading.}, archive = {J_PNAS}, author = {Hong, Hu and Wei, Zhiquan and Wang, Yiqiao and Yang, Xinru and Guo, Xun and Nian, Qingshun and Li, Xinliang and Li, Qing and Wang, Shixun and Li, Shimei and Zhang, Dechao and Xiong, Qi and Huang, Zhaodong and Zhi, Chunyi}, doi = {10.1073/pnas.2511121122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2511121122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A solid-state battery capable of 180 c superfast charging and 100% energy retention at –30 °C}, volume = {122}, year = {2025}, }
• (2025). Endothelial αvβ3 integrin induction during hypoxia protects blood–brain barrier integrity. PNAS, 122(38), e2510931122. (www)

  @article{ , abstract = {The blood–brain barrier (BBB) is critical for maintaining cerebral homeostasis, and its deterioration with age is an important pathogenic factor in the etiology of vascular dementia. Extracellular matrix–integrin interactions play a central role in regulating vascular stability. The αvβ3 integrin is not expressed by brain endothelial cells under stable conditions but is strongly induced by hypoxia. However, it is currently unclear whether αvβ3 integrin exerts a destructive or protective influence on BBB integrity. In young (8 to 10 wk) and aged (20 mo) mice, we examined the impact of a function-blocking β3 integrin antibody as well as the inhibitory peptide cilengitide on BBB disruption during exposure to CMH (8% O 2 ). Hypoxic induction of brain endothelial β3 integrin was much stronger in aged mice. In both young and aged mice, β3 integrin inhibition greatly amplified hypoxia-induced BBB disruption, correlating with loss of tight junction proteins and induction of the leaky BBB marker mouse endothelial cell antigen (MECA)-32. Consistent with this, β3 integrin null mice showed increased levels of hypoxia-induced BBB disruption and MECA-32 expression. Cilengitide also reduced the integrity of a brain endothelial monolayer in vitro, prevented β3 integrin localization to focal adhesions, and reduced expression of vascular endothelial (VE)-cadherin and tight junction proteins. These observations suggest that hypoxic induction of endothelial αvβ3 integrin enhances BBB integrity by stabilizing endothelial adhesion. This raises the interesting possibility that pharmacological upregulation of endothelial αvβ3 integrin in the aged brain might hold therapeutic promise for vascular dementia.}, archive = {J_PNAS}, author = {Halder, Sebok K. and Delorme-Walker, Violaine D. and Milner, Richard}, doi = {10.1073/pnas.2510931122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2510931122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Endothelial αvβ3 integrin induction during hypoxia protects blood–brain barrier integrity}, volume = {122}, year = {2025}, }
• (2025). Fracture of liquid crystal elastomers. PNAS, 122(38), e2510727122. (www)

  @article{ , abstract = {Liquid crystal elastomers (LCEs) are anisotropic, viscoelastic materials integrating polymer networks and liquid crystals. While their mechanical responses have been extensively studied, their fracture behavior remains largely unexplored. Specifically, the effect of the deformation-director coupling on LCE fracture paths is unknown, and fracture criteria for LCEs are not yet established. To address this gap, we combine experimental and theoretical approaches to investigate fracture propagation in LCEs. We stretch edge-cracked monodomain LCE samples, recording their stress-stretch responses and crack paths under varying initial directors and stretching rates. Our findings reveal that cracks can change direction during propagation, which are highly dependent on both the initial director and the stretching rate. To further understand LCE fracture behavior, we develop a rate-dependent phase-field fracture model, which is validated through experiments, and demonstrates the ability to predict complex fracture paths. Our study paves the way for designing LCEs with enhanced fracture properties, imperative for their future applications.}, archive = {J_PNAS}, author = {Zhou, Yu and Wei, Chen and Jin, Lihua}, doi = {10.1073/pnas.2510727122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2510727122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fracture of liquid crystal elastomers}, volume = {122}, year = {2025}, }
• (2025). Optimal transitions between nonequilibrium steady states. PNAS, 122(38), e2510654122. (www)

  @article{ , abstract = {The optimal control of finite-time processes on the microscale is of significant theoretical and practical interest, particularly for the energy-efficient operation of nanomachines. While previous studies have primarily focused on transitions between equilibrium states, many biologically and technologically relevant processes occur far from equilibrium. In such nonequilibrium settings, memory, a ubiquitous feature in realistic systems, plays an intricate role, as any driving necessarily excites internal memory modes. This motivates a deeper exploration of optimal control strategies in nonequilibrium regimes. Here, we combine experiments, theory, and computational methods to investigate the transition of a colloidal particle confined in an optical trap between two nonequilibrium steady states (NESS). We identify optimal control protocols that minimize the thermodynamic work during the finite-time transition between two NESS. We compare optimal protocols in viscous and viscoelastic fluid environments, which are common in realistic technical and biological processes and introduce memory due to a delayed response. Regardless of the presence of memory effects, optimal protocols consistently balance energy extraction with dissipation minimization. In the presence of memory, optimal control is achieved if the protocol matches the time response of the environment. These findings offer key insights for designing optimal control strategies for finite-time, nonequilibrium processes in complex environments.}, archive = {J_PNAS}, author = {Monter, Samuel and Loos, Sarah A. M. and Bechinger, Clemens}, doi = {10.1073/pnas.2510654122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2510654122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Optimal transitions between nonequilibrium steady states}, volume = {122}, year = {2025}, }
• (2025). USP14-mediated metabolic competition impairs CD8+ t cell immunosurveillance in hepatocellular carcinoma. PNAS, 122(38), e2510576122. (www)

  @article{ , abstract = {Hepatocellular carcinoma (HCC) frequently develops resistance to CD8+ T cell–based immunotherapy, yet the mechanisms driving this immune evasion remain poorly understood. To identify tumor-intrinsic regulators of immunotherapy resistance and explore therapeutic strategies to restore T cell–mediated tumor control, we employed three functional genomics approaches using in vitro and in vivo CRISPR screening. Cancer USP14 was identified as the critical immune evasion driver. USP14-high HCC patients exhibited poorer anti-PD1 antibody therapy responses and reduced CD8+ T cell infiltration. Inhibition of USP14 suppressed HCC cell growth in coculture with activated CD8+ T cells and restored cocultured CD8+ T cell cytotoxicity. In vivo USP14 targeting synergized with anti-PD1 antibody therapy. Mechanistically, USP14 deubiquitinated and stabilized GLUT1 through the removal of Lys-48-linked ubiquitin chains at Lys-245, which enabled HCC cells to outcompete CD8+ T cells for glucose, generating a glucose-deprived tumor microenvironment that suppressed CD8+ T cell function. Our findings show USP14 in cancer has a proimmunoevasive role in CD8+ T cell–based tumor immunity through GLUT1-mediated glucose competition. These findings position USP14 inhibitors as promising adjuvants to enhance immunotherapy efficacy in HCC, providing actionable insights for overcoming resistance.}, archive = {J_PNAS}, author = {Yuan, Yichuan and Niu, Yi and Huang, Zhenkun and Shi, Yunxing and Lin, Zhu and Zuo, Dinglan and Zhong, Chengrui and Li, Kai and Guan, Xin-Yuan and Yuan, Yunfei and Li, Binkui}, doi = {10.1073/pnas.2510576122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2510576122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {USP14-mediated metabolic competition impairs CD8+ t cell immunosurveillance in hepatocellular carcinoma}, volume = {122}, year = {2025}, }
• (2025). Protein-mediated stabilization and nicking of the nontemplate DNA strand dramatically affect R-loop formation in vitro. PNAS, 122(38), e2509309122. (www)

  @article{ , abstract = {R-loops are an important class of non-B DNA structures that form co-transcriptionally. Using in vitro transcription and unbiased quantitative sequencing readouts, we show that the addition of single-strand DNA binding proteins co-transcriptionally can drive a 3- to 5-fold increase of R-loop frequency without significant changes to R-loop distribution. We propose that this is caused by stabilizing and preventing the collapse of short nascent R-loops. This suggests that R-loop formation is highly dynamic and highlights single strand binding proteins as players in cellular R-loop regulation. We further show that nontemplate strand DNA nicks are powerful initiators of R-loop formation, increasing R-loop frequencies by up to two orders of magnitude. Atomic force microscopy revealed that the nontemplate strand in nick-initiated structures is often flayed away from the RNA:DNA hybrid and engaged in self-pairing, creating unique forked R-loop features. DNA nicks, one of the most frequent DNA lesions in cells, are therefore potential hotspots for opportunistic R-loop initiation and may cause the formation of a distinct class of R-loops. Overall, this work highlights the importance of the displaced single-strand on R-loop initiation and dynamics.}, archive = {J_PNAS}, author = {Holleman, Ethan and Catley, Thomas E. and Sereiva, Tadas and Hartono, Stella R. and Pyne, Alice L. B. and Chédin, Frédéric}, doi = {10.1073/pnas.2509309122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2509309122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Protein-mediated stabilization and nicking of the nontemplate DNA strand dramatically affect R-loop formation in vitro}, volume = {122}, year = {2025}, }
• (2025). Discovering neural elastoplasticity from kinematic observations. PNAS, 122(38), e2508732122. (www)

  @article{ , abstract = {Inferring accurate and precise material models necessary for high-fidelity predictions has been a central challenge in constitutive modeling. Both traditional regression methods and modern machine-learning approaches require specialized data labels, which often cannot be sufficiently obtained from experiments. This data demand makes many sophisticated models impractical for real-world problems. Improvements in digital image correlation techniques have enabled accurate measurements of displacement data, providing an alternative kinematics-based approach for model identification. However, for materials undergoing plastic deformation, fracture, and damage, the corresponding inverse problem could be inherently challenging due to the dependence on loading history. We overcome this by formulating an inverse problem to discover interpretable plasticity models parameterized by neural networks (NN) from kinematic observations, leveraging a differentiable simulator with a smooth constitutive update that enables backpropagation for the NN training. The ability to use kinematic observations to infer complex material models may pave the way for a massive generation of material models that can be game-changing for emerging applications such as the design of metamaterials, response surface analyses, and the design of experiments.}, archive = {J_PNAS}, author = {Gavris, Georgios Barkoulis and Sun, WaiChing}, doi = {10.1073/pnas.2508732122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2508732122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Discovering neural elastoplasticity from kinematic observations}, volume = {122}, year = {2025}, }
• (2025). Pseudouridine prevalence in kaposi’s sarcoma–associated herpesvirus transcriptome reveals an essential mechanism for viral replication. PNAS, 122(38), e2508523122. (www)

  @article{ , abstract = {Pseudouridylation is a prevalent RNA modification occurring in transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small non-coding RNAs (snoRNAs), and has been most recently identified in mRNAs and lncRNAs. Emerging evidence suggests that this dynamic RNA modification is implicated in altering gene expression by regulating RNA stability, modulating translation elongation, and modifying amino acid substitution rates. However, the role of pseudouridylation in infection is poorly understood. Herein, we demonstrate that Kaposi’s sarcoma–associated herpesvirus (KSHV) manipulates the pseudouridylation pathway to enhance replication. We show that the pseudouridine synthases (PUS), PUS1, and PUS7 are essential for efficient KSHV lytic replication, supported by their redistribution to viral replication and transcription complexes. We present a comprehensive analysis of KSHV RNA pseudouridylation, revealing hundreds of modified RNAs at single-nucleotide resolution. Notably, we demonstrate that pseudouridylation of the KSHV-encoded polyadenylated nuclear RNA (PAN) plays a significant role in the expression of PAN RNA. These findings reveal an essential role of pseudouridine modification in the KSHV replication cycle.}, archive = {J_PNAS}, author = {Mottram, Timothy J. and Harper, Katherine L. and Vasconcelos, Elton J. R. and Whitehouse, Adrian}, doi = {10.1073/pnas.2508523122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2508523122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pseudouridine prevalence in kaposi’s sarcoma–associated herpesvirus transcriptome reveals an essential mechanism for viral replication}, volume = {122}, year = {2025}, }
• (2025). Inverse design of parameter-controlled disclination paths. PNAS, 122(38), e2508362122. (www)

  @article{ , abstract = {Topological defects, such as disclination lines in nematic liquid crystals, are fundamental to many physical systems and applications. In this work, we study the behavior of nematic disclinations in thin parallel-plate geometries with strong patterned planar anchoring. Building on prior models, we solve both the forward problem–predicting disclination trajectories from given surface patterns–and an extended inverse problem–designing surface patterns to produce a tunable family of disclination curves under varying system parameters. We present an explicit calculation for pattern construction, analyze parameter limitations and stability constraints, and highlight experimental and technological applications.}, archive = {J_PNAS}, author = {Tsubery, Yehonatan and Aharoni, Hillel}, doi = {10.1073/pnas.2508362122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2508362122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inverse design of parameter-controlled disclination paths}, volume = {122}, year = {2025}, }
• (2025). The balance between microbial arsenic methylation and demethylation in paddy soils underpins global arsenic risk and straighthead disease in rice. PNAS, 122(38), e2508311122. (www)

  @article{ , abstract = {Arsenic contamination in rice poses a global challenge to food safety and agricultural productivity, as toxic methylated arsenic species—dimethylarsinic acid (DMA) and its highly toxic derivative, methylated monothioarsenate (DMMTA)—accumulate in rice grains. These arsenic species endanger human health and trigger rice straighthead disease, a crop disorder that drastically reduces yields. However, the microbial ecological processes driving arsenic speciation in paddy soils, and their link to striking geographic disparities in rice arsenic speciation profiles and disease prevalence, remain poorly understood. Here, we integrate soil chronosequences spanning 1 to 2,000 y of rice cultivation, a global metagenomic survey of 801 paddy soils, controlled incubations, and field surveys to demonstrate that the balance between arsenic-methylating and arsenic-demethylating microbes is the key determinant of rice grain arsenic speciation and straighthead disease susceptibility. We show that young and moderate-age paddy soils (<700 y), common in regions such as the Americas and Europe, are enriched in arsenic-methylating bacteria, leading to elevated DMA and DMMTA in soils and rice grains. In contrast, ancient paddies in Southeast Asia harbor robust populations of DMA-demethylating methanogenic archaea that effectively mitigate the buildup of these toxic arsenic species. We identify core microbial taxa whose abundances serve as predictive biomarkers and construct a global risk map linking a high methylator-to-demethylator ratio in soils with increased straighthead disease incidence. These findings advance our understanding of arsenic biogeochemistry in agroecosystems and establish a predictive framework for identifying regions at elevated risk of arsenic-induced crop disorders and food contamination.}, archive = {J_PNAS}, author = {Dai, Jun and Chen, Chuan and Zhai, Zhi-Qiang and Gao, A-Xiang and Johnson, David R. and Kopittke, Peter M. and Zhao, Fang-Jie and Wang, Peng}, doi = {10.1073/pnas.2508311122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2508311122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The balance between microbial arsenic methylation and demethylation in paddy soils underpins global arsenic risk and straighthead disease in rice}, volume = {122}, year = {2025}, }
• (2025). Reprogrammable sequencing for physically intelligent underactuated robots. PNAS, 122(38), e2508310122. (www)

  @article{ , abstract = {Programming physical intelligence into mechanisms holds great promise for machines that can accomplish tasks such as navigation of unstructured environments while utilizing a minimal amount of computational resources and electronic components. In this study, we introduce a design approach for physically intelligent underactuated mechanisms capable of autonomously adjusting their motion in response to environmental interactions. Specifically, multistability is harnessed to sequence the motion of different degrees of freedom in a programmed order. A key aspect of this approach is that this order can be passively reprogrammed through mechanical stimuli arising from interactions with the environment. To showcase our approach, we construct a mechanism that passively sorts objects based on their mass and a four-degree-of-freedom robot capable of autonomously moving away from obstacles. Remarkably, these devices operate without relying on traditional computational architectures and utilize only a single linear actuator.}, archive = {J_PNAS}, author = {Kamp, Leon M. and Zanaty, Mohamed and Zareei, Ahmad and Gorissen, Benjamin and Wood, Robert J. and Bertoldi, Katia}, doi = {10.1073/pnas.2508310122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2508310122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reprogrammable sequencing for physically intelligent underactuated robots}, volume = {122}, year = {2025}, }
• (2025). Circadian-informed modeling predicts regional variation in obesity and stroke outcomes under different permanent US time policies. PNAS, 122(38), e2508293122. (www)

  @article{ , abstract = {Seasonal changes in time policy, such as switching between Standard Time (SDT) and Daylight Saving Time (DST), have been adopted by many countries, including the United States. While transitioning between SDT and DST has notable acute negative population health impacts, the chronic impact of these time policies on health has not been well evaluated. To estimate the impact of permanent SDT or DST on health, we modeled the circadian impact of SDT, DST, and Biannual Shifting (BAS) across a year in the contiguous, continental United States. We find that BAS produces a greater burden on the circadian system as compared to either permanent SDT or DST. Chronotype as well as location (latitude and location within time zones) impact this burden. Analyzing these data relative to county-level health data (Centers for Disease Control and Prevention Places dataset), we find that, under idealized light exposure conditions and after controlling for health and socioeconomic factors, there would be a decrease in the prevalence of both obesity [ − 0.78% ( − 0.06% to − 1.49%)] and stroke [ − 0.09% ( − 0.04% to − 0.14%)] under SDT compared with the current policy. The prevalence of both obesity [ − 0.51% ( − 0.09% to − 0.93%)] and stroke [ − 0.07% ( − 0.04% to − 0.09%)] would also decrease under permanent DST, though to a lesser degree. Our data, reflecting the impact of time policy on circadian burden and subsequent health benefits, support the cessation of BAS.}, archive = {J_PNAS}, author = {Weed, Lara and Zeitzer, Jamie M.}, doi = {10.1073/pnas.2508293122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2508293122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Circadian-informed modeling predicts regional variation in obesity and stroke outcomes under different permanent US time policies}, volume = {122}, year = {2025}, }
• (2025). Nuclear receptor coregulator NRIP1 R448G modulates t cell gut homing to control intestinal inflammation. PNAS, 122(38), e2508269122. (www)

  @article{ , abstract = {Nuclear receptors (NRs) are crucial to integrate metabolite sensing and immune responses in the gut. NR-interacting protein 1 (NRIP1) is an important coregulator of various NRs that has been implicated in inflammatory bowel disease risk, but mechanistic details of how NRIP1 controls NR activities mediating immune homeostasis and inflammation remain elusive. We demonstrate that a missense risk variant, NRIP1 R448G, promotes activated CD4 + T cell gut homing and inflammatory cytokine production, ultimately leading to exacerbated intestinal inflammation. Mechanistically, NRIP1 acts as a corepressor in retinoic acid signaling by expression of a gut-homing transcriptional program. Our study reveals the impacts of NRIP1 on CD4 + T cells in immune regulation during intestinal inflammation, providing insights into mechanisms by which an NR coregulator controls immune homeostasis and tissue inflammation.}, archive = {J_PNAS}, author = {Chen, Xiangjun and Hwang, Hee Seung and Li, Bihua and Zhao, Yanhua and Ghosh, Koushik and Deng, Lei and Creasey, Elizabeth A. and Ashenberg, Orr and Graham, Daniel B. and Xavier, Ramnik J.}, doi = {10.1073/pnas.2508269122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2508269122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nuclear receptor coregulator NRIP1 R448G modulates t cell gut homing to control intestinal inflammation}, volume = {122}, year = {2025}, }
• (2025). An in vitro BRAF activation assay elucidates molecular mechanisms driving disassembly of the autoinhibited BRAF state. PNAS, 122(38), e2508169122. (www)

  @article{ , abstract = {The RAF kinases (ARAF, BRAF, and CRAF) are essential components of the RAS-ERK signaling pathway, which controls vital cellular processes and is frequently dysregulated in human disease. Notably, mutations that alter BRAF function are prominent drivers of human cancer and certain RASopathy disorders, making BRAF an important target for therapeutic intervention. Despite extensive research, several aspects of BRAF regulation remain unclear. In this study, we developed an in vitro BRAF activation assay using purified autoinhibited BRAF:14-3-3 2 :MEK complexes. Our results show that fully processed, active-state KRAS alone can promote dimer-dependent BRAF activation. Moreover, we found that phosphatidylserine (PS)-containing liposomes synergized with KRAS to promote BRAF activation, achieving activity levels comparable to those observed with BRAF proteins that constitutively dimerize. In contrast, the SMP phosphatase complex had only a minimal effect on BRAF catalytic activity in this system but mediated the dephosphorylation of the negative regulatory pS365 14-3-3 binding site in a manner that was accelerated by the presence of KRAS alone or KRAS and 30% PS liposomes. Finally, we show that inhibitors blocking the BRAF RBD:KRAS interaction were able to suppress the in vitro activation of BRAF, underscoring the critical role of RAS binding in initiating the disassembly of the BRAF autoinhibited state. Thus, this assay provides valuable insights into the steps required for BRAF activation and can serve as an effective screening tool for identifying compounds that may inhibit this process and have therapeutic potential.}, archive = {J_PNAS}, author = {Ritt, Daniel A. and Durrant, David E. and Drew, Matthew R. and Sandin, Suzanne I. and Martinez Fiesco, Juliana A. and Zhang, Xiaohua and Aydin, Fikret and Carpenter, Timothy S. and Scheidemantle, Grace M. and D’Ippolito, Robert A. and Sohn, Alexandria L. and DeHart, Caroline J. and Shrestha, Rebika and Snead, Kelly and Hull, Jenna and Tempkin, Jeremy O. B. and Yang, Yue and Lightstone, Felice C. and Streitz, Frederick H. and Zhang, Ping and Turbyville, Thomas J. and Stephen, Andrew G. and Esposito, Dominic and Ingólfsson, Helgi I. and Nissley, Dwight V. and Morrison, Deborah K.}, doi = {10.1073/pnas.2508169122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2508169122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An in vitro BRAF activation assay elucidates molecular mechanisms driving disassembly of the autoinhibited BRAF state}, volume = {122}, year = {2025}, }
• (2025). Functional unfolding of the integrin αX transmembrane helix. PNAS, 122(38), e2507966122. (www)

  @article{ , abstract = {In biological membranes, proteins face a fundamentally different environment than in water. To avoid untenable lipid contacts with polar backbone atoms, they use the continuous hydrogen bonding achieved by α-helices or β-barrels to traverse membranes. Here, we show that integrin αX, and by homology αM, undermine this paradigm by partially unfolding the N-terminal third of their transmembrane (TM) helix. Unfolding results in a dynamic, frayed helix that weakens the association with its partnering β2 subunit to lower the activation threshold of integrin αXβ2-mediated cell adhesion. The extent of unfolding depends on membrane geometry, thereby establishing a mechanism for sensing membrane properties. The combination of adhesive control with sensory capacity in integrin αXβ2 and αMβ2 may achieve membrane localization-dependent receptor activation in leukocyte phagocytosis. The unfolding of the αX TM helix arises from a high number of α-helix-destabilizing residues that TM helices in general approach but do not exceed. Accordingly, backbone dynamics of TM helices may disrupt hydrogen bonds, modulate protein function, and optimize TM helix rigidity.}, archive = {J_PNAS}, author = {Vu, Han N. and Lee, Minhyeong and Situ, Alan J. and An, Woojin and Ley, Klaus and Kim, Chungho and Ulmer, Tobias S.}, doi = {10.1073/pnas.2507966122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2507966122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Functional unfolding of the integrin αX transmembrane helix}, volume = {122}, year = {2025}, }
• (2025). Amplification of particle collision through contact electrification in isotropic turbulence. PNAS, 122(38), e2507580122. (www)

  @article{ , abstract = {Recent discovery of “extreme clustering” of inertial particles in isotropic turbulent flow suggests a hidden mechanism of particle–particle interaction at sub-Kolmogorov separations unexplained by hydrodynamic interaction. The near-contact radial distribution function (RDF) reaches O ( 10 4 ) , resulting in a collision kernel four orders larger than direct numerical simulation predictions. Statistical stationarity is lost in the particle-laden turbulence, suggesting the particles experience a nonequilibrium process. We hypothesize dielectric particles in isotropic turbulence experience contact electrification through interparticle collisions, creating inhomogeneous mosaic surface charge. These mosaic charges lead to attractive forces and thereby extreme clustering and collision amplification, forming a positive feedback loop. To explore this potential mechanism, we investigated hollow glass spheres dispersed in a high-Reynolds-number homogeneous isotropic air turbulence chamber using high-resolution 3D particle tracking velocimetry and Kelvin Probe Force Microscopy (KPFM). We measured RDF, particle-pair mean-inward radial relative velocity, and mean radial relative acceleration (RA) with time up to 10 min. We sampled particles from the flow chamber through time and evaluated their nanoscopic charge distribution using KPFM. We found that both RDF and mosaic surface charge increase with time; RA at close separations is attractive, intensifies as particles approach, and grows in time; and the turbulence-exposed RA curves collapse when nondimensionalized by the dipole–dipole acceleration calculated from mosaic charge distributions. These results support the proposed mechanism—Inhomogeneous Mosaic Potential Amplified Collisions in Turbulence (IMPACT). Better understanding and modeling of these effects could improve predictions for air pollution, weather patterns, and drug manufacturing—where particle interactions have big impacts.}, archive = {J_PNAS}, author = {Johnson, Danielle R. and Bocanski, Adam and Diorio, Emily M. and Chen, James and Meng, Hui}, doi = {10.1073/pnas.2507580122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2507580122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Amplification of particle collision through contact electrification in isotropic turbulence}, volume = {122}, year = {2025}, }
• (2025). Nanoscale restructuring of the immune synapse with an engager enhances NK cell function. PNAS, 122(38), e2507336122. (www)

  @article{ , abstract = {Engagers are antibody-based therapies which bind immune cell receptors and a target cell ligand. Next-gen engagers typically bind two activating receptors, but the effect of this on immune synapse formation and signaling is unknown. Here, we coligated activating receptors CD16a and NKG2D on natural killer (NK) cells with a CD33-binding anti-acute myeloid leukemia (AML) engager. Superresolution microscopy revealed that coligating CD16a and NKG2D with a single molecule triggered their nanoscale coclustering. This enhanced phosphorylation of CD3ζ, ZAP70, and SLP-76 which augmented secretion of IFN-γ and TNF-α, by NK cells from healthy donors and AML patients. Thus, in addition to connecting immune cells to target cells, the clinical promise of engagers results from their ability to manipulate the nanoscale architecture of the immune synapse.}, archive = {J_PNAS}, author = {Hazime, Khodor S. and Sheppard, Sam and Niembro-Vivanco, Olatz and Hosty, Cathal and Thomas, Heather and Loosbroock, Christopher and Peiser, Leanne and Davis, Daniel M.}, doi = {10.1073/pnas.2507336122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2507336122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nanoscale restructuring of the immune synapse with an engager enhances NK cell function}, volume = {122}, year = {2025}, }
• (2025). Intercellular propagation of RIPK1/RIPK3 amyloid fibrils. PNAS, 122(38), e2507028122. (www)

  @article{ , abstract = {The canonical necrosome formed by receptor-interacting protein kinase 1 (RIPK1) and RIPK3 is a functional amyloid fibril structure critical to intracellularly drive necroptosis. Since necroptosis leads to the release of intracellular content, the fate of RIPK1/RIPK3 fibrils after necroptotic cell death has not been investigated. Here, we tracked RIPK1 and RIPK3 coassemblies and found that these fibrillar aggregates could be released into the culture medium after the membrane rupture in necroptotic cells. Interestingly, these RIPK1/RIPK3 fibrils were capable of infiltrating recipient cells and acting as seeds for the nucleation and formation of the endogenous necrosome. Cryo electron microscopy structural analysis unveiled a distinctive S-shaped conformation common to RHIM fibrils of RIPK1 and RIPK3, which can facilitate the cross-seeding of RIPK3 by RIPK1 or RIPK1/RIPK3 fibrils. Our findings suggest the ability of functional RIPK1/RIPK3 amyloid fibrils in intercellular spreading to induce protein conformation change in recipient cells and provide structural insights into the mechanism of RIPK1 and RIPK3 cross-templating to drive necroptosis.}, archive = {J_PNAS}, author = {Ma, Yeyang and Zhang, Qiuyuan and Li, Dekang and Zhao, Kun and Li, Zefei and Liu, Yuan and Wang, Chu and Sun, Bo and Li, Dan and Yuan, Junying and Liu, Cong}, doi = {10.1073/pnas.2507028122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2507028122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intercellular propagation of RIPK1/RIPK3 amyloid fibrils}, volume = {122}, year = {2025}, }
• (2025). How palytoxin transforms the Na+,K+ pump into a cation channel. PNAS, 122(38), e2506450122. (www)

  @article{ , abstract = {Palytoxin (PTX), a potent marine toxin, has long been known to transform Na + ,K + -ATPase (NKA), an indispensable ion pump, into a nonselective cation channel. It has been postulated that PTX takes control of the two gates on either side of a channel-like pore. These gates normally open and close alternately, synchronized with chemical events, never opening simultaneously. A critical question is whether palytoxin takes over the control of the two gates or creates a new pathway. Here, we present structures of NKA with bound palytoxin in three different states. PTX binds to NKA in E2P, occupying the physiological Na + exit pathway, similar to istaroxime, a new-generation cardiotonic steroid. Adding Na + and ATP/ADP to the NKA·PTX complex induces an open channel traversing the entire membrane alongside the physiological ion pathway. As AlF x , a stable transition state analog of phosphate replaces phosphate in the NKA·PTX complex preformed in E2P, the complex appears to undergo the normal reaction cycle from E2P to E1· n Na + . PTX occupies the space between the transmembrane helices M4 and M6, thereby preventing the closure of the extracellular half of the ion pathway. These structures demonstrate that the architecture of NKA is fundamentally different from “a pore with two gates.” Each half of the ion pathway comprises three segments, including a movable component that plays a pivotal role in translocating the bound cations by connecting the constant part to an appropriate inlet. The ion pathway of NKA transforms dynamically, ensuring that the two halves never exist simultaneously.}, archive = {J_PNAS}, author = {Kanai, Ryuta and Tsunekawa, Naoki and Cornelius, Flemming and Vilsen, Bente and Toyoshima, Chikashi}, doi = {10.1073/pnas.2506450122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2506450122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How palytoxin transforms the Na+,K+ pump into a cation channel}, volume = {122}, year = {2025}, }
• (2025). A reanalysis of population dynamics in the casas grandes region of northern mexico using mitochondrial DNA. PNAS, 122(38), e2506162122. (www)

  @article{ , abstract = {The Casas Grandes region in northwest Chihuahua, Mexico, is ideally situated to explore the notion of contact between the US Southwest/Northwest Mexico and Mesoamerica, as it lies geographically in a region where cultural traditions were combined in unique ways. In order to explain these dynamics, past researchers have suggested that the primary catalyst for the flourishing Casas Grandes population in the thirteenth century A.D. was caused by migrants from Mesoamerica or from larger populations to the north. We analyzed mitochondrial genetic data from individuals interred at sites that date to earlier (A.D. 700–1200) and later (A.D. 1200–1450) time periods, which allowed us to examine changes in gene pools over time and to test these migration hypotheses. Comparing the full mitogenomes from 114 individuals, we show that low levels of migration occurred diachronically, although they still may have contributed to hybridized cultural practices. These data counter the long-standing assumption that widescale population replacement was the cause for the rise of Paquimé, the center of the Casas Grandes world in the thirteenth-century A.D.}, archive = {J_PNAS}, author = {Snow, Meradeth and Searcy, Michael T. and Summers, Rachel and Blohm, Tre and Hazelwood, Lacy and McDonald, Holli and Jensen, Samuel J. and Punzo-Díaz, Jose Luis}, doi = {10.1073/pnas.2506162122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2506162122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A reanalysis of population dynamics in the casas grandes region of northern mexico using mitochondrial DNA}, volume = {122}, year = {2025}, }
• (2025). Tubular ACSM3 deficiency impairs medium-chain fatty acid metabolism and aggravates kidney fibrosis. PNAS, 122(38), e2505752122. (www)

  @article{ , abstract = {Kidney fibrosis is driven by multiple factors, among which impaired fatty acid oxidation has emerged as a critical determinant. Acyl-Coenzyme A (CoA) synthetase medium-chain family member 3 (ACSM3), a key enzyme of medium-chain fatty acid (MCFA) metabolism, has been implicated in metabolic syndrome, but its function in fibrotic kidney remains unexplored. Here, we found that tubular epithelial ACSM3 expression was downregulated in kidney fibrotic mice and patients and inversely correlated with disease severity. Systemic and tubular-specific knockout of ACSM3 both exacerbated renal fibrosis, whereas adeno-associated virus (AAV)-mediated ACSM3 overexpression alleviated fibrotic kidneys in mice. Mechanistically, ACSM3 deficiency disrupted MCFA metabolism and resulted in abnormal mitochondrial homeostasis. Notably, we identified that dodecanoic acid (C12:0) could improve kidney fibrosis, which was primarily utilized via ACSM3 in kidneys. Furthermore, C12:0 oxidation impairment caused by tubular ACSM3 deficiency aggravated fibrotic kidney. Together, ACSM3-regulated MCFA metabolism played a pivotal role in kidney fibrosis, highlighting a potent drug target of ACSM3 and a potential supplementary therapy of MCFA against chronic kidney disease.}, archive = {J_PNAS}, author = {Li, Jinxi and Xiang, Ting and Zhang, Fengping and Feng, Li and Wu, Yiting and Guo, Fan and Li, Lingzhi and Fu, Ping and Ma, Liang}, doi = {10.1073/pnas.2505752122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2505752122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tubular ACSM3 deficiency impairs medium-chain fatty acid metabolism and aggravates kidney fibrosis}, volume = {122}, year = {2025}, }
• (2025). Circular RNA lipid nanoparticle vaccine against SARS-CoV-2. PNAS, 122(38), e2505718122. (www)

  @article{ , abstract = {With the advent and widespread use of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), RNA vaccines have emerged as an exciting class of vaccine offering low cost, rapid development, and high modularity and manufacturability. Protein-coding circular RNA (circRNA) is an emerging class of RNA cargo that offers increased stability compared to mRNA with potentially reduced immunogenicity, but delivery technologies for intracellular delivery of circRNA remain underexplored. Here, we develop an optimized lipid nanoparticle (LNP) platform for circRNA delivery to immune cells, observing strong and durable transgene expression in vitro and in vivo. We employ a design-of-experiments (DoE) methodology to identify key formulation parameters for enhanced circRNA delivery and, upon intramuscular administration of our optimized circRNA LNPs to mice, observe substantial accumulation within draining lymph nodes and strong dendritic cell (DC) maturation at short time points. Applying this optimized circRNA LNP platform to vaccination against SARS-CoV-2, we demonstrate robust antibody production and enhanced immune responses in mice compared to vaccination with mRNA LNPs, including strong T h 1-biased cellular responses and a 3.8-fold increase in antigen-specific reciprocal endpoint IgG titers. These results provide insights into design criteria for circRNA LNP formulations and support the use of circRNA LNPs for vaccination against infectious diseases.}, archive = {J_PNAS}, author = {Swingle, Kelsey L. and Hamilton, Alex G. and Han, Xuexiang and Liao, Kuo-Chieh and Safford, Hannah C. and Thatte, Ajay S. and Geisler, Hannah C. and Xu, Junchao and Saw, Tzuen Yih and Wan, Yue and Mitchell, Michael J.}, doi = {10.1073/pnas.2505718122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2505718122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Circular RNA lipid nanoparticle vaccine against SARS-CoV-2}, volume = {122}, year = {2025}, }
• (2025). Lymphatic dysfunction is linked to disease pathogenesis in duchenne muscular dystrophy animal models. PNAS, 122(38), e2505656122. (www)

  @article{ , abstract = {Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder characterized by progressive muscle weakness and inflammation caused by mutations in the DMD gene. Chronic inflammation in DMD exacerbates the complications associated with disease progression. Since the lymphatic system plays a crucial role in regulating and resolving inflammation, our primary goal was to investigate whether lymphatics were dysregulated in skeletal muscle of DMD animals. We used the D2.mdx murine and golden retriever muscular dystrophy (GRMD) canine models, as well as mouse and rat lymphatic muscle cells (LMCs) to determine the role of dystrophin in lymphatic structure and function in skeletal muscles. Single-cell RNA sequencing data from control LMCs showed dystrophin expression, and protein results demonstrated that the 427-, 140-, and 71-kDa dystrophin isoforms were detectable in the LMCs from control mice, whereas the 427 kDa isoform was undetectable in LMCs derived from D2.mdx mice. Microlymphangiography and magnetic resonance lymphangiogram results showed a significant decrease in lymph transport in D2. mdx mice and GRMD dogs, respectively. Isolated flank lymphatic vessels from D2. mdx mice exhibited an increase in tonic contraction and a significant decrease in the phasic contractile frequency and amplitude, supporting lymphatic vessel dysfunction. The gene expression profile and immunofluorescence analyses of dystrophic muscle revealed inflammatory lymphangiogenesis in dystrophic muscle. Skeletal muscle tissues that showed improvement in function after adeno-associated virus-microdystrophin treatment also showed significant improvement in inflammatory lymphangiogenesis in GRMD dogs. Thus, these results show a linkage between lymphatic function and DMD pathogenesis that merits further investigation in DMD patients.}, archive = {J_PNAS}, author = {Subramanian, Bhuvaneshwaran and Johnson, Shedreanna and Narayanan, Akshaya and Wang, Wei and Seaberg, Bonnie L. and Ball, Jillian and Paredes Mares, Ilse M. and Majumder, Ahana and Aceves, Alexandria and Frazier, Sarah E. and Rutledge, Alexis and Griffin, John F. and Pal, Soumiya and Zawieja, Scott and Davis, Michael J. and Rutkowski, Joseph M. and Nghiem, Peter P. and Rimer, Mendell and Muthuchamy, Mariappan}, doi = {10.1073/pnas.2505656122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2505656122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lymphatic dysfunction is linked to disease pathogenesis in duchenne muscular dystrophy animal models}, volume = {122}, year = {2025}, }
• (2025). DNA-utilization loci enable exogenous DNA metabolism in gut bacteroidales. PNAS, 122(38), e2505388122. (www)

  @article{ , abstract = {The human gut microbiome plays a central role in nutrient metabolism, yet the fate of exogenous nucleic acids within this ecosystem remains poorly understood. Here, we show that multiple Bacteroidales species efficiently metabolize exogenous DNA, with Bacteroides thetaiotaomicron converting it into the deaminated nucleobases uracil and xanthine. Using genetic and biochemical approaches, we identify ddbABCDEF , a six-gene locus encoding secreted nucleases and an outer membrane transporter, essential for exogenous DNA metabolism in B. thetaiotaomicron . Colonization of gnotobiotic mice with ddbABCDEF mutants reveals that this pathway significantly alters nucleobase pools in a gnotobiotic mouse model. Comparative genomic analyses demonstrate that ddbABCDEF is evolutionarily related to a natural transformation system present in Bacteroidota and has diversified into four distinct subtypes, each linked to unique DNA-processing activities in closely related gut Bacteroidales strains. These findings thus expand our understanding of DNA metabolism in the gut microbiome and reveal a distinctive pathway for nucleobase production with implications for host–microbe interactions.}, archive = {J_PNAS}, author = {Sharan, Deepti and Nurek, Agnieszka and Stemczynski, Joshua and Turan, Kristof and Little, Alexander S. and Coyne, Michael J. and McMillin, Mary and Sidebottom, Ashley M. and Comstock, Laurie E. and Light, Samuel H.}, doi = {10.1073/pnas.2505388122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2505388122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {DNA-utilization loci enable exogenous DNA metabolism in gut bacteroidales}, volume = {122}, year = {2025}, }
• (2025). A model for boundary-driven tissue morphogenesis. PNAS, 122(38), e2505160122. (www)

  @article{ , abstract = {Tissue deformations during morphogenesis can be active, driven by internal processes, or passive, resulting from stresses applied at their boundaries. Here, we introduce the Drosophila hindgut primordium as a model for studying boundary-driven tissue morphogenesis. We characterize its deformations and show that its complex shape changes can be a passive consequence of the deformations of the active regions of the embryo that surround it. First, we find an intermediate characteristic “triangular keyhole” shape in the 3D deformations of the hindgut. We construct a minimal model of the hindgut primordium as an elastic ring deformed by active midgut invagination and germ band extension on an ellipsoidal surface, which robustly captures the symmetry-breaking into this triangular keyhole shape. We then quantify the 3D kinematics of the tissue by a set of contours and find that the hindgut deforms in two stages: An initial translation on the curved embryo surface followed by a rapid breaking of shape symmetry. We extend our model to show that the contour kinematics in both stages are consistent with our passive picture. Our results suggest that the role of in-plane deformations during hindgut morphogenesis is to translate the tissue to a region with anisotropic embryonic curvature and show that uniform boundary conditions are sufficient to generate the observed nonuniform shape change. Our work thus provides a possible explanation for the various characteristic shapes of blastopore-equivalents in different organisms and a framework for the mechanical emergence of global morphologies in complex developmental systems.}, archive = {J_PNAS}, author = {Alber, Daniel S. and Zhao, Shiheng and Jacinto, Alexandre O. and Wieschaus, Eric F. and Shvartsman, Stanislav Y. and Haas, Pierre A.}, doi = {10.1073/pnas.2505160122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2505160122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A model for boundary-driven tissue morphogenesis}, volume = {122}, year = {2025}, }
• (2025). Does AI help humans make better decisions? a statistical evaluation framework for experimental and observational studies. PNAS, 122(38), e2505106122. (www)

  @article{ , abstract = {The use of AI, or more generally data-driven algorithms, has become ubiquitous in today’s society. Yet, in many cases and especially when stakes are high, humans still make final decisions. The critical question, therefore, is whether AI helps humans make better decisions compared to a human-alone or AI-alone system. We introduce a methodological framework to answer this question empirically with minimal assumptions. We measure a decision maker’s ability to make correct decisions using standard classification metrics based on the baseline potential outcome. We consider a single-blinded and unconfounded treatment assignment, in which the provision of AI-generated recommendations is assumed to be randomized across cases, conditional on observed covariates, with final decisions made by humans. Under this study design, we show how to compare the performance of three alternative decision-making systems—human-alone, human-with-AI, and AI-alone. Importantly, the AI-alone system encompasses any individualized treatment assignment, including those not used in the original study. We also show when AI recommendations should be provided to a human-decision maker, and when one should follow such recommendations. We apply the proposed methodology to our own randomized controlled trial evaluating a pretrial risk assessment instrument. We find that the risk assessment recommendations do not improve the classification accuracy of a judge’s decision to impose cash bail. Furthermore, replacing a human judge with algorithms—the risk assessment score and a large language model in particular—yields worse classification performance.}, archive = {J_PNAS}, author = {Ben-Michael, Eli and Greiner, D. James and Huang, Melody and Imai, Kosuke and Jiang, Zhichao and Shin, Sooahn}, doi = {10.1073/pnas.2505106122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2505106122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Does AI help humans make better decisions? a statistical evaluation framework for experimental and observational studies}, volume = {122}, year = {2025}, }
• (2025). Experimental evidence for the continuous transition between elastic and elastoinertial turbulence. PNAS, 122(38), e2505007122. (www)

  @article{ , abstract = {Elastic turbulence (ET) and elastoinertial turbulence (EIT) of viscoelastic fluids are unique flow states with features distinct from the inertial turbulence of Newtonian fluids. Whether these two states are connected or entirely decoupled remains controversial. We here resolve this controversy by providing experimental evidence of a continuous transition between ET and EIT in Taylor-Couette flow. Through experimentally quantifying the roles of elasticity and inertia in flow stability, we find that elasticity is the primary driving mechanism for both elastic and elastoinertial instabilities, and inertia plays a secondary role in the latter. Remarkably, the critical condition for these instabilities can be described by a unified function derived from stability analysis, revealing that the transition between elastic instability to elastoinertial instability is continuous. Moreover, we show that the flow structures and the energy spectrum evolve seamlessly from ET to elasticity-dominated EIT, transitional EIT, and inertia-modulated EIT, with inertia playing an increasingly important role in the last three regimes. Our results offer insights into the fundamental nature of turbulence in viscoelastic flows and would have implications for applications involving drag reduction and polymer processing.}, archive = {J_PNAS}, author = {Zhang, Yi-Bao and Li, Lu and Fan, Yaning and Su, Jinghong and Xi, Heng-Dong and Sun, Chao}, doi = {10.1073/pnas.2505007122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2505007122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Experimental evidence for the continuous transition between elastic and elastoinertial turbulence}, volume = {122}, year = {2025}, }
• (2025). Characterization of SrUGT76G4 reveals a key residue for regioselectivity and efficient reb m synthesis. PNAS, 122(38), e2504698122. (www)

  @article{ , abstract = {Steviol glycosides (SGs) from Stevia rebaudiana are prized as noncaloric sweeteners, with rebaudioside M (Reb M)—a next-generation SG known for its sucrose-like sweetness and lack of off-tastes—standing out for its superior sensory profile. However, Reb M’s limited natural abundance impedes its commercial production. Here, we report the identification of a glucosyltransferase, UGT76G4 that efficiently catalyzes the conversion of Reb D to Reb M with a strong preference for C19 glycosylation. Structural and functional analyses, including X-ray crystallography, molecular dynamics simulations, and mutagenesis, revealed key residues in UGT76G4 that dictate its regioselectivity, with residue 200 playing a pivotal role. Engineered UGT76G4 variants, including Q199I/G200Y and H155S/Q199I/G200Y, enhanced Reb E and Reb D conversion efficiency by 1.46-fold and 23-fold, respectively, compared to UGT76G1. The engineered variants offer a promising pathway for increasing Reb M production, advancing biotechnological strategies for steviol glycoside biosynthesis and optimizing plant metabolic engineering approaches. Our findings deepen the understanding of SG biosynthesis and provide a basis for sustainable production of high-value sweeteners.}, archive = {J_PNAS}, author = {Wang, Yu and Li, Tang and Zheng, Yangjie and Guo, Chenxin and Li, Kuikui and Jia, Xiaochen and Zhu, Liping and Chen, Kecai and Yin, Heng}, doi = {10.1073/pnas.2504698122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2504698122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Characterization of SrUGT76G4 reveals a key residue for regioselectivity and efficient reb m synthesis}, volume = {122}, year = {2025}, }
• (2025). Peritumoral macrophages recruit eosinophils to promote antitumor immune responses in breast cancer. PNAS, 122(38), e2504645122. (www)

  @article{ , abstract = {Breast tumors harbor dynamic microenvironments, with multiple immune cell types playing opposing roles during tumor progression and/or response to therapy. Tumor-associated macrophages promote mammary tumorigenesis, whereas the role of mammary tissue macrophages (MTMs) remains incompletely understood. High-dimensional immunostaining of murine mammary tumor progression revealed that MTMs were localized in the peritumoral stroma and associated with eosinophils, which were previously shown to facilitate antitumor T cell responses. The depletion of MTMs accelerated tumorigenesis in both spontaneous and orthotopically transplanted mammary tumor models. Upon induction of a productive antitumor response via the depletion of regulatory T cells, MTMs assumed an alternatively activated state and expressed eotaxins, thereby attracting eosinophils to peritumoral regions. MTMs expressed the receptor for the alarmin IL-33, which induced both MTM activation and eosinophil recruitment. These results suggest that MTMs can sense IL-33 and recruit eosinophils to facilitate antitumor immunity, a mechanism that may operate during tumor progression and be further enhanced during productive antitumor responses.}, archive = {J_PNAS}, author = {Saglimbeni, Joseph and Esteva, Eduardo and Canales, Josue and Perez, Oriana A. and Eichinger, Anna and Huntley, William and Khanna, Kamal M. and Dolgalev, Igor and Klar, Natalie and Adams, Sylvia and Reizis, Boris}, doi = {10.1073/pnas.2504645122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2504645122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Peritumoral macrophages recruit eosinophils to promote antitumor immune responses in breast cancer}, volume = {122}, year = {2025}, }
• (2025). The glass-ceiling convective regime and the origin and diversity of coronae on venus. PNAS, 122(38), e2504491122. (www)

  @article{ , abstract = {Venus and Earth are rocky planets of roughly the same size and bulk density, yet their surface volcanic and tectonic features appear substantially different. On Venus, the coexistence of large volcanic highlands—interpreted as the surface expression of long-lived mantle plumes—alongside coronae, smaller features thought to be caused by transient thermal diapirs, remains enigmatic. Using two-dimensional numerical models of mantle convection with sharp and broad mineral phase transitions for pyrolite, we show that both scales of upwellings can be generated in a stagnant lid planet with an interior temperature 250 to 400 K warmer than Earth’s. The smaller plumes originate from a ~600 km deep internal layer that exists as a consequence of the different sequence of mineral phase transitions that occur in warmer mantles less processed and differentiated by partial melting and volcanism. Future models that include melting will provide further tests of our hypothesis.}, archive = {J_PNAS}, author = {Kerr, Madeleine C. and Stegman, Dave R. and Smrekar, Suzanne E. and Adams, Andrea C.}, doi = {10.1073/pnas.2504491122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2504491122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The glass-ceiling convective regime and the origin and diversity of coronae on venus}, volume = {122}, year = {2025}, }
• (2025). Heterogeneity in the coordination of delta cells with beta cells is driven by both paracrine signals and low-density cx36 gap junctions. PNAS, 122(38), e2504151122. (www)

  @article{ , abstract = {Insulin potently decreases blood glucose; thus, tight control is required to prevent excessive insulin release and hypoglycemia. Central to this inhibition is somatostatin released from delta cells that are clustered with beta cells in pancreatic islets. This communication is of interest because the loss of functional beta cells in diabetes leads to uncontrolled delta cell activity that disrupts islet paracrine crosstalk. While it is established that insulin and somatostatin secretion are coordinated, the specific mechanism is unsettled. We have previously demonstrated that beta cells release the hormone Urocortin 3 to stimulate delta cells at high glucose, demonstrating a paracrine negative feedback loop. Others have proposed direct coordination via gap junctions. To resolve this conundrum, we used the genetically encoded fluorescent Ca 2+ reporter GCaMP6s to simultaneously record the activity of hundreds of beta and delta cells in low (2.8 mM) (LG) and high (16.8 mM) glucose (HG). Surprisingly, while many delta cells exhibit Ca 2+ oscillations in HG that are coordinated with beta cells, the activation of these delta cells precedes beta cells and is more variable than beta cell responses. The selective delta cell knockout of connexin 36 confirmed the involvement of gap junctions. However, blockade of vesicle release with the Rho-GTPase inhibitor ML-141 completely removed coupling between beta and most delta cells in HG. Our data reveal considerable functional heterogeneity among delta cells, where most delta cells are entrained by oscillatory Ca 2+ behaviors of beta cells that are mediated by a combination of paracrine signaling and low-density gap junction coupling.}, archive = {J_PNAS}, author = {Pourhosseinzadeh, Mohammad S. and Huang, Jessica L. and Shin, Donghan and Hart, Ryan G. and Framroze, Luhaiza Y. and Guillen, Jaresley V. and Sanchez, Joel and Tirado, Ramir V. and Unanwa, Kelechi and Huising, Mark O.}, doi = {10.1073/pnas.2504151122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2504151122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Heterogeneity in the coordination of delta cells with beta cells is driven by both paracrine signals and low-density cx36 gap junctions}, volume = {122}, year = {2025}, }
• (2025). Bacillus subtilis σA and escherichia coli σ70 lacking σ region 1.1 are not released during transcription initiation and elongation. PNAS, 122(38), e2503801122. (www)

  @article{ , abstract = {A “σ cycle” in which the initiation factor σ associates with RNA polymerase (RNAP) core enzyme to permit transcription initiation and dissociates from RNAP core enzyme to permit transcription elongation, has been proposed to occur and to be an essential step for σ-exchange, with all principal σ factors from all bacteria. These proposals were based on studies of the principal σ factor of Escherichia coli , σ 70 , which generally, albeit not obligatorily, is released from RNAP upon the transition from transcription initiation to elongation. Here, we show that, in contrast to E. coli σ 70 , the Bacillus subtilis principal σ factor, σ A , is not released and is retained on RNAP core throughout transcription elongation. We further show that a mutant E. coli σ 70 derivative lacking σ region 1.1 (σ R1.1) is not released and is retained on RNAP core throughout transcription elongation. We also observe that B. subtilis σ A and the mutant E. coli σ 70 derivative lacking σ R1.1 interact much more stably with RNAP than full-length E. coli σ 70 . Our results indicate that the σ cycle is not a universal phenomenon in bacteria.}, archive = {J_PNAS}, author = {Tewary, Aniruddha and Sengupta, Shreya and Mukherjee, Soumya and Hazra, Nilanjana and Ebright, Yon W. and Ebright, Richard H. and Mukhopadhyay, Jayanta}, doi = {10.1073/pnas.2503801122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2503801122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bacillus subtilis σA and escherichia coli σ70 lacking σ region 1.1 are not released during transcription initiation and elongation}, volume = {122}, year = {2025}, }
• (2025). A widespread family of molecular chaperones promotes the intracellular stability of type VIIb secretion system–exported toxins. PNAS, 122(38), e2503581122. (www)

  @article{ , abstract = {To survive in highly competitive environments, bacteria use specialized secretion systems to deliver antibacterial toxins into neighboring cells, thereby inhibiting their growth. In many Gram-positive bacteria, the export of such toxins requires a membrane-bound molecular apparatus known as the type VIIb secretion system (T7SSb). Recently, it was shown that toxin recruitment to the T7SSb requires a physical interaction between a toxin and two or more so-called targeting factors, which harbor key residues required for T7SS-dependent protein export. However, in addition to these targeting factors, some toxins additionally require a protein belonging to the DUF4176 protein family. Here, by examining two toxin–DUF4176 protein pairs, we demonstrate that DUF4176 constitutes a family of toxin-specific molecular chaperones. In addition to being required for toxin stability in producing cells, we find that DUF4176 proteins facilitate toxin export by specifically interacting with a previously uncharacterized intrinsically disordered region found in many T7SS toxins. Using X-ray crystallography, we determine structures of several DUF4176 chaperones in their unbound state, and of a DUF4176 chaperone in complex with the binding site of its cognate toxin. These structures reveal that this binding site consists of a disordered amphipathic α-helix that requires interaction with its cognate chaperone for proper folding. Overall, we have identified a family of secretion system associated molecular chaperones found throughout T7SSb-containing Gram-positive bacteria.}, archive = {J_PNAS}, author = {Gkragkopoulou, Polyniki and Garrett, Stephen R. and Shah, Prakhar Y. and Grebenc, Dirk W. and Klein, Timothy A. and Kim, Youngchang and Whitney, John C.}, doi = {10.1073/pnas.2503581122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2503581122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A widespread family of molecular chaperones promotes the intracellular stability of type VIIb secretion system–exported toxins}, volume = {122}, year = {2025}, }
• (2025). Community notes reduce engagement with and diffusion of false information online. PNAS, 122(38), e2503413122. (www)

  @article{ , abstract = {Social networks scaffold the diffusion of information on social media. Much attention has been given to the spread of true vs. false content on online social platforms, including the structural differences between their diffusion patterns. However, much less is known about how platform interventions on false content alter the engagement with and diffusion of such content. In this work, we estimate the causal effects of Community Notes, a novel fact-checking feature adopted by X (formerly Twitter) to solicit and vet crowd-sourced fact-checking notes for false content. We gather detailed time series data for 40,078 posts for which notes have been proposed and use synthetic control methods to estimate a range of counterfactual outcomes. We find that attaching fact-checking notes significantly reduces the engagement with and diffusion of false content. We estimate that, on average, the notes resulted in reductions of 46.1% in reposts, 44.1% in likes, 21.9% in replies, and 13.5% in views after being attached. Over the posts’ entire lifespans, these reductions amount to 11.6% fewer reposts, 13.3% fewer likes, 6.9% fewer replies, and 5.5% fewer views on average. In reducing reposts, we observe that diffusion cascades for fact-checked content are less deep and less “viral,” but not less broad, than synthetic control estimates for non-fact-checked content with similar reach. This structural difference contrasts notably with differences between false vs. true content diffusion itself, where false information diffuses farther, but with structural patterns that are otherwise indistinguishable from those of true information, conditional on reach.}, archive = {J_PNAS}, author = {Slaughter, Isaac and Peytavin, Axel and Ugander, Johan and Saveski, Martin}, doi = {10.1073/pnas.2503413122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2503413122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Community notes reduce engagement with and diffusion of false information online}, volume = {122}, year = {2025}, }
• (2025). Microbial conservation is essential for sustaining ecosystem functions and services. PNAS, 122(38), e2503013122. (www)

  @article{ , archive = {J_PNAS}, author = {Junker, Robert R. and Farwig, Nina}, doi = {10.1073/pnas.2503013122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2503013122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Microbial conservation is essential for sustaining ecosystem functions and services}, volume = {122}, year = {2025}, }
• (2025). Divergent sustainability profiles of molnupiravir synthesis routes are governed by solvent use and process design. PNAS, 122(38), e2502336122. (www)

  @article{ , abstract = {This study presents a comparative cradle-to-gate environmental and economic evaluation of nine synthetic routes for Molnupiravir (EIDD-2801), a broad-spectrum antiviral drug. Integrating Life Cycle Assessment (LCA) with Life Cycle Costing (LCC), we quantified the environmental impacts alongside capital and operational costs, net present costs, and break-even prices of each route. The results reveal significant variation across the schemes, with Schemes #1 and #2 exhibiting the highest impacts and costs due to intensive use of chloroform and diethyl ether, while Scheme #8 demonstrated the lowest impacts and costs, benefitting from higher batch output, greener solvents, and process intensification. Scenario analyses showed that solvent recovery improves sustainability only when high recovery rates are combined with clean electricity; otherwise, the additional energy demand may offset benefits. Scale-up analysis confirmed that higher production scales substantially reduce per-gram impacts and costs, supporting economies of scale. These findings highlight the critical role of solvent management, energy sourcing, the use of sustainability assessment at the earliest stages of innovation, and process design in aligning green chemistry with economic viability. The proposed integrated LCA-LCC framework provides transferable insights to guide sustainable pharmaceutical manufacturing and supports the development of evidence-based policy for greener antiviral drug production.}, archive = {J_PNAS}, author = {Chen, Zhengyun and Lian, Justin Z. and Huang, Haozhou and Zhu, Hengyi and Kanye, Lynda Thubelihle and Chen, Mateng and Zhang, Zhihao and Liu, Boxin and Zhang, Jiawei and Ahmed, Ajaz and Barbarossa, Valerio and Cucurachi, Stefano and Dong, Bin}, doi = {10.1073/pnas.2502336122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2502336122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Divergent sustainability profiles of molnupiravir synthesis routes are governed by solvent use and process design}, volume = {122}, year = {2025}, }
• (2025). Enhanced visualization of influenza a virus entry into living cells using virus-view atomic force microscopy. PNAS, 122(38), e2500660122. (www)

  @article{ , abstract = {Influenza A virus (IAV) entry into host cells begins with interactions between the viral envelope proteins hemagglutinin (HA)/neuraminidase (NA) and sialic acid moieties on the cell plasma membrane. These interactions drive IAV’s lateral diffusion along the cell membrane and trigger membrane morphological changes required for endocytosis. However, directly visualizing these dynamic processes, which are crucial for IAV entry, has been challenging using conventional microscopy techniques. In this study, we enabled live-cell observation of nanoscale morphological dynamics of IAV and the cell membrane by reducing the mechanical invasiveness of atomic force microscopy (AFM). A customised cantilever with less than half the spring constant of conventional cantilevers enabled virus-view AFM imaging that preserved IAV–membrane interactions. By combining virus-view AFM with confocal microscopy, we performed correlative morphological and fluorescence observations of IAV lateral diffusion and endocytosis in living cells. Variations in diffusion coefficients of single virions suggested heterogeneity in sialic acid density on the cell membrane. NA inhibition decreased diffusion coefficients, while reduced sialic acid density increased them. The timing of clathrin accumulation at virion binding sites coincided with a decrease in diffusion coefficients, a relationship that was maintained independent of NA activity or sialic acid density. As clathrin assembly progressed, ~100-nm-high membrane bulges emerged adjacent to the virus, culminating in the complete membrane envelopment of the virus at peak clathrin accumulation. Our virus-view AFM will deepen our understanding of various virus–cell interactions, facilitate the evaluation of drug effects and promote future translational research.}, archive = {J_PNAS}, author = {Yoshida, Aiko and Uekusa, Yoshitsugu and Suzuki, Takeshi and Bauer, Michael and Sakai, Nobuaki and Yamauchi, Yohei}, doi = {10.1073/pnas.2500660122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2500660122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Enhanced visualization of influenza a virus entry into living cells using virus-view atomic force microscopy}, volume = {122}, year = {2025}, }
• (2025). Distinct timescales dissociate spontaneous thought dimensions. PNAS, 122(38), e2427088122. (www)

  @article{ , abstract = {Our spontaneous thoughts encompass various dimensions, such as task-relatedness (off vs. on task), and thought orientation (internal vs. external). However, their distinction remains unclear. Our study addresses this issue by focusing on their timescales at both the behavioral level (using fast and slow finger tapping) and the neural level (using EEG) using two independent datasets (N = 84 and 35). Behavioral results revealed a double dissociation: Task-relatedness was linked to fast tapping only, whereas thought orientation was associated with slow tapping only. At the neural level, we assessed topographic similarity in EEG to quantify the temporal influence of past neural activity on current ones. Task-relatedness modulated topographic similarity only during fast tapping, while thought orientation did so only during slow tapping. Critically, topographic similarity was phase-based, as shown by its correlation with phase-locking value and the loss of associations with thought after phase-shuffling. This indicates that the neural signatures of both thought dimensions are strongly phase-dependent. Finally, we demonstrate that nonlinearity plays a distinct role mediating the impact of different timescales (slow and fast finger tapping) on spontaneous thoughts at both behavioral (precision error) and neural levels (topographic similarity). Overall, these results demonstrate that task-relatedness is associated with short timescales, whereas thought orientation is associated with long timescales. This highlights how distinct temporal dynamics shape different spontaneous thought dimensions on both their behavioral and neural features.}, archive = {J_PNAS}, author = {Hua, Jingyu and Ge, Xianliang and Dou, Min and Zhang, Yuqi and Ge, Liezhong and Fogel, Stuart and Zhang, Jianfeng and Northoff, Georg}, doi = {10.1073/pnas.2427088122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2427088122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Distinct timescales dissociate spontaneous thought dimensions}, volume = {122}, year = {2025}, }
• (2025). Active billiards: Engineering boundaries for the spatial control of confined active particles. PNAS, 122(38), e2426715122. (www)

  @article{ , abstract = {Unlike gas molecules at equilibrium, the spatial organization of self-propelled particles can be very sensitive to what happens at the boundaries of their container. Understanding the link between boundary phenomena and bulk stationary distributions could enable the design of optimized container shapes for the geometric control of confined active particles. Here, we propose a boundary method based on the flux transfer formalism typical of radiometry problems, where surface elements transmit and receive “rays” of active particles with infinite persistence length. We demonstrate the power of this boundary method in the case of the swimming microalgae Euglena gracilis trapped in light-defined billiard geometries. Quite surprisingly, we found that Euglena scatters with a nearly Lambertian cosine law, resembling the behavior of blackbody radiation and consequently resulting in nearly uniform distributions inside simple cavity geometries. Nevertheless, leveraging our boundary method, we were able to design a stacked multistage billiard geometry, with a connection scheme between subunits that breaks spatial symmetry and achieves an exponential amplification of cell concentration between its two ends. Our method can be applied to confined active matter in contexts ranging from spatial control and sorting of microorganisms to the design of efficient navigation strategies for microscopic and macroscopic robots.}, archive = {J_PNAS}, author = {Di Leonardo, Roberto and Búzás, András and Kelemen, Lóránd and Tóth, Dávid and Tóth, Szilvia Z. and Ormos, Pál and Vizsnyiczai, Gaszton}, doi = {10.1073/pnas.2426715122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2426715122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Active billiards: Engineering boundaries for the spatial control of confined active particles}, volume = {122}, year = {2025}, }
• (2025). An open-source photobleacher for fluorescence imaging of large pigment-rich tissues. PNAS, 122(38), e2426628122. (www)

  @article{ , abstract = {Fluorescence imaging enables visualization of the specific molecules of interest with high contrast, and the use of multiple fluorophores in a single tissue sample allows visualization of complex relationships between biological molecules, cell types, and anatomy. The utility of fluorescence imaging in human tissue has been limited by endogenous pigments that can block the light path or emit an autofluorescence, thereby interfering with the specific imaging of target molecules. Although photobleachers have been developed to quench endogenous pigments, the lack of customizability limits their utility for a broad range of applications. Here, we present a high luminous-intensity photobleacher that is based on rigorous simulations of illumination patterns, along with the framework to maximize bleaching efficiency. This open-source project is designed to help scientists customize and scale the device according to their research goals. The photobleacher is applicable to both thin tissue slices and large-volume cleared tissue samples to enable serial three-dimensional imaging of postmortem human brain using multiplexed antibody or oligonucleotide probes.}, archive = {J_PNAS}, author = {Murakami, Tatsuya C. and Belenko, Nick and Dennis, Griffin and Wang, Cuidong and Siantoputri, Maria Esterlita and Maeda, Yurie and Pressl, Christina and Heintz, Nathaniel}, doi = {10.1073/pnas.2426628122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2426628122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An open-source photobleacher for fluorescence imaging of large pigment-rich tissues}, volume = {122}, year = {2025}, }
• (2025). Humanization of CD47 enables development of functional human neutrophils via postirradiation remodeling of the bone marrow. PNAS, 122(38), e2426546122. (www)

  @article{ , abstract = {Murine and human immune systems differ significantly, particularly within the myeloid lineage. Humanized mice, generated by transplanting human hematopoietic stem, progenitor cells into genetically modified mice, are invaluable to study human immune development and function in vivo. However, a major limitation of current models is suboptimal myelopoiesis, particularly lack of functional human neutrophils, hampering the modeling of human immune responses and chronic diseases. Here, we describe a humanized mouse model, named MaGIC for genes replaced, in the C57Bl/6 N strain, which improves human myelopoiesis and enables development of functional human neutrophils. In MaGIC mice, human cytokines M-CSF/CSF1(M), GM-CSF/CSF2(G) and IL-6(I) are knocked-in replacing mouse genes and murine IL2rg and Rag1 (a) are deleted. Human THPO in these mice supports human hematopoiesis. More importantly, insertion of human CD47 (C) under the control of endogenous mouse CD47 promoter enables xenotransplantation and human neutrophil development. MaGIC mice support all human neutrophil subsets found in human bone marrow and blood, a major improvement. This is achieved by creating a niche postirradiation for human granulocyte–macrophage progenitors via reduced murine CD47 and physiological levels of human CD47. These mice also have mature human monocytes, tissue macrophages, alveolar macrophages, dendritic cells, and NK cells, enabled by humanized M-CSF and GM-CSF. Human neutrophils in MaGIC mice are fully functional in chemotaxis, phagocytosis, reactive oxygen species production, and neutrophil extracellular trap formation in response to inflammation. MaGIC mice address critical gaps in current models and enable incisive translational research on human neutrophils, advancing studies in infectious, autoimmune, and inflammatory diseases.}, archive = {J_PNAS}, author = {Sefik, Esen and Philbrick, William and Zhang, Fengrui and Agrawal, Kriti and Van Lee, Brian and Sam, Johannes and Karatepe, Kutay and Zheng, Yunjiang and Liang, Kaixin and Peng, Sophia and Mirza, Haris and Rangavajhula, Athreya and Simon, Perrine and Arun, Neha and Babu, Priyanka and Eynon, Elizabeth and Chiorazzi, Michael and Shan, Liang and Halene, Stephanie and Luo, Hongbo R. and Rongvaux, Anthony and Kluger, Yuval and Flavell, Richard A.}, doi = {10.1073/pnas.2426546122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2426546122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Humanization of CD47 enables development of functional human neutrophils via postirradiation remodeling of the bone marrow}, volume = {122}, year = {2025}, }
• (2025). SLC39A8-mediated zinc dyshomeostasis potentiates kidney disease. PNAS, 122(38), e2426352122. (www)

  @article{ , abstract = {While numerous genetic risk loci are linked to kidney disease, a unifying therapeutic target for diverse renal pathologies remains elusive. Here, through large-cohort polymorphic locus screening, we identify the SLC39A8 A391T variant (rs13107325) as a shared modifier of multiple kidney diseases. Functional characterization using Slc39a8 A391T knock-in mice and kidney-specific Slc39a8 knockout mice reveals that loss of SLC39A8 function reduces renal zinc accumulation, thereby mitigating susceptibility to kidney injury and disease progression. Mechanistically, we demonstrate that perturbed zinc homeostasis drives renal damage, and limiting zinc levels—whether via impaired SLC39A8 activity or direct chelation—activates the zinc–AKT–FOXO1–G6PC axis to confer protection. Critically, zinc chelation with EDTA recapitulates this benefit, significantly preventing and ameliorating experimental acute and chronic kidney disease. These findings establish renal zinc homeostasis as a key therapeutic node, with SLC39A8 and zinc-modulating strategies representing promising avenues for treating a broad range of kidney diseases.}, archive = {J_PNAS}, author = {Cai, Zhaoxian and Wu, Xiaotian and Wang, Tianyi and Song, Zijun and Ni, Pu and Zhong, Meijuan and Su, Yunxing and Xie, Enjun and Sun, Shumin and Lin, Yangjun and Min, Junxia and Wang, Fudi}, doi = {10.1073/pnas.2426352122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2426352122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SLC39A8-mediated zinc dyshomeostasis potentiates kidney disease}, volume = {122}, year = {2025}, }
• (2025). Methionine synthesis and glycine betaine demethylation are intricately intertwined in cosmopolitan marine bacteria. PNAS, 122(38), e2426167122. (www)

  @article{ , abstract = {Across all domains of life, cobalamin-dependent methyltransferases have diversified to perform a range of crucial functions, such as methionine synthesis and the demethylation of various reduced nitrogen and sulfur compounds. These large modular enzymes typically possess three substrate-binding domains, two binding either the methyl donor or methyl acceptor, as well as a cobalamin-binding domain. Here, by challenging the current paradigm of glycine betaine (GBT) catabolism, we have identified a unique methyltransferase in aerobic environmental bacteria that has a dual function both as a methionine synthase and a GBT methyltransferase. Using the marine bacterium Ruegeria pomeroyi DSS-3 as a model, we demonstrate that a core cobalamin-binding domain (MtgC) and a bidirectional methyltransferase (MtgD) are essential for both methionine synthesis and GBT demethylation. MtgC is phylogenetically distinct from the cobalamin-binding domains of either the classical methionine synthase (MetH) or the GBT methyltransferases found in anaerobic bacteria and archaea. Across the global ocean, mtgC expression is frequently greater than previously known GBT catabolic pathways due to its occurrence in abundant cosmopolitan marine bacteria. Thus, we uncover a unique relationship between GBT catabolism and methionine synthesis in nature and identify a major route for N-osmolyte demethylation in the global ocean.}, archive = {J_PNAS}, author = {Mausz, Michaela A. and Murphy, Andrew R. J. and del Mar Aguilo-Ferretjans, Maria and Hitchcock, Andrew and Moran, Mary Ann and Scanlan, David J. and Chen, Yin and Lidbury, Ian D. E. A.}, doi = {10.1073/pnas.2426167122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2426167122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Methionine synthesis and glycine betaine demethylation are intricately intertwined in cosmopolitan marine bacteria}, volume = {122}, year = {2025}, }
• (2025). Virion proteomics of genetically intact HCMV reveals a regulator of envelope glycoprotein composition that protects against humoral immunity. PNAS, 122(38), e2425622122. (www)

  @article{ , abstract = {Human cytomegalovirus (HCMV) is a clinically important herpesvirus that has coevolved for millions of years with its human host, and establishes lifelong persistent infection. A substantial proportion of its 235 kb genome is dedicated to manipulating host immunity through targeting antiviral host proteins for degradation or relocalization. Quantitative proteomics of the infected cell has extensively characterized these processes, but the cell-free virion has been less well studied. We therefore carried out proteomic analysis of a clinical HCMV strain (Merlin) virion. This revealed 18 novel components, including the viral protein gpUL141, which is recognized as an NK immune-evasin that targets several host proteins (CD155, CD112, and TRAILR) when expressed within the cell. Coimmunoprecipitation of gpUL141 from virions identified interactions with viral entry glycoproteins from the trimer (gH/gL/gO), pentamer (gH/gL/UL128/UL130/UL131A), and gH/gpUL116 complexes, as well as gB. Only interactions with gH/gB occurred in the absence of other viral proteins. Analysis supported a model in which gpUL141 homodimers independently interacted with separate gB/gH-containing complexes. gpUL141 encodes an ER retention domain that restricts trafficking through the ER/Golgi, and limited the transport of glycoprotein complexes bound by gpUL141. As a result, gpUL141 reduced levels of multiple glycoprotein complexes on the infected cell surface as well as in the virion. This reduced syncytium formation, inhibited antibody-dependent cellular cytotoxicity (ADCC), and reduced susceptibility to neutralizing antibodies. Thus, gpUL141 represents an immune-evasin that not only targets host proteins to limit NK-cell attack, but also alters the trafficking of multiple viral glycoprotein complexes in order to evade humoral immunity.}, archive = {J_PNAS}, author = {Bentley, Kirsten and Statkute, Evelina and Murrell, Isa and Fielding, Ceri A. and Antrobus, Robin and Preston, Hannah and Kerr-Jones, Lauren and Cochrane, Daniel and Brizic, Ilija and Lehner, Paul J. and Wilkinson, Gavin W. G. and Wang, Eddie C. Y. and Graham, Stephen C. and Weekes, Michael P. and Stanton, Richard J.}, doi = {10.1073/pnas.2425622122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2425622122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Virion proteomics of genetically intact HCMV reveals a regulator of envelope glycoprotein composition that protects against humoral immunity}, volume = {122}, year = {2025}, }
• (2025). Parametrically guided design of beta barrels and transmembrane nanopores using deep learning. PNAS, 122(38), e2425459122. (www)

  @article{ , abstract = {Francis Crick’s global parameterization of coiled coil geometry has been widely useful for guiding design of new protein structures and functions. However, design guided by similar global parameterization of beta barrel structures has been less successful, likely due to the deviations from ideal barrel geometry required to maintain interstrand hydrogen bonding without introducing backbone strain. Instead, beta barrels have been designed using two-dimensional structural blueprints; while this approach has successfully generated new fluorescent proteins, transmembrane nanopores, and other structures, it requires expert knowledge and provides only indirect control over the global shape. Here, we show that the simplicity and control over shape and structure provided by parametric representations can be generalized beyond coiled coils by taking advantage of the rich sequence–structure relationships implicit in RoseTTAFold-based design methods. Starting from parametrically generated barrel backbones, both RFjoint inpainting and RFdiffusion readily incorporate backbone irregularities necessary for proper folding with minimal deviation from the idealized barrel geometries. We show that for beta barrels across a broad range of beta sheet parameterizations, these methods achieve high in silico and experimental success rates, with atomic accuracy confirmed by an X-ray crystal structure of a rare barrel topology, and de novo designed transmembrane nanopores with conductances ranging from 200 to 500 pS. By combining the simplicity and control of parametric generation with the high success rates of deep learning–based protein design methods, our approach makes the design of proteins where global shape confers function, such as beta barrel nanopores, more precisely specifiable and accessible.}, archive = {J_PNAS}, author = {Kim, David E. and Watson, Joseph L. and Juergens, David and Majumder, Sagardip and Sonigra, Ria and Gerben, Stacey R. and Kang, Alex and Bera, Asim K. and Li, Xinting and Baker, David}, doi = {10.1073/pnas.2425459122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2425459122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Parametrically guided design of beta barrels and transmembrane nanopores using deep learning}, volume = {122}, year = {2025}, }
• (2025). Historical and experimental evidence that inherent properties are overweighted in early scientific explanation. PNAS, 122(38), e2424725122. (www)

  @article{ , abstract = {Scientific explanation is one of the most sophisticated forms of human reasoning. Nevertheless, here we hypothesize that scientific explanation is susceptible to some of the same biases that influence everyday thinking—particularly during the initial stages of theory building, when scientists are first grappling with complex phenomena and are thus more likely to rely on explanatory “guesses.” Specifically, we investigated whether scientific explanation exhibits an inherence bias—a tendency to explain phenomena through inherent or intrinsic features rather than extrinsic factors such as context or relations. Consistent with this hypothesis, a comprehensive analysis of major explanatory transitions across the history of Western science revealed that initial scientific explanations systematically favored inherent properties, while subsequent explanations incorporated extrinsic factors more consistently. Seven experiments with lay participants (both adults and children; N = 1,673) and two experiments with practicing scientists from top departments worldwide ( N = 275) provided converging evidence for this bias and identified the psychological mechanisms involved. When explaining unfamiliar phenomena, even leading scientists showed a robust tendency to overweight inherent properties and underweight extrinsic factors relative to established scientific understanding. This bias appears rooted in basic cognitive constraints on attention and memory that excessively narrow the space of hypotheses initially considered. These findings advance our understanding of both the psychology of explanation and the development of scientific knowledge, while suggesting specific ways to improve scientific training and education.}, archive = {J_PNAS}, author = {Horne, Zachary and Kobaş, Mert and Cimpian, Andrei}, doi = {10.1073/pnas.2424725122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2424725122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Historical and experimental evidence that inherent properties are overweighted in early scientific explanation}, volume = {122}, year = {2025}, }
• (2025). Tropical cyclones expand faster at warmer relative sea surface temperature. PNAS, 122(38), e2424385122. (www)

  @article{ , abstract = {Tropical cyclones are expected to intensify more rapidly with warming, but relatively little work has examined whether they could expand more rapidly with warming, too. Recent theory predicts that peak expansion rate should increase with sea surface temperature (SST), and physical arguments suggest this dependence should be specifically on the relative SST, i.e. the SST difference from the tropical mean. We test this hypothesis with historical observational data, in which SST variations are primarily variations in relative SST. Both average and peak expansion rates are found to systematically increase with relative SST globally across the Northern Hemisphere (27.2 and 37.5 km/d/K) and within each individual basin. Results are robust across both reanalysis and Best Track observational datasets. Uniform-SST aquaplanet simulations show a much weaker dependence of maximum expansion rate on absolute SST, suggesting that the dominant dependence is on relative SST. Hence, mean global warming is not expected to strongly change storm size dynamics, but patterns of sea surface warming may play an important role in determining how storm size, and hence coastal risk, may change in the future. This work can also help improve forecasting of the wind field and its hazards and impacts at landfall.}, archive = {J_PNAS}, author = {Wang, Danyang and Chavas, Daniel R. and Schenkel, Benjamin A.}, doi = {10.1073/pnas.2424385122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2424385122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tropical cyclones expand faster at warmer relative sea surface temperature}, volume = {122}, year = {2025}, }
• (2025). High-resolution tephrochronology resolves stratigraphic complexities in archaeologically significant nariokotome tuffs, turkana basin. PNAS, 122(38), e2424142122. (www)

  @article{ , abstract = {The Turkana Basin is a renowned paleoanthropological region in Kenya and Ethiopia and is famous for discoveries of numerous hominin fossils and their associated cultural technologies. The Plio-Pleistocene sedimentary sequences hosting these important remains are interbedded with volcanic ash (tuff) beds that provide crucial bracketing age constraints. The Nariokotome Tuff Complex, comprising the Upper, Middle, and Lower Nariokotome Tuffs, preserves deposits that cover an important time interval during the late Early Pleistocene that saw milestone events for Homo erectus and associated technological development. Unfortunately, characterization of these tuffs has been hampered by a) overlapping published eruption ages and b) indistinguishable major element compositions. In addition, fluvial reworking of feldspar-bearing pumice clasts (the target rock for age determinations) from older volcanic deposits into younger tuff layers complicates correct age assignments. Here, we use multiple tephrochronological correlation tools, including high-resolution 40 Ar/ 39 Ar geochronology and grain-specific major- and trace-element geochemistry, to establish a well-characterized geochemical and geochronological framework for the Nariokotome tuffs. Utilizing a modern-generation mass-spectrometer, we report distinct ages for the Upper Nariokotome Tuff at 1,233.1 ± 1.3 ka (± 1.9 ka, 2σ; including external uncertainties), the Middle Nariokotome Tuff at 1,263.4 ± 1.2 ka (± 1.9 ka) and the Lower Nariokotome Tuff at 1,285.8 ± 1.0 ka (± 2.1 ka). In addition, high-spatial resolution Laser Ablation Inductively Coupled Mass Spectrometry trace element compositions provide distinct characterization of each tuff, aiding intrabasin correlation of these units. This combined methodology demonstrates the potential to resolve the stratigraphic complexities associated with assigning ages to key paleoanthropological sites.}, archive = {J_PNAS}, author = {Samim, Saini and Dalton, Hayden and Phillips, David and Hergt, Janet}, doi = {10.1073/pnas.2424142122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2424142122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High-resolution tephrochronology resolves stratigraphic complexities in archaeologically significant nariokotome tuffs, turkana basin}, volume = {122}, year = {2025}, }
• (2025). More 26S and 30S proteasomes are beneficial in proteinopathy. PNAS, 122(38), e2422570122. (www)

  @article{ , abstract = {Despite the many studies on the ubiquitin–proteasome system, our understanding of the proteasome itself is limited. The balance and regulation of 26S and 30S proteasomes are not yet known. Here, we show that among the proteasome base assembly chaperones, only S5b/PSMD5 determines the levels of proteasome holoenzymes, especially the 30S proteasome, in mammals. In a variety of cell lines and mouse tissues, we found that apart from its role in yeast 19S proteasome assembly, loss of S5b/PSMD5 increased assembly toward the 26S and 30S proteasomes. During the process, we identified proteasome complexes that may represent alternative assembly intermediates, including the 19S base complex and 20S complexes harboring 19S subunits, eventually leading to a shift in the overall steady-state level of the 26S and 30S proteasomes. Intriguingly, the addition of the S5b/PSMD5 protein in vitro and its increase in cells efficiently disassembled the 30S proteasome into the 20S and 19S complexes. Increase in the 26S and 30S proteasomes over the 20S proteasome enhances the degradation of the aggregation-prone proteins and ubiquitinated proteins in cells and ameliorates cognitive impairment through the reduction of tau pathology in PS19 mice. These results suggest that 26S and 30S proteasomes are manipulated by S5b/PSMD5 and are beneficial for mitigating proteinopathy in mammals.}, archive = {J_PNAS}, author = {Kim, Youngwon and Kim, Namhoon and Lee, WonJae and Kim, Youbin and Kim, Donghyeon and Park, Jisu and Jung, Yong-Keun}, doi = {10.1073/pnas.2422570122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2422570122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {More 26S and 30S proteasomes are beneficial in proteinopathy}, volume = {122}, year = {2025}, }
• (2025). A universal wind–wave–bubble formulation for air–sea gas exchange and its impact on oxygen fluxes. PNAS, 122(38), e2419319122. (www)

  @article{ , abstract = {Bubble-mediated gas exchange associated with wave breaking is a critical pathway for ocean–atmosphere exchange of low solubility gases such as oxygen. Yet, ocean and climate models, as well as observation-based products, usually rely on wind-only air–sea flux formulations derived from carbon constraints that ignore the asymmetric nature of the bubble flux, contributing to discrepancies between estimates of oxygen inventories and their response to climate change. Without bubbles, gas exchange is controlled by a symmetric wind-driven exchange, with the ocean–atmosphere gas partial pressure difference controlling whether outgassing or uptake occurs. Bubbles entrained by wave breaking can enhance this symmetric turbulent exchange, and contribute an additional asymmetric flux, always leading to an uptake, as they get squeezed by hydrostatic pressure (large bubbles) or collapse and fully dissolve (small bubbles). We present an observation-constrained theoretical framework of the air–sea flux accounting for air entrainment due to wave breaking and symmetric and asymmetric bubble exchange. The combined evidence from theory, laboratory, and field measurements of carbon dioxide fluxes, oxygen concentration, and noble gas supersaturation yields a universal formulation of gas exchange which we implement into a global ocean biogeochemical model. We discuss the resulting oxygen fluxes and demonstrate that our wind–wave–bubble formulation better reproduces observed in situ oxygen concentrations in water mass formation regions, where air–sea exchange is high, than a commonly used wind-only formulation. We show that the asymmetric bubble flux is essential for evaluating air–sea oxygen fluxes and estimating the magnitude of the ocean oxygen loss associated with global warming.}, archive = {J_PNAS}, author = {Deike, Luc and Zhou, Xiaohui and Rustogi, Paridhi and Stanley, Rachel H. R. and Reichl, Brandon G. and Bushinsky, Seth M. and Resplandy, Laure}, doi = {10.1073/pnas.2419319122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2419319122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A universal wind–wave–bubble formulation for air–sea gas exchange and its impact on oxygen fluxes}, volume = {122}, year = {2025}, }
• (2025). Life without sex: Large-scale study links sexlessness to physical, cognitive, and personality traits, socioecological factors, and DNA. PNAS, 122(38), e2418257122. (www)

  @article{ , abstract = {Romantic (typically sexual) relationships are important to personal, physical, mental, social, and economic well-being, and to human evolution. Yet little is known about factors contributing to long-term lack of intimate relationships. We investigated phenotypic and genetic correlates of never having had sex in ~400,000 UK residents aged 39 to 73 and ~13,500 Australian residents aged 18 to 89. The strongest associations revealed that sexless individuals were more educated, less likely to use alcohol and smoke, more nervous, lonelier, and unhappier. Sexlessness was more strongly associated with physical characteristics (e.g., upper body strength) in men than in women. Sexless men tended to live in regions with fewer women, and sexlessness was more prevalent in regions with more income inequality. Common genetic variants explained 17% (SE = 4%) and 14% (SE = 3%) of variation in sexlessness in men and women, with a genetic correlation between sexes of 0.56 (SE = 0.17). Polygenic scores predicted a range of related outcomes in the Australian dataset. Our findings uncover multifaceted correlates of human intimacy and raise important lines of enquiry in the evolutionary and social sciences.}, archive = {J_PNAS}, author = {Abdellaoui, Abdel and Wesseldijk, Laura W. and Gordon, Scott D. and Pasman, Joëlle A. and Smit, Dirk J. A. and Androvičová, Renáta and Martin, Nicholas G. and Ullén, Fredrik and Mosing, Miriam A. and Zietsch, Brendan P. and Verweij, Karin J. H.}, doi = {10.1073/pnas.2418257122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2418257122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Life without sex: Large-scale study links sexlessness to physical, cognitive, and personality traits, socioecological factors, and DNA}, volume = {122}, year = {2025}, }
• (2025). SUMO conjugation to promoter-proximal sequence elements–associated proteins impacts on snRNA transcription. PNAS, 122(38), e2417409122. (www)

  @article{ , abstract = {The noncoding small nuclear RNAs (snRNAs) associate with a large set of proteins to form small nuclear ribonucleoprotein particles (snRNPs). While the function of snRNAs is well characterized, the regulation of their transcription remains poorly understood. Recently, we demonstrated that SUMO conjugation regulates snRNA3′ end processing. To further study the connection between SUMOylation and snRNA biogenesis, we generated a CRISPR/dCas9 tool comprising a catalytically inactive Cas9 (dCas9) fused to the catalytic domain of the SUMO protease SENP1 (dCas9-SENP1). Here, we show that snRNA transcription decreases when dCas9-SENP1 is delivered to their promoter-proximal sequence elements (PSE), indicating that SUMO conjugation to proteins associated with snRNA promoters is necessary for proper transcriptional activity. Focusing on SNAPC1, a subunit of the snRNA-specific transcription complex SNAPc, we identified lysine residues 245 and 333 as SUMO acceptor sites and generated a SUMOylation-deficient mutant of this protein (SNAPC1 2KR). To explore the relevance of SNAPC1 SUMOylation on snRNA transcription, we generated a cell line carrying an inducible degron system for depletion of the endogenous SNAPC1 protein. This system led us to demonstrate that SNAPC1 2KR is unable to sustain basal levels of snRNA transcription. By tagging endogenous SNAPC3 and SNAPC4, two other subunits of SNAPc, we show that while SNAPC1 SUMOylation-deficient mutant is able to interact with SNAPC3, its interaction with SNAPC4 is affected, despite the fact it is still recruited to the PSE. Altogether, these results indicate that SNAPC1 SUMOylation is required for proper snRNA transcription and SNAPc complex assembly.}, archive = {J_PNAS}, author = {Bragado, Laureano and Pozzi, Berta and Beckerman, Inés and Magalnik, Melina and Srebrow, Anabella}, doi = {10.1073/pnas.2417409122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2417409122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SUMO conjugation to promoter-proximal sequence elements–associated proteins impacts on snRNA transcription}, volume = {122}, year = {2025}, }
• (2025). Wnt inhibition alleviates resistance to anti-PD1 therapy and improves antitumor immunity in glioblastoma. PNAS, 122(38), e2414941122. (www)

  @article{ , abstract = {Wnt signaling plays a crucial role for many developmental processes. It is also pivotal in the generation and limited treatment outcomes of glioblastoma (GBM). Here, we identified Wnt7b, which is markedly upregulated in GBM patients, as a determinant of resistance to immune checkpoint blockers (αPD1; anti-Programmed Cell Death Protein 1) in a clinically relevant, αPD1-resistant GBM murine model with abundant stem cells. We observed that increased levels of Wnt7b and β-catenin correlated with the resistance to αPD1. Treatment combining a porcupine inhibitor WNT974 with αPD1 reprogrammed the immune suppressive tumor microenvironment (TME) to bolster antitumor immune responses and extended the survival of mice bearing orthotopic GBM, with 25% long-term survivors. Our causal studies revealed that WNT974 potentiated αPD1 therapy by the expansion of antigen presenting DC3-like dendritic cells (DCs). Additionally, WNT974 combination with αPD1 was associated with a reduction in immune suppressive granulocytic myeloid-derived suppressor cells (MDSCs), an increase in the Ki67+CD8/Ki67+regulatory T cells (Treg) ratio, tilting the CD8:Treg balance in the TME toward antitumor immune response, and more pronounced GrzB+CD8+ effector T cells. Conversely, an increase in monocytic MDSCs and phosphorylation of pro-oncogenic proteins was associated with resistance to the combination therapy. Collectively, our preclinical findings provide a strong rationale to test Wnt7b/β-catenin inhibition with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling.}, archive = {J_PNAS}, author = {Krishnan, Shanmugarajan and Lee, Somin and Amoozgar, Zohreh and Subudhi, Sonu and Srinivasan Kumar, Ashwin and Posada, Jessica M. and Lindeman, Neal and Lei, Pinji and Duquette, Mark and Steinbuch, Sophie and Charabati, Marc and Huang, Peigen and Andersson, Patrik and Datta, Meenal and Munn, Lance L. and Fukumura, Dai and Jain, Rakesh K.}, doi = {10.1073/pnas.2414941122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2414941122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Wnt inhibition alleviates resistance to anti-PD1 therapy and improves antitumor immunity in glioblastoma}, volume = {122}, year = {2025}, }
• (2025). Large-scale surveys of woodrats (Neotoma spp.) reveal constraints on diet breadth in herbivorous mammals. PNAS, 122(38), e2413556122. (www)

  @article{ , abstract = {Characterizing niche space is critical for predicting species interactions and responses to environmental change. To enhance our understanding of dietary niche breadth, we used DNA metabarcoding to examine how diets of a widespread, model herbivore (woodrats, genus Neotoma ) respond to changing resources and the extent to which dietary specialization is conserved across space and time. We used diet data from 13 species, 57 populations, and over 500 individuals to examine predictors of niche breadth and interindividual diet variation at a landscape scale. Then, to test whether these patterns are conserved across scales, we explored the same questions using a single population sampled over 5 y and mark-recapture data from individuals sampled at least three times. We found that woodrats exhibited a continuum of dietary specialization that included species-level dietary generalists and specialists. Specialist species maintained narrow population-level niche breadths with little evidence of interindividual diet variation. In contrast, generalist species consisted of populations with varying degrees of dietary specialization and interindividual diet variation. Across sampling scales, increased population-level niche breadth was explained by both increased interindividual diet variation and increased diet richness. These results are consistent with the Niche Variation Hypothesis and suggest that diet breadth is constrained by costs of both specialization and generalization.}, archive = {J_PNAS}, author = {Weinstein, Sara B. and Klure, Dylan M. and Symeonidi, Efthymia and Greenhalgh, Robert and Mayes, Marc T. and Doolin, Margaret L. and Stapleton, Tess E. and Swei, Andrea and Cove, Michael V. and Dearing, M. Denise}, doi = {10.1073/pnas.2413556122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2413556122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Large-scale surveys of woodrats (Neotoma spp.) reveal constraints on diet breadth in herbivorous mammals}, volume = {122}, year = {2025}, }
• (2025). The power of bridging decision scales: Model coupling for advanced climate policy analysis. PNAS, 122(38), e2411592122. (www)

  @article{ , abstract = {Climate policy faces increasingly complex challenges that span multiple human decision scales in nature–society systems. Contemporary climate policy models, while valuable and increasingly versatile in handling spatial and temporal scales, struggle to capture interacting multiscale decisions on the socioeconomic side. This perspective draws attention to the power of coupling among different modeling families, taking integrated assessment models (IAM), computable general equilibrium models (CGE), and agent-based models (ABM) as examples. Recent computational advances, maturity of models, availability of data, and interdisciplinary expertise make model coupling an increasingly feasible, effective, and useful tool for climate policy analysis. We examine the unique contributions of each modeling approach, highlight synergies from uniting their strengths, and discuss alternatives to and conditions for coupling. In addressing methodological challenges, we present examples of effective coupling of IAM–ABM–CGE, emphasizing the importance of maintaining model integrity while enhancing policy relevance. By bridging human decision scales and leveraging complementary strengths, coupled models can provide nuanced insights into climate–economy interactions, ultimately supporting effective and equitable—not just efficient and optimal—climate policies.}, archive = {J_PNAS}, author = {Filatova, Tatiana and Akkerman, Joos and Bosello, Francesco and Chatzivasileiadis, Theodoros and Cortés Arbués, Ignasi and Ghorbani, Amineh and Ivanova, Olga and Knittel, Nina and Kwakkel, Jan and Lamperti, Francesco and Magliocca, Nicholas R. and Marangoni, Giacomo and Nabernegg, Stefan and Pichler, Anton and Poujon, Adrian and Safarzynska, Karolina and Taberna, Alessandro and van Sluisveld, Mariësse A. E. and Verbeek, Liz and Wei, Taoyuan}, doi = {10.1073/pnas.2411592122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {38}, pages = {e2411592122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The power of bridging decision scales: Model coupling for advanced climate policy analysis}, volume = {122}, year = {2025}, }
• (2025). Correction for sharma and DiVincenzo, g-factor symmetry and topology in semiconductor band states. PNAS, 122(37), e2522920122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2522920122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2522920122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for sharma and DiVincenzo, g-factor symmetry and topology in semiconductor band states}, volume = {122}, year = {2025}, }
• (2025). Correction for gibbons et al., motivational trade-offs and modulation of nociception in bumblebees. PNAS, 122(37), e2522767122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2522767122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2522767122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for gibbons et al., motivational trade-offs and modulation of nociception in bumblebees}, volume = {122}, year = {2025}, }
• (2025). Urban water security and the historical pools of jerusalem. PNAS, 122(37), e2520435122. (www)

  @article{ , archive = {J_PNAS}, author = {Bar-Oz, Guy and Avni, Gideon}, doi = {10.1073/pnas.2520435122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2520435122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Urban water security and the historical pools of jerusalem}, volume = {122}, year = {2025}, }
• (2025). Cystic fibrosis: Correction of a fatal disease. PNAS, 122(37), e2519780122. (www)

  @article{ , abstract = {The 2025 Lasker~DeBakey Clinical Medical Research Award has been given to Michael Welsh, Jesús (Tito) González, and Paul Negulescu for their key roles in developing a novel treatment for cystic fibrosis (CF)—a three-drug combination that saves the lives of people with this lethal genetic disease [D. Keating et al. , N. Engl. J. Med. 379, 1612–1620 (2018)]. The disease is caused by mutations that disrupt the function of a gene known as CF Transmembrane Conductance Regulator which encodes a chloride channel expressed in epithelial cells including the lung. Collectively the three recipients were responsible for the development of novel high-throughput drug screens that led to the development of the new drugs. Welsh is a pulmonologist who played a key role in understanding the physiology and pathophysiology of the disease. González is a physical organic chemist who developed a novel technology that enabled robust high-throughput screens for drugs that correct the channel defects. Negulescu led a group of extremely talented biologists, chemists, and physicians who built on these advances to develop novel three-drug combinations that have miraculous benefits for the majority of afflicted patients. This advance represents a true milestone in medicine and fulfills a dream of research scientists and families—the conversion of a fatal disease into a fully treatable one. It is also a stunning example of the power of medical research to save people’s lives.}, archive = {J_PNAS}, author = {Friedman, Jeffrey M.}, doi = {10.1073/pnas.2519780122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2519780122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cystic fibrosis: Correction of a fatal disease}, volume = {122}, year = {2025}, }
• (2025). Making sense of low-complexity domains: The 2025 lasker basic science award. PNAS, 122(37), e2519778122. (www)

  @article{ , abstract = {Up to 10 to 20% of the proteome contains regions with much lower amino acid diversity than would be expected by chance. This year’s Lasker Basic Science Award is given to Steven McKnight and Dirk Görlich for their pioneering work on such low-complexity domains (LCDs). They showed, using a variety of elegant approaches, that such LCDs can form homotypic and heterotypic interactions that lead to reversible phase separations in cells. These phase separations, which in the laboratory manifest as hydrogels and in cells as membrane free structures (liquid condensates) such as P bodies and stress granules, form hubs for molecular processes such as transcription and messenger RNA (mRNA) splicing and also underlie the selectivity of nuclear pore complexes (NPCs), which act a barriers to large molecules unless they are escorted by specific LCD containing nuclear transporters that interact with LCD containing nucleoporins within NPC channels. Naturally occurring LCD mutations linked to neurodegeneration and other diseases cause the formation of irreversible (rather than reversible) LCD polymers, resulting in insoluble, amyloid-like, fibrils, underscoring the critical importance of these domains.}, archive = {J_PNAS}, author = {Kaelin, William G.}, doi = {10.1073/pnas.2519778122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2519778122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Making sense of low-complexity domains: The 2025 lasker basic science award}, volume = {122}, year = {2025}, }
• (2025). The Lasker~Koshland special achievement award in medical science awarded to lucy shapiro. PNAS, 122(37), e2519777122. (www)

  @article{ , abstract = {Scientists can contribute to society in numerous ways. Some scientists discover new biological principles and found entirely new fields. Some scientists are inspiring mentors and create the next generation of inclusive lab leaders. Some scientists are entrepreneurs who develop clinically effective therapeutics. Some scientists are trusted advisors to government and pharmaceutical companies. Some scientists are visionary institutional leaders who build new departments. From this menu of activities, most scientists select two or at most three. It is exceedingly rare for a single scientist to excel in all of these areas, consistently, over the course of a career. Lucy Shapiro is this extraordinary scientist. She founded the field of bacterial cell biology and trained the next generation of microbiologists, launched biotech companies to develop new antifungal drugs, served as an unofficial advisor to two presidential administrations and numerous companies, institutions, and foundations, and built and led successful academic departments. The 2025 Lasker~Koshland Special Achievement Award in Medical Science is awarded to Lucy Shapiro “for a 55-y career in biomedical science—honored for discovering how bacteria coordinate their genetic logic in time and space to generate distinct daughter cells; for founding Stanford’s distinguished Department of Developmental Biology; and for exemplary leadership at the national level.”}, archive = {J_PNAS}, author = {Vosshall, Leslie B.}, doi = {10.1073/pnas.2519777122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2519777122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The Lasker~Koshland special achievement award in medical science awarded to lucy shapiro}, volume = {122}, year = {2025}, }
• (2025). Is nav1.8-specific inhibition the only path? preferential nav blockers offer a compelling alternative. PNAS, 122(37), e2519744122. (www)

  @article{ , archive = {J_PNAS}, author = {Xiang, Bingbing and Deng, Chaoyi and Yang, Han and Zhang, Wensheng}, doi = {10.1073/pnas.2519744122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2519744122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Is nav1.8-specific inhibition the only path? preferential nav blockers offer a compelling alternative}, volume = {122}, year = {2025}, }
• (2025). Adaptation of seed dormancy to maternal climate occurs via intergenerational transport of abscisic acid. PNAS, 122(37), e2519319122. (www)

  @article{ , abstract = {How or whether organisms can inherit parental adaptations to the prevailing environment is a major topic in biology. In plants, seed traits such as size, yield, and dormancy are all affected by the environment during reproduction, but whether developing progeny sense temperature within the fruit or whether seasonal climate information is inherited intergenerationally from the parents remains unclear. In this study, we use intergenerational single-nucleus omics to understand the mechanisms underlying the effects of seasonal temperature changes in fruits containing developing seeds of the next generation. We show that the sensing of temperature takes place specifically in maternal fruit tissues and that mothers preadapt their progeny to maternal temperature through the intergenerational flux of the hormone ABA to the zygote itself where it is sensed to affect dormancy. We conclude that mothers can control filial traits via direct transfer of hormones to progeny and propose that this is an important mechanism by which populations can rapidly adapt to environmental change.}, archive = {J_PNAS}, author = {Chen, Xiaochao and Bezodis, William and González-Suárez, Pablo and Knitlhoffer, Vanda and Goldson, Andrew and Lister, Ashleigh and Macaulay, Iain and Penfield, Steven}, doi = {10.1073/pnas.2519319122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2519319122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Adaptation of seed dormancy to maternal climate occurs via intergenerational transport of abscisic acid}, volume = {122}, year = {2025}, }
• (2025). The redox rhythm gates immune-induced cell death distinctly from the genetic clock. PNAS, 122(37), e2519251122. (www)

  @article{ , abstract = {Organisms use circadian clocks to synchronize physiological processes to anticipate the Earth’s day-night cycles and regulate responses to environmental signals to gain competitive advantage. While divergent genetic clocks have been studied extensively in bacteria, fungi, plants, and animals, an ancient conserved circadian redox rhythm has been recently reported. However, its biological function and physiological outputs remain elusive. Here, we uncovered the coexistence of redox and genetic rhythms with distinct period lengths and transcriptional targets through concurrent metabolic and transcriptional time-course measurements in an Arabidopsis long-period clock mutant. Analysis of the target genes indicated regulation of the immune-induced programmed cell death (PCD) by the redox rhythm. Moreover, this time-of-day-sensitive PCD was eliminated by redox perturbations and by blocking the signaling pathway of the plant defense hormones jasmonic acid/ethylene, while remaining intact in genetic clock-defective backgrounds. This study shows that compared to robust genetic clocks, the more sensitive circadian redox rhythm serves as a signaling hub in regulating incidental energy-intensive processes, such as immune-induced PCD involving reprogramming of chloroplast and mitochondria activities, to provide organisms a flexible strategy to mitigate metabolic overload during stress responses.}, archive = {J_PNAS}, author = {Karapetyan, Sargis and Mwimba, Musoki and Chen, Tianyuan and Yao, Zhujun and Dong, Xinnian}, doi = {10.1073/pnas.2519251122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2519251122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The redox rhythm gates immune-induced cell death distinctly from the genetic clock}, volume = {122}, year = {2025}, }
• (2025). DNA polymerase α-primase can function as a translesion DNA polymerase. PNAS, 122(37), e2517556122. (www)

  @article{ , abstract = {Replication of cellular chromosomes requires a primase to generate short RNA primers to initiate genomic replication. While bacterial and archaeal primase generate short RNA primers, the eukaryotic primase, Polα-primase, contains both RNA primase and DNA polymerase (Pol) subunits that function together to form a >20 base hybrid RNA–DNA primer. Interestingly, the DNA Pol1 subunit of Polα lacks a 3’-5’ proofreading exonuclease, contrary to the high-fidelity normally associated with DNA replication. However, Polδ and Polε synthesize the majority of the eukaryotic genome, and both contain 3’-5’ exonuclease activity for high fidelity. Nonetheless, even the small amount of DNA produced by Pol1 in each of the many RNA/DNA primers during chromosome replication adds up to tens of millions of nucleotides in a human genome. Thus, it has been a longstanding question why Pol1 lacks a proofreading exonuclease. We show here that Polα is uniquely capable of traversing common oxidized or hydrolyzed template nucleotides and propose that Polα evolved to bypass these common template lesions when they are encountered during chromosome replication. Additionally, we show a unique ability of replication factor C (RFC) to stimulate Polδ lesion bypass, independent of its sliding clamp. This suggests that there may be a coordination between Polδ and RFC that does not involve RFC loading of PCNA.}, archive = {J_PNAS}, author = {Mayle, Ryan and Georgescu, Roxana and O’Donnell, Michael E.}, doi = {10.1073/pnas.2517556122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2517556122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {DNA polymerase α-primase can function as a translesion DNA polymerase}, volume = {122}, year = {2025}, }
• (2025). Binding of fusobacterium nucleatum autotransporter adhesin CbpF to human CEACAM1 and CEACAM5: A velcro model for bacterium adhesion. PNAS, 122(37), e2516574122. (www)

  @article{ , abstract = {In eukaryotic systems, three major types of cell junctions have been well characterized. While bacterial adhesion mechanisms also exhibit remarkable diversity, the molecular processes that regulate the dynamic modulation of binding strength between elongated bacterial cells and host cells remain poorly understood. Fusobacterium nucleatum ( F. nucleatum ) utilizes the surface adhesin CbpF to interact with the highly expressed host receptors CEACAM1 and CEACAM5 on cancer cells to facilitate tumor colonization. By elucidating the structural details of CbpF binding to human CEACAM1/CEACAM5 receptors, and through mechanistic investigations, we identified that the prominent EFNGQYQ loop on CbpF and the key Q78 residue of CEACAM1/CEACAM5 constitute the molecular linchpin of this pathogen–host interface. Furthermore, we found a distinct type of binding particle and proposed a Velcro-like adhesion model. In this model, CbpF mediates robust attachment through the simultaneous interaction of multiple binding sites, akin to the interlocking mechanism of Velcro. This multivalent interaction allows F. nucleatum to dynamically switch between firm anchoring and easy detachment, adapting to varying physiological microenvironments. Our study elucidates the dynamic modulation of bacterial adhesion strength and lays the foundation for developing therapeutic interventions to disrupt the bacterium–host interface.}, archive = {J_PNAS}, author = {Shen, Fan and Li, Linjie and Yang, Dongchun and Tang, Zhexiao and Zhang, Lu and Liu, Kefang and Hou, Wenzhe and Lu, Zhuozhuang and Fang, Jing-Yuan and Qi, Jianxun and Zhao, Xin and Gao, George F.}, doi = {10.1073/pnas.2516574122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2516574122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Binding of fusobacterium nucleatum autotransporter adhesin CbpF to human CEACAM1 and CEACAM5: A velcro model for bacterium adhesion}, volume = {122}, year = {2025}, }
• (2025). Microglia-to-neuron signaling links APOE4 and inflammation to enhanced neuronal lipid metabolism and network activity. PNAS, 122(37), e2516103122. (www)

  @article{ , abstract = {Microglia regulate neuronal circuit plasticity. Disrupting their homeostatic function has detrimental effects on neuronal circuit health. Neuroinflammation contributes to the onset and progression of neurodegenerative diseases, including Alzheimer’s disease (AD), with several microglial activation genes linked to increased risk for these conditions. Inflammatory microglia alter neuronal excitability, inducing metabolic strain. Interestingly, expression of APOE4 , the strongest genetic risk factor for AD, affects both microglial activation and neuronal excitability, highlighting the interplay between lipid metabolism, inflammation, and neuronal function. It remains unclear how microglial inflammatory state is conveyed to neurons to affect circuit function and whether APOE4 expression alters this intercellular communication. Here, we use a reductionist model of human iPSC-derived microglial and neuronal monocultures to dissect how the APOE genotype in each cell type independently contributes to microglial regulation of neuronal activity during inflammation. Conditioned media (CM) from LPS-stimulated microglia increased neuronal network activity, assessed by calcium imaging, with APOE4 microglial CM driving greater neuronal activity than APOE3 CM. Both APOE3 and APOE4 neurons increase network activity in response to CM treatments, while APOE4 neurons uniquely increase presynaptic puncta in response to APOE4 microglial CM. CM-derived exosomes from LPS-stimulated microglia can mediate increases to network activity. Finally, increased network activity is accompanied by increased lipid droplet (LD) metabolism, and blocking LD metabolism abolishes network activity. These findings illuminate how microglia-to-neuron communication drives inflammation-induced changes in neuronal circuit function, demonstrate a role for neuronal LDs in network activity, and support a potential mechanism through which APOE4 increases neuronal excitability.}, archive = {J_PNAS}, author = {Verduzco Espinoza, Ana P. and Na, Na and Campanati, Loraine and Ngo, Priscilla and Baldwin, Kristin K. and Cline, Hollis T.}, doi = {10.1073/pnas.2516103122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2516103122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Microglia-to-neuron signaling links APOE4 and inflammation to enhanced neuronal lipid metabolism and network activity}, volume = {122}, year = {2025}, }
• (2025). S-nitrosylation of pVHL regulates β2 adrenergic receptor function. PNAS, 122(37), e2515326122. (www)

  @article{ , abstract = {The β 2 -adrenergic receptor (β 2 AR), a prototype G protein–coupled receptor, controls cardiopulmonary function underpinning O 2 delivery. Abundance of the β 2 AR is canonically regulated by G protein–coupled receptor kinases and β-arrestins, but neither controls constitutive receptor levels, which are dependent on ambient O 2 . Basal β 2 AR expression is instead regulated by the prolyl hydroxylase/pVHL-E3 ubiquitin ligase system, explaining O 2 responsivity. Interplay between O 2 and nitric oxide (NO, a potent bronchodilator) is central to cardiopulmonary function. Here, we demonstrate that pVHL-mediated β 2 AR degradation is counteracted by NO, revealing pVHL control of pulmonary function. NO S-nitrosylates Cys77 in human pVHL (cognate to mouse Cys43), which induces binding of the E3 ubiquitin ligase c-Cbl to degrade pVHL, thereby increasing β 2 AR expression. pVHL–C43S mutant mice refractory to S-nitrosylation exhibit decreases in β 2 AR signaling and increases in airway tone. Thus, pVHL controls adrenergic pulmonary function and contributes to bronchodilation by NO. Our findings suggest therapeutic approaches to asthma and obstructive airway disease.}, archive = {J_PNAS}, author = {Grimmett, Zachary W. and Hayashi, Hiroki and Raffay, Thomas M. and Lin, Justin and Premont, Richard T. and Stamler, Jonathan S.}, doi = {10.1073/pnas.2515326122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2515326122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {S-nitrosylation of pVHL regulates β2 adrenergic receptor function}, volume = {122}, year = {2025}, }
• (2025). Wild bats hunt insects faster under lit conditions by integrating acoustic and visual information. PNAS, 122(37), e2515087122. (www)

  @article{ , abstract = {Animals can improve their decision-making abilities by integrating information from multiple senses, which is especially beneficial when living in fluctuating environments. However, understanding how wild predators may use multimodal sensing when hunting prey in split-second interactions remains largely unexplored. As nocturnal hunters, bats rely on echolocation to navigate and to locate evasive prey, yet they have retained functional vision, despite the associated costs. We therefore hypothesized that bats use vision to enhance sensory redundancy when commuting and tracking small insects. To test this, we equipped 21 wild common noctule bats ( Nyctalus noctula ) with high-resolution light, sound, and motion sensor loggers and measured their echolocation and movements while commuting and foraging in both dark and lit environments. When commuting, the bats maintained consistent echolocation sampling across light levels. However, when tracking prey in illuminated environments, the bats emitted calls with half the rate and with 7 dB higher call levels compared to in dark conditions, but at much faster approach speeds (from 5.2 in darkness to 7.9 m/s in lit conditions). This suggests that, in illuminated environments, hunting bats integrate acoustic and visual information, resulting in more efficient approaches to prey. Our findings demonstrate how a wild sensory specialist predator uses multimodal sensing to hunt efficiently in highly dynamic resource landscapes.}, archive = {J_PNAS}, author = {Stidsholt, Laura and Zebele, Mara and Scholz, Carolin and Voigt, Christian C.}, doi = {10.1073/pnas.2515087122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2515087122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Wild bats hunt insects faster under lit conditions by integrating acoustic and visual information}, volume = {122}, year = {2025}, }
• (2025). Bridging feeling and motion: Insula–premotor dynamics in the processing of action vitality forms. PNAS, 122(37), e2514139122. (www)

  @article{ , abstract = {Typically, people perform actions in a valenced—positive or negative—way, depending on their attitudes or desires. These forms of action are named vitality forms (VFs). While it is well established that action goals are mediated by a parieto-frontal network, less is known about the processing of VFs. Recent fMRI studies suggest that the insula (INS)—and its connections with the parieto-frontal circuit—plays a crucial role in VFs processing. However, a key question remains: How does our internal affective state shape our motor behavior? To explore this issue, we conducted an fMRI study. Participants were required to perform two sequential tasks: 1) to evoke either a positive (enthusiastic) or a negative (angry) affective state (feeling task); 2) to execute an action while maintaining these affective states (execution task). Univariate analysis revealed activation of the INS and dorsolateral prefrontal cortex (PFC) during the feeling task, which extended to the premotor (PM) and parietal areas during the execution task. To determine the directionality of information flow among these nodes, we employed dynamic causal modeling. Bayesian model comparison showed that, during the feeling task, affect generation involves INS, which, together with the PFC, modulates the activity of PM. In contrast, during execution, motor commands emerge from PM and influence activity in the INS and PFC. These findings indicate that while the internal states crucially imply the INS, their regulation is mediated by PFC. The PM cortex plays a crucial role in the selection of the corresponding action VFs.}, archive = {J_PNAS}, author = {Di Cesare, Giuseppe and Koush, Yury and Zeidman, Peter and Sciutti, Alessandra and Friston, Karl and Rizzolatti, Giacomo}, doi = {10.1073/pnas.2514139122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2514139122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bridging feeling and motion: Insula–premotor dynamics in the processing of action vitality forms}, volume = {122}, year = {2025}, }
• (2025). Quantifying phage infectivity from characteristics of bacterial population dynamics. PNAS, 122(37), e2513377122. (www)

  @article{ , abstract = {A frequent goal of phage biology is to quantify how well a phage kills a population of host bacteria. Unfortunately, traditional methods to quantify phage success can be time-consuming, limiting the throughput of experiments. Here, we use theory to show how the effects of phages on their hosts can be quantified using bacterial population dynamics measured in a high-throughput microplate reader (automated spectrophotometer). We use mathematical models to simulate bacterial population dynamics where specific phage and bacterial traits are known a priori. We then test common metrics of those dynamics (e.g., growth rate, time and height of peak bacterial density, death rate, extinction time, area under the curve) to determine which best predict: 1) infectivity over the short-term, and 2) phage suppression over the long term. We find that many metrics predict infectivity and are strongly correlated with one another. We also find that metrics can predict phage growth rate, providing an effective way to quantify the combined effects of multiple phage traits. Finally, we show that peak density, time of peak density, and extinction time are the best metrics when comparing across different bacterial hosts or over longer timescales where plasticity or evolution may play a role. In all, we establish a foundation for using bacterial population dynamics to quantify the effects of phages on their bacterial hosts, supporting the design of in vitro empirical experiments using microplate readers.}, archive = {J_PNAS}, author = {Blazanin, Michael and Vasen, Eli and Vilaró Jolis, Cèlia and An, William and Turner, Paul E.}, doi = {10.1073/pnas.2513377122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2513377122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantifying phage infectivity from characteristics of bacterial population dynamics}, volume = {122}, year = {2025}, }
• (2025). From simplicity to complexity: A path to innovation in science and art. PNAS, 122(37), e2513128122. (www)

  @article{ , abstract = {Simple reductionist systems can serve as powerful catalysts for unlocking complex innovations in science and art. The evolution from simplicity to complexity is illustrated by the career journeys of the scientist Earl W. Sutherland, who discovered cyclic adenosine 3′-5′-monophosphate (cyclic AMP) and opened the field of cell signaling, and the artist Frank Stella, who pioneered geometrical patterns and shapes in both painting and sculpture. Their work profoundly influenced biomedical science and modern art. How one navigates the journey from simplicity to complexity is a fundamental challenge to scientists and artists who aim to identify fresh ideas that lead to insights with lasting impact.}, archive = {J_PNAS}, author = {Goldstein, Joseph L.}, doi = {10.1073/pnas.2513128122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2513128122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {From simplicity to complexity: A path to innovation in science and art}, volume = {122}, year = {2025}, }
• (2025). Climate warming is expanding dengue burden in the americas and asia. PNAS, 122(37), e2512350122. (www)

  @article{ , abstract = {Climate change is expected to pose significant threats to public health, particularly vector-borne diseases. Despite dramatic recent increases in dengue that many anecdotally connect with climate change, the effect of anthropogenic climate change on dengue remains poorly quantified. To assess this link, we assembled local-level data on dengue across 21 countries in Asia and the Americas. We found a nonlinear relationship between temperature and dengue incidence with the largest impact of warming at lower temperatures, peak incidence at 27.8°C, and a decline at higher temperatures. Using this inferred temperature response, we estimate 18% (95% CI: 11 to 27%) of historical dengue incidence on average across our study countries is attributable to anthropogenic warming. Future warming could further increase incidence by 49% (95% CI: 16 to 136%) to 76% (95% CI: 27 to 239%) by midcentury for low or high emissions scenarios, respectively, with cooler regions projected to double in incidence due to warming while other currently hot regions experience little impact or even small declines. Under the highest emissions scenario, we estimate that 262 million people are currently living in places in these 21 countries where dengue incidence is expected to more than double due to climate change by midcentury. These insights highlight the major impacts of anthropogenic warming on dengue burden across most of its endemic range, providing a foundation for public health planning and the development of strategies to mitigate future risks due to climate change.}, archive = {J_PNAS}, author = {Childs, Marissa L. and Lyberger, Kelsey and Harris, Mallory J. and Burke, Marshall and Mordecai, Erin A.}, doi = {10.1073/pnas.2512350122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2512350122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Climate warming is expanding dengue burden in the americas and asia}, volume = {122}, year = {2025}, }
• (2025). Dynamic and precise electromagnetic levitation of single cells. PNAS, 122(37), e2512246122. (www)

  @article{ , abstract = {The biophysical properties of single cells are crucial for understanding cellular function and behavior in biology and medicine. However, precise manipulation of cells in 3-D microfluidic environments remains challenging, particularly for heterogeneous populations. Here, we present “Electro-LEV,” a unique platform integrating electromagnetic and magnetic levitation principles for dynamic 3-D control of cell position during separation. We demonstrated that small current adjustments in electromagnets significantly alter the levitation heights of diverse particles and cell types. By periodically modulating and tracking cell positions along the z-axis, Electro-LEV identified distinct levitation behaviors between single cells and cell clusters, with clusters responding more rapidly to magnetic field changes. Furthermore, we demonstrated that Electro-LEV significantly enhances the purity and efficiency of levitational sorting, achieving 10-fold enrichment of live cells from 50% starting viability samples and 18.8-fold enrichment from 10% starting viability samples. These results establish Electro-LEV as a powerful tool for investigating cellular heterogeneity, differentiating cell sizes and types, and improving cell sorting efficiency. Thus, Electro-LEV is broadly applicable, offering different possibilities for high-resolution cell analysis and label-free cell sorting in various biomedical fields, including but not limited to single-cell sequencing and drug screening.}, archive = {J_PNAS}, author = {Ramarao, Malavika and Garcia-Gradilla, Victor and Burcin Unlu, Mehmet and Davis, Ronald W. and Gozde Durmus, Naside}, doi = {10.1073/pnas.2512246122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2512246122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic and precise electromagnetic levitation of single cells}, volume = {122}, year = {2025}, }
• (2025). Critical exponents of the spin-glass transition in a field at zero temperature. PNAS, 122(37), e2511882122. (www)

  @article{ , abstract = {We analyze the spin-glass transition in a field in finite dimension D below the upper critical dimension directly at zero temperature using a recently introduced perturbative loop expansion around the Bethe lattice solution. The expansion is generated by the so-called M -layer construction, and it has 1 / M as the associated small parameter. Computing analytically and numerically these nonstandard diagrams at first order in the 1 / M expansion, we construct an ϵ -expansion around the upper critical dimension D uc = 8 , with ϵ = D uc − D . Following standard field theoretical methods, we can write a β function, finding a new zero-temperature fixed-point associated with the spin-glass transition in a field in dimensions D < 8 . We are also able to compute, at first order in the ϵ -expansion, the three independent critical exponents characterizing the transition, plus the correction-to-scaling exponent.}, archive = {J_PNAS}, author = {Angelini, Maria Chiara and Palazzi, Saverio and Parisi, Giorgio and Rizzo, Tommaso}, doi = {10.1073/pnas.2511882122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2511882122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Critical exponents of the spin-glass transition in a field at zero temperature}, volume = {122}, year = {2025}, }
• (2025). Toughness enhancement by massive dislocation absorption at the crack front. PNAS, 122(37), e2511830122. (www)

  @article{ , abstract = {Low-cost yet high-performance structural materials have been invariantly sought for modern engineering applications. However, due to the localized stress concentration induced by a high Peierls-Nabarro stress and limited dislocation mobility, increasing material strength usually comes at the expense of ductility and toughness, resulting in a trade-off between strength–ductility/strength–toughness. Here, we report an anomalous phenomenon of dislocation absorption at the crack front, which is unlike typically observed dislocation emission at the crack tip, in a heterogeneous “plain” steel consisting of tempered lath martensite embedded with stable carbon-enriched retained austenite. The continuous absorption of dislocations emitted from the tempered martensite into the tough austenite significantly alleviates the localized stress concentration, and as such retards crack propagation in the tempered martensite matrix. This allows the plain high-carbon low-alloyed steel subjected to simple quenching–partitioning–tempering processes to achieve remarkable properties comprising a multiplication of strength and elongation over 50 GPa·% with an exceptionally high fracture toughness over 130 MPa·m 1/2 . The toughening strategy based on this mechanism provides a promising route for developing cost-effective plain steels with ultrahigh strength, ductility, and toughness that is a persistent pursuit in the steel industry.}, archive = {J_PNAS}, author = {Zhang, Jiazhi and Yu, Qin and Tian, Jiazhuang and Yang, Shanglu and Zuo, Xunwei and Li, Ying and Chen, Nailu and Rong, Yonghua and Ritchie, Robert O. and Lu, Jian}, doi = {10.1073/pnas.2511830122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2511830122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Toughness enhancement by massive dislocation absorption at the crack front}, volume = {122}, year = {2025}, }
• (2025). Muricholic acid mediates puberty initiation via the hypothalamic TGR5 signaling pathway. PNAS, 122(37), e2511404122. (www)

  @article{ , abstract = {The onset of puberty is increasingly observed at earlier ages in children, especially in girls with obesity, a trend that predisposes them to long-term metabolic and reproductive disorders in adulthood. Bile acids have emerged as pivotal signaling molecules in both metabolic and reproductive disorders, but remain unexplored in the early onset of puberty in children. Herein, we find elevated levels of muricholic acid (MCA) species in the serum of girls with central precocious puberty, which strongly correlate with indices of hypothalamic–pituitary–gonadal axis activation and can reach peak levels during puberty among healthy children. Intriguingly, reduction of MCA species can lead to decreased expression of gonadotropin-releasing hormone (GnRH) and delay the early onset of puberty, while elevated MCA levels induced premature sexual development in female mice. Mechanistically, we demonstrated that MCA had strong activation effects on Takeda G-protein-coupled receptor 5 (TGR5), and MCA enhanced GnRH expression in GnRH neurons through activation of the TGR5-PI3K/Akt-mTOR signaling pathway. Our findings reveal a link between metabolic status and reproductive maturation, highlighting MCA as a potential therapeutic target for managing early puberty initiation.}, archive = {J_PNAS}, author = {Wang, Shan and Huang, Ke and Liu, Ana and Wang, Senjie and Jiang, Runqiu and Chen, Wenlian and Wang, Huiying and Ullah, Rahim and Xue, Chuqing and Wu, Wei and Dong, Guanping and Jiang, Peifang and Fu, Junfen and Ni, Yan}, doi = {10.1073/pnas.2511404122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2511404122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Muricholic acid mediates puberty initiation via the hypothalamic TGR5 signaling pathway}, volume = {122}, year = {2025}, }
• (2025). Sensitization of cancer cells to DNA-damaging agents by expression of the REV1 C-terminal domain: Implications for chemotherapy. PNAS, 122(37), e2511136122. (www)

  @article{ , abstract = {The mutagenic translesion synthesis (TLS) pathway, which is critically dependent on REV1’s ability to recruit inserter TLS polymerases and the POLζ extender polymerase, enables cancer cells to bypass DNA lesions while introducing mutations that likely contribute to the development of chemotherapy resistance and secondary malignancies. Targeting this pathway represents a promising therapeutic strategy. Here, we demonstrate that the expression of the C-terminal domain (CTD) of human REV1, a ca. 100 amino acid scaffold essential for TLS polymerase interactions, disrupts REV1/POLζ-dependent TLS in mammalian cells. Inducible expression of REV1-CTD in multiple human and murine cancer cell lines sensitizes cells to DNA-damaging agents such as cisplatin, benzo[a]pyrene diol epoxide, and methyl methanesulfonate, without intrinsic cytotoxicity. REV1-CTD expression increases genomic instability, decreases mutagenesis, and enhances G2 arrest following genotoxic stress. Mutational disruption of the CTD’s interaction interfaces abrogates these effects, confirming a dominant-negative mechanism via sequestration of TLS components. In a xenograft mouse model, REV1-CTD expression markedly enhances cisplatin efficacy, significantly reducing tumor burden. These findings establish the REV1-CTD as an effective dominant-negative inhibitor of TLS and support its development as a therapeutic agent delivered to cancer cells to enhance the efficacy of genotoxic chemotherapy.}, archive = {J_PNAS}, author = {Bian, Ke and Gruber, Charley C. and Byers, Emine and Leclerc, Paul and Hemann, Michael T. and Walker, Graham C.}, doi = {10.1073/pnas.2511136122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2511136122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sensitization of cancer cells to DNA-damaging agents by expression of the REV1 C-terminal domain: Implications for chemotherapy}, volume = {122}, year = {2025}, }
• (2025). Directed evolution of a plant rubisco chaperone with altered client recognition. PNAS, 122(37), e2510701122. (www)

  @article{ , abstract = {Improving the Calvin–Benson–Bassham cycle enzyme Ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) has the potential to increase crop productivity. However, the selectivity of the chaperones mediating Rubisco assembly in vascular plants toward their cognate Rubisco presents a substantive roadblock to both Rubisco protein engineering and transgenic expression of heterologous Rubisco orthologs, both of which necessitate changes to the Rubisco sequence. Here, we ask whether a plant Rubisco chaperone can be reprogrammed by directed evolution to accommodate a nonnative client. We developed a selection strategy to assess Rubisco assembly factor activity in high-throughput and used this selection to identify mutants of the chaperone Raf1 from Arabidopsis thaliana ( At Raf1) that assemble Nicotiana tabacum Rubisco, for which wild-type At Raf1 has minimal activity. We show that directed evolution can generate At Raf1 variants that enable significantly increased N. tabacum Rubisco assembly compared to wild-type At Raf1. Evaluation of evolved At Raf1s indicates that they retain the ability to assemble their native client and can assemble other dicot Rubisco orthologs that they were not evolved to recognize. This work may provide a strategy for addressing the constraints chaperone selectivity impose upon Rubisco-centric efforts to improve plant photosynthesis.}, archive = {J_PNAS}, author = {Li, Siyu and Lee, ByungUk and Lao, Yichong and Lertwiriyapiti, Sirawit and Huang, Xuhui and Wang, Tina}, doi = {10.1073/pnas.2510701122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2510701122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Directed evolution of a plant rubisco chaperone with altered client recognition}, volume = {122}, year = {2025}, }
• (2025). Spontaneous glutamate release activates mGluR signaling to drive rapid antidepressant responses. PNAS, 122(37), e2510642122. (www)

  @article{ , abstract = {Major depressive disorder affects millions worldwide, yet current treatments require prolonged administration. In contrast, ketamine produces rapid antidepressant effects by blocking spontaneous N-Methyl-D-Aspartate (NMDA) receptor signaling, which lifts the suppression of protein synthesis and triggers homeostatic synaptic plasticity. Here, we identify a parallel signaling pathway involving metabotropic glutamate receptor 5 (mGluR5) that promotes rapid antidepressant-like effects. We show that enhancing the endogenous mGluR5 signaling produces synaptic potentiation in the hippocampus and triggers the rapid antidepressant effect, similar to ketamine. Importantly, blocking mGluR5 prevents ketamine’s effects, revealing a synergy between the two pathways. At the cellular level, spontaneous calcium transients mediated by mGluR5 activate the phosphatase calcineurin and promote eukaryotic elongation factor 2 (eEF2) dephosphorylation, increasing BDNF translation to drive synaptic plasticity. We show that quantal glutamate release activates two spatially segregated Ca 2+ signals—NMDAR- and mGluR5-driven—which exert opposing effects on protein synthesis. Together, these findings highlight mGluR5 as a promising therapeutic target for rapid antidepressant action, harnessing the complex nanoscale organization of synapses.}, archive = {J_PNAS}, author = {McCarthy, Clara I. and Zack Ma, Z. and Monteggia, Lisa M. and Kavalali, Ege T.}, doi = {10.1073/pnas.2510642122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2510642122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spontaneous glutamate release activates mGluR signaling to drive rapid antidepressant responses}, volume = {122}, year = {2025}, }
• (2025). Adrenal lipoma formation via PI(3,4,5)P3/AKT-dependent transdifferentiation of adrenocortical cells into adipocytes. PNAS, 122(37), e2510306122. (www)

  @article{ , abstract = {Adrenal lipomas are benign tumors containing ectopic adipose tissue in the adrenal gland, an organ that normally lacks both adipocytes and their progenitors. The origin of this ectopic fat remains enigmatic, and the absence of a genetic animal model has hindered its investigation. Phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ], a key signaling lipid that regulates cellular growth and differentiation, is tightly regulated by the lipid phosphatases PTEN (phosphatase and tensin homolog) and SHIP2 (SH2-containing inositol phosphatase 2). Here, we demonstrate that simultaneous loss of Pten and Ship2 in the adrenal cortex induces adrenal lipoma formation in mice. These lipomatous cells display both adipocyte-like morphology and adipocyte-specific gene expression. Lineage tracing revealed that these lipomas originate from the adrenal cortex. Mechanistically, PI(3,4,5)P 3 hyperaccumulation in the adrenal cortex activates AKT (AKT8 virus oncogene cellular homolog), leading to ectopic PPARγ (peroxisome proliferator activated receptor gamma) expression, a key driver of adipocyte differentiation. This study suggests that the PI(3,4,5)P 3 /AKT-driven transdifferentiation of adrenocortical cells may represent a central mechanism underlying adrenal lipoma formation, thereby providing insights into lipoma pathogenesis and cellular reprogramming in vivo.}, archive = {J_PNAS}, author = {Yanai, Shogo and Sasaki, Junko and Lee-Okada, Hyeon-Cheol and Takahashi, Fumiya and Kikuchi, Yuto and Morioka, Shin and Yamamoto, Toshiyoshi and Yuguchi, Katsuya and Oikawa, Miko and Kajiho, Hiroaki and Baba, Takashi and Yokoyama, Chikako and Morohashi, Ken-Ichirou and Suzuki, Akira and Yokomizo, Takehiko and Sasaki, Takehiko}, doi = {10.1073/pnas.2510306122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2510306122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Adrenal lipoma formation via PI(3,4,5)P3/AKT-dependent transdifferentiation of adrenocortical cells into adipocytes}, volume = {122}, year = {2025}, }
• (2025). 3D cryoimaging of cell-mediated cholesterol crystal clearance in human atherosclerotic lesions. PNAS, 122(37), e2510133122. (www)

  @article{ , abstract = {We applied micro-computed tomography, high-resolution cryo-scanning electron microscopy (SEM) combined with cathodoluminescence, and cryo-focused ion beam Milling-SEM to perform three-dimensional imaging of human atherosclerotic tissues with tens of nanometers resolution, under hydrated, near-native conditions with minimal sample processing. The same technology was applied to cultured macrophages exposed to cholesterol crystals, and the observations made on the macrophages were compared to those made on the pathological tissue. We observed that cholesterol crystal digestion and, eventually, cholesterol crystal clearance occurs in the advanced human plaques through cellular processing. Our findings suggest that cholesterol crystal disassembly occurs through the esterification of crystalline cholesterol to cholesteryl-ester in isolated volumes, whereby the ester aggregates into intra- and extracellular pools. The hypothesis is supported by the close similarity of the processes imaged in the human tissue and in the macrophages and is in agreement with earlier biochemical studies performed on cultured macrophages.}, archive = {J_PNAS}, author = {Capua-Shenkar, Jenny and Kaestner, Antonia and Rechav, Katya and Brumfeld, Vlad and Kaplan-Ashiri, Ifat and Varsano, Neta and Avinoam, Ori and Speter, Chen and Halak, Moshe and Kruth, Howard and Addadi, Lia}, doi = {10.1073/pnas.2510133122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2510133122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {3D cryoimaging of cell-mediated cholesterol crystal clearance in human atherosclerotic lesions}, volume = {122}, year = {2025}, }
• (2025). Structural basis for rad54- and hed1-mediated regulation of rad51 during the transition from mitotic to meiotic recombination. PNAS, 122(37), e2510007122. (www)

  @article{ , abstract = {Rad51 catalyzes the DNA pairing reactions that take place during homologous recombination (HR), and HR must be tightly regulated to ensure physiologically appropriate outcomes. Rad54 is an ATP-dependent DNA motor protein that stimulates Rad51 activity during mitosis. In meiosis Rad51 is downregulated by the protein Hed1, which blocks Rad54 binding to Rad51, and allows Dmc1 to function as the active recombinase. We currently have a poor understanding of the regulatory interplay between Rad54, Hed1, Rad51, and Dmc1. Here, we identify a conserved Rad51 interaction motif within Rad54, and we solve a CryoEM structure of this motif bound to Rad51. We also identify a distinct Rad51 interaction motif within Hed1 and solve its structure bound to Rad51. These structures explain how Rad54 engages Rad51 to promote recombination between sister chromatids during mitosis and how Rad51 is downregulated by Hed1 upon entry into meiosis such that its meiosis-specific homolog Dmc1 can promote recombination between homologous chromosomes.}, archive = {J_PNAS}, author = {Shin, Yeonoh and Petassi, Michael T. and Jessop, Aidan M. and Kim, Stefan Y. and Matei, Razvan and Morse, Katherine and Raina, Vivek B. and Roy, Upasana and Greene, Eric C.}, doi = {10.1073/pnas.2510007122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2510007122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis for rad54- and hed1-mediated regulation of rad51 during the transition from mitotic to meiotic recombination}, volume = {122}, year = {2025}, }
• (2025). From molecular damage and viscoelasticity to interfacial fracture in soft polymer networks: Insights from mechanochemistry. PNAS, 122(37), e2509322122. (www)

  @article{ , abstract = {Many soft, tough materials have emerged in recent years, paving the way for advances in wearable electronics, soft robotics, and flexible displays. However, understanding the interfacial fracture behavior of these materials remains a significant challenge, owing to the difficulty of quantifying the respective contributions from viscoelasticity and damage to energy dissipation ahead of cracks. This work aims to address this challenge by labeling a series of polymer networks with fluorogenic mechanophores, subjecting them to T-peel tests at various rates and temperatures, and quantifying their force-induced damage using a confocal microscope. The results challenge longstanding assumptions underlying linear viscoelastic fracture theories, revealing a complex interplay between viscoelasticity and damage governed by the Weissenberg number, W i . Specifically, they suggest a molecular picture in which the interfacial toughness increases due to polymer chain breakage and enlarged strains when W i < 0.3 , and significant chain friction and network stiffening when W i > 0.3 , with the damage being negligible in the limits of W i ≪ 0.3 and W i ≫ 0.3 either due to insufficient strains at the peel front or because of excessive stress at weak interfacial bonds. Overall, these results illustrate the molecular and mesoscopic mechanisms underpinning interfacial fracture, aiding to refine current viscoelastic fracture theories and accelerating the development of advanced polymer networks for increasingly demanding applications.}, archive = {J_PNAS}, author = {Arrowood, Anthony and Frazier, Jackson and Ciccotti, Matteo and Sanoja, Gabriel E.}, doi = {10.1073/pnas.2509322122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2509322122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {From molecular damage and viscoelasticity to interfacial fracture in soft polymer networks: Insights from mechanochemistry}, volume = {122}, year = {2025}, }
• (2025). Could humans and AI become a new evolutionary individual?. PNAS, 122(37), e2509122122. (www)

  @article{ , archive = {J_PNAS}, author = {Rainey, Paul B. and Hochberg, Michael E.}, doi = {10.1073/pnas.2509122122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2509122122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Could humans and AI become a new evolutionary individual?}, volume = {122}, year = {2025}, }
• (2025). Female membrane proteins regulate postmating ovulation in drosophila melanogaster by ovulin-dependent and -independent pathways. PNAS, 122(37), e2508783122. (www)

  @article{ , abstract = {Ovulation is an intricate process that is essential for reproductive success. In Drosophila melanogaster , ovulation increases after mating. This increase is initiated by the male seminal fluid protein ovulin and is executed by female pathways, including octopamine (OA) neuronal signaling. Despite OA signaling’s central role in ovulation regulation, the broader molecular landscape underlying female control of ovulation remains poorly understood. Here, using ovulin as a probe, we performed evolutionary rate covariation and AlphaFold-Multimer prediction screens to identify candidate female ovulation-regulating proteins. Ovulation assays performed on knockdowns or mutants of identified membrane-protein candidates revealed seven important female ovulation regulators: Lgr3, GabaβR1, SIFaR, mthl9, Smog, Cirl, and CG6067. Lgr3 and GabaβR1 function in an ovulin-dependent manner, while SIFaR and mthl9 regulate ovulation independently of ovulin. For proteins with known nervous system expression, we examined their requirement in OA neurons and their expression in female reproductive tract neurons. Tissue-specific knockdown revealed that Lgr3, GabaβR1, SIFaR, and CG6067 act in OA neurons to influence ovulation, highlighting OA neurons as a key signaling hub. Additionally, Lgr3, GabaβR1, SIFaR, Smog, and Cirl are expressed in OA neurons innervating the reproductive tract, suggesting a potential local function. Finally, we identified evidence of recurrent positive selection having acted on residues within Smog’s ligand binding region, which is interesting in light of ovulin’s rapid evolution. Together, these findings significantly expand our understanding of the molecular networks regulating ovulation following mating in Drosophila .}, archive = {J_PNAS}, author = {Yang, Mengye and White, Melissa A. and Findlay, Geoffrey D. and Vignogna, Ryan C. and Apger-McGlaughon, Jennifer and Clark, Nathan L. and Choi, Jae Young and Fromme, J. Christopher and Wolfner, Mariana F.}, doi = {10.1073/pnas.2508783122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2508783122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Female membrane proteins regulate postmating ovulation in drosophila melanogaster by ovulin-dependent and -independent pathways}, volume = {122}, year = {2025}, }
• (2025). Teeth outside the jaw: Evolution and development of the toothed head clasper in chimaeras. PNAS, 122(37), e2508054122. (www)

  @article{ , abstract = {Chimaeras ( Holocephali ) are an understudied group of mostly deep-ocean cartilaginous fishes ( Chondrichthyes ) with unique characteristics that distinguish them from their distant relatives, sharks, skates, and rays. Unlike sharks, chimaeras lack scales and do not have serially replacing rows of serrated teeth crowned with enameloid. Instead, they possess a fused dentition of dentine tooth plates. Additionally, male chimaeras develop an articulated cartilaginous facial appendage, the tenaculum, which is covered in an arcade of tooth-like structures. These extraoral teeth remain poorly understood, and their evolutionary origin is unclear. We investigate the development of the tenaculum and its teeth throughout the ontogeny of the Spotted Ratfish, Hydrolagus colliei , to assess homology and convergence between this novel craniofacial feature and oral jaws. Our study aims to 1) describe the development of the tenaculum, 2) assess tenaculum tooth development in comparison to oral teeth and denticles, and 3) characterize the genes and tissues responsible for tenaculum tooth emergence. We found that juvenile male chimaeras develop a full tenaculum before tooth development is complete and that only mature males possess a fully toothed tenaculum. These extraoral teeth emerge from within the tenaculum rather than from the surrounding epithelium. We integrate our developmental data with fossil evidence of the tenacular dentition from the Carboniferous holocephalan Helodus simplex . Our findings show that the tenaculum is closely associated with the upper jaw and that tenacular dentition resembles separate shark-like oral tooth whorls more than modified dermal denticles.}, archive = {J_PNAS}, author = {Cohen, Karly E. and Coates, Michael I. and Fraser, Gareth J.}, doi = {10.1073/pnas.2508054122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2508054122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Teeth outside the jaw: Evolution and development of the toothed head clasper in chimaeras}, volume = {122}, year = {2025}, }
• (2025). A genetically encoded nanobody sensor reveals conformational diversity in β-arrestins orchestrated by distinct seven transmembrane receptors. PNAS, 122(37), e2507384122. (www)

  @article{ , abstract = {Agonist-induced interaction of G protein–coupled receptors (GPCRs) with β-arrestins (βarrs) is a critical mechanism that regulates the spatiotemporal pattern of receptor localization and signaling. While the underlying mechanism governing GPCR–βarr interaction is primarily conserved and involves receptor activation and phosphorylation, there are several examples of receptor-specific fine-tuning of βarr-mediated functional outcomes. Considering the key contribution of conformational plasticity of βarrs in driving receptor-specific functional responses, it is important to develop novel sensors capable of reporting distinct βarr conformations in cellular context. Here, we design an intrabody version of a βarr-recognizing nanobody (nanobody32), referred to as intrabody32 (Ib32), in NanoLuc enzyme complementation assay format and measure its ability to recognize βarr1 and 2 in live cells upon activation of a broad set of GPCRs. Ib32 robustly recognizes activated βarr1 and 2 in the plasma membrane and endosomes, and effectively mirrors βarr recruitment profile upon stimulation of selected GPCRs. We also design an Ib32 sensor for polarization microscopy with a change in linear dichroism as readout and demonstrate its utility for monitoring βarr activation upon stimulation of selected GPCRs by natural and biased agonists. Taken together with a previously described sensor of βarr1 activation, Ib32 underscores the inherent flexibility encoded in βarrs and conformational diversity imparted by different GPCRs, which is further corroborated using an orthogonal limited proteolysis assay. Our study presents Ib32 as a sensor of βarr activation and highlights the structural diversity of βarrs, which likely allows their ability to interact with, and regulate, a large repertoire of GPCRs.}, archive = {J_PNAS}, author = {Sarma, Parishmita and Nagy Marková, Vendula and Dalal, Annu and Mishra, Sudha and Zaidi, Nashrah and Tiwari, Divyanshu and Yadav, Manish K. and Roy, Nabarun and Mahajan, Gargi and Miclea, Paul and Lazar, Josef and Shukla, Arun K.}, doi = {10.1073/pnas.2507384122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2507384122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A genetically encoded nanobody sensor reveals conformational diversity in β-arrestins orchestrated by distinct seven transmembrane receptors}, volume = {122}, year = {2025}, }
• (2025). 3D pattern formation of a protein–membrane suspension. PNAS, 122(37), e2506401122. (www)

  @article{ , abstract = {Many essential cellular processes, including cell division and the establishment of cell polarity during embryogenesis, are regulated by pattern-forming proteins. These proteins often need to bind to a substrate, such as the cell membrane, onto which they interact and form two-dimensional (2D) patterns. It is unclear how the membrane’s continuity and dimensionality impact pattern formation. Here, we address this gap using the MinDE system, a prototypical example of pattern-forming membrane proteins. We show that when the lipid substrate is fragmented into submicrometer-sized diffusive liposomes, adenosine triphosphate-driven protein–protein interactions generate three-dimensional (3D) spatially extended patterns, despite the complete loss of membrane continuity. Remarkably, these 3D patterns emerge at scales four orders of magnitude larger than the individual liposomes. By systematically varying protein concentration, liposome size, and density, we observed and characterized a variety of 3D dynamical patterns not seen on continuous 2D membranes, including traveling waves, dynamical spirals, and a coexistence phase. Simulations and linear stability analysis of a coarse-grained model revealed that the physical properties of the dispersed membrane effectively rescale both the protein–membrane binding rates and diffusion, two key parameters governing pattern formation and wavelength selection. These findings highlight the robustness of Min’s pattern-forming ability, suggesting that protein–membrane suspensions could serve as an adaptable template for studying out-of-equilibrium self-organization in 3D, beyond in vivo contexts.}, archive = {J_PNAS}, author = {Chardac, Amélie and Norton, Michael M. and Touboul, Jonathan and Duclos, Guillaume}, doi = {10.1073/pnas.2506401122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2506401122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {3D pattern formation of a protein–membrane suspension}, volume = {122}, year = {2025}, }
• (2025). Deep reinforcement learning control unlocks enhanced heat transfer in turbulent convection. PNAS, 122(37), e2506351122. (www)

  @article{ , abstract = {Turbulent convection governs heat transport in both natural and industrial settings, yet optimizing it under extreme conditions remains a significant challenge. Traditional control strategies, such as predefined temperature modulation, struggle to achieve substantial enhancement. Here, we introduce a deep reinforcement learning (DRL) framework that autonomously discovers optimal control policies to maximize heat transfer in turbulent Rayleigh-Bénard convection. By dynamically adjusting wall temperature fluctuations, the DRL agent achieves a heat transfer enhancement of up to 38.5%, exceeding the 20 to 25% limit of conventional methods. The learned strategy reveals a nonlinear state–action relationship, inducing a fully modulated boundary layer regime. Furthermore, we distill the DRL insights into a simplified bang-bang control model, which retains comparable performance (up to 40.0% enhancement) and, crucially, generalizes to unseen, higher Rayleigh number cases without additional training. Our results demonstrate the power of machine learning in turbulence control and reveal a framework with potential for intelligent heat transfer optimization in real-world applications.}, archive = {J_PNAS}, author = {Zhou, Zisong and Zhu, Xiaojue}, doi = {10.1073/pnas.2506351122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2506351122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deep reinforcement learning control unlocks enhanced heat transfer in turbulent convection}, volume = {122}, year = {2025}, }
• (2025). The arabidopsis TIRome informs the design of artificial TIR (Toll/interleukin-1 receptor) domain proteins. PNAS, 122(37), e2505893122. (www)

  @article{ , abstract = {The TIR (Toll/interleukin-1 receptor) domain is an ancient protein module that functions in immune and cell death responses across the Tree of Life. TIR domains encoded by plants and prokaryotes function as enzymes to produce diverse small molecule immune signals. Plant genomes can encode hundreds of TIR-domain containing proteins—many of which confer important agricultural disease resistance as TIR-NLR (nucleotide-binding, leucine-rich repeat) immune receptors. Despite their importance, how natural variation influences TIR enzymatic output and immunity-associated cell death is largely unexplored. We assayed a complete collection of the TIR domains of Arabidopsis thaliana Col-0 (the “AtTIRome”) to explore variation in TIR metabolite production and cell death signaling. Roughly half of the AtTIRome triggered cell death in transient assays. Artificial TIR proteins designed based on consensus sequences of the AtTIRome’s cell death phenotypic classes revealed polymorphisms controlling variation in TIR cell death elicitation and metabolite production. Structure–function analyses of artificial TIRs revealed that natural variation in the “BB-loop”, a flexible region overlying the catalytic pocket, determines differences in function across Arabidopsis TIR-containing proteins. We further demonstrate that artificial TIRs are functional on an NLR chassis and that BB-loop variation can tune the activity of a natural TIR-NLR protein. These findings shed light on the diversity of TIR outputs and reveal methods to design and engineer TIR-based immune receptors.}, archive = {J_PNAS}, author = {Bayless, Adam M. and Song, Lijiang and Sorbello, Mitchell and Ogden, Sam C. and Todd, Tyler S. and Flint, Alice and Maruta, Natsumi and Tulu, Jedidiah and Drenichev, Mikhail and Ntoukakis, Vardis and Ve, Thomas and Mobli, Mehdi and Wan, Li and Liu, Qingli and Dangl, Jeffery L. and Kobe, Bostjan and Grant, Murray and Nishimura, Marc T.}, doi = {10.1073/pnas.2505893122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2505893122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The arabidopsis TIRome informs the design of artificial TIR (Toll/interleukin-1 receptor) domain proteins}, volume = {122}, year = {2025}, }
• (2025). Giant mobility of surface-trapped ionic charges following liquid tribocharging. PNAS, 122(37), e2505841122. (www)

  @article{ , abstract = {The sliding motion of aqueous droplets on hydrophobic surfaces leads to charge separation at the trailing edge, with implications from triple-line friction to hydrovoltaic energy generation. Charges deposited on the solid surface have been attributed to ions or electrons ripped off from the liquid drop. However, the dynamics and exact physicochemical nature of these surface-trapped charges remains poorly explored. Here, we take advantage of a scanning-based electrostatic mapping technique, to directly quantify the spatiotemporal dynamics of surface deposited charges in the wake of droplets sliding on hydrophobic surfaces. We confirm the ionic nature of these interfacially trapped charges, and evidence that they undergo very fast bidimensional diffusive transport, gliding with low friction at the solid/gas interface. We interpret our observations in the framework of molecular dynamics simulation of hydrated ions adsorbed on solid surfaces, revealing a peculiar transport mechanism limited by purely interfacial friction of the ionic solvation shell with the solid surface. By uncovering the unexpected dynamics of these ionic puddles—a distinct state of interfacial ionic matter—our findings have general implications for molecular-scale ionic transport, electrified matter, and wetting dynamics at interfaces.}, archive = {J_PNAS}, author = {Benrahla, Zouhir and Saide, Tristan and Burnaz, Louis and Verneuil, Emilie and Gravelle, Simon and Comtet, Jean}, doi = {10.1073/pnas.2505841122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2505841122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Giant mobility of surface-trapped ionic charges following liquid tribocharging}, volume = {122}, year = {2025}, }
• (2025). CpG-A induces liquid–liquid phase separation of HMGB1 to activate the RAGE-mediated inflammatory pathway. PNAS, 122(37), e2505826122. (www)

  @article{ , abstract = {High-mobility group box protein 1 (HMGB1) is a chromatin-associated nonhistone protein widely distributed in the nucleus of eukaryotic cells. It is transported extracellularly as a proinflammatory mediator or late warning protein to induce immune and inflammatory reactions upon stimuli such as microbial infection. Here, we have found that HMGB1 directly interacts with bacterial DNA analogue CpG-A in the extracellular environment to undergo liquid–liquid phase separation (LLPS) via its positively charged DNA-binding domain. We have demonstrated that the receptor for advanced glycosylation end products (RAGE) responds to stimulation of the extracellular HMGB1-CpG-A complex and triggers phase separation of the downstream adaptor protein, Src76kDa structural domain leukocyte protein (SLP76), which promotes activation of the MAPK pathway and release of inflammatory cytokines. These results not only designate that LLPS serves as a gain-of-function mechanism involved in the axis of DNA-HMGB1 stimulated RAGE-SLP76 signaling pathway but also provide evidence that the activity of HMGB1 is regulated by LLPS, highly relevant to immune responses of inflammatory cells toward microbial infection. Especially, the finding that the intracellular SLP76 forms condensates with the cytosol domain of RAGE may represent a general downstream phenomenon when an inflammatory cell membrane receptor is activated.}, archive = {J_PNAS}, author = {Peng, Kaihui and Fu, Gaohong and Chen, Long and Xie, Jiazhi and Bao, Kai and Li, Jin-Ping and Luo, Shi-Zhong}, doi = {10.1073/pnas.2505826122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2505826122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CpG-A induces liquid–liquid phase separation of HMGB1 to activate the RAGE-mediated inflammatory pathway}, volume = {122}, year = {2025}, }
• (2025). Chelation-induced anti-ostwald ripening: Ultrafine bismuth nanocrystals for ultrastable aqueous sodium storage. PNAS, 122(37), e2505640122. (www)

  @article{ , abstract = {Aqueous sodium-ion batteries (ASIBs) are gaining attention for their inherent safety and the use of abundant sodium resources. Bismuth (Bi) anode, with its high theoretical capacity and low cost, enhances the performance and competitiveness of ASIBs in energy storage applications. However, as a conversion-type material, Bi inevitably undergoes dramatic volume changes during cycling, limiting the structural stability and calendar life of the electrode. Herein, we present a Bi-carbon composite electrode with ultrafine Bi nanocrystals (< 10 nm) uniformly integrated into nitrogen-doped carbon nanofibers (UF Bi@NCF). Despite Bi’s low melting point (271 °C), Ostwald ripening of metallic Bi during carbonization (750 °C) is effectively suppressed by incorporating polyacrylic acid as a chelating polymer in the electrospun Bi(III)/polyacrylonitrile precursor solutions. The high dispersity of Bi nanocrystals at elevated temperature is attributed to the strong coordination and electrostatic interactions between carboxyl groups and Bi 3+ . This structural refinement significantly reduces localized stress concentrations during sodiation/desodiation. The UF Bi@NCF anode demonstrates a reversible capacity of 237.5 mAh g −1 at 0.5 C, and negligible capacity decay even after 5,700 cycles at an extremely high current rate of 20 C for ASIBs. These findings highlight the potential of the anti-Ostwald ripening effect in enhancing the stability and performance of metal-carbon composite electrodes, providing valuable insights into the design of advanced materials for next-generation aqueous batteries.}, archive = {J_PNAS}, author = {Zhu, Haojie and Cai, Xinlei and Zhu, Dianhui and Kang, Feiyu and Peng, Lu and Zhi, Chunyi and Yang, Cheng}, doi = {10.1073/pnas.2505640122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2505640122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chelation-induced anti-ostwald ripening: Ultrafine bismuth nanocrystals for ultrastable aqueous sodium storage}, volume = {122}, year = {2025}, }
• (2025). Distinct prelimbic cortex ensembles encode response execution and inhibition. PNAS, 122(37), e2505378122. (www)

  @article{ , abstract = {Learning when to initiate or withhold actions is essential for survival, requiring the integration of past experiences with new information to adapt to changing environments. The prelimbic cortex (PL) plays a central role in this process, with a stable PL neuronal population (ensemble) recruited during operant reward learning to encode response execution. However, it is unknown how this established reward-learning ensemble adapts to changing reward contingencies, such as reward omission during extinction. Specifically, does the same ensemble adjust its activity to support behavior suppression, or is a distinct ensemble recruited for this new learning? Our data reveal that operant extinction learning recruits a distinct PL Extinction ensemble to support response inhibition, and concerted engagement of both ensembles encodes both ongoing and subsequent context-specific behavior. Using single-cell calcium imaging, we longitudinally tracked PL neurons in rats as they pressed a lever for food rewards (Training), learned to suppress responding upon reward omission (Extinction), and reinstated responding following a noncontingent “priming” pellet (Reinstatement). We trained decoders on individual rats’ PL activity patterns to predict trial-wise responses and used an in silico deletion approach to identify separate PL Training and Extinction ensembles associated with response execution and inhibition, respectively. Critically, both ensembles were reengaged and maintained their distinct roles during Reinstatement. These findings highlight ensemble-based encoding of multiple, even opposing, learned associations within the same region, demonstrating how selective ensemble recruitment enables behavioral flexibility under changing contingencies.}, archive = {J_PNAS}, author = {Madangopal, Rajtarun and Zhao, Yuan and Heins, Conor and Zhou, Jingfeng and Liang, Bo and Barbera, Giovanni and Lam, Ka Chun and Komer, Lauren E. and Weber, Sophia J. and Thompson, Drake J. and Gera, Yugantar and Pham, Diana Q. and Savell, Katherine E. and Warren, Brandon L. and Caprioli, Daniele and Venniro, Marco and Bossert, Jennifer M. and Ramsey, Leslie A. and Jedema, Hank P. and Schoenbaum, Geoffrey and Lin, Da-Ting and Shaham, Yavin and Pereira, Francisco and Hope, Bruce T.}, doi = {10.1073/pnas.2505378122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2505378122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Distinct prelimbic cortex ensembles encode response execution and inhibition}, volume = {122}, year = {2025}, }
• (2025). Evolution of cross-tolerance to metals in yeast. PNAS, 122(37), e2505337122. (www)

  @article{ , abstract = {Organisms often face multiple selective pressures simultaneously (e.g., mine tailings with multiple heavy metal contaminants), yet we know little about when adaptation to one stressor provides cross-tolerance or cross-intolerance to other stressors. To explore the potential for cross-tolerance, we adapted Saccharomyces cerevisiae to high concentrations of six single metals in a short-term evolutionary rescue experiment. We then measured cross-tolerance of each metal-adapted line to the other five metals. We tested three predictors for the degree of cross-tolerance, based on similarity in 1) the physiochemical properties of each metal pair, 2) the overlap in genes known to impact tolerance to both metals, and 3) their co-occurrence in the environment. None of these predictors explained significant variation in cross-tolerance. Instead, the strongest predictor was the metal in which adaptation occurred: Cobalt-adapted lines performed well in most metals (generalists) while manganese-adapted lines typically performed poorly (specialists). To determine the genetic basis, we sequenced the genomes of 109 metal-adapted lines. Broader cross-tolerance characterized lines bearing mutations affecting phosphorus metabolism, with three genes related to phosphate metabolism bearing several independent mutations ( PHO84 , SIW14 , VTC4 ). Thus, while a genome-wide analysis failed to predict cross-tolerance, a subset of genes facilitated growth in multiple metals. We also observed two “mutator” lines (both in manganese) and report evidence that cadmium, cobalt, and manganese altered the mutation spectrum. While it is challenging to predict how evolutionary adaptation to one stressor will impact tolerance to other stresses, our work helps reveal the environments and pathways that contribute to cross-tolerance among metals.}, archive = {J_PNAS}, author = {Bazzicalupo, Anna L. and Kahn, Penelope C. and Ao, Eully and Campbell, Joel and Otto, Sarah P.}, doi = {10.1073/pnas.2505337122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2505337122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolution of cross-tolerance to metals in yeast}, volume = {122}, year = {2025}, }
• (2025). Interventions to bolster benefits take-up: Assessing intensity, framing, and targeting of government outreach. PNAS, 122(37), e2504747122. (www)

  @article{ , abstract = {Behaviorally informed “nudges” are widely used in government outreach but are often seen as too modest to address poverty at scale. In four field experiments over 2 y ( n = 542,804 low-income households), we test whether more proactive communication, varying message framing, and more precise targeting can boost take-up of tax-based benefits in California above and beyond traditional light-touch approaches. Our interventions focused on extremely vulnerable households, most with no prior-year earnings, who were at risk of missing out on two crucial benefits: the 2021 expanded Child Tax Credit and pandemic-relief Economic Impact Payments. Light-touch outreach consistently increased take-up of these benefits by 0.14 to 2 percentage points—a 150% to over 500% relative increase—regardless of message, sample, timing, or modality. These light-touch approaches resulted in over $4 million disbursed, with a highly cost-effective return of $50 to over $8,000 per $1 spent. However, higher-touch proactive outreach, varying messaging, and more precise targeting yielded minimal additional benefits, with proactive outreach even showing negative returns. These findings demonstrate that light-touch outreach can effectively shift behavior among very vulnerable households in contexts with reduced compliance burdens, but also underscore an urgent need to rethink the role of higher-touch strategies in closing take-up gaps in social safety net programs.}, archive = {J_PNAS}, author = {Linos, Elizabeth and Lasky-Fink, Jessica and Dorie, Vincent and Rothstein, Jesse}, doi = {10.1073/pnas.2504747122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2504747122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Interventions to bolster benefits take-up: Assessing intensity, framing, and targeting of government outreach}, volume = {122}, year = {2025}, }
• (2025). Synovial MS4A4A correlates with inflammation and counteracts response to corticosteroids in arthritis. PNAS, 122(37), e2504529122. (www)

  @article{ , abstract = {MS4A4A belongs to the MS4A tetraspan protein superfamily and is selectively expressed by the monocyte–macrophage lineage. In this study, we aimed to evaluate the role of MS4A4A+ macrophages in rheumatoid arthritis (RA) pathogenesis and response to treatment. RNA sequencing and immunohistochemistry of synovial samples from either early treatment-naïve or active chronic RA patients showed that MS4A4A expression positively correlated with synovial inflammation. Synovial macrophages from patients treated with corticosteroids (CS) exhibited an enhanced expression of MS4A4A and Fc γ receptor (FcγR) 3. Accordingly, CS enhanced in vitro the expression of MS4A4A and FcγR3 in human and murine macrophages. In an experimental model of arthritis, Ms4a4a deletion had no effect on the disease course but was associated with enhanced therapeutic response selectively to CS. These results suggest that macrophage expression of MS4A4A represents a biomarker of joint inflammation in RA and that its upregulation in concert with FcγR3 by CS counteracts the therapeutic activity of these drugs. Macrophage MS4A4A may represent a biomarker of joint inflammation in RA and a target to amplify the therapeutic activity of CS.}, archive = {J_PNAS}, author = {Boutet, Marie-Astrid and Mattiola, Irene and Silva-Gomes, Rita and Nerviani, Alessandra and Sironi, Marina and Ghirardi, Giulia Maria and Troilo, Alessia and Gianoli, Stefano and Rivellese, Felice and Cubuk, Cankut and Goldmann, Katriona and Putignano, Anna Rita and Di Silvestre, Dario and Lomagno, Andrea and Borroni, Elena Monica and Sobacchi, Cristina and Lewis, Myles J. and Bottazzi, Barbara and Locati, Massimo and Mantovani, Alberto and Pitzalis, Costantino}, doi = {10.1073/pnas.2504529122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2504529122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synovial MS4A4A correlates with inflammation and counteracts response to corticosteroids in arthritis}, volume = {122}, year = {2025}, }
• (2025). Salmonella produces sulfide to compete with escherichia coli in the gut lumen. PNAS, 122(37), e2504095122. (www)

  @article{ , abstract = {Hydrogen sulfide production is a characteristic that distinguishes Salmonella serovars from closely related species, such as Escherichia coli , but its biological significance remains obscure. Here, we show that PhsABC and AsrABC-mediated hydrogen sulfide production by Salmonella enterica serovar ( S. ) Typhimurium was linked to an increased abundance of Deltaproteobacteria and inhibition of cytochrome bd oxidase-mediated aerobic respiration of Escherichia coli in the murine large intestine. Functional phsABC and asrABC operons provided a growth benefit to S. Typhimurium in the cecum of Enterobacterales- free conventional mice only upon inoculation with commensal E. coli. In gnotobiotic mice engrafted with a defined community of 17 human Clostridia isolates, S. Typhimurium infection inhibited cytochrome bd oxidase-mediated aerobic respiration in E. coli only in the presence of Desulfovibrio piger , a sulfide-producing representative of the Deltaproteobacteria. A S. Typhimurium strain deficient for hydrogen sulfide production ( phsA asrA mutant) did not inhibit cytochrome bd oxidase-mediated aerobic respiration in E. coli , even when D. piger was present. Collectively, these data suggest that the phsABC and asrABC operons of Salmonella serovars provide a benefit during competition with closely related bacteria, such as E. coli , by inhibiting cytochrome bd oxidase-mediated aerobic respiration of the commensal.}, archive = {J_PNAS}, author = {Larabi, Anaïs B. and Tiffany, Connor R. and Masson, Hugo L. P. and Nguyen, Henry and Bejarano, Eli J. and Liou, Megan J. and Radlinski, Lauren C. and Demars, Aurore M. and Tsolis, Renée M. and Bäumler, Andreas J.}, doi = {10.1073/pnas.2504095122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2504095122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Salmonella produces sulfide to compete with escherichia coli in the gut lumen}, volume = {122}, year = {2025}, }
• (2025). The RecBC complex protects single-stranded DNA gaps during lesion bypass. PNAS, 122(37), e2503839122. (www)

  @article{ , abstract = {Following encounter with an unrepaired DNA lesion, replication is halted and can restart downstream of the lesion leading to the formation of a single-stranded DNA (ssDNA) gap. To complete replication, this ssDNA gap is filled in by one of the two lesion tolerance pathways: the error-prone Translesion Synthesis (TLS) or the error-free Homology Directed Gap Repair (HDGR). In the present work, we evidence a role for the RecBC complex distinct from its canonical function in homologous recombination at DNA double strand breaks. We show that upon lesion encounter RecBC (independently of its catalytic activity and of the RecD subunit) is required to protect the nascent DNA in order to promote efficient lesion bypass. In the absence of RecBC, our data indicate that the nuclease ExoI can access and degrade the nascent DNA, affecting both TLS and HDGR mechanisms. We show that the recruitment of RecBC becomes particularly important at strong blocking lesions, when postreplicative ssDNA gaps persist and are covered by the ssDNA binding proteins. This protective role of RecBC is reminiscent of the role of BRCA2 in protecting the nascent DNA in human cells, highlighting once again the evolutionary conservation of DNA replication mechanisms across all living organisms.}, archive = {J_PNAS}, author = {Philippin, Gaëlle and Dupaigne, Pauline and Chrabaszcz, Élodie and Iturralde, Maialen and Modesti, Mauro and Le Cam, Eric and Pagès, Vincent and Laureti, Luisa}, doi = {10.1073/pnas.2503839122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2503839122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The RecBC complex protects single-stranded DNA gaps during lesion bypass}, volume = {122}, year = {2025}, }
• (2025). Ecosystem consequences of a nitrogen-fixing proto-organelle. PNAS, 122(37), e2503108122. (www)

  @article{ , abstract = {Microscale symbioses can be critical to ecosystem functions, but the mechanisms of these interactions in nature are often cryptic. Here, we use a combination of stable isotope imaging and tracing to reveal carbon (C) and nitrogen (N) exchanges among three symbiotic primary producers that fuel a salmon-bearing river food web. Bulk isotope analysis, nanoSIMS (secondary ion mass spectrometry) isotope imaging, and density centrifugation for quantitative stable isotope probing enabled quantification of organism-specific C- and N-fixation rates from the subcellular scale to the ecosystem. After winters with riverbed-scouring floods, the macroalga Cladophora glomerata uses nutrients in spring runoff to grow streamers up to 10 m long. During summer flow recession, riverine N concentrations wane and Cladophora becomes densely epiphytized by three species of Epithemia , diatoms with N-fixing endosymbionts (proto-organelles) descended from a free-living Crocosphaera cyanobacterium. Over summertime epiphyte succession on Cladophora , N-fixation rates increased as Epithemia spp. became dominant, Cladophora C-fixation declined to near zero, and Epithemia C-fixation increased. Carbon transfer to caddisflies grazing on Cladophora with high densities of Epithemia was 10-fold higher than C transfer to caddisflies grazing Cladophora with low Epithemia loads. In response to demand for N, Epithemia allocates high levels of newly fixed C to its endosymbiont. Consequently, these endosymbionts have the highest rates of C and N accumulation of any taxon in this tripartite symbiosis during the biologically productive season and can produce one of the highest areal rates of N-fixation reported in any river ecosystem.}, archive = {J_PNAS}, author = {Marks, Jane C. and Zampini, Michael C. and Fitzpatrick, Raina and Kariunga, Saeed H. and Sitati, Augustine and Samo, Ty J. and Weber, Peter K. and Thomas, Steven and Hungate, Bruce A. and Ramon, Christina E. and Wulf, Michael and Leshyk, Victor O. and Schwartz, Egbert and Pett-Ridge, Jennifer and Power, Mary E.}, doi = {10.1073/pnas.2503108122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2503108122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ecosystem consequences of a nitrogen-fixing proto-organelle}, volume = {122}, year = {2025}, }
• (2025). Relationship dynamics and behavioral adaptations in the control of the 2022 mpox epidemic. PNAS, 122(37), e2502861122. (www)

  @article{ , abstract = {We analyzed the patterns of transmission in the 2022 clade IIb mpox epidemic as it unfolded in the European population of men who have sex with men (MSM). We developed an agent-based model that simulates sexual pair formation, incorporating both brief and longer-term sexual relationships. The model implements survey data on the sexual behavior of MSM and accounts for the highly heterogeneous nature of the sexual contact network within this community. When simulating the mpox epidemic, the model reproduces the reported numbers of sexual partners of mpox-infected individuals. We find that infection-derived immunity had little impact on ending the European outbreak. Instead, we suggest that the marked decrease in serial interval observed across the epidemic reflects a substantial increase in self-isolating behavior among infected persons and that this is sufficient to explain the early control of the epidemic. Our work highlights the critical interplay between relationship dynamics and adaptive behaviors in shaping mpox epidemic patterns and achieving control in 2022. Despite continued propagation of clade IIb mpox, the European MSM population remains protected by immunity, primarily vaccine-induced.}, archive = {J_PNAS}, author = {Hvid, Ulrik and Simonsen, Lone and Frisch, Morten and Sneppen, Kim}, doi = {10.1073/pnas.2502861122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2502861122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Relationship dynamics and behavioral adaptations in the control of the 2022 mpox epidemic}, volume = {122}, year = {2025}, }
• (2025). A geometric condition for robot-swarm cohesion and cluster–flock transition. PNAS, 122(37), e2502211122. (www)

  @article{ , abstract = {We present a geometric design rule for size-controlled clustering of self-propelled particles. We show that active particles that tend to rotate under an external force have an intrinsic, signed parameter with units of curvature which we call curvity, that can be derived from first principles. Experiments with robots and numerical simulations show that properties of individual robots (radius and curvity) control pair cohesion in a binary system, and the stability of flocking and self-limiting clustering in a swarm, with applications in metamaterials and in embodied decentralized control.}, archive = {J_PNAS}, author = {Casiulis, Mathias and Arbel, Eden and van Waes, Charlotte and Lahini, Yoav and Martiniani, Stefano and Oppenheimer, Naomi and Zion, Matan Yah Ben}, doi = {10.1073/pnas.2502211122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2502211122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A geometric condition for robot-swarm cohesion and cluster–flock transition}, volume = {122}, year = {2025}, }
• (2025). Extracellular salt bridge networks around s4 implicated in HCN channel gating and heart disease. PNAS, 122(37), e2502136122. (www)

  @article{ , abstract = {The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is a voltage-gated cation channel that plays a crucial role in regulating cellular excitability, especially in cardiac pacemaker cells and neurons. Its dysregulation is linked to heart diseases such as bradycardia and neurological disorders such as epilepsy, Parkinson’s disease, and neuropathic pain. Structural and functional studies have revealed that the S4 voltage sensor of the HCN channel moves downward during hyperpolarization. Recent structural studies of HCN channels have shown that the extracellular portion of the S4 segment is approximately three helical turns longer than that of voltage-gated K + (Kv) channels. However, whether this extended extracellular part of S4 plays a functional role in gating is still unknown. In this study, utilizing the available HCN4 channel structures, we examined the formation of salt bridges in the extracellular part of S4 with the S5 segment and the S1-S2 linker. Results from charge-swapped mutants and double cysteine mutants suggested that sequential, stepwise salt bridge formation involving the extracellular positively charged amino acids of S4 plays a role in the voltage-dependent gating of HCN channels. Furthermore, we applied voltage clamp fluorometry to confirm that the extracellular salt bridge network affects the S4 movement. This extracellular S4 portion includes disease-related arginine residues, R375 and R378. Our results suggest that disruption of salt bridge formation may perturb the smooth transition of S4 movement and cause HCN channel dysfunction.}, archive = {J_PNAS}, author = {Ryu, Kaei and Kasuya, Go and Nakajo, Koichi}, doi = {10.1073/pnas.2502136122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2502136122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Extracellular salt bridge networks around s4 implicated in HCN channel gating and heart disease}, volume = {122}, year = {2025}, }
• (2025). Cooling outweighs warming across phenological transitions in the northern hemisphere. PNAS, 122(37), e2501844122. (www)

  @article{ , abstract = {Vegetation phenology, i.e., seasonal biological events such as leaf-out and leaf-fall, regulates local climate through biophysical processes like evapotranspiration (ET) and albedo. However, the net surface temperature impact of these processes—whether ET cooling or albedo-induced warming predominates—and how the dominance changes across phenological transitions and regions remains poorly understood. Here, we investigated the effects of vegetation foliage on daytime land surface temperature (LST) following six phenological transitions, spanning from the start of season to end of season, in deciduous and mixed forests across the mid- to high-latitude Northern Hemisphere during 2013–2021 using multiple satellite products and ground observations. We quantified vegetation effect as the difference between observed LST and LST estimates from the Annual Temperature Cycle (ATC) model, representing a no-foliage scenario. We found that vegetation-induced cooling consistently outweighs warming following all phenological transitions except for the end of the season. Cooling intensity increased with vegetation greenness, ranging from 1.0 ± 0.5 °C (mean ± 0.15 SD) in 59% of forests after the start of the season (SOS) to 6.1 ± 0.8 °C in 89% of forests following the onset of maturity, before declining toward the end of the season. Over half of the regions experiencing cooling showed intensification of surface cooling with climate warming, suggesting an amplified vegetation-mediated cooling under future climate change. The findings provide a more precise understanding of the role of vegetation in modulating climate at the intraseasonal scale, highlighting the importance of integrating phenological impacts into climate adaptation strategies and Earth system modeling.}, archive = {J_PNAS}, author = {Li, Yizhuo and Meng, Lin and Richardson, Andrew D. and Lee, Xuhui and Menzel, Annette and Mao, Jiafu and Diehl, Jen L. and Wang, Anzhi}, doi = {10.1073/pnas.2501844122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2501844122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cooling outweighs warming across phenological transitions in the northern hemisphere}, volume = {122}, year = {2025}, }
• (2025). The coherence of US cities. PNAS, 122(37), e2501504122. (www)

  @article{ , abstract = {Diversified economies are critical for cities to sustain their growth and development, but they are also costly because diversification often requires expanding a city’s capability base. We analyze how cities manage this trade-off by measuring the coherence of the economic activities they support, defined as the technological distance between randomly sampled productive units in a city. We use this framework to study how the US urban system developed over almost two centuries, from 1850 to today. To do so, we rely on historical census data, covering over 600M individual records to describe the economic activities of cities between 1850 and 1940, as well as 8 million patent records and detailed occupational and industrial profiles of cities for more recent decades. Despite massive shifts in the economic geography of the United States over this 170-y period, average coherence in its urban system remains unchanged. Moreover, across different time periods, datasets, and relatedness measures, coherence falls with city size at the exact same rate, pointing to constraints to diversification that are governed by a city’s size in universal ways.}, archive = {J_PNAS}, author = {Daniotti, Simone and Hartog, Matté and Neffke, Frank}, doi = {10.1073/pnas.2501504122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2501504122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The coherence of US cities}, volume = {122}, year = {2025}, }
• (2025). Excitatory glycine receptors control ventral hippocampus synaptic plasticity and anxiety-related behaviors. PNAS, 122(37), e2501118122. (www)

  @article{ , abstract = {Excitatory glycine receptors (eGlyRs), composed of the glycine-binding NMDA receptor subunits GluN1 and GluN3A, have recently emerged as a novel neuronal signaling modality that challenges the traditional view of glycine as an inhibitory neurotransmitter. Unlike conventional GluN1/GluN2 NMDARs, the distribution and role of eGlyRs remain poorly understood. Here, we show that eGlyRs are highly enriched in the ventral hippocampus (VH) and confer distinct properties on this brain region. eGlyRs display a massive expression in both VH CA1 pyramidal cells and SST- and PV-positive interneurons, whereas in the dorsal hippocampus (DH) pyramidal cells lack these receptors. eGlyRs mediate excitatory tonic currents and control VH network excitability. They are also responsible for the attenuated long-term potentiation (LTP) in the VH compared with the DH, providing a molecular basis for this difference. Furthermore, eGlyRs are required for regulation of VH LTP by corticosterone, pointing to eGlyRs as mediators of the neuroendocrine stress response. Consistent with this pervasive influence in the ventral division of the hippocampus, eGlyRs contribute to the modulation of anxiety-related behaviors. Our work identifies eGlyRs as key players in VH circuitry and function, demonstrating their intimate association with brain regions that control internal states and emotional processing.}, archive = {J_PNAS}, author = {Pizzamiglio, Lara and Morice, Elise and Cardoso, Cécile and Bossi, Simon and Mailhes-Hamon, Caroline and Heimendahl, Moritz von and Girardeau, Gabrielle and Paoletti, Pierre}, doi = {10.1073/pnas.2501118122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2501118122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Excitatory glycine receptors control ventral hippocampus synaptic plasticity and anxiety-related behaviors}, volume = {122}, year = {2025}, }
• (2025). Measuring multisubunit mechanics of geometrically programmed colloidal assemblies via cryo-EM multi-body refinement. PNAS, 122(37), e2500716122. (www)

  @article{ , abstract = {Programmable self-assembly has recently enabled the creation of complex structures through precise control of the interparticle interactions and the particle geometries. Targeting ever more structurally complex, dynamic, and functional assemblies necessitates going beyond the design of the structure itself, to the measurement and control of the local flexibility of the intersubunit connections and its impact on the collective mechanics of the entire assembly. In this study, we demonstrate a method to infer the mechanical properties of multisubunit assemblies using cryogenic electron microscopy (cryo-EM) and RELION’s multi-body refinement. Specifically, we analyze the fluctuations of pairs of DNA-origami subunits that self-assemble into tubules. By measuring the fluctuations of dimers using cryo-EM, we extract mechanical properties such as the bending modulus and interparticle spring constant. These properties are then applied to elastic models to predict assembly outcomes, which align well with experimental observations. This approach not only provides a deeper understanding of nanoparticle mechanics but also opens pathways to refining subunit designs to achieve precise assembly behavior. This methodology could have broader applications in the study of nanomaterials, including protein assemblies, where understanding the interplay of mechanical properties and subunit geometry is essential for controlling complex self-assembled structures.}, archive = {J_PNAS}, author = {Videbæk, Thomas E. and Hayakawa, Daichi and Hagan, Michael F. and Grason, Gregory M. and Fraden, Seth and Rogers, W. Benjamin}, doi = {10.1073/pnas.2500716122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2500716122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Measuring multisubunit mechanics of geometrically programmed colloidal assemblies via cryo-EM multi-body refinement}, volume = {122}, year = {2025}, }
• (2025). Reciprocity in dynamics of supramolecular biosystems for the clustering of ligands and receptors. PNAS, 122(37), e2500686122. (www)

  @article{ , abstract = {Multivalent binding and the resulting dynamical clustering of receptors and ligands are known to be key features in biological interactions. For optimizing biomaterials capable of similar dynamical features, it is essential to understand the first step of these interactions, namely the multivalent molecular recognition between ligands and cell receptors. Here, we present the reciprocal cooperation between dynamic ligands in supramolecular polymers and dynamic receptors in model cell membranes, determining molecular recognition and multivalent binding via receptor clustering. The nonlinear dependences of the ligand concentration, receptors, and their binding affinity are observed experimentally by fluorescence and superresolution fluorescence microscopies, revealing a valency-dependent clustering mode of anchoring. The mechanism is supported by stochastic modeling demonstrating that such nonlinear dependence is unlikely in the absence of any dynamics and superselectivity. Using a coarse-grained molecular model, the subtle competition between local and global entropies that controls this anchoring mechanism explains the clustering. Further investigation using single particle tracking reveals the presence of two populations of bound and unbound receptors after the clustering process. The result of this study highlights the importance of reciprocity of dynamics in supramolecular polymer and lipid membrane for recruitment, multivalent binding, and clustering, all of which are crucial elements in the design of materials capable of actively interacting with biological targets.}, archive = {J_PNAS}, author = {Dhiman, Shikha and Vleugels, Marle E. J. and Post, Richard A. J. and Crippa, Martina and Cardellini, Annalisa and Korver, Esmee de and Su, Lu and Palmans, Anja R. A. and Pavan, Giovanni M. and van der Hofstad, Remco W. and Albertazzi, Lorenzo and Meijer, E. W.}, doi = {10.1073/pnas.2500686122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2500686122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reciprocity in dynamics of supramolecular biosystems for the clustering of ligands and receptors}, volume = {122}, year = {2025}, }
• (2025). Characterizing population-level changes in human behavior during the COVID-19 pandemic in the united states. PNAS, 122(37), e2500655122. (www)

  @article{ , abstract = {The transmission of communicable diseases in human populations is known to be modulated by behavioral patterns. However, detailed characterizations of how population-level behaviors change over time during multiple disease outbreaks and spatial resolutions are still not widely available. We used data from 431,211 survey responses collected in the United States, between April 2020 and June 2022, to provide a description of how human behaviors fluctuated during the first 2 y of the COVID-19 pandemic. Our analysis suggests that at the national and state levels, people’s adherence to recommendations to avoid contact with others (a preventive behavior) was highest early in the pandemic but gradually—and linearly—decreased over time. Importantly, during periods of intense COVID-19 mortality, adaption to preventive behaviors increased—despite the overall temporal decrease. These spatial-temporal characterizations help improve our understanding of the bidirectional feedback loop between outbreak severity and human behavior. Our findings should benefit both computational modeling teams developing methodologies to predict the dynamics of future epidemics and policymakers designing strategies to mitigate the effects of future disease outbreaks.}, archive = {J_PNAS}, author = {Urmi, Tamanna and Pant, Binod and Dewey, George and Quintana-Mathe, Alexi and Lang, Iris and Druckman, James and Ognyanova, Katherine and Baum, Matthew and Perlis, Roy and Riedl, Christoph and Lazer, David and Santillana, Mauricio}, doi = {10.1073/pnas.2500655122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2500655122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Characterizing population-level changes in human behavior during the COVID-19 pandemic in the united states}, volume = {122}, year = {2025}, }
• (2025). Cooperative mixing through hydrodynamic interactions in stylonychia lemnae. PNAS, 122(37), e2500588122. (www)

  @article{ , abstract = {Aquatic microorganisms typically inhabit a heterogeneous resource landscape, composed of localized and transient patches. To effectively exploit these resources, they have evolved a wide range of feeding strategies that combine chemotactic motility with active feeding flows. However, there is a notable lack of experimental studies that examine how these active flows shape resource fields to optimize feeding. In particular, the suspected cooperative hydrodynamics provided by groups of cells remains largely unexplored due to the difficulties in visualizing these dynamic three-dimensional flows. Here, we experimentally investigate how Stylonychia lemnae ciliates form feeding clusters of independent cells around food patches. Individual feeding flows interact hydrodynamically to create a chaotic collective flow at the population scale. Using a combination of experimental and numerical techniques, we measure and predict the entire collective flow, enabling us to assess its remarkable mixing and dispersion properties. We show that the active spreading of the food patch accelerates its detection by starving cells. As many fitness advantages provided by collective flows can be envisioned, we propose that this feeding cluster represents a form of intraspecific by-product cooperative behavior.}, archive = {J_PNAS}, author = {Turuban, Régis and Noselli, Giovanni and Beran, Alfred and DeSimone, Antonio}, doi = {10.1073/pnas.2500588122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2500588122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cooperative mixing through hydrodynamic interactions in stylonychia lemnae}, volume = {122}, year = {2025}, }
• (2025). Disentanglement of prosodic meaning: Toward a framework for the analysis of nonverbal information in speech. PNAS, 122(37), e2500510122. (www)

  @article{ , abstract = {We propose a theoretical framework and a cost-effective automated method for the interpretation of prosodic messages (e.g., chunking of information, emphasis, conversation action, emotion). At the core of the proposal is a hierarchy of layered prosodic messages that co-occur within the same intonation unit (0.5 to 2 s long). Motivated by this hierarchy, a procedure for the differential detection of three such co-occurring nonverbal messages is then described. In way of implementation, we produce a variant model of the WHISPER automatic speech recognition system that flags intonation unit boundaries, intonation unit prototypes, and emphases therein. The procedure required us to alter WHISPER’s token combinations and significantly adjust its prediction process. The variant model was tested on four datasets that contain spontaneous and read speech, and performs on a par with similar human annotation, and often better, using relatively modest training data. Several insights regarding this implementation, such as model size and encoding methods, are described as well. We believe that the proposed framework, coupled with the results of its application herein, can greatly improve the analysis of speech and language, integrating contextual information and speaker intentions into linguistic descriptions for a large array of purposes with modest means.}, archive = {J_PNAS}, author = {Biron, Tirza and Barboy, Moshe and Ben-Artzy, Eran and Golubchik, Alona and Marmor, Yanir and Marron, Assaf and Szekely, Smadar and Winter, Yaron and Harel, David}, doi = {10.1073/pnas.2500510122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2500510122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Disentanglement of prosodic meaning: Toward a framework for the analysis of nonverbal information in speech}, volume = {122}, year = {2025}, }
• (2025). Microglia contribute to bipolar depression through serinc2-dependent phospholipid synthesis. PNAS, 122(37), e2500116122. (www)

  @article{ , abstract = {Although clinical research has revealed microglia-related inflammatory and immune responses in bipolar disorder (BD) patient brains, it remains unclear how microglia contribute to the pathogenesis of BD. Here, we demonstrated that Serinc2 is associated with susceptibility to BD and showed a reduced expression in BDII patient plasma, which correlated with the disease severity. Using induced pluripotent stem cell (iPSC) models of sporadic and familial BDII patients, we found that Serinc2 expression showed deficits in iPSC-derived microglia-like cells, resulting in decreased synaptic pruning. Further, combining the microglia-specific Serinc2-deficient mouse and iPSC-microglia models, we found that microglial Serinc2 deficits functioned through attenuating the synthesis of serine-related phospholipids in the plasma membrane, thus resulting in depression-like behavioral abnormalities in the animals. Finally, we showed that the Serinc2-dependent lipid deficits diminished microglial membrane CR3 formation to interrupted synaptic pruning signals from neurons. Therefore, our results indicated that Serinc2 deficits in microglia might contribute to the pathogenesis of BD.}, archive = {J_PNAS}, author = {Wang, Ying-Han and Fu, Chong-Lei and Chen, Lin-Bo and Zhang, Chu-Yi and Chen, Jian-Shan and Zhang, Qiao-Ming and Liang, Yirui and Yang, Rui-Lan and Li, Yu and Zhang, Ya-Ni and Han, Yi-Nuo and Yuan, Zhen-Liang and Chen, Yi-Ni and Li, Haimei and Pan, Yanmeng and Hu, Shaohua and Li, Ming and Cao, Li-Ping and Yao, Jun}, doi = {10.1073/pnas.2500116122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2500116122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Microglia contribute to bipolar depression through serinc2-dependent phospholipid synthesis}, volume = {122}, year = {2025}, }
• (2025). Stress-induced organismal death is genetically regulated by the mTOR–Zeste–Phae1 axis. PNAS, 122(37), e2427014122. (www)

  @article{ , abstract = {All organisms are exposed to various stressors, which can sometimes lead to organismal death, depending on their intensity. While stress-induced organismal death has been observed in many species, the underlying mechanisms remain unclear. In this study, we investigated the molecular mechanisms of stress-induced organismal death in the fruit fly Drosophila melanogaster . We identified a chymotrypsin-like serine protease Phaedra1 ( Phae1 ) as a death mediator in D. melanogaster larvae. Phae1 expression was up-regulated by lethal heat stress (40 °C) but not nonlethal heat stress (38 °C or lower). The most prominent induction of Phae1 occurred in the central nervous system (CNS). We found neuro-specific knockdown of Phae1 increased survival and reduced neuronal caspase activity following exposure to lethal heat stress, suggesting that the transcriptional upregulation of Phae1 in the CNS is essential for stress-induced organismal death. We next found via bioinformatic and biochemical analyses that the transcription factor Zeste (Z) bound the Phae1 enhancer region and that z loss-of-function impaired Phae1 induction in the CNS, increasing survival following lethal heat stress. In addition, we found via chemical screening that rapamycin, a chemical inhibitor of mechanistic target of rapamycin (mTOR), suppressed Phae1 expression. Neuro-specific knockdown of mTor reduced the protein levels of both Phae1 and Z, leading to an increase in survival following lethal heat stress. Together, these results indicate that heat stress–induced organismal death in D. melanogaster larvae is regulated by a genetically encoded transcriptional signaling pathway involving the mTOR–Z–Phae1 axis.}, archive = {J_PNAS}, author = {Matsumura, Takashi and Ryuda, Masasuke and Matsumoto, Hitoshi and Kamiyama, Takumi and Jinnai, Kyoko and Kondo, Shu and Nakamura, Akira and Hayakawa, Yoichi and Niwa, Ryusuke}, doi = {10.1073/pnas.2427014122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2427014122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stress-induced organismal death is genetically regulated by the mTOR–Zeste–Phae1 axis}, volume = {122}, year = {2025}, }
• (2025). Sorting nexin 3 promotes ischemic retinopathy through RIP1- and RIP3-mediated myeloid cell necroptosis and mitochondrial fission. PNAS, 122(37), e2426578122. (www)

  @article{ , abstract = {Proliferative retinopathy is a leading cause of irreversible blindness in humans; however, the molecular mechanisms behind the immune cell–mediated retinal angiogenesis remain poorly elucidated. Here, using single-cell RNA sequencing in an oxygen-induced retinopathy (OIR) model, we identified an enrichment of sorting nexin (SNX)-related pathways, with SNX3, a member of the SNX family that is involved in endosomal sorting and trafficking, being significantly upregulated in the myeloid cell subpopulations of OIR retinas. Immunostaining showed that SNX3 expression is markedly increased in the retinal microglia/macrophages of mice with OIR, which is mainly located within and around the neovascular tufts. Myeloid cell-specific deficiency of Snx3 inhibited retinal neovascularization, hyperpermeability, and dysfunction in OIR mice. Using glutathione S-transferase pull-down, coimmunoprecipitation, and immunofluorescent staining, we found that SNX3 interacted with receptor-interacting protein 1/3 (RIP1 and RIP3). We further demonstrated that RIP1/3 degradation was accelerated in SNX3-deleted microglia/macrophages, causing an inhibition of hypoxia-induced necroptosis and mitochondrial fission, thereby decreasing the production of proinflammatory and proangiogenic factors (FGF2 and MMP12). Moreover, OIR retinas from myeloid cell–specific SNX3 overexpression transgenic mice presented more angiogenic tufts, while RIP1/3 inhibition largely ablated SNX3 overexpression–induced pathological angiogenesis. Based on the structure of SNX3, we identified a small-molecule inhibitor, W1122. Intriguingly, we found that W1122 effectively inhibited retinal angiogenesis in the OIR model, and combination treatment with anti-Vascular Endothelial Growth Factor (VEGF) yielded enhanced antiangiogenic effects. Collectively, our findings disclose a link between SNX3 and RIP1/3 signaling and implicate SNX3 in the development of ischemic retinopathy.}, archive = {J_PNAS}, author = {Wang, Jiaojiao and Zhou, Chunhong and Zhuang, Kai and Zou, Jiami and Qiu, Wanlu and Jin, Mei and Ye, Weile and Yang, Pinglian and Zheng, Zhihua and Zhou, Qing and Huang, Zunnan and Wang, Yuanxiang and Liu, Peiqing and Lu, Jing and Huo, Yuqing and Liu, Zhiping}, doi = {10.1073/pnas.2426578122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2426578122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sorting nexin 3 promotes ischemic retinopathy through RIP1- and RIP3-mediated myeloid cell necroptosis and mitochondrial fission}, volume = {122}, year = {2025}, }
• (2025). Conflicting roles of cell geometry, microtubule deflection, and orientation-dependent dynamic instability in cortical array organization. PNAS, 122(37), e2426171122. (www)

  @article{ , abstract = {The self-organization of cortical microtubule (MT) arrays within plant cells is an emergent phenomenon with important consequences for the synthesis of the cell wall, cell shape, and subsequently the structure of plants. Mathematical modeling and experiments have elucidated the underlying processes involved. There has been recent interest in the influence of geometric cues on array orientation, be it direct (cell shape) or indirect (tension in the membrane). However, the mechanical influence of membrane curvature on these elastic filaments has largely been ignored. A previous model was proposed to describe how the anchoring process may control the deflection of individual MTs seeking to minimize bending on a cylindrical cell. We incorporate this process into a model of interacting MTs and find the cell curvature influence to be significant: the array favors orientations parallel to the direction of elongation rather than the expected transverse direction. Even without elasticity, the geometry of large cells hinders robust MT organization. These results suggest the necessity of additional processes to overcome these factors. We propose an orientation-dependent catastrophe rate, hypothetically caused by cellulose microfibrils impeding MT polymerization. We find a combination of anchoring and impedance to be sufficient to generate transverse arrays despite the geometric influences.}, archive = {J_PNAS}, author = {Tian, Tim Y. Y. and Wasteneys, Geoffrey O. and Macdonald, Colin B. and Cytrynbaum, Eric N.}, doi = {10.1073/pnas.2426171122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2426171122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Conflicting roles of cell geometry, microtubule deflection, and orientation-dependent dynamic instability in cortical array organization}, volume = {122}, year = {2025}, }
• (2025). Long-term evolutionary persistence of a cryptic color polymorphism in frogs. PNAS, 122(37), e2425898122. (www)

  @article{ , abstract = {Color polymorphism can influence the evolutionary fate of cryptic species because it increases populations’ chances of survival in heterogenous or variable environments. Yet, little is known about the molecular and evolutionary mechanisms underlying the persistence of cryptic color polymorphisms, or the impact these polymorphisms have on the macroevolutionary dynamics of lineages. Here, we examine the evolutionary history of the most widespread cryptic color polymorphism in anurans, involving green and brown morphs. Using an order-scale comparative analysis, we show that these morphs can coexist within species over long evolutionary periods and that polymorphic lineages switch habitat more frequently and have greater diversification rates than other groups. We then identify the locus responsible for the green/brown polymorphism in a group of African grass frogs, and demonstrate that it evolves under long-term balancing selection, resulting in trans-specific polymorphism. These results provide a microevolutionary mechanism for the long-term persistence of multiple color morphs within species observed at a macroevolutionary scale. This study underscores the importance of cryptic color polymorphism in the ecology and evolution of anurans, and provides a framework for future research on the genetic architecture and selective forces underlying cryptic coloration traits.}, archive = {J_PNAS}, author = {Goutte, Sandra and Boissinot, Stéphane}, doi = {10.1073/pnas.2425898122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2425898122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Long-term evolutionary persistence of a cryptic color polymorphism in frogs}, volume = {122}, year = {2025}, }
• (2025). Wild, scenic, and toxic: Recent degradation of an iconic arctic watershed with permafrost thaw. PNAS, 122(37), e2425644122. (www)

  @article{ , abstract = {The streams of Alaska’s Brooks Range lie within a vast (~14M ha) tract of protected wilderness and have long supported both resident and anadromous fish. However, dozens of historically clear streams have recently turned orange and turbid. Thawing permafrost is thought to have exposed sulfide minerals to weathering, delivering iron and other potentially toxic metals to aquatic ecosystems. Here, we report stream water metal concentrations throughout the federally designated Wild and Scenic Salmon River watershed and compare them with United States Environmental Protection Agency (EPA) chronic (4-d) exposure thresholds for toxicity to aquatic life. The main stem of the Salmon had elevated SO 4 2− concentrations and elevated SO 4 2− : Ca relative to a predisturbance baseline for most of its length, consistent with increased sulfide mineral weathering. Most of the tributaries also had elevated SO 4 2− concentrations and elevated SO 4 2− : Ca, especially those in the upper watershed. The Salmon River mainstem consistently exceeded EPA chronic exposure thresholds for total recoverable iron, total recoverable aluminum, and dissolved cadmium from its first major tributary to its mouth. Nine of ten major tributaries that we sampled exceeded EPA thresholds for at least one metal on at least one of three sampling dates. Our findings indicate that habitat quality for resident and anadromous fish has been severely degraded in the Salmon River watershed. Loss of important spawning habitat in the Salmon and many other streams in the region might help explain a recent crash in chum salmon returns, which local communities depend upon for commercial and subsistence harvest.}, archive = {J_PNAS}, author = {Sullivan, Patrick F. and Dial, Roman J. and Cooper, David J. and Diamond, Charles and Tino, Christopher J. and Gregory, Daniel D. and Wong, Russell E. and Lyons, Timothy W.}, doi = {10.1073/pnas.2425644122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2425644122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Wild, scenic, and toxic: Recent degradation of an iconic arctic watershed with permafrost thaw}, volume = {122}, year = {2025}, }
• (2025). Convergent evolution of NFP-facilitated root nodule symbiosis. PNAS, 122(37), e2424902122. (www)

  @article{ , abstract = {The origin and phylogenetic distribution of symbiotic associations between nodulating angiosperms and nitrogen-fixing bacteria have long intrigued biologists. Recent comparative evolutionary analyses have yielded alternative hypotheses: a multistep pathway of independent gains and losses of root nodule symbiosis vs. a single gain followed by numerous losses. A detailed reconstruction of the history of genes involved in signaling between nitrogen-fixing bacteria and potential hosts, particularly lipo-chitooligosaccharide (LCO) signaling, is needed to distinguish between these hypotheses. LCO recognition by plants involves the Nod Factor Perception ( NFP ) gene family; in the legume model Medicago truncatula (Fabales), MtNFP is essential for establishing rhizobial symbiosis. Here, we document convergent evolution of NFP , indicating multiple origins of LCO-driven symbiosis. In contrast to previous models that explain the recruitment of NFP via a single duplication in the ancestor of the nitrogen-fixing clade, our phylogenomic and synteny results suggest this duplication does not span the entire clade. Tandem duplication in a common ancestor of Cucurbitales and Rosales resulted in the NFP1 and NFP2 groups. In contrast, the phylogenetically closest paralog of MtNFP is MtLYR1 , located on a different chromosome within a large syntenic block. All available data indicate that a large-scale duplication resulted in MtNFP and MtLYR1 , likely corresponding to a whole-genome duplication in an ancestor of subfamily Papilionoideae of Fabaceae. We show that MtNFP and the NFP2 -like group are not orthologous, indicating multiple independent gains of NFP -based LCO signaling. This molecular convergence provides a possible mechanism for multiple gains of root nodule symbiosis across the nitrogen-fixing clade.}, archive = {J_PNAS}, author = {Finegan, Christina and Kates, Heather R. and Guralnick, Robert P. and Soltis, Pamela S. and Resende, Marcio F. R. and Ané, Jean-Michel and Kirst, Matias and Folk, Ryan A. and Soltis, Douglas E.}, doi = {10.1073/pnas.2424902122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2424902122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Convergent evolution of NFP-facilitated root nodule symbiosis}, volume = {122}, year = {2025}, }
• (2025). Elastocaloric evidence for a multicomponent superconductor stabilized within the nematic state in Ba(Fe1−xCox)2As2. PNAS, 122(37), e2424833122. (www)

  @article{ , abstract = {The iron-based high- T c superconductors (SCs) exhibit rich phase diagrams with intertwined phases, including magnetism, nematicity, and superconductivity. The superconducting T c in many of these materials is maximized in the regime of strong nematic fluctuations, making the role of nematicity in influencing the superconductivity a topic of intense research. Here, we use the AC elastocaloric effect (ECE) to map out the phase diagram of Ba(Fe 1− x Co x ) 2 As 2 near optimal doping. The ECE signature at T c on the overdoped side, where superconductivity condenses without any nematic order, is quantitatively consistent with other thermodynamic probes that indicate a single-component superconducting state. In contrast, on the slightly underdoped side, where superconductivity condenses within the nematic phase, ECE reveals a second thermodynamic transition proximate to and below T c . We rule out magnetism and reentrant tetragonality as the origin of this transition and find that our observations strongly suggest a phase transition into a multicomponent superconducting state. This implies the existence of a subdominant pairing instability that competes strongly with the dominant s ± instability. Our results highlight the significant role of nematic order in determining the pairing symmetry close to optimal doping in this extensively studied iron-based SC, while also demonstrating the power of ECE in uncovering strain-tuned phase diagrams of quantum materials.}, archive = {J_PNAS}, author = {Ghosh, Sayak and Ikeda, Matthias S. and Chakraborty, Anzumaan R. and Worasaran, Thanapat and Theuss, Florian and Peralta, Luciano B. and Lozano, P. M. and Kim, Jong-Woo and Thompson, P. J. and Ryan, Philip J. and Ye, Linda and Kapitulnik, Aharon and Kivelson, Steven A. and Ramshaw, B. J. and Fernandes, Rafael M. and Fisher, Ian R.}, doi = {10.1073/pnas.2424833122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2424833122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Elastocaloric evidence for a multicomponent superconductor stabilized within the nematic state in Ba(Fe1−xCox)2As2}, volume = {122}, year = {2025}, }
• (2025). Replication stress–induced nuclear hypertrophy alters chromatin topology and impacts cancer cell fitness. PNAS, 122(37), e2424709122. (www)

  @article{ , abstract = {Microscopic examination of biopsy tissues remains essential for cancer diagnosis, despite advancements in sequencing technologies. Alterations in nuclear size or the nuclear-to-cytoplasmic ratio are hallmark features of cancer cells and often correlate with disease progression. However, the mechanisms underlying nuclear size abnormalities and their impact on tumor progression remain unclear. In this study, we demonstrate that nuclear hypertrophy occurs in response to enhanced DNA replication stress, a key characteristic of cancer cells. Increased actin polymerization within the nucleus appears to be the primary mechanism driving nuclear hypertrophy downstream of the ATR-CHEK1 pathway. Replication stress–induced nuclear hypertrophy alters transcriptomic profiles and chromatin topology, while reducing the migratory and metastatic capacity of cancer cells. In addition, nuclear hypertrophy in cancer cells is associated with increased infiltration of antitumor immune cells. Our findings suggest that cell-autonomous effects of nuclear hypertrophy do not promote cellular fitness or aggressive characteristics in cancer cells. This may explain why cells with nuclear hypertrophy are not positively selected and persist as a subpopulation during tumor progression and metastasis. Furthermore, the link between replication stress and nuclear hypertrophy provides insights into why enlarged nuclei are consistently observed in advanced-stage cancers.}, archive = {J_PNAS}, author = {Kim, Changgon and Hong, Semyeong and Ma, Soo Hyeon and Lee, Joochan and So, Hee and Kim, Jun Young and Shin, Eunbie and Lee, Kippeum and Choi, Sohee and Park, Juyeon and Park, YongKeun and Kim, You-Me and Kim, Ji Hun and Kim, Joon}, doi = {10.1073/pnas.2424709122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2424709122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Replication stress–induced nuclear hypertrophy alters chromatin topology and impacts cancer cell fitness}, volume = {122}, year = {2025}, }
• (2025). Hybridoma-inspired strategy crafts tailored multifunctional exosomes for precision therapy. PNAS, 122(37), e2424547122. (www)

  @article{ , abstract = {Engineering functional exosomes represents a cutting-edge approach in biomedicine, holding the promise to transform targeted therapy. However, challenges such as achieving consistent modification and scalability have limited their wider adoption. Herein, we introduce a universal and effective strategy for engineering multifunctional exosomes through cell fusion. The hybrid-cell-derived exosomes could combine the functional properties of both parental cells and be readily produced by passaging. This method enables customization and large-scale production of exosomes with specific functionalities, potentially advancing precision therapies across a wide array of diseases. As demonstrated in Alzheimer’s disease (AD) models, exosomes derived from hybrid cells (HCs) (H/Exos) of mesenchymal stem cells (MSCs) and neutrophils efficiently targeted AD-affected areas via LFA-1/ICAM-1 and improved the cognition of AD mice. Beyond directly promoting neural repair and inhibiting inflammation, we surprisingly found that H/Exos increased microglia abundance, modulated microglia gene expression, enhanced the endocytic and lysosomal function, and promoted microglial phagocytic phenotypic differentiation to clear Aβ. This hybridoma-inspired strategy offers a versatile and practical way to engineer exosomes with desired therapeutic functions, representing a promising direction for personalized therapies.}, archive = {J_PNAS}, author = {Dong, Zhufeng and Yin, Tieying and Deng, Zhiqin and Zou, Hang and Kuang, Lei and Wang, Yang and Shi, Wen and Han, Mengwei and Zhu, Siqing and Wang, Zheng and Hu, Xiaoye and Wang, Yazhou Z.}, doi = {10.1073/pnas.2424547122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2424547122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hybridoma-inspired strategy crafts tailored multifunctional exosomes for precision therapy}, volume = {122}, year = {2025}, }
• (2025). Single-cell transcriptome combined with genetic tracing reveals a roadmap of fibrosis formation during proliferative vitreoretinopathy. PNAS, 122(37), e2424487122. (www)

  @article{ , abstract = {Ocular fibrosis, a severe consequence of excessive retinal wound healing, can lead to vision loss following retinal injury. Proliferative vitreoretinopathy (PVR), a common form of ocular fibrosis, is a major cause of blindness, characterized by the formation of extensive fibrous proliferative membranes. Understanding the cellular origins of PVR-associated fibroblasts (PAFs) is essential to decipher the mechanisms of ocular wound healing. In this study, we combined single-cell transcriptomics with genetic lineage tracing to map the contributions of retinal pigment epithelial (RPE) cells, immune cells, and Müller cells to disease progression. RPE cells were found to constitute the largest fraction of cells within PVR lesions, transitioning through metabolic, proliferative, and epithelial-to-mesenchymal transition stages during their conversion to PAFs. These cells exhibited remarkable plasticity and heterogeneity. Notably, Pdgfrb + RPE cells demonstrated significant morphological plasticity, transitioning toward a fibroblast-like phenotype, while macrophage-like RPE cells acquired inflammation-related functions post-PVR. Cell communication network analysis identified Thbs1 (encoding TSP-1) as a key hub gene driving RPE cell fate transitions during PVR. Importantly, therapeutic antibodies targeting TSP-1 significantly mitigated PVR progression. This study provides a detailed roadmap of fibrosis formation during ocular wound healing and highlights the therapeutic potential of targeting TSP-1 in the management of PVR.}, archive = {J_PNAS}, author = {Liao, Mengyu and Ye, Zhisheng and Zhao, Yumeng and Nan, Jiaying and Liu, Yuming and Yao, Xueming and Yang, Tianjing and Guo, Ju and Jin, Xin and Zhang, Hong and You, Caiyun and Xu, Heping and Yu, Jinguo and Chen, Yupeng and Wang, Xiaohong and Yan, Hua}, doi = {10.1073/pnas.2424487122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2424487122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Single-cell transcriptome combined with genetic tracing reveals a roadmap of fibrosis formation during proliferative vitreoretinopathy}, volume = {122}, year = {2025}, }
• (2025). ApoD mediates age-associated increase in vulnerability to influenza virus infection. PNAS, 122(37), e2423973122. (www)

  @article{ , abstract = {Influenza A virus (IAV) infection causes significantly greater morbidity and mortality in the elderly population, but the molecular mechanisms in the aging process responsible for severe infection remain unclear. In this study, we found that increased severity in IAV infection and reduced innate immune response correlated with extensive mitophagy in senescent human cells and in the lung of aged mice. Apolipoprotein D (ApoD) was identified as strongly elevated in the lungs and sera of aged human (>65 y old) and mouse (>21 mo old). ApoD was able to localize to mitochondria and interact, through its WXXI motif in the LC3B-Interacting Region domain, with LC3B to trigger mitophagy during IAV infection, in a PINK1 pathway independent manner, which attenuated type I interferon response and promoted virus replication. ApoD deficiency, on the other hand, protected older mice from severe influenza and improved survival. Likewise, depletion of senescent cells by ABT-263, a senolytic compound, in aged mice lowered ApoD level and restored innate immune antiviral response, limiting virus propagation and associated pulmonary damage. Thus, age-induced ApoD drives IAV-mediated mitophagy, and promotes virus replication and infection severity, and is therefore a promising target for inhibition to improve disease outcome in older patients.}, archive = {J_PNAS}, author = {Jiang, Zhimin and Pan, Wenliang and Chen, Yu and Zhou, Dongliang and Ren, Shuning and Tong, Qi and Liu, Litao and Sun, Honglei and Sun, Yipeng and Bi, Yuhai and Wang, Dayan and Lu, Lu and Pu, Juan and Chang, Kin-Chow and Liu, Jinhua}, doi = {10.1073/pnas.2423973122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2423973122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ApoD mediates age-associated increase in vulnerability to influenza virus infection}, volume = {122}, year = {2025}, }
• (2025). Emergent depth-mechanosensing of epithelial collectives regulates cell clustering and dispersal on layered matrices. PNAS, 122(37), e2423875122. (www)

  @article{ , abstract = {During wound healing, tumor growth, and organ formation, epithelial cells migrate and cluster in layered tissue environments. Although cellular mechanosensing of adhered extracellular matrices is now well recognized, it is unclear how deeply cells sense through distant matrix layers. Since single cells can mechanosense stiff basal surfaces through soft hydrogels of <10 μm thickness, here we ask whether cellular collectives can perform such “depth-mechanosensing” through thicker matrix layers. Using a collagen-polyacrylamide double-layer hydrogel, we found that epithelial cell collectives can mechanosense basal substrates at a depth of >100 μm, assessed by cell clustering and collagen deformation. On collagen layers with stiffer basal substrates, cells initially migrate slower while performing higher collagen deformation and stiffening, resulting in reduced dispersal of epithelial clusters. These processes occur in two broad phases: cellular clustering and dynamic collagen deformation, followed by cell migration and dispersal. Using a cell-populated collagen-polyacrylamide computational model, we show that stiffer basal substrates enable higher collagen deformation, which in turn extends the clustering phase of epithelial cells and reduces their dispersal. Disruption of collective collagen deformation, by either α-catenin depletion or myosin-II inhibition, disables the depth-mechanosensitive differences in epithelial responses between soft and stiff basal substrates. These findings suggest that depth-mechanosensing is an emergent property that arises from collective collagen deformation caused by epithelial cell clusters. This work broadens the conventional understanding of epithelial mechanosensing from immediate surfaces to underlying basal matrices, providing insights relevant to tissue contexts with layers of varying stiffness, such as wound healing and tumor invasion.}, archive = {J_PNAS}, author = {Yu, Hongsheng and Pathak, Amit}, doi = {10.1073/pnas.2423875122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2423875122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Emergent depth-mechanosensing of epithelial collectives regulates cell clustering and dispersal on layered matrices}, volume = {122}, year = {2025}, }
• (2025). Ice gliding diatoms establish record-low temperature limits for motility in a eukaryotic cell. PNAS, 122(37), e2423725122. (www)

  @article{ , abstract = {Despite periods of permanent darkness and extensive ice coverage in polar environments, photosynthetic ice diatoms display a remarkable capability of living inside the ice matrix. How these organisms navigate such hostile conditions with limited light and extreme cold remains unknown. Using a custom subzero temperature microscope during an Arctic expedition, we present the finding of motility at record-low temperatures in a Eukaryotic cell. By characterizing the gliding motility of several ice diatom species, collected from ice cores in the Chukchi Sea, we record that they retain motility at temperatures as low as − 15 ° C. Remarkably, ice diatoms can glide on ice substrates, a capability absent in temperate diatoms of the same genus. This unique ability arises from adaptations in extracellular mucilage that allow ice diatoms to adhere to ice, essential for gliding. Even on glass substrates where both cell types retain motility at freezing temperatures, ice diatoms move an order of magnitude faster, with their optimal motility shifting toward colder temperatures. Combining field and laboratory experiments with thermo-hydrodynamic modeling, we reveal adaptive strategies that enable gliding motility in cold environments. These strategies involve increasing internal energy efficiency with minimal changes in heat capacity and activation enthalpy, and reducing external dissipation by minimizing the temperature sensitivity of mucilage viscosity. The finding of diatoms’ ice gliding motility opens new routes for understanding their survival within a harsh ecological niche and their migratory responses to environmental changes. Our work highlights the robust adaptability of ice diatoms in one of Earth’s most extreme settings.}, archive = {J_PNAS}, author = {Zhang, Qing and Leng, Hope T. and Li, Hongquan and Arrigo, Kevin R. and Prakash, Manu}, doi = {10.1073/pnas.2423725122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2423725122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ice gliding diatoms establish record-low temperature limits for motility in a eukaryotic cell}, volume = {122}, year = {2025}, }
• (2025). Modeling human retinal ganglion cell axonal outgrowth, development, and pathology using pluripotent stem cell–based microfluidic platforms. PNAS, 122(37), e2423682122. (www)

  @article{ , abstract = {Retinal ganglion cells (RGCs) are highly compartmentalized neurons whose long axons serve as the sole connection between the eye and the brain. In both injury and disease, RGC degeneration occurs in a similarly compartmentalized manner, with distinct molecular and cellular responses in the axonal and somatodendritic regions. The goal of this study was to establish a microfluidic-based platform to investigate RGC compartmentalization in both health and disease states. Human pluripotent stem cell (hPSC)-derived RGCs were seeded into microfluidic devices that allow physical separation of axons from the somatodendritic compartment, enabling precise study of each region. Initial experiments characterized axonal outgrowth and the specific segregation of axons and dendrites. We then examined compartment-specific phenotypes in RGCs carrying the OPTN(E50K) glaucoma mutation compared to isogenic controls, including differences in axonal growth and axonal transport efficiency, with OPTN-mutant RGCs showing reduced axon length and slower transport, hallmarks of neurodegeneration. Axonal RNA-seq analyses revealed transcriptomic alterations related to disease states, including specific transcriptomic changes along OPTN axons. To assess glial influences on axonal health, we developed models with astrocytes localized specifically to the proximal axonal compartment and modulated their disease states to simulate pathological conditions. Importantly, the induction of diseased astrocytes solely along proximal axons triggered compartment-specific neurodegenerative changes in RGCs. Collectively, this platform represents a successful recapitulation of the spatially distinct features of hPSC-derived RGCs under both healthy and disease conditions, offering a physiologically relevant, human-specific in vitro system to study neuronal development, axon–glia interactions, and mechanisms underlying neurodegeneration.}, archive = {J_PNAS}, author = {Gomes, Cátia and Huang, Kang-Chieh and Lavekar, Sailee S. and Harkin, Jade and Prosser, Carson G. and Fang, Yue and Kalem, Claire and Oblak, Adrian and Zhang, Chi and Meyer, Jason S.}, doi = {10.1073/pnas.2423682122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2423682122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Modeling human retinal ganglion cell axonal outgrowth, development, and pathology using pluripotent stem cell–based microfluidic platforms}, volume = {122}, year = {2025}, }
• (2025). Experimentally enhancing dispersal reveals the outsized importance of transient dynamics in a fluctuating environment. PNAS, 122(37), e2422454122. (www)

  @article{ , abstract = {The size and composition of local species pools are, in part, determined by past dispersal events. Predicting how communities respond to future disturbances, such as fluctuating environmental conditions, requires knowledge of such histories. We assessed the influence of a historical dispersal event on community assembly by simulating various scales of dispersal for 240 serpentine annual plant communities that experienced a large shift from drought to high rainfall conditions over three years. We collected, aggregated, and redistributed the aboveground seed bank (i.e., all loose seed present on the soil surface before the growing season initiates) from 30 sites across five nested spatial scales ( ∼ 1 m, 5 m, 100 m, 5 km, and 10 km), and annually censused communities to identify change in community structure among dispersal scales and over time. Our one-time dispersal manipulation diversified aboveground seed banks, provided insurance against temporal variability at intermediate and large dispersal distances ( ≥ 100 m), and even supported community reassembly toward a new compositional state at the 10 km scale. We also found evidence that temporal lags directed community responses to environmental fluctuations, preventing rare species extirpations and providing subordinate species discrete windows of time to supplement their seed banks. Our results reveal a joint spatiotemporal equilibrium in this system where dispersal through space interacts with temporal fluctuations in climate to support species’ persistence via aboveground seed banks. This experiment underscores the importance of dispersal for diversity maintenance in this global biodiversity hotspot, where the magnitude and frequency of future climate fluctuations is uncertain.}, archive = {J_PNAS}, author = {Kowalski, Jessica J. and Gilbert, Benjamin and Strauss, Sharon Y. and Germain, Rachel M.}, doi = {10.1073/pnas.2422454122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2422454122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Experimentally enhancing dispersal reveals the outsized importance of transient dynamics in a fluctuating environment}, volume = {122}, year = {2025}, }
• (2025). Posttranscriptional control of the b cell receptor by HuR is essential for innate b cell maintenance and function. PNAS, 122(37), e2421149122. (www)

  @article{ , abstract = {Innate B-1 cells constitute a self-maintained layer of defense for early detection of bacteria, clearance of apoptotic cell debris, and removal of autoantigens driving autoimmunity. B-1 cells are originated from fetal tissues, but, as opposed to B-2 cells, the molecular mechanisms behind their development and homeostatic maintenance remain largely unknown. Here, we demonstrate that posttranscriptional regulation by the RNA binding protein HuR is essential for the homeostatic self-replenishment of innate B-1a cells, the expansion of B-1 cell clones targeting self-antigens, and the production of natural autoantibodies. HuR KO B-1 cells fail to express the high levels of surface B-cell receptor (BCR), TACI, and BAFFR required for tonic signaling and cell survival. At the molecular level, HuR promotes the translation of messenger RNAs encoding the IgM heavy chain and modules, in a direct or indirect manner, the expression of TACI and BAFFR. In summary, we reveal the need for posttranscriptional regulation in BCR expression, tonic signaling, and homeostatic maintenance of functional innate B-1 cells.}, archive = {J_PNAS}, author = {Capitan-Sobrino, Dunja and Mouysset, Mailys and Maloudi, Orlane and Aubert, Yann and Osma-Garcia, Ines C. and Nguyen, Trang-My M. and Dunga, Greta and Nestor-Martin, Maia and Mieulet, Virginie and Diaz-Muñoz, Manuel D.}, doi = {10.1073/pnas.2421149122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2421149122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Posttranscriptional control of the b cell receptor by HuR is essential for innate b cell maintenance and function}, volume = {122}, year = {2025}, }
• (2025). Learning stochastic processes with intrinsic noise from cross-sectional biological data. PNAS, 122(37), e2420621122. (www)

  @article{ , abstract = {Inferring dynamical models from data continues to be a significant challenge in computational biology, especially given the stochastic nature of many biological processes. We explore a common scenario in omics, where statistically independent cross-sectional samples are available at a few time points, and the goal is to infer the underlying diffusion process that generated the data. Existing inference approaches often simplify or ignore noise intrinsic to the system, compromising accuracy for the sake of optimization ease. We circumvent this compromise by inferring the phase-space probability flow that shares the same time-dependent marginal distributions as the underlying stochastic process. Our approach, probability flow inference (PFI), disentangles force from intrinsic stochasticity while retaining the algorithmic ease of ordinary differential equation (ODE) inference. Analytically, we prove that for Ornstein–Uhlenbeck processes the regularized PFI formalism yields a unique solution in the limit of well-sampled distributions. In practical applications, we show that PFI enables accurate parameter and force estimation in high-dimensional stochastic reaction networks, and that it allows inference of cell differentiation dynamics with molecular noise, outperforming state-of-the-art approaches.}, archive = {J_PNAS}, author = {Maddu, Suryanarayana and Chardès, Victor and Shelley, Michael J.}, doi = {10.1073/pnas.2420621122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2420621122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Learning stochastic processes with intrinsic noise from cross-sectional biological data}, volume = {122}, year = {2025}, }
• (2025). Driving the grid forward: How electric vehicle adoption shapes power system infrastructure and emissions. PNAS, 122(37), e2420609122. (www)

  @article{ , abstract = {We model the effect of plug-in electric vehicle (EV) adoption on U.S. power system generator capacity investment, operations, and emissions through 2050 by estimating power systems outcomes under a range of EV adoption trajectory scenarios. Our EV adoption scenarios are informed by 1) an Energy Information Administration scenario with no policy intervention, 2) EV growth expected under the Inflation Reduction Act (IRA), 3) a Biden Administration 50% EV sales target by 2030, 4) the Environmental Protection Agency’s projections under vehicle emissions standards, and 5) the International Energy Agency’s roadmap to Net Zero by 2050. We find across these scenarios that increasing EV adoption induces investment in new wind, solar, storage, and natural gas capacity, affecting power generation mix and emissions. The net effect of increasing EV adoption beyond our IRA base case is to increase power sector emissions by about 5 mtCO 2 eq per EV-year in 2026 (comparable to displaced gasoline vehicle combustion emissions), but this effect rapidly drops to annual levels below 1 mtCO 2 eq per EV-year by 2032 and continues below this level through 2050. Consequential effects of EV adoption vary regionally, with most regions primarily increasing wind or solar capacity and some regions primarily increasing natural gas capacity, even in 2050. Our national emissions estimates per EV-year are relatively robust to the level of EV adoption beyond our baseline and to variation in assumptions about power systems, EV behavior, and policy.}, archive = {J_PNAS}, author = {Hanig, Lily and Harper, Corey D. and Nock, Destenie and Michalek, Jeremy J.}, doi = {10.1073/pnas.2420609122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2420609122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Driving the grid forward: How electric vehicle adoption shapes power system infrastructure and emissions}, volume = {122}, year = {2025}, }
• (2025). Subtype-specific structural features of the hearing loss–associated human P2X2 receptor. PNAS, 122(37), e2417753122. (www)

  @article{ , abstract = {The P2X2 receptor (P2X2R) is a slowly desensitizing adenosine triphosphate (ATP)-gated ion channel that is highly expressed in the cochlea. When mutated, the P2X2R exacerbates age- and noise-related hearing loss, but selective modulators of the receptor are lacking, and the molecular basis of activation and desensitization remains poorly understood. Here, we determine high-resolution cryoelectron microscopy structures of the full-length wild-type human P2X2R in an apo closed state and two distinct ATP-bound desensitized states. In the apo closed state structure, we observe features unique to the P2X2R and locate disease mutations within or near the transmembrane domain. In addition, our ATP-bound structures show how free anionic ATP forms subtype-specific interactions with the orthosteric binding site. We identify and characterize two different ATP-bound desensitized state structures, one similar to published models for other P2XR subtypes, and a second alternate conformation not previously observed. A loop adjacent to the orthosteric binding site between these two ATP-bound desensitized state structures undergoes significant conformational changes. These movements are supported by multireplicate, microsecond-scale molecular dynamics simulation studies and suggest a path by which ATP could enter or leave the orthosteric pocket. Together, our results provide structural insights into the P2X2R, facilitating structure-based drug development for this therapeutically important target.}, archive = {J_PNAS}, author = {Westermann, Franka G. and Oken, Adam C. and Granith, Philip K. E. and Marimuthu, Parthiban and Müller, Christa E. and Mansoor, Steven E.}, doi = {10.1073/pnas.2417753122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2417753122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Subtype-specific structural features of the hearing loss–associated human P2X2 receptor}, volume = {122}, year = {2025}, }
• (2025). In vivo pirt-marina voltage sensor imaging detects primary sensory neuron–specific voltage dynamics and neuronal plasticity changes. PNAS, 122(37), e2416712122. (www)

  @article{ , abstract = {In vivo voltage imaging is a powerful tool for monitoring action potentials and dynamic electrical events in heterogeneous sensory neurons enabling the deciphering of rapid somatosensory information processing. Virus-driven expression of genetically encoded voltage indicator (GEVI) suffers from inconsistent expression levels and offers a limited time window for optimal voltage imaging. Here, we generated and characterized a knock-in mouse line with Pirt-driven expression of Marina, a positively tuned GEVI, in primary sensory neurons. Pirt-Marina mice enable optical reporting of touch, itch, and nociceptive sensations in vivo and distinct action potential patterns in the trigeminal and dorsal root ganglion neurons. Notably, Pirt-Marina mice display robust fluorescence signals in response to mechanical, thermal, or chemical stimuli, allowing visualization of transformations in sensory coding following inflammation and injury. This Pirt-Marina mouse line provides optical access to dynamic neuronal activity and plasticity in the peripheral nervous system (PNS) with high temporal accuracy, fidelity, and reliability.}, archive = {J_PNAS}, author = {Zhang, Yan and Son, Hyeonwi and Shannonhouse, John and Gomez, Ruben and Kim, Eungyung and Ai, Chih-Hsuan and Chung, Man-Kyo and Platisa, Jelena and Pieribone, Vincent A. and Kim, Yu Shin}, doi = {10.1073/pnas.2416712122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2416712122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In vivo pirt-marina voltage sensor imaging detects primary sensory neuron–specific voltage dynamics and neuronal plasticity changes}, volume = {122}, year = {2025}, }
• (2025). Structure of a polymorphic repeat at the CACNA1C schizophrenia locus. PNAS, 122(37), e2415650122. (www)

  @article{ , abstract = {Genetic variation within intron 3 of the CACNA1C calcium channel gene is associated with schizophrenia and other neuropsychiatric disorders, but analysis of the causal variants and their effect is complicated by a nearby variable-number tandem repeat (VNTR). Here, we explored the structure and population variability of the CACNA1C intron 3 VNTR using 155 long-read genome assemblies from 78 diverse individuals. Based on sequence differences among repeat units, we clustered individual sequences into 7 VNTR structural alleles called Types. Three Types were related through large duplications, but the other Types diverged much earlier such that only 12 repeat units at the 5′ end of the VNTR were shared across most Types. The most diverged Types were rare and present only in individuals with African ancestry, but a multiallelic structural polymorphism was present across populations at different frequencies, consistent with expansion of the VNTR preceding the emergence of early hominins. We demonstrated that this polymorphism was in complete linkage disequilibrium with fine-mapped schizophrenia variants from genome-wide association studies (GWAS) and that this risk haplotype was associated with decreased CACNA1C gene expression in the brain. Our work suggests that sequence variation within a human-specific VNTR affects gene expression and provides a detailed characterization of new alleles at a flagship neuropsychiatric GWAS locus.}, archive = {J_PNAS}, author = {Moya, Raquel and Wang, Xiaohan and Tsien, Richard W. and Maurano, Matthew T.}, doi = {10.1073/pnas.2415650122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2415650122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure of a polymorphic repeat at the CACNA1C schizophrenia locus}, volume = {122}, year = {2025}, }
• (2025). Adjusting the management of the antarctic krill fishery to meet the challenges of the 21st century. PNAS, 122(37), e2412624122. (www)

  @article{ , abstract = {Antarctic krill ( Euphausia superba ) is the central prey species in the Southern Ocean food web, supporting the largest and fastest-growing fishery in the region, managed by the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR). Climate change is threatening krill populations and their predators, while current catch limits do not take into account climate variability or krill population dynamics. In 2024, CCAMLR was unable to renew its spatial catch limits, highlighting the urgent need for improved management of the krill fishery to prevent any harm to the Southern Ocean ecosystem. To address this, we propose a management framework that integrates variability in krill recruitment and key pathways between spawning and nursery areas—a krill stock hypothesis—to inform decisions on catch limits and conservation measures. Implementing this approach will require targeted data collection, which we propose can be achieved through a multisector collaborative network that combines traditional and new technologies, including the use of fishing vessels as data collection platforms. We use case studies to demonstrate how fisheries can contribute to data collection while promoting sustainable management. A major challenge in this effort is securing long-term funding for data collection, which is critical for managing climate-sensitive populations of high commercial interest. We therefore recommend using the industry as a source of funding, research platform and data provider, alongside national research funding opportunities. Given the fundamental role of krill in the Southern Ocean ecosystem, its decline would have cascading effects on predators and essential ecosystem services.}, archive = {J_PNAS}, author = {Meyer, Bettina and Arata, Javier A. and Atkinson, Angus and Bahlburg, Dominik and Bernard, Kim and Cárdenas, César A. and Grant, Susie M. and Hill, Simeon L. and Hüppe, Lukas and Ichii, Taro and Kawaguchi, So and Krafft, Bjørn A. and Labrousse, Sara and Maschette, Dale and Piñones, Andrea and Reiss, Christian and Siebenhüner, Bernd and Sylvester, Zephyr and Ziegler, Philippe}, doi = {10.1073/pnas.2412624122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {37}, pages = {e2412624122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Adjusting the management of the antarctic krill fishery to meet the challenges of the 21st century}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(36), eiti3625122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti3625122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {eiti3625122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Correction for ninomiya and isoda, dynamic spatial representation of self and others’ actions in the macaque frontal cortex. PNAS, 122(36), e2522320122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2522320122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2522320122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for ninomiya and isoda, dynamic spatial representation of self and others’ actions in the macaque frontal cortex}, volume = {122}, year = {2025}, }
• (2025). Correction for pang et al., structural elucidation of how ARF small GTPases induce membrane tubulation for vesicle fission. PNAS, 122(36), e2522054122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2522054122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2522054122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for pang et al., structural elucidation of how ARF small GTPases induce membrane tubulation for vesicle fission}, volume = {122}, year = {2025}, }
• (2025). Rethinking early-life pathogen exposure: Lessons from a natural experiment controlling hookworms. PNAS, 122(36), e2521265122. (www)

  @article{ , archive = {J_PNAS}, author = {Schofield, Heather}, doi = {10.1073/pnas.2521265122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2521265122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rethinking early-life pathogen exposure: Lessons from a natural experiment controlling hookworms}, volume = {122}, year = {2025}, }
• (2025). William s. sly (1932–2025): A compassionate pioneer in biochemical genetics. PNAS, 122(36), e2520590122. (www)

  @article{ , abstract = {William S. Sly, MD (1932–2025) was a biochemical geneticist who received his medical degree from Saint Louis University. He received additional training at the NIH with several members of the National Academy of Science and Nobel Prize winner Marshall Nirenberg. He is best known for discovering mucopolysaccharidosis type VII and developing a Food and Drug Administration-approved treatment for it. He served in several long-term leadership roles and won many accolades, including the Passano Foundation Award and induction into the National Academy of Sciences. Sly was equally well known as a kind and caring person who always made time for family, friends, colleagues, and patients. He is the personification of the caring and compassionate physician-scientist.}, archive = {J_PNAS}, author = {Sands, Mark S. and Grubb, Jeffrey H. and Vogler, Carole A. and Waheed, Abdul and Montaño, Adriana M.}, doi = {10.1073/pnas.2520590122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2520590122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {William s. sly (1932–2025): A compassionate pioneer in biochemical genetics}, volume = {122}, year = {2025}, }
• (2025). The molecular structure of the master growth regulator in plants emerges into the spotlight. PNAS, 122(36), e2519807122. (www)

  @article{ , archive = {J_PNAS}, author = {Yoshida, Hideki and Matsuoka, Makoto}, doi = {10.1073/pnas.2519807122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2519807122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The molecular structure of the master growth regulator in plants emerges into the spotlight}, volume = {122}, year = {2025}, }
• (2025). Using bioinformatics for identifying and plugging metabolic pathway holes. PNAS, 122(36), e2518071122. (www)

  @article{ , archive = {J_PNAS}, author = {Galperin, Michael Y.}, doi = {10.1073/pnas.2518071122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2518071122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Using bioinformatics for identifying and plugging metabolic pathway holes}, volume = {122}, year = {2025}, }
• (2025). Daily liver rhythms: Coupling morphological and molecular oscillations. PNAS, 122(36), e2517648122. (www)

  @article{ , abstract = {In mammals, a hierarchically organized circadian timing system orchestrates daily rhythms of nearly all physiology. A master pacemaker in the brain’s suprachiasmatic nucleus (SCN) synchronizes subsidiary clocks in most peripheral organs. By driving anabolic and catabolic cycles of proteins, lipids, and carbohydrates and by detoxifying endo- and xenobiotic components, the liver plays an important role in adapting the metabolic needs to rest-activity rhythms. In keeping with these functions, the liver expresses many clock-controlled genes that are required for these processes. Remarkably, however, this organ also fluctuates in size and morphological parameters. In mice, the mass of the liver increases and decreases by 30 to 40% during the 24-h day. The oscillation in liver mass is accompanied by daily rhythms of similar amplitudes in hepatocyte cell size and global RNA and protein accumulation. The number of ribosomes, which parallels the ups and downs of liver size, appears to be the rate-limiting factor in driving the diurnal rhythms of overall protein synthesis. Obviously, the rapid increase in hepatocyte size within the liver engenders mechanical stress, which must be dealt with by increasing the physical robustness of cells. Indeed, the actin cytoskeleton of hepatocytes undergoes dramatic polymerization cycles. Thus, massive intracellular and subcortical F-actin bundles are assembled during the night, at which the liver reaches its maximal size. In turn, the oscillation in actin polymerization elicits rhythms in myocardin-related transcription factors-serum response factor signaling, which participate in the circadian transcription of the core clock gene Per2 and thereby contribute to the synchronization of hepatocyte clocks.}, archive = {J_PNAS}, author = {Schibler, Ueli and Sinturel, Flore and Naef, Felix and Gerber, Alan and Gatfield, David}, doi = {10.1073/pnas.2517648122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2517648122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Daily liver rhythms: Coupling morphological and molecular oscillations}, volume = {122}, year = {2025}, }
• (2025). Preschool teachers provide fewer participation opportunities to working-class students than those from more privileged backgrounds. PNAS, 122(36), e2515833122. (www)

  @article{ , abstract = {Social class disparities exist from the earliest stages of education. Research has suggested that class-based differences in factors such as socialization practices and access to resources partly explain this phenomenon, but less work has explored whether teachers’ practices also exacerbate these inequalities. Using whole-class observations of 63 preschool classroom discussions ( N = 226 students, 10 teachers), we coded 7,941 student participation attempts and subsequent responses from teachers. Mixed-effects Bayesian logistic regressions showed that whether students played by the rules by raising their hands or broke the rules by calling out, they were less likely to have their participation attempts accepted if they came from a working-class background, even when their perceived language skills were matched to their middle- and upper-class peers. These results suggest that early schooling experiences may serve to exacerbate inequalities rather than level the playing field.}, archive = {J_PNAS}, author = {Doyle, Lewis and Cimpian, Andrei and Goupil, Louise and Goudeau, Sébastien}, doi = {10.1073/pnas.2515833122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2515833122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Preschool teachers provide fewer participation opportunities to working-class students than those from more privileged backgrounds}, volume = {122}, year = {2025}, }
• (2025). Reply to loh and ren: Motivating action among climate change believers. PNAS, 122(36), e2515426122. (www)

  @article{ , archive = {J_PNAS}, author = {Sinclair, Alyssa H. and Cosme, Danielle and Lydic, Kirsten and Reinero, Diego A. and Mann, Michael E. and Falk, Emily B.}, doi = {10.1073/pnas.2515426122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2515426122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to loh and ren: Motivating action among climate change believers}, volume = {122}, year = {2025}, }
• (2025). Inflammation awakens dormant cancer cells by modulating the epithelial–mesenchymal phenotypic state. PNAS, 122(36), e2515009122. (www)

  @article{ , abstract = {The awakening of dormant disseminated cancer cells appears to be responsible for the clinical relapses of patients whose primary tumors have been successfully cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, nonproliferative phenotypic state. The awakening of these cells is not triggered by a cancer cell-autonomous process. Instead, lung inflammation induced by the chemotherapeutic agent bleomycin effectively awakens dormant cancer cells, providing useful models for studying metastatic awakening. Mechanistically, the awakened cells shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire tumorigenicity and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their tumor-initiating ability, doing so without ongoing heterotypic signaling from the lung microenvironment. Epidermal growth factor receptor ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is critical for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse.}, archive = {J_PNAS}, author = {Zhang, Jingwei and Zhang, Jingwen and Han, Longfei and Wu, Shiyi and Li, Jie and Eaton, Elinor Ng and Yuan, Bingbing and Reinhardt, Ferenc and Li, Hao and Strasser, Patrick C. and Das, Sunny and Liu Donaher, Joana and Khalil, Md Imtiaz and Jiang, Haiping and Deuschel, Alexander and Lin, Danni and Sebastiany, Carolin and Maranga, Mariana and Shubitidze, Salomé and Liu, Xiaofei and Lambert, Arthur W. and Zhang, Yun and Liu, Yana and Sui, Lufei and Elmiligy, Sarah and Pozza, Umberto and Günsay, Rauf and Mishra, Ranjan and Velarde, Jose and Iyer, Sonia and Henry, Whitney S. and Weiskopf, Kipp and Feng, Guihai and Oni, Tobiloba E. and Watnick, Randolph S. and Li, Xin and Weinberg, Robert A.}, doi = {10.1073/pnas.2515009122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2515009122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inflammation awakens dormant cancer cells by modulating the epithelial–mesenchymal phenotypic state}, volume = {122}, year = {2025}, }
• (2025). Upscaling behavioral interventions requires addressing selection bias. PNAS, 122(36), e2513887122. (www)

  @article{ , archive = {J_PNAS}, author = {Loh, Wen Wei and Ren, Dongning}, doi = {10.1073/pnas.2513887122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2513887122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Upscaling behavioral interventions requires addressing selection bias}, volume = {122}, year = {2025}, }
• (2025). Unprecedented suppression of panama’s pacific upwelling in 2025. PNAS, 122(36), e2512056122. (www)

  @article{ , abstract = {The Gulf of Panama’s (GOP) seasonal upwelling system has consistently delivered cool, nutrient-rich waters via northerly trade winds every January–April for at least 40 y. Here, we document the failure of this normally highly predictable phenomenon in 2025. Data suggest that the cause was a reduction in Panama wind-jet frequency, duration, and strength, possibly related to the Intertropical Convergence Zone (ITCZ) position during the 2024–2025 La Niña, though the mechanisms remain unclear. Nevertheless, the consequences are likely significant, including decreases in fisheries productivity and exacerbated thermal stress on corals that typically benefit from upwelling’s cooling. This event underscores how climate disruption can threaten wind-driven tropical upwelling systems, which remain poorly monitored and studied despite their importance to ecology and coastal economies.}, archive = {J_PNAS}, author = {O’Dea, Aaron and Sellers, Andrew J. and Pérez-Medina, Carmen and Pardo Díaz, Javier and Guzmán Bloise, Alexandra and Pöhlker, Christopher and Chiliński, Michał T. and Aardema, Hedy M. and Cybulski, Jonathan D. and Heins, Lena and Paton, Steven R. and Slagter, Hans A. and Schiebel, Ralf and Haug, Gerald H.}, doi = {10.1073/pnas.2512056122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2512056122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unprecedented suppression of panama’s pacific upwelling in 2025}, volume = {122}, year = {2025}, }
• (2025). Fatty acid 2-hydroxylase facilitates rotavirus uncoating and endosomal escape. PNAS, 122(36), e2511911122. (www)

  @article{ , abstract = {Despite the clinical significance of many nonenveloped viruses, the molecular mechanisms of their internalization and membrane penetration are not well understood. Rotaviruses (RVs) are nonenveloped double-stranded RNA viruses and the leading cause of severe dehydrating diarrhea in infants and young children. We identified fatty acid 2-hydroxylase (encoded by FA2H ) in the fatty acid 2-hydroxylation pathway as a proviral gene that supports RV infection. Genetic ablation of FA2H interfered with an early step in RV entry for multiple human and animal strains. Intestinal epithelial cell–specific deletion of Fa2h limited RV replication and diarrhea incidence in vivo. Using transmission electron microscopy and immunofluorescence, we found that viral particles were trapped in early and late endosomes in FA2H knockout cells, preventing their further exit into the cytosol. The defect in RV infectivity could be partially restored by treatment of cells with long-chain 2-hydroxy ceramides or a calcium channel activator that promotes Ca 2+ efflux from endosomes. Both Junín virus, an arenavirus, and Shiga toxin, dependent on endosomal Ca 2+ transport, required FA2H for efficient entry. Together, this study highlights a role of fatty acid 2-hydroxylation in RV entry into host cells and implicates 2-hydroxy ceramides as potential key regulators of endosomal Ca 2+ levels, offering important insights for the development of host-directed therapies targeting fatty acid 2-hydroxylation to control microbial infections.}, archive = {J_PNAS}, author = {Li, Enkai and Zang, Ruochen and Kawagishi, Takahiro and Zhang, Wei and Iyer, Kruthika and Hou, Gaopeng and Zeng, Qiru and Meganck, Rita M. and Ross, Susan R. and Wang, Xin and Su, Xiong and Ding, Siyuan}, doi = {10.1073/pnas.2511911122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2511911122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fatty acid 2-hydroxylase facilitates rotavirus uncoating and endosomal escape}, volume = {122}, year = {2025}, }
• (2025). Action at a distance: The remarkable coupling of CO2 uptake to electron transfer in specialized cyanobacterial NDH-1 complexes. PNAS, 122(36), e2511786122. (www)

  @article{ , abstract = {Cyanobacteria achieve highly efficient photosynthesis using a CO 2 -concentrating mechanism relying on specialized Type I (NDH-1) complexes. Among these, NDH-1 3 and NDH-1 4 catalyze redox-coupled hydration of CO 2 to bicarbonate, supporting carbon fixation in carboxysomes. The mechanism of coupling electron transfer to CO 2 -hydration by these variant NDH-1 complexes remains unknown. We engineered a Synechococcus PCC7942 strain that expresses exclusively the high flux/low affinity NDH-1 4 complex, enabling the observation of the coupling of CO 2 hydration to cyclic electron flow in isolation from the other NDH-1 isoforms normally present in cells. We found that inhibition of the CupB protein by the carbonic anhydrase inhibitor ethoxzolamide (EZ) suppressed CO 2 uptake, slowed photosystem I rereduction, and abolished proton pumping as probed by acridine orange fluorescence. These effects were absent in strains lacking Cup proteins, confirming specificity. The results demonstrate that CO 2 hydration and electron transfer through NDH-1 4 are tightly coupled via proton translocation across the thylakoid membrane. These findings provide direct evidence for the bidirectional interaction in bioenergetic coupling between the plastoquinone reduction and the CO 2 uptake at the distal Zn-site over a span of ~150 Å and support a proton-removal hypothesis involving the proton transfer pathways from the Zn-site of CO 2 hydration to an energetically coupled proton loading site evolutionarily repurposed from the ancestral proton pumping mechanism to enable energetic CO 2 uptake.}, archive = {J_PNAS}, author = {Zhang, Zhifen and Zhang, Minquan and Burnap, Robert L.}, doi = {10.1073/pnas.2511786122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2511786122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Action at a distance: The remarkable coupling of CO2 uptake to electron transfer in specialized cyanobacterial NDH-1 complexes}, volume = {122}, year = {2025}, }
• (2025). Atomic armor for thermal stability in nanoporous structures. PNAS, 122(36), e2510746122. (www)

  @article{ , abstract = {Nanoporous structures play a critical role in a wide range of applications, including catalysis, thermoelectrics, energy storage, gas adsorption, and thermal insulation. However, their thermal instability remains a persistent challenge. Inspired by the extraordinary resilience of tardigrades, an “atomic armor” strategy is introduced to enhance the stability of nanoporous structures. Applied to mesoporous silica at parts-per-million levels, the atomic armor provides thermal resistance exceeding that of existing stabilization techniques. Thermal treatment at 1,000 °C for 168 h results in a fivefold increase in specific surface area, 66% lower thermal conductivity, and a sixfold increase in pore volume compared to untreated samples. Surface viscosity is linked to sintering resistance, and glass transition temperature and fragility are introduced as design parameters. Machine-learned interatomic potentials and metabasin escape algorithm-assisted molecular dynamics simulations are employed to reveal that materials traditionally classified as nonglass formers can exhibit glass transition temperatures and display intrinsic fragility. Alumina is identified as having a record-high glass transition temperature. By modulating the surface viscosity of nanoparticles, this approach stabilizes nanoporous structures effectively. The proposed method offers a simple and universal posttreatment process for improving the thermal stability of nanoporous structures.}, archive = {J_PNAS}, author = {Yang, Rui and Si, Qiaoling and Sheng, Qiang and Yang, Mingyang and Du, Mu and Zhang, Hu and Shi, Xiao-Lei and Tang, Guihua and Chen, Zhi-Gang}, doi = {10.1073/pnas.2510746122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2510746122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Atomic armor for thermal stability in nanoporous structures}, volume = {122}, year = {2025}, }
• (2025). Digital SERS bioanalysis of single-enzyme biomarkers. PNAS, 122(36), e2510559122. (www)

  @article{ , abstract = {Digital bioanalysis enables highly sensitive detection of biomolecules at the single-molecule level, making it a widely used technique in biomedical research. However, conventional approaches typically rely on fluorescence detection of single-enzyme reactions, which limits molecular selectivity and the ability to analyze multiple targets simultaneously. To address these limitations, we developed a digital bioanalysis platform based on surface-enhanced Raman scattering spectroscopy and microchamber arrays decorated with silver nanoparticles. This platform achieves a million-fold amplification of Raman signals from products generated by single-enzyme reactions, enabling precise digital counting of enzyme biomarkers with high molecular selectivity and multiplexing capability. We applied this platform to detect and distinguish two closely related enzyme biomarkers, acetylcholinesterase (AChE) and butyrylcholinesterase. By leveraging the sharp and distinct Raman spectral signatures of the reaction products, the platform achieved multiplexed biomarker quantification with femtomolar-level sensitivity. As a proof-of-concept, the platform successfully quantified AChE in human cerebrospinal fluid within 8.5 min, highlighting its potential utility in clinical diagnostics, particularly for differentiating types of dementia based on subtle differences in enzyme levels. Hence, this study presents a valuable alternative to fluorescence-based digital bioanalysis by offering enhanced molecular selectivity and multiplexing capability. Its application extends the scope of digital bioanalysis and broadens its capacity to quantify multiple biomarkers in complex biological samples with high precision and efficiency.}, archive = {J_PNAS}, author = {Ando, Jun and Murai, Kazue and Michiyuki, Tomoe and Takahashi, Ikuko and Iida, Tatsuya and Kogo, Yasushi and Toyoda, Masashi and Saito, Yuko and Murayama, Shigeo and Kurihara, Masanori and Watanabe, Rikiya}, doi = {10.1073/pnas.2510559122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2510559122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Digital SERS bioanalysis of single-enzyme biomarkers}, volume = {122}, year = {2025}, }
• (2025). Subaerial oxidative uranium mobilization at the culmination of the great oxidation event. PNAS, 122(36), e2510289122. (www)

  @article{ , abstract = {Redox-sensitive elements figure prominently in studies of the evolution of Earth’s surface redox state, including the first major rise in atmospheric O 2 , the Paleoproterozoic Great Oxidation Event. Most Precambrian rocks endured multistage tectonothermal histories, however, adding ambiguity to interpretation of their chemistry. Here, we apply U-Th-Pb isotope geochronology to the highly oxidized ~2.06 Ga Kuetsjärvi Volcanic Formation, Pechenga Greenstone Belt, Russia, to constrain the age and extent of U oxidation. By contrasting the relative mobility of U and Th using Pb isotopes, we find that complete to near-complete oxidation and removal of U occurred shortly after eruption. We argue that this likely indicates relatively high atmospheric O 2 , where oxidative weathering and alteration produced a global pulse of U to the oceans. Such a pulse could explain widespread shifts in the U-Th-Pb isotope character of mantle reservoirs at ~2 Ga, including a decrease in the 232 Th/ 238 U ratio of the mid-ocean ridge basalt source and inception of the high- 238 U/ 204 Pb (HIMU) source to ocean island basalts, underscoring the connections between the redox character of the Paleoproterozoic surface and deep Earth. Using 207 Pb- 206 Pb, 238 U- 206 Pb, 235 U- 207 Pb, and 232 Th- 208 Pb geochronology, ~2.06 Ga oxidative loss of U may be distinguished from reintroduction of U at ~1.8 Ga during regional metamorphism, as well as Pb loss during a Phanerozoic tectonothermal event. Our results therefore establish the complex history of redox-sensitive element behavior in the rocks, highlighting the fact that elemental abundances, by themselves, are unlikely to capture straightforward proxy information in rocks that have seen multistage geologic histories.}, archive = {J_PNAS}, author = {Bauer, Ann M. and Li, Weiqiang and Rybacki, Kyle S. and Roden, Eric E. and Kump, Lee R. and Johnson, Clark M.}, doi = {10.1073/pnas.2510289122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2510289122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Subaerial oxidative uranium mobilization at the culmination of the great oxidation event}, volume = {122}, year = {2025}, }
• (2025). Manipulating anthracyclines for deeper tissue penetration and implications for glycolytic tissues. PNAS, 122(36), e2510263122. (www)

  @article{ , abstract = {How drugs penetrate tissues is poorly understood yet important, since drugs that fail to reach their target will be ineffective. We followed the fate of anthracycline cancer drugs at high resolution by exploiting their intrinsic fluorescence. In a cell-based spheroid model, the soluble compound fluorescein penetrates the entire spheroid, unlike hydrophobic fluorescent lipids, which only enter the outermost cell layer. Anthracyclines have intermediate hydrophobicity. They enter the nucleus of a few outer cell layers at neutral pH, but penetrate the spheroids more deeply under acidic conditions, with a reduction in cell entry and cytotoxicity. The glycolytic conditions that prevail in the tumor microenvironment may thus limit cell entry and contribute to anthracycline drug resistance. We evaluated a library of anthracycline variants to determine the physicochemical properties related to tissue penetration depth. We find that this is determined by only three chemical properties: molar refractivity, topological polar surface area, and water solubility. Our findings suggest that modifications of anthracyclines may improve access and activity to deeply tissue-embedded targets such as pancreatic cancer.}, archive = {J_PNAS}, author = {Abels, Erik R. and ter Linden, Esther and Rohling, Jos H. T. and Voortman, Lennard M. and Janssen, Lennert and Hornsveld, Marten and Overkleeft, Herman S. and van der Zanden, Sabina Y. and Broekman, Marike L. D. and Neefjes, Jacques}, doi = {10.1073/pnas.2510263122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2510263122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Manipulating anthracyclines for deeper tissue penetration and implications for glycolytic tissues}, volume = {122}, year = {2025}, }
• (2025). Mechanisms underlying allosteric modulation of antiseizure medication binding to synaptic vesicle protein 2A (SV2A). PNAS, 122(36), e2510239122. (www)

  @article{ , abstract = {Brivaracetam (BRV) and levetiracetam (LEV) are antiseizure medications (ASMs); UCB-J is a PET tracer targeting synaptic vesicle protein 2A (SV2A); UCB7361 is closely related to padsevonil, an experimental anticonvulsant; while UCB1244283 acts as an allosteric modulator for BRV and LEV binding but not for these other ligands. The SV2A-BRV-UCB1244283 structure reveals how UCB1244283 allosterically enhances BRV binding by occupying an allosteric site near the primary binding site, preventing BRV dissociation. This allosteric site, formed by hydrophobic and uncharged residues, is an uncharacterized small-molecule binding site in SV2A. Structural analysis and mutagenesis demonstrate that an allosteric network between the primary and allosteric sites governs high-affinity ASM binding. Our studies suggest that UCB1244283 selectively binds SV2A over SV2B and SV2C, with specific mutations disrupting binding. Structures of SV2A-UCB-J and SV2A-UCB7361 show that UCB1244283 binding is only possible when the primary site ligand does not overlap with the allosteric site, and that repositioning of Ser601, Thr605, and Leu655 is critical for allosteric ligand binding. Structural comparison of multiple SV2A complexes reveals that primary site occupancy shapes the conformation of the lumenal half of the transmembrane domain, influencing how UCB1244283 binds via a connected network that differentially stabilizes TM1 in either an open or closed conformation and repositions key allosteric and primary site residues. These insights provide a foundation for developing therapeutics targeting the allosteric site and modulating SV2A function.}, archive = {J_PNAS}, author = {Mittal, Anshumali and Martin, Matthew F. and Provins, Laurent and Hall, Adrian and Ledecq, Marie and Wolff, Christian and Gillard, Michel and Horanyi, Peter S. and Coleman, Jonathan A.}, doi = {10.1073/pnas.2510239122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2510239122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mechanisms underlying allosteric modulation of antiseizure medication binding to synaptic vesicle protein 2A (SV2A)}, volume = {122}, year = {2025}, }
• (2025). Loss of the ESX-5 secretion locus in mycobacterium tuberculosis reshapes the mycomembrane and enhances ESX-1 substrate secretion. PNAS, 122(36), e2509997122. (www)

  @article{ , abstract = {The ESX-5 secretion system, uniquely found in slow-growing mycobacteria, is predicted to secrete over 150 proteins across the inner membrane of Mycobacterium tuberculosis ( M.tb ). Although many of these substrates are believed to promote M.tb virulence, most remain poorly characterized. Here, we use a complete locus deletion strain of ESX-5 in M.tb to examine the molecular changes caused by a broad loss in ESX-5 secretory substrates. We confirmed the selective loss of PE/PPE proteins secreted by ESX-5 into both the culture filtrate (CF) and outer mycomembrane (OMM) fractions of the M.tb ∆esx5 mutant. In examining other ESX systems, we found that ESX-1 substrate levels were increased in both the CF and OMM fractions of the ∆esx5 mutant. Conversely, the ESX-3 locus was transcriptionally repressed upon ESX-5 deletion. We noted that the ∆esx5 mutant had altered morphology in the form of wrinkled distortions of the bacterial surface. Likewise, we identified increased susceptibility of the ∆esx5 mutant to a variety of large (molecular weight >550 g/mol) antimicrobial compounds, suggesting that an intact ESX-5 system is required for M.tb to exclude such molecules. Our findings suggest that removing the ESX-5 system from M.tb fundamentally alters the properties of the mycobacterial OMM and impacts the expression and secretion activity of other ESX systems.}, archive = {J_PNAS}, author = {Koleske, Benjamin and Rajagopalan, Saranathan and Schill, Courtney and Lun, Shichun and Vilchèze, Catherine and Das, Lahari and Gupta, Manish and Martinez-Martinez, Yazmin B. and Bishai, William R. and Jacobs, William R.}, doi = {10.1073/pnas.2509997122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2509997122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Loss of the ESX-5 secretion locus in mycobacterium tuberculosis reshapes the mycomembrane and enhances ESX-1 substrate secretion}, volume = {122}, year = {2025}, }
• (2025). Ultracold cryogenic TEM with liquid helium and high stability. PNAS, 122(36), e2509736122. (www)

  @article{ , abstract = {Cryogenic transmission electron microscopy has revolutionized structural biology and materials science. To image below liquid nitrogen temperatures, various liquid helium stages have been constructed but have proven to be complex and unstable, making high-resolution imaging challenging. This problem is even more pronounced in side-entry specimen holders common on modern transmission electron microscopes. Here, we introduce an ultracold liquid helium transmission electron microscope side-entry specimen holder, featuring continuous cryogen flow and vibration decoupling. This instrument is compatible with modern aberration-corrected microscopes and achieves sub-25 K base temperature, ± 2 mK thermal stability over many hours, and atomic resolution—setting the stage for a new era of cryogenic electron microscopy.}, archive = {J_PNAS}, author = {Rennich, Emily and Sung, Suk Hyun and Agarwal, Nishkarsh and Gates, Maya and Kerns, Robert and Hovden, Robert and Baggari, Ismail El}, doi = {10.1073/pnas.2509736122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2509736122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ultracold cryogenic TEM with liquid helium and high stability}, volume = {122}, year = {2025}, }
• (2025). Complementary biomolecular coassemblies direct energy transport for cardiac photostimulators. PNAS, 122(36), e2509467122. (www)

  @article{ , abstract = {Charge and energy transport within living systems are fundamental processes that enable the autonomous function of excitable cells and tissues. To date, localized control of these transport processes has been enabled by genetic modification approaches to render light sensitivity to cells. Here, we present peptidic nanoassemblies as constituents of a cardiac biomaterial platform that leverages complementary sequence interactions to direct photoinduced energy transport at the cellular interface. Photophysical characterizations and conductivity measurements confirm the occurrence of energy/charge transfer and photocurrent generation upon optical excitation in both dry and electrolytic environments. Comparing an electrostatic sequence pair against a sequence-matched donor–acceptor coassembly, we demonstrate that the sequence design with charge complementarity shows more prominent photocurrent behavior. With the flanking bioadhesive units, the primary and stem cell–derived cardiomyocytes interfaced with covalently stabilized films of the optoelectronic nanostructures exhibited material-stimulated genotypic, structural, or functional cardiac features. Collectively, our findings introduce an optoelectronic cardiac biomaterial where coassembled peptide nanostructures are molecularly designed to induce light sensitivity in excitable cells without gene modification, influencing in vitro cardiac contractile behavior and expression of cardiac markers.}, archive = {J_PNAS}, author = {Yao, Ze-Fan and Lim, Sujeung and Kuang, Yuyao and Lundqvist, Emil M. and Celt, Natalie and Chung, Caleb O. and Lee, Kathryn K. and Nguyen, Krystal and Le, Lanie and Tang, Sheng Wei and Milligan, Griffin M. and Kohl, Phillip and Sudarshan, Tarunya Rao and Li, Youli and Eguchi, Asuka and Paravastu, Anant K. and Zaragoza, Michael V. and Fishman, Dmitry A. and Ardoña, Herdeline Ann M.}, doi = {10.1073/pnas.2509467122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2509467122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Complementary biomolecular coassemblies direct energy transport for cardiac photostimulators}, volume = {122}, year = {2025}, }
• (2025). Resurfacing promotes antibacterial activity of a lipid a–binding nanobody. PNAS, 122(36), e2509305122. (www)

  @article{ , abstract = {Nanobodies have been pursued as candidates for antimicrobial design due to their small size and versatile binding capacities, but direct antibacterial activity of a nanobody has yet to be described. Here, we employed a bacterial surface display platform to screen a synthetic library of nanobody variants for antimicrobial potential. We identified a candidate that binds the essential lipid A component of gram-negative lipopolysaccharide. Nonetheless, this nanobody required a weakened outer membrane to access its target and elicit its toxic activity. Borrowing from observations of innate immune proteins, we found that resurfacing nanobodies with positively charged residues enabled them to bind and perturb the gram-negative outer membrane, but this alone was not sufficient for toxic activity. However, when we resurface our lipid A-targeting nanobody, it gained the ability to disrupt the outer membrane and enact its antibacterial function against wild-type bacteria. This development of a dual-function nanobody that can reach and bind previously inaccessible gram-negative targets introduces a route for antimicrobial biologic advancement.}, archive = {J_PNAS}, author = {O’Donnell, Angela C. and Wang, Xun and Kadeřábková, Nikol and Groover, Kyra E. and Perez, Bethany C. and Helms, Amanda and Brodbelt, Jennifer S. and Mavridou, Despoina A. I. and Davies, Bryan W.}, doi = {10.1073/pnas.2509305122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2509305122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Resurfacing promotes antibacterial activity of a lipid a–binding nanobody}, volume = {122}, year = {2025}, }
• (2025). Identification of AMOTL2 as an antiviral factor that enhances the human type i interferon response against zika virus. PNAS, 122(36), e2507955122. (www)

  @article{ , abstract = {Zika virus (ZIKV) has caused multiple human outbreaks, with more recent epidemics associated with severe outcomes in infants. Today, ZIKV is endemic to many countries and presents a persistent threat for future epidemics. The host innate immune proteins that regulate ZIKV replication are incompletely defined. We developed a CRISPR knockout screen to identify host factors that impact ZIKV replication, resulting in the finding of angiomotin-like protein 2 (AMOTL2), a protein that inhibits ZIKV by regulating the host type I interferon (IFN) response. AMOTL2 affects IFN signaling by modulating STAT1 levels and activation in response to type I IFN. Thus, AMOTL2, which has largely been studied for its role in cancer, represents an antiviral protein that interacts with the IFN signaling pathway to promote downstream expression of IFN stimulated genes, resulting in restriction of ZIKV.}, archive = {J_PNAS}, author = {Willcox, Alexandra C. and Gobillot, Theodore A. and Kikawa, Caroline and Baumgarten, Nell E. and Stoddard, Caitlin I. and Sung, Kevin and Bhattacharya, Tamanash and Freeman, Tiia S. and Marceau, Joshua and Humes, Daryl and Overbaugh, Julie}, doi = {10.1073/pnas.2507955122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2507955122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identification of AMOTL2 as an antiviral factor that enhances the human type i interferon response against zika virus}, volume = {122}, year = {2025}, }
• (2025). Testis expressed 50 is essential for maintaining sperm acrosome integrity during epididymal transit. PNAS, 122(36), e2507930122. (www)

  @article{ , abstract = {In mammals, sperm formation is completed in the seminiferous tubules within the testis, and sperm maturation occurs during the epididymal transit of the spermatozoa. Sperm morphology drastically changes when abnormal spermatozoa migrate from the testis to the epididymis. Detailed molecular mechanisms for sperm survival in the epididymis have not been determined yet. Globozoospermia is a cause of male infertility and is characterized by round-headed spermatozoa without acrosomes, an abnormal sperm nuclear membrane, and sperm midpiece defects. Testis expressed 50 ( Tex50 ) is a testis-enriched gene that is expressed in mice and humans. Using CRISPR-Cas9, we generated Tex50 knockout (KO) mice and found that the KO males were sterile due to epididymal sperm malformations and impaired sperm motility. Surprisingly, electron microscopy, sperm morphology, and globozoospermia-related protein expression and localization in the KO testis were all normal. To understand this phenotype in more detail, we created TEX50-mCherry knockin mice to determine the localization of the TEX50 protein during spermatogenesis. The mCherry signals detected a ring-shaped structure surrounding the sperm acrosome and migrated to the posterior region of the sperm head. After the acrosome reaction, most of the spermatozoa retained mCherry signals. These results indicate that the Tex50 KO globozoospermia phenotype occurs after the migration of spermatozoa from the testis to the epididymis. We found that sperm membrane protein TEX50 is a putative key molecule to survive against globozoospermia-like malformations in the epididymis. It is essential for complete sperm formation and male fertility in mice.}, archive = {J_PNAS}, author = {Haga, Saori and Nozawa, Kaori and Abbasi, Ferheen and Kent, Katarzyna and Nagasawa, Naoko and Endo, Tsutomu and Miyata, Haruhiko and Ikawa, Masahito and Matzuk, Martin M. and Fujihara, Yoshitaka}, doi = {10.1073/pnas.2507930122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2507930122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Testis expressed 50 is essential for maintaining sperm acrosome integrity during epididymal transit}, volume = {122}, year = {2025}, }
• (2025). Direct measurement of plume velocity to characterize point source emissions. PNAS, 122(36), e2507350122. (www)

  @article{ , abstract = {An explosion of recent research uses remote imaging spectroscopy from aircraft and spacecraft to detect and quantify methane point source emissions. These instruments first map the methane enhancement field and then combine this information with the effective wind speed to estimate the source emission rate. This wind speed is typically the largest uncertainty in derived emission rates. It is often, by necessity, inferred from coarse-resolution meteorological reanalysis products which do not match the spatial or temporal extent of wind experienced by the gas plume. Here, we circumvent this problem by simultaneously measuring plume velocity using the same spectrometer that maps the methane plume. Our approach acquires multiple consecutive views of the same point source, with visual tracking of the plume’s features to estimate its ground velocity. This resolves the representational mismatch between reanalysis and effective wind speeds. It provides data with exact spatiotemporal coincidence to the plume being measured. The approach facilitates dramatic improvement in the precision of remote methane point source quantification.}, archive = {J_PNAS}, author = {Eastwood, Michael L. and Thompson, David R. and Green, Robert O. and Fahlen, Jay E. and Adams, Taylor J. and Brandt, Adam R. and Brodrick, Philip G. and Chlus, Adam and Kort, Eric A. and Reuland, Frances and Thorpe, Andrew K.}, doi = {10.1073/pnas.2507350122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2507350122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Direct measurement of plume velocity to characterize point source emissions}, volume = {122}, year = {2025}, }
• (2025). Inverse stable isotope probing–metabolomics (InverSIP) identifies an iron acquisition system in a methane-oxidizing bacterial community. PNAS, 122(36), e2507323122. (www)

  @article{ , abstract = {Methane is a potent greenhouse gas and a target for near-term climate change mitigation. In many natural ecosystems, methane is sequestered by microbial communities, yet little is known about how constituents of methane-oxidizing communities interact with each other and their environment. This lack of mechanistic understanding is a common issue for many important microbial communities, but it is difficult to draw links between available sequencing information and the metabolites that govern community interactions. Here, we develop and apply a technique called inverse stable isotope probing–metabolomics (InverSIP) to bridge the gap between metagenomic and metabolomic information and functionally characterize interactions in a complex methane-oxidizing community. Using InverSIP, we link a highly transcribed biosynthetic gene cluster in the community with its secondary metabolite product: methylocystabactin, a triscatecholate siderophore not previously observed in nature. We find that production of methylocystabactin is widespread among methanotrophic alphaproteobacteria and that it can be used by another methanotroph in the community that does not produce this siderophore itself. Functional assays reveal that methylocystabactin supports methanotroph growth and the activity of the methane-oxidizing enzyme soluble methane monooxygenase under conditions where bioavailable iron is limited, establishing an important molecular link between methane-oxidation and the insoluble iron found in many natural environments. These findings contribute to a molecular-level understanding of these environmentally important bacterial communities and establish InverSIP as a broadly applicable genomics-guided strategy for characterizing metabolites in microbial ecosystems.}, archive = {J_PNAS}, author = {Robes, Jose Miguel D. and Liebergesell, Tashi C. E. and Beals, Delaney G. and Yu, Xinhui and Brazelton, William J. and Puri, Aaron W.}, doi = {10.1073/pnas.2507323122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2507323122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inverse stable isotope probing–metabolomics (InverSIP) identifies an iron acquisition system in a methane-oxidizing bacterial community}, volume = {122}, year = {2025}, }
• (2025). Long-term history of continental weathering and particle transport to the sea. PNAS, 122(36), e2507312122. (www)

  @article{ , abstract = {Here, we explore the long-term history of chemical weathering and particle transport from the continents to the oceans by leveraging the histories of Zr/Al, Rb/Al, and Na/Al in marine sediments over the last 2000 My. We interpret these data in the context of elemental behavior in modern weathering environments and modern marine sediments. We find that from 2000 Mya to ca. 650 Mya, physical erosion was effective, where braided rivers efficiently delivered particles from land to the sea. Overall, chemical weathering was less efficient than now, although many easily weatherable minerals were as weathered as today. We suggest a dramatic change in weathering dynamics after 650 Mya when modern-like deep subduction originated. With this development, mantle dynamics, by promoting periodic vigorous subduction and intense mountain building, began to control the intensity of chemical weathering and particle transport to the oceans. Through spectral analysis of several geochemical records, we find that during times of enhanced subduction and mountain building, continents underwent periods of net erosion and less intense chemical weathering, while during periods of less intense subduction, continents accumulated particles, and chemical weathering was more intense. The evolution and proliferation of land plants changed chemical weathering intensity but had little apparent impact on the cyclic nature of particle transport and storage on the continents. These results could offer a framework to better understand the evolution of elemental cycling from the continents to the oceans over the last 2000 My.}, archive = {J_PNAS}, author = {Canfield, Don E. and Zhang, Shuichang and Mitchell, Ross N. and Wang, Xiaomei and Naemi, Amin and Spencer, Christopher J. and Zhang, Pengyaun}, doi = {10.1073/pnas.2507312122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2507312122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Long-term history of continental weathering and particle transport to the sea}, volume = {122}, year = {2025}, }
• (2025). Bouncing microdroplets on hydrophobic surfaces. PNAS, 122(36), e2507309122. (www)

  @article{ , abstract = {Intuitively, slow droplets stick to a surface and faster droplets splash or bounce. However, recent work suggests that on nonwetting surfaces, whether microdroplets stick or bounce depends only on their size and fluid properties, but not on the incoming velocity. Here, we show using theory and experiments that even poorly wetting surfaces have a velocity-dependent criterion for bouncing of aqueous droplets, which is as high as 6 m/s for diameters of 30 to 50 μ m on hydrophobic surfaces such as Teflon. We quantify this criterion by analyzing the interplay of dissipation, surface adhesion, and incoming kinetic energy, and describe a wealth of associated phenomena, including air bubbles and satellite droplets. Our results on inertial microdroplets elucidate fundamental processes crucial to aerosol science and technology.}, archive = {J_PNAS}, author = {McLauchlan, Jamie and Walker, Jim S. and Sanjay, Vatsal and Jalaal, Maziyar and Reid, Jonathan P. and Squires, Adam M. and Souslov, Anton}, doi = {10.1073/pnas.2507309122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2507309122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bouncing microdroplets on hydrophobic surfaces}, volume = {122}, year = {2025}, }
• (2025). Mutations in the circadian cycle drive adaptive plasticity in cyanobacteria. PNAS, 122(36), e2506928122. (www)

  @article{ , abstract = {Circadian clocks allow organisms to anticipate daily fluctuations in light and temperature, but how this anticipatory role promotes adaptation to different environments remains poorly understood. Here, we subjected the cyanobacterium Synechococcus elongatus PCC 7942 to a long-term evolution experiment under high light, high temperature, and elevated CO 2 levels. After 1,200 generations, we obtained a strain exhibiting a 600% increase in growth rate. Whole-genome sequencing revealed three mutations fixed in the evolved population, two of which were sufficient to recapitulate the fast-growing phenotype in the wild type. A mutation in the promoter of the shikimate kinase aroK led to its overexpression, while a mutation in the central circadian regulator sasA disrupted both the phase and amplitude of the circadian rhythm. Changes in circadian control led to widespread perturbations in the transcriptome and metabolome. These included major shifts in the Calvin–Benson–Bassham cycle and glycogen storage dynamics. While these changes increased fitness under the experimental conditions, they caused maladaptation when light or CO 2 levels were altered, revealing a trade-off between fitness and environmental flexibility. Our results demonstrate that mutations in circadian control can drive fast adaptation by modulating central metabolism, underscoring the circadian cycle as a cornerstone of cellular plasticity. Thus, targeting the circadian cycle could be key to engineering cyanobacterial strains optimized for carbon fixation and biomass production.}, archive = {J_PNAS}, author = {Mendaña, Alfonso and Santos-Merino, María and Gutiérrez-Lanza, Raquel and Domínguez-Quintero, Marina and Medina-Méndez, Juan Manuel and González-Guerra, Ana and Campa, Víctor and Baez, Miguel and Ducos-Galand, Magaly and López-Igual, Rocío and Volke, Daniel C. and Gugger, Muriel and Nikel, Pablo I. and Mazel, Didier and de la Cruz, Fernando and Fernández-López, Raúl}, doi = {10.1073/pnas.2506928122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2506928122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mutations in the circadian cycle drive adaptive plasticity in cyanobacteria}, volume = {122}, year = {2025}, }
• (2025). Founders predict trait evolution and population performance after evolutionary rescue in the red flour beetle. PNAS, 122(36), e2506244122. (www)

  @article{ , abstract = {Evolutionary rescue helps populations survive environmental change, but the phenotypic and demographic factors associated with rescue dynamics and its long-term effects remain unclear. We experimentally evolved 10 wild-collected populations of flour beetles from across India in a suboptimal corn resource for 70 generations (>5 y), collecting >10,000 population census points book-ended by measurements of fitness-related traits for 30 experimental lines. Despite clear ancestral trait differences, all lines showed highly parallel evolutionary rescue within 20 generations. Long-term average population size varied across source populations and was positively correlated with ancestral development rate, which increased convergently across populations and emerged as the single best predictor of population performance during and after evolutionary rescue. Notably, specific demographic events during rescue (such as the rate of population decline and recovery) were uncorrelated both with ancestral trait distributions and post-rescue adaptation. Our results support prior work showing founder traits as key predictors of adaptation, and highlight their role in long-term adaptation and trait evolution following evolutionary rescue.}, archive = {J_PNAS}, author = {Ravi Kumar, Vrinda and Buddh, Shyamsunder and Singhal, Shivansh and Prakash, Arun and Agashe, Deepa}, doi = {10.1073/pnas.2506244122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2506244122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Founders predict trait evolution and population performance after evolutionary rescue in the red flour beetle}, volume = {122}, year = {2025}, }
• (2025). The RNA-binding protein TRIM71 is essential for hearing in humans and mice and times auditory sensory organ development. PNAS, 122(36), e2505811122. (www)

  @article{ , abstract = {The RNA-binding protein TRIM71 is essential for brain development, and recent genetic studies in humans have identified TRIM71 as a risk gene for congenital hydrocephal-us (CH). Here, we show that monoallelic missense mutations in TRIM71 are associated with hearing loss (HL) and inner ear aplasia in humans. Utilizing conditional Trim71 knockout mice carrying a CH and HL-associated mutation, we demonstrate that loss of TRIM71 function during early otic development (embryonic day 9 to 10) causes severe HL. While inner ear morphogenesis occurs normally in Trim71 knockout mice, we find that early otic loss of TRIM71 function disrupts the highly stereotyped timing of cell cycle exit and differentiation within the inner ear auditory sensory organ (cochlea), resulting in the premature formation and innervation of mechanosensory hair cells. Transcriptomic profiling of Trim71 -deficient cochlear progenitor cells identifies Inhba and Tgfbr2 as targets of TRIM71 repression, and our analysis of Inhba-Tgfbr1 double knockout mice indicates that TRIM71 maintains hair cell progenitors in a proliferative and undifferentiated state by restricting TGFβ-type signaling. Characterization of hair cells and their associated neurons in adult Trim71 knockout mice revealed reduced presynaptic terminals and neuronal degeneration in the outer hair cell region, providing a basis for the observed hearing deficits in Trim71 knockout mice.}, archive = {J_PNAS}, author = {Li, Xiao-Jun and Morgan, Charles and Duy, Phan Q. and Evsen, Lale and Hao, Le T. and Machavoine, Roxane and Belhous, Kahina and Ernest, Sylvain and Denoyelle, Françoise and Mignot, Cyril and Brioude, Frederic and Parodi, Marine and Li, Lin and Huang, He and Nadar Ponniah, Prathamesh T. and Kolanus, Waldemar and Kahle, Kristopher T. and Marlin, Sandrine and Doetzlhofer, Angelika}, doi = {10.1073/pnas.2505811122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2505811122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The RNA-binding protein TRIM71 is essential for hearing in humans and mice and times auditory sensory organ development}, volume = {122}, year = {2025}, }
• (2025). MiR444b.2–HsfA1–AOC1 module mediates heat priming–enhanced blast resistance in rice. PNAS, 122(36), e2505764122. (www)

  @article{ , abstract = {As global climate change exacerbates extreme heat events, the interplay between heat stress and blast disease resistance in rice remains poorly understood. In this study, through integrated transcriptome profiling and systematic phenotyping of mutants in several thermosensory pathways, we identified HsfA1 as a positive regulator of heat priming–enhanced blast resistance in rice. Systematic analysis of microRNA (miRNA) dynamics, bioinformatics prediction, and RNA pull-down experiments revealed that miR444b.2 , a temperature-responsive miRNA, directly suppresses the expression of HsfA1 by targeting the second exon of HsfA1 messenger RNA (mRNA). Genetic analyses demonstrated that heat stress–mediated suppression of miR444b.2 expression relieves the repression of HsfA1 , thereby enhancing blast resistance in rice. Furthermore, HsfA1 directly binds to the promoter of AOC1 , a key jasmonic acid (JA) biosynthesis gene, to activate its expression. Knockout of HsfA1 or AOC1 abolishes heat priming–enhanced JA accumulation and blast disease resistance, and the phenotypes are largely restored via AOC1 overexpression and MeJA treatment. Further identification of HsfA1 natural variants and generation of the HsfA1 uORF -edited lines with improved blast resistance offer potential strategies for breeding disease-resistant rice varieties. This study elucidates the miR444b.2 –HsfA1– AOC1 module that links thermal sensing to JA-mediated blast resistance, providing a molecular blueprint for engineering climate-resilient crops with concurrent biotic–abiotic stress tolerance.}, archive = {J_PNAS}, author = {Qiu, Jiehua and Cao, Xiuxiu and Shi, Huanbin and Chen, Zhengting and Zhang, Xiaoyu and Cao, Zijian and Huang, Dongmei and Wen, Hui and Chen, Ya and Kou, Yanjun}, doi = {10.1073/pnas.2505764122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2505764122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MiR444b.2–HsfA1–AOC1 module mediates heat priming–enhanced blast resistance in rice}, volume = {122}, year = {2025}, }
• (2025). De novo design of protein binders to stabilize monomeric TDP-43 and inhibit its pathological aggregation. PNAS, 122(36), e2505320122. (www)

  @article{ , abstract = {Pathological aggregation of transactive response DNA binding protein of 43 kDa (TDP-43), primarily driven by its low-complexity domain, is closely associated with various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the therapeutic potential of preventing TDP-43 aggregation, no effective small molecule or biomacromolecule therapeutics have been successfully developed so far. Here, we introduce a protein design strategy that yields de novo designed proteins capable of stabilizing the key amyloidogenic region of TDP-43 in its native helical conformation with nanomolar binding affinity. The binding mechanism was further characterized by the NMR and mutagenesis study. More importantly, we demonstrated that our designed protein binders efficiently reduced TDP-43 amyloid aggregation both in vitro and in cells. Our work provides a strategy for designing protein stabilizer of the native conformation of pathological proteins for preventing its amyloid aggregation, shedding light on the development of potential therapeutic approaches for ALS, FTLD, and other protein aggregation-associated diseases.}, archive = {J_PNAS}, author = {Sun, Gangyu and Li, Xiang and Hu, Jiaojiao and Yang, Tianbin and Liu, Cong and Wang, Zhizhi and Li, Dan and Xu, Wenqing}, doi = {10.1073/pnas.2505320122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2505320122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {De novo design of protein binders to stabilize monomeric TDP-43 and inhibit its pathological aggregation}, volume = {122}, year = {2025}, }
• (2025). A thermodynamic perspective on mammalian neural crest ingression. PNAS, 122(36), e2504185122. (www)

  @article{ , abstract = {The ingression of neural crest cells from an ectodermal to a mesodermal layer is regulated by instructive, directional cues and potentially stochastic, biophysical parameters such as differential cell adhesion and tension heterogeneity. However, a cohesive framework in which to consider how various influences contribute to ingression remains elusive. Here, we observe the cell behaviors of the murine neural crest in three dimensions over time and apply a free energy framework to more wholly understand why cells ingress. Guided by work on granular matter that provides a path by which to define the roles of stochastic mechanisms in nonequilibrium systems, we measured and manipulated biophysical parameters in vivo. The data suggest that an energy barrier to cell ingression is overcome by a combination of relatively favorable cell adhesion energies, high cell shape fluctuations, and entropic cell packing configurations. Under those conditions, cell ingression may proceed spontaneously. Recognized biophysical cues likely tilt these parameters to make the process more robust. The results imply that dissipative mechanisms which transiently disorder tissue may underlie some morphogenetic events. Variations of a thermodynamic framework can potentially be applied to integrate various inputs that drive morphogenesis in different contexts.}, archive = {J_PNAS}, author = {Pasiliao, Clarissa C. and Thomas, Evan C. and Yung, Theodora and Zhu, Min and Tao, Hirotaka and Sun, Yu and Goyal, Sidhartha and Hopyan, Sevan}, doi = {10.1073/pnas.2504185122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2504185122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A thermodynamic perspective on mammalian neural crest ingression}, volume = {122}, year = {2025}, }
• (2025). Oyster farming acts as a marine carbon dioxide removal (mCDR) hotspot for climate change mitigation. PNAS, 122(36), e2504004122. (www)

  @article{ , abstract = {Bivalve farming, a vital component of global aquaculture, has been proposed as a potential marine carbon dioxide removal (mCDR) strategy, yet its role remains contentious. Using field mesocosms, we demonstrate that oyster filter-feeding enhances mCDR by accelerating the formation of particulate and dissolved organic carbon in the water column and promoting organic carbon deposition in sediments. This process shifts the water column toward a more autotrophic and alkaline state, effectively sequestering CO 2 from the atmosphere. Over the full culture period, the net carbon sequestered by oyster-driven organic carbon production is 2.39 times greater than the CO 2 sequestered in oyster shells. These findings position oyster farming as a scalable, nature-based solution for climate change mitigation, offering dual benefits of carbon sequestration and enhanced food security. Our results underscore the potential of oyster farming to address global challenges such as rising food demand and ocean acidification, making it a critical component of sustainable marine resource management.}, archive = {J_PNAS}, author = {Chen, Xue-Wei-Jie and Zhang, Zhou and Pan, Miao-Jun and Liu, Yang and Li, Chang-Lin and Zhou, Yan-Gen and Li, Li and Dong, Xuan and Dong, Yun-Wei and Li, Jing-Yu and Liu, Su-Mei and Wang, Xiao-Nan and Tian, Shuang-Jie and Liu, Yi and Zhang, Ji-Hong and Qiu, Yan-Guo and Wang, Xue-Gang and Cai, Wei-Jun and Tian, Xiang-Li and Kao, Shuh-Ji and Dong, Shuang-Lin}, doi = {10.1073/pnas.2504004122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2504004122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Oyster farming acts as a marine carbon dioxide removal (mCDR) hotspot for climate change mitigation}, volume = {122}, year = {2025}, }
• (2025). 8,000 years of wild and domestic animal body size data reveal long-term synchrony and recent divergence due to intensified human impact. PNAS, 122(36), e2503428122. (www)

  @article{ , abstract = {The long-term evolution of domestic mammal body size in Western Europe since the Early Neolithic is mainly attributed to human selection. However, the relative influence of environmental and anthropogenic factors in animal body size evolution, and the coevolution of wild and domestic species remain poorly understood. In the Northwestern Mediterranean, abundant archaeozoological data from well-contextualized sites and reliable paleoenvironmental reconstructions provide a unique opportunity to explore long-term morphological changes and their drivers over time. This study analyzes 81,211 biometric measurements from 311 archaeological sites in Mediterranean France, spanning the past 8,000 y. It examines body size evolution in key wild (red deer, red fox, brown hare, rabbit) and domestic (sheep, goat, cattle, pig, chicken) species alongside vegetation, climate, and human activity changes. Our analyses reveal a long-standing synchrony between wild and domestic species until the last millennium, both influenced by a complex interplay of environmental and anthropogenic factors. From the Early Neolithic to the Roman period, environmental conditions exerted comparable effects on wild and domestic species, though the magnitude and timing of changes varied, reflecting species-specific interactions with humans. From the Middle Ages onward, evolutionary trajectories diverged. Domestic species experienced intensified human selection, while human activities increasingly impacted wild populations and their habitat. These findings highlight the dynamic and interwoven roles of environmental and anthropogenic factors in shaping animal morphological evolution, emphasizing the importance of environmental factors in the evolution of domestic species, and illustrating the growing impact of human activities on wild populations.}, archive = {J_PNAS}, author = {Mureau, Cyprien and d’Oliveira, Léa and Peyron, Odile and Blaise, Emilie and Renaud, Audrey and Balcarcel, Ana and Jeanjean, Marine and Bonhomme, Vincent and Bouby, Laurent and Ros, Jérôme and Evin, Allowen}, doi = {10.1073/pnas.2503428122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2503428122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {8,000 years of wild and domestic animal body size data reveal long-term synchrony and recent divergence due to intensified human impact}, volume = {122}, year = {2025}, }
• (2025). Ecology and sexual conflict drive the macroevolutionary dynamics of female-limited color polymorphisms in damselflies. PNAS, 122(36), e2503400122. (www)

  @article{ , abstract = {Sexual conflict over mating has been documented in many species, both in the field and in experimental studies. In pond damselflies (family Coenagrionidae), sexual conflict maintains female-limited color polymorphisms, with one female morph typically being a male mimic. However, it is not known whether sexual conflict can also explain the evolutionary origin of novel female morphs, and if so, what ecological factors play a role in this macroevolutionary transition, by modulating the strength of the conflict. Here, we use phylogenetic comparative methods to show that female color polymorphisms are more likely to evolve in temperate regions and open landscapes, whereas region and habitat shifts are independent of female-color states. We also show that these macroecological patterns are mediated by population densities at breeding sites. Temperate and open habitats are associated with female-polymorphic lineages because they harbor higher densities of adults, promoting more frequent encounters between females and males. Finally, we found that female-limited polymorphisms typically evolve from sexually dimorphic ancestors through the addition of a male-like female morph, consistent with the hypothesis of selection for male mimicry. We conclude that female color polymorphisms evolve in a predictable fashion and are likely driven by ecological conditions that increase the rate of premating interactions and thus the intensity of sexual conflict.}, archive = {J_PNAS}, author = {Willink, Beatriz and Ho, Tammy Ai Tian and Svensson, Erik I.}, doi = {10.1073/pnas.2503400122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2503400122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ecology and sexual conflict drive the macroevolutionary dynamics of female-limited color polymorphisms in damselflies}, volume = {122}, year = {2025}, }
• (2025). HLA-b*15:01-positive severe COVID-19 patients lack CD8+ t cell pools with highly expanded public clonotypes. PNAS, 122(36), e2503145122. (www)

  @article{ , abstract = {Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8 + T-cells directed against HLA-B*15:01-restricted Spike-derived S 919-927 peptide (B15/S 919 + CD8 + T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8 + T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S 919 + CD8 + T-cell responses in COVID-19 patients from independent HLA-typed COVID-19 patient cohorts across three continents, Australia, Asia and Europe. We assessed B15/S 919 + CD8 + T-cells in COVID-19 patients across disease outcomes ranging from asymptomatic to hospitalized critical illness. We found that severe/critical COVID-19 patients mounted B15/S 919 + CD8 + T-cell responses lacking a highly expanded key public B15/S 919 + CD8 + T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S 919 + CD8 + T-cell responses in life-threatening disease had a prevalence of an alternate TCR clonotypic motif (TRAV38-2/DV8/TRBV20-1), potentially contributing, at least in part, to why B15/S 919 + CD8 + T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S 919 + CD8 + T-cells did not differ across disease severity. Moreover, B15/S 919 + CD8 + T-cells were better maintained into convalescence compared to other SARS-CoV-2-specificities. Our study thus provides evidence on the differential nature of the TCR clonal repertoire in 22.37% of HLA-B*15:01-positive COVID-19 patients who developed severe or critical disease in our cohorts, comparing to HLA-B*15:01-expressing individuals with mild COVID-19.}, archive = {J_PNAS}, author = {Rowntree, Louise C. and Allen, Lilith F. and Hagen, Ruth R. and McQuilten, Hayley A. and Quadeer, Ahmed A. and Chaurasia, Priyanka and Kaewpreedee, Prathanporn and Lee, Kelly W. K. and Cohen, Carolyn A. and Petersen, Jan and Littler, Dene R. and Habel, Jennifer R. and Zhang, Wuji and Cheng, Samuel M. S. and Chan, Ken Ka Pang and Kwok, Janette S. Y. and Leung, Kathy S. M. and Wu, Joseph T. and Lee, Cheuk-Kwong and Davies, Jane and Pannaraj, Pia S. and Kaity Allen, E. and Thomas, Paul G. and Tosif, Shidan and Crawford, Nigel W. and Lappas, Martha and Thevarajan, Irani and Lewin, Sharon R. and Kent, Stephen J. and Juno, Jennifer A. and Bond, Katherine A. and Williamson, Deborah A. and Holmes, Natasha E. and Smibert, Olivia C. and Gordon, Claire L. and Trubiano, Jason A. and Kotsimbos, Tom C. and Cheng, Allen C. and Efstathiou, Claudia and Turtle, Lance and Thwaites, Ryan S. and Brightling, Christopher E. and null, null and Rossjohn, Jamie and McKay, Matthew R. and Tian, Jinmin and Liu, William Jun and Gao, George Fu and Xu, Jianqing and Sonehara, Kyuto and Ishii, Ken J. and Namkoong, Ho and Okada, Yukinori and Peiris, Malik and Hui, David S. C. and Poon, Leo L. M. and Doherty, Peter C. and Nguyen, Thi H. O. and Valkenburg, Sophie A. and Kedzierska, Katherine}, doi = {10.1073/pnas.2503145122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2503145122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {HLA-b*15:01-positive severe COVID-19 patients lack CD8+ t cell pools with highly expanded public clonotypes}, volume = {122}, year = {2025}, }
• (2025). Tumor-expressed GPNMB orchestrates siglec-9+ TAM polarization and EMT to promote metastasis in triple-negative breast cancer. PNAS, 122(36), e2503081122. (www)

  @article{ , abstract = {Metastasis remains the leading cause of cancer-related mortality, driven by complex interactions within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play a pivotal role in metastatic progression, yet their molecular diversity and upstream regulators remain poorly defined. Glycoprotein nonmetastatic melanoma protein B (GPNMB), overexpressed in subsets of tumors including triple-negative breast cancer (TNBC), is implicated in epithelial–mesenchymal transition (EMT) and cancer stemness. Recent single-cell RNA sequencing (scRNA-seq) identified GPNMB as a marker of immunosuppressive TAMs associated with poor prognosis, but its mechanistic role in TNBC has remained unclear. Coculturing monocytic cells with three-dimensional TNBC spheres induced GPNMB + TAMs expressing sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9). Tumor-expressed GPNMB promotes monocyte-to-TAM polarization by inducing secondary GPNMB expression in monocytes, establishing a feed-forward amplification loop. GPNMB knockdown in TNBC cells inhibited immunosuppressive TAM subsets, including Siglec-9 + and EMT-associated populations, as determined by deconvolution of bulk RNA-seq data using a custom TAM signature matrix derived from publicly available TNBC scRNA-seq datasets. TNBC-derived GPNMB carried α2,3-sialylation, whereas macrophage-derived GPNMB carried α2,6-sialylation, enabling differential Siglec-9 recognition. Elevated GPNMB and Siglec-9 correlated with poor prognosis in TNBCcohorts. Importantly, dual inhibition of Siglec-E (murine Siglec-9 ortholog) and PD-1 reduced tumor stemness, suppressed IL-6-dependent EMT, and limited lung metastasis in vivo. The GPNMB–Siglec-9 axis thus represents a critical glyco-immunological checkpoint driving TAM-mediated metastasis, providing a promising therapeutic target in TNBC.}, archive = {J_PNAS}, author = {Dang Cao, Thuy Linh and Kawanishi, Kunio and Hashimoto, Sachie and Hengphasatporn, Kowit and Nagai-Okatani, Chiaki and Kimura, Takaharu and Abdelaziz, Mohammed and Shiratani, Rie and Poullikkas, Thanasis and Azmi, Nuriza Ulul and Baba, Masaki and Okita, Yukari and Watanabe, Yukihide and Bando, Hiroko and Yamazaki, Satoshi and Shigeta, Yasuteru and Kuno, Atsushi and Kato, Mitsuyasu}, doi = {10.1073/pnas.2503081122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2503081122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tumor-expressed GPNMB orchestrates siglec-9+ TAM polarization and EMT to promote metastasis in triple-negative breast cancer}, volume = {122}, year = {2025}, }
• (2025). 12/15-lipoxygenase orchestrates murine wound healing via PPARγ-activating oxylipins acting holistically to dampen inflammation. PNAS, 122(36), e2502640122. (www)

  @article{ , abstract = {12/15-lipoxygenase (12/15-LOX, Alox15 ) generates bioactive oxygenated lipids during inflammation, however its homeostatic role(s) in normal healing are unclear. Here, the role of 12/15-LOX in resolving skin wounds was elucidated, focusing on how its lipids act together in physiologically relevant amounts. In mice, wounding caused acute appearance of 12/15-LOX-expressing macrophages and stem cells, coupled to early generation of ~12 monohydroxy-oxylipins and enzymatically oxidized phospholipids (eoxPL). Alox15 deletion increased collagen deposition, stem cell/fibroblast proliferation, IL6/pSTAT3, pSMAD3, and interferon (IFN)-γ levels. Conversely, CD206 expression, F480+ cells, and MMP9 and MMP2 activities were reduced. Alox15 −/− skin was deficient in PPARγ/adiponectin activity. Furthermore, while pro-inflammatory genes were upregulated as normal during wounding, many including Il6, Il1b, ccl4, Cd14, Cd274, Clec4d, Clec4e, Csf3, Cxcl2, and miR-21 failed to revert to baseline during healing, indicating disruption of PPARγ’s anti-inflammatory brake on NLRP3/inflammasome and TGF-β signaling. Reconstituting Alox15 −/− wounds with a physiological mixture of Alox15 -derived primary oxylipins generated by healing wounds restored MMP and dampened collagen deposition. The oxylipin mixture activated the PPARγ response element in vitro, while in vivo, its coactivator, Helz2 , was significantly upregulated as well as several fatty acid and prostaglandin PPARγ ligands. Additional inflammatory and proliferative gene networks impacted by Alox15 −/− included Elf4, Cebpb , and Tcf3. In summary, 12/15-LOX generates abundant monohydroxy oxylipins that act together via PPARγ. The identification of multiple gene alterations reveals several targets for treating nonhealing wounds. Our studies demonstrate that 12/15-LOX oxylipins act in concert, dampening inflammation in vivo, revealing the need to consider lipid signaling holistically.}, archive = {J_PNAS}, author = {Thomas, Christopher P. and Tyrrell, Victoria J. and Burston, James J. and Johnson, Sam R. C. and Aldrovandi, Maceler and Alvarez-Jarreta, Jorge and Inglis, Rossa and Leonard, Adam and Fice, Lydia and Costales, Jeremie and Vidal-Puig, Antonio and Protty, Majd and Guy, Carol and Andrews, Robert and Szomolay, Barbara and Cossins, Ben C. and Cardus Figueras, Ana and Carobbio, Stefania and Jones, Simon A. and O’Donnell, Valerie B.}, doi = {10.1073/pnas.2502640122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2502640122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {12/15-lipoxygenase orchestrates murine wound healing via PPARγ-activating oxylipins acting holistically to dampen inflammation}, volume = {122}, year = {2025}, }
• (2025). Restoring mitochondrial quantity and quality to reverse the warburg effect and drive neuroblastoma differentiation. PNAS, 122(36), e2502483122. (www)

  @article{ , abstract = {Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U- 13 C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the tricarboxylic acid cycle and switching substrate preference from glutamine to glucose. These effects were abolished by electron transport chain (ETC) inhibitors or in ρ 0 cells lacking mitochondrial DNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing of xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, potentially improving patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.}, archive = {J_PNAS}, author = {Jiang, Haowen and Tiche, Sarah Jane and He, Clifford Jiajun and Liu, Junyan and Bian, Fuyun and Jedoui, Mohamed and Forgo, Balint and Islam, Md Tauhidul and Zhao, Meng and Emengo, Pamela and He, Bo and Li, Yang and Li, Albert M. and Truong, Anh T. and Ho, Jestine and Simmermaker, Cathyrin and Yang, Yanan and Zhou, Meng-Ning and Hu, Zhen and Svensson, Katrin J. and Cuthbertson, Daniel J. and Hazard, Florette K. and Xing, Lei and Shimada, Hiroyuki and Chiu, Bill and Ye, Jiangbin}, doi = {10.1073/pnas.2502483122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2502483122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Restoring mitochondrial quantity and quality to reverse the warburg effect and drive neuroblastoma differentiation}, volume = {122}, year = {2025}, }
• (2025). From relaxation to buckling: A continuum elastic framework connecting surface instabilities of highly compressed lipid thin films. PNAS, 122(36), e2502369122. (www)

  @article{ , abstract = {Self-assembled thin films respond to external loads via surface instabilities that are critical to their functionality in both biology and technology. Lipid monolayers at the air–liquid interface are one such system. Tunability between out-of-plane buckling (e.g., folding) and in-plane relaxation (e.g., reorganization of lipid domains) in highly compressed lipid monolayers suggests underlying mechanistic generality. Yet, how in-plane relaxation occurs and how it is distinguished from folding remains elusive. Here, we use continuum mechanics, finite element (FE) simulations, and Langmuir trough fluorescence microscopy (FM) data to elucidate the underlying mechanisms of these elastic instability modes. Uniaxial loading of the Langmuir trough is evaluated in FE simulations, where the lipid monolayer is modeled as a thin sheet with a hyperelastic energy function developed to exhibit a relaxation mechanism. Results show that this material relaxation mechanism triggers tunable in-plane shear localization (shear banding). Furthermore, the simulation results of a heterogeneous model, built from fluorescence micrographs of lipid domains distributed in a continuous matrix, are rigorously compared with experimental data by domain organizational analyses. These analyses suggest shear bands are sufficient in inducing domain symmetry breaking that is characteristic of in-plane relaxation and, without such shear bands, domain organization remains in powder structure, characteristic of folding lipid monolayers. Our findings develop a hyperelastic model validated against experimental FM images that can connect the observed lipid monolayer instabilities of folding and in-plane relaxation, establishing a generalized framework with the potential to unify all other monolayer instability modes and characterize other thin film systems.}, archive = {J_PNAS}, author = {Gaffney, Anna D. and Liu, Dongxu and Samal, Deepanjali and Carotenuto, Angelo R. and Deseri, Luca and Fraldi, Massimiliano and Lee, Ka Yee C. and Pocivavsek, Luka and Nguyen, Nhung}, doi = {10.1073/pnas.2502369122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2502369122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {From relaxation to buckling: A continuum elastic framework connecting surface instabilities of highly compressed lipid thin films}, volume = {122}, year = {2025}, }
• (2025). Joint models reveal human subcortical underpinnings of choice and learning behavior. PNAS, 122(36), e2502269122. (www)

  @article{ , abstract = {Decision making and learning processes together enable adaptive strategic behavior. Animal studies demonstrated the importance of subcortical regions in these cognitive processes, but the human subcortical contributions remain poorly characterized. Here, we study choice and learning processes in the human subcortex, using a tailored ultra-high field 7T functional MRI protocol combined with joint models. Joint models provide unbiased estimates of brain–behavior relations by simultaneously including behavioral and neural data at the participant and group level. Results demonstrate relations between subcortical regions and the adjustment of decision urgency. Value-related blood-oxygenation level dependent (BOLD) differences were found with opposite BOLD polarity in different parts of the striatum. Multiple subcortical regions showed BOLD signatures of reward prediction error processing, but contrary to expectations, these did not include the dopaminergic midbrain. Combined, this study characterizes the human subcortical contributions to choice and learning, and demonstrates the feasibility and value of joint modeling in facilitating our understanding of brain–behavior relationships.}, archive = {J_PNAS}, author = {Miletić, Steven and Stevenson, Niek and Bazin, Pierre-Louis and Alkemade, Anneke and Isherwood, Scott J. S. and Trutti, Anne C. and Tse, Desmond H. Y. and Håberg, Asta K. and Forstmann, Birte U.}, doi = {10.1073/pnas.2502269122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2502269122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Joint models reveal human subcortical underpinnings of choice and learning behavior}, volume = {122}, year = {2025}, }
• (2025). Pdgf mediates a transient regeneration-activated cell state in planarian tissue regeneration. PNAS, 122(36), e2501874122. (www)

  @article{ , abstract = {The role of induced gene expression is crucial for tissue regeneration. The transient regenerative cellular state that discriminates between missing-tissue and non-missing-tissue injuries remains to be fully elucidated. In this study, we identified a homolog of Platelet-Derived Growth Factor (PDGF), named pdgf-like ( pdgfl ), in the planarian Schmidtea mediterranea . This gene exhibits inducible expression following missing-tissue injury in a back-and-forth manner between myosin + muscular cells and piwi-1 + stem cells. The dynamic expression of pdgfl is induced through the elevation of reactive oxygen species (ROS) levels and phosphorylated extracellular signal-regulated kinase (pERK) signaling over short distances. Suppression of pdgfl expression impairs the regrowth of essential structures, including the intestine and central nervous system. Evidence on the decrease of notum and sfrp-1 at the anterior pole, together with the accumulation of myoD + PIWI-1 + progenitors, suggests a role of pdgfl in pole muscular cell differentiation. These findings highlight the significant impact of pdgfl in orchestrating the behavior of specific cell types by the regional specificity of this gene expression.}, archive = {J_PNAS}, author = {Xu, Hao and Li, Yucong and Yang, Ling and Li, Nan and Lei, Kai}, doi = {10.1073/pnas.2501874122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2501874122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pdgf mediates a transient regeneration-activated cell state in planarian tissue regeneration}, volume = {122}, year = {2025}, }
• (2025). A mosquito-inspired theoretical framework for acoustic signal detection. PNAS, 122(36), e2500938122. (www)

  @article{ , abstract = {Distortion products are tones produced through nonlinear effects of a system simultaneously detecting two or more frequencies. These combination tones are ubiquitous to vertebrate auditory systems and are generally regarded as byproducts of nonlinear signal amplification. It has previously been shown that several species of infectious-disease-carrying mosquitoes utilize these distortion products for detecting and locating potential mates. Furthermore, the mechanical tuning curve of the male mosquito flagellum was shown not to be aligned with that of its sensory neural elements. Using a generic theoretical model for acoustic sensing, we evaluate the signal-detection advantages and disadvantages that are implied by these two schemes: distortion product detection and cascading a signal through multiple layers of oscillator elements of different characteristic frequency. Last, we show that the combination of these two schemes yields a signal detector with enhanced frequency selectivity and speed of response, thus enabling the detection of transient, narrowband flight tones.}, archive = {J_PNAS}, author = {Faber, Justin and Alampounti, Alexandros C. and Georgiades, Marcos and Albert, Joerg T. and Bozovic, Dolores}, doi = {10.1073/pnas.2500938122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2500938122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A mosquito-inspired theoretical framework for acoustic signal detection}, volume = {122}, year = {2025}, }
• (2025). Lysosomal reduced thiols are essential for mouse embryonic development. PNAS, 122(36), e2427125122. (www)

  @article{ , abstract = {While it has been appreciated for decades that lysosomes can import cysteine, its significance for whole-organism physiology has remained uncertain. Recent work identified MFSD12 as a transmembrane protein required for cysteine import into lysosomes (and melanosomes), enabling genetic interrogation of this pathway. Here, we show that Mfsd12 knockout mice die between embryonic days 10.5 and 12.5, indicating that MFSD12 is essential for organogenesis. Mfsd12 loss results in the expression of genes involved in cellular stress and thiol metabolism and likely disproportionately affects the erythroid, myeloid, and neuronal lineages. Within lysosomes, imported cysteine is largely oxidized to cystine, which is exported to the cytosol by the cystinosin (CTNS) transporter. However, unlike Mfsd12 , loss of Ctns is compatible with viability, suggesting that the essential role of MFSD12 lies not in supplying cystine to the cytosol, but in providing reduced cysteine within the lysosomal lumen. Supporting this model, maternal treatment with cysteamine—a lysosome-penetrant thiol—rescued the development of Mfsd12 knockout embryos, yielding viable adult offspring. These findings establish lysosomal thiol import as a critical metabolic pathway and provide genetic tools to further clarify its physiological and biochemical roles.}, archive = {J_PNAS}, author = {Adelmann, Charles H. and Venkatachalam, Avanthika and Huang, Lingjuan and Liu, Michelle and Germana, Sharon and Harry, Stefan A. and Rosen, Paul C. and Herron, Joshua and Tien, Pei-Chieh and Bar-Peled, Liron and Sabatini, David M. and Fisher, David E.}, doi = {10.1073/pnas.2427125122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2427125122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lysosomal reduced thiols are essential for mouse embryonic development}, volume = {122}, year = {2025}, }
• (2025). Topology and kinetic pathways of colloidosome assembly and disassembly. PNAS, 122(36), e2427024122. (www)

  @article{ , abstract = {Closed capsules, such as lipid vesicles, soap bubbles, and emulsion droplets, are ubiquitous throughout biology, engineered matter, and everyday life. Their creation and disintegration are defined by a singularity that separates a topologically distinct extended liquid film from a boundary-free closed shell. Such topology-changing processes are of fundamental interest. They are also essential for intercellular transport, transcellular communication, and drug delivery. However, studies of vesicle formation are challenging because of the rapid dynamics and small length scale involved. We develop fluid colloidosomes, micrometer-sized analogues of lipid vesicles. The mechanics of colloidosomes and lipid vesicles are described by the same theoretical model. We study colloidosomes close to their disk-to-sphere topological transition. Intrinsic colloidal length and time scales slow down the dynamics to reveal colloidosome conformations in real time during their assembly and disassembly. Remarkably, the lowest-energy pathway by which a closed vesicle transforms into a flat disk involves a topologically distinct cylinder-like intermediate. These results reveal aspects of topological changes that are relevant to all liquid capsules. They also provide a robust platform for the encapsulation, transport, and delivery of nanosized cargoes.}, archive = {J_PNAS}, author = {Adkins, Raymond and Robaszewski, Joanna and Shin, Seungwoo and Brauns, Fridtjof and Jia, Leroy and Khanra, Ayantika and Sharma, Prerna and Pelcovits, Robert A. and Powers, Thomas R. and Dogic, Zvonimir}, doi = {10.1073/pnas.2427024122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2427024122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Topology and kinetic pathways of colloidosome assembly and disassembly}, volume = {122}, year = {2025}, }
• (2025). Therapeutic restoration of mitochondria–endoplasmic reticulum cross talk for osteoarthritis. PNAS, 122(36), e2426992122. (www)

  @article{ , abstract = {Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondrocyte homeostasis and whether such processes can be explored as therapeutic targets for osteoarthritis remain unclear. Here, we show that impaired mitochondrial function and disrupted cartilage matrix metabolism due to loss of mitofusin-2 (MFN2) expression in chondrocytes leads to the development of osteoarthritis. Sirtuin-3 (SIRT3), a key regulator of mitochondrial function, plays a critical role in modulating MFN2 to restore mitochondrial dynamics, reduce fragmentation, and preserve mitochondrial function in chondrocytes. Specifically, SIRT3 directly deacetylates and indirectly deubiquitinates MFN2, preventing its degradation. MFN2-mediated mitochondrial–endoplasmic reticulum (ER) junctions support cellular homeostasis, alleviate ER stress, and maintain mitochondrial calcium ion balance, which collectively mitigate chondrocyte senescence. Extracellular vesicles engineered with MFN2 mRNA effectively prevented cartilage degeneration and restored mobility in osteoarthritic mice. These findings suggest that targeting MFN2 is a promising strategy to prevent cartilage degeneration and alleviate progression of osteoarthritis.}, archive = {J_PNAS}, author = {Hou, Mingzhuang and Ma, Yifan and Deng, Yaoge and Wu, Yubin and Zhu, Yanrun and Liu, Yang and Li, Xiaoping and Yu, Lili and He, Zirui and Wang, Yifan and Dong, Shiyan and Xia, Xiaowei and Yu, Jianfeng and Yu, Chenqi and Kang, Kang and Lu, Yingjie and Sun, Lili and Kim, Betty Y. S. and Yuan, Yuan and Zhang, Yijian and Jiang, Wen and Zhu, Xuesong}, doi = {10.1073/pnas.2426992122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2426992122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Therapeutic restoration of mitochondria–endoplasmic reticulum cross talk for osteoarthritis}, volume = {122}, year = {2025}, }
• (2025). PD-1 expression identifies proliferating malignant CLL b cells and is a potential biomarker of response to BTK inhibitor therapy. PNAS, 122(36), e2426935122. (www)

  @article{ , abstract = {Chronic lymphocytic leukemia (CLL) remains incurable despite treatment advances, and a major challenge is that biomarkers that predict response and resistance to current therapies are lacking. We report that activated and proliferating malignant CLL B cells in circulation express PD-1, a protein normally expressed in T cells. PD-1 expression is absent in circulating B cells from healthy controls and nonmalignant B cells from patients with CLL. Circulating PD-1 + CLL cells are found in all treatment naïve patients, regardless of immunoglobulin heavy-chain variable region gene mutation status or cytogenetic abnormalities. PD-1 + CLL cells are transcriptionally distinct compared to PD-1 − CLL cells and upregulate genes associated with cell activation, proliferation, and B cell receptor (BCR) and toll-like receptor (TLR) signaling. Indeed, ex vivo stimulation of the BCR and TLR9 readily increased PD-1 expression in CLL cells from treatment-naïve patients within 24 h, an effect that was blocked by Bruton’s tyrosine kinase inhibitors (BTKi). More importantly, patients initiating BTKi therapy experienced profound reductions in circulating PD-1 + CLL cell numbers within 1 mo, which is in line with reduction in Ki-67 + CLL cells. Elevated percentages of circulating PD-1 + CLL cells also preceded a clinical diagnosis of disease progression in patients receiving BTKi. Thus, our findings indicate that PD-1 expression is a potential biomarker to identify proliferating CLL cells in vivo and will be useful to predict response and resistance to BTKi. In addition, eliminating PD-1 + CLL cells with depleting anti-PD-1 monospecific or bispecific antibodies should be explored as a potential therapeutic strategy.}, archive = {J_PNAS}, author = {Chang, Andres and Pelletier, Adam N. and McGuire, Donald J. and Tsagiopoulou, Maria and Karipidou, Maria and Ayers, Amy and Leal, Alyssa M. K. and Churnetski, Michael C. and O’Leary, Colin B. and Switchenko, Jeffrey M. and Davis, Carl and Frank, David A. and Koff, Jean L. and Cohen, Jonathon B. and Sekaly, Rafick P. and Stamatopoulos, Kostas and Flowers, Christopher R. and Ahmed, Rafi}, doi = {10.1073/pnas.2426935122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2426935122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PD-1 expression identifies proliferating malignant CLL b cells and is a potential biomarker of response to BTK inhibitor therapy}, volume = {122}, year = {2025}, }
• (2025). Collective behavior of “flexicles”. PNAS, 122(36), e2426850122. (www)

  @article{ , abstract = {In recent years the functionality of synthetic active microparticles has edged even closer to that of their biological counterparts. However, we still lack the understanding needed to recreate at the microscale key features of autonomous behavior exhibited by microorganisms or swarms of macroscopic robots. In this study, we propose a model for a three-dimensional deformable cellular composite particle consisting of self-propelled rod-shaped colloids confined within a flexible vesicle—representing a superstructure we call a “flexicle” that couples particle deformation to the internal dynamics of the internal active components. Using molecular dynamics simulations, we investigate the collective behavior of dense systems composed of many flexicles. We show that individual flexicles exhibit shape changes upon collisions with other flexicles that lead to rearrangements of the internal active rods, which slows flexicle motion. This shape deformability gives rise to a diverse set of motility-induced phase separation phenomena and the spontaneous flow of flexicles reminiscent of the migration of cells in dense tissues. Our findings establish a foundation for designing responsive, cell-like active particles and developing strategies for controlling swarm migration and other autonomous swarm behaviors at cellular and colloidal scales.}, archive = {J_PNAS}, author = {Schönhöfer, Philipp W. A. and Glotzer, Sharon C.}, doi = {10.1073/pnas.2426850122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2426850122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Collective behavior of “flexicles”}, volume = {122}, year = {2025}, }
• (2025). Origami frustration and its influence on energy landscapes of origami assemblies. PNAS, 122(36), e2426790122. (www)

  @article{ , abstract = {Harnessing instabilities of multicomponent multistable structural assemblies can potentially lead to scalable and reversible functionalities, which can be enhanced by exploring frustration. For instance, standard Kresling origami cells exhibit nontunable intrinsic energy landscapes determined by their geometry and material properties, limiting their adaptability after fabrication. To overcome this limitation, we introduce frustration to enable fine-tuning of the energy landscape and resulting deformation states. By prestressing the Kresling cell by means of special springs with individual control, we induce either global or localized (i.e., crease level) frustration, which allows changing the energy barrier (cell or assembly). We investigate the mechanical behavior of frustrated Kresling assemblies, both theoretically and experimentally, under various loading and boundary conditions. Our findings reveal that changing the frustration state leads to precise control of folding sequences, enabling previously inaccessible folding paths. The proposed concept paves the way for applications in mechanical metamaterials and other fields requiring highly programmable and reconfigurable systems – e.g., prosthetic limbs.}, archive = {J_PNAS}, author = {Zang, Shixi and Zhao, Tuo and Misseroni, Diego and Paulino, Glaucio H.}, doi = {10.1073/pnas.2426790122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2426790122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Origami frustration and its influence on energy landscapes of origami assemblies}, volume = {122}, year = {2025}, }
• (2025). Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT). PNAS, 122(36), e2426135122. (www)

  @article{ , abstract = {Creatine plays a vital role in cellular energy production and adenosine triphosphate (ATP) homeostasis and has also been identified as a neurotransmitter in the mammalian brain. Creatine is transported into cells by the human creatine transporter (hCRT) (SLC6A8), an Na + /Cl − -dependent symporter encoded on the X chromosome. Mutations in hCRT cause cerebral creatine deficiency syndrome 1, a neurological disorder marked by intellectual disability, speech delay, and seizures. Beyond its role in the brain and muscle, hCRT is highly expressed in metabolically active tumors. Many cancer cells, including colorectal cancer and glioblastoma, upregulate hCRT to sustain intracellular creatine levels and buffer ATP under energy stress. Pharmacological blockade of hCRT by RGX202 has been shown to impair tumor growth by disrupting energy homeostasis. Here, we report the high-resolution cryo-Electron Microscopy (cryo-EM) structures of human hCRT in three states: apo, creatine-bound, and RGX202-bound. hCRT adopts a canonical LeuT-fold with 12 transmembrane helices and two pseudosymmetric inverted repeats. Creatine is coordinated in the central substrate-binding site through interactions with transmembrane helices TM1, TM3, TM6, and TM8, while the inhibitor RGX202 occupies the same binding pocket, engaging in overlapping contacts that competitively block creatine access. Our structural and mechanistic findings clarify substrate recognition and inhibitory binding of hCRT, providing a molecular rationale for targeting hCRT in both inherited metabolic diseases and cancer therapy.}, archive = {J_PNAS}, author = {Yuan, Xinyi and Yin, Jian and Liu, Chang and Chen, Xudong and Chen, Meiying and Wang, Yixue and Yang, Zi and Wang, Yue and Jiang, Li and Zhou, Niyun and Wang, Xiaojuan and Liu, Botong and Ma, Zhaoqi and Wang, Kaiyan and Li, Hongen and Zhang, Sensen and Shang, Yongfeng and Yang, Maojun}, doi = {10.1073/pnas.2426135122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2426135122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT)}, volume = {122}, year = {2025}, }
• (2025). A general genome editing strategy using CRISPR lipid nanoparticle spherical nucleic acids. PNAS, 122(36), e2426094122. (www)

  @article{ , abstract = {Genome editing with CRISPR–Cas systems hold promise for treating a wide range of genetic disorders and cancers. However, efficient delivery of genome editors remains challenging due to the requirement for the simultaneous delivery or intracellular generation of Cas proteins, guide RNAs, and, in some applications, donor DNAs. Furthermore, the immunogenicity and toxicity of delivery vehicles can limit the safety and efficacy of genetic medicines. Here, we combine two nucleic acid delivery approaches to create CRISPR lipid nanoparticle–spherical nucleic acids (LNP–SNAs) that are both efficient and biocompatible. Compared to lipid nanoparticles (LNPs) lacking a surface-bound DNA shell, CRISPR LNP–SNAs exhibit two- to three-fold higher cellular uptake, reduced cytotoxicity, and improved gene transfection efficiency. Across multiple cell lines and genomic loci, CRISPR LNP–SNAs induce insertion–deletion mutations at average frequencies two- to three-fold higher than those observed with LNPs. When codelivered with donor templates, CRISPR LNP–SNAs enable homology-directed repair at an average efficiency of 21 ± 7%, a 2.5-fold improvement over LNPs (8 ± 4%). The ease of synthesis and biocompatibility of CRISPR LNP–SNAs highlight their potential as a versatile delivery platform for CRISPR–Cas and other gene therapies.}, archive = {J_PNAS}, author = {Han, Zhenyu and Huang, Chi and Luo, Taokun and Mirkin, Chad A.}, doi = {10.1073/pnas.2426094122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2426094122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A general genome editing strategy using CRISPR lipid nanoparticle spherical nucleic acids}, volume = {122}, year = {2025}, }
• (2025). 9,000-year-old barley consumption in the foothills of central asia. PNAS, 122(36), e2424093122. (www)

  @article{ , abstract = {Scholars are increasingly favoring models for the origins of agriculture that involve a protracted process of increasing interdependence within a series of mutualistic relationships between humans and plants, as opposed to a rapid single event or innovation. Nonetheless, these scholars continue to debate over when people first started foraging for grass seeds, when they began to readily utilize sickles, how prominent the early selection pressures were, and when the first traits of domestication fully introgressed into the cultivated grass population. Here, we present complementary archaeobotanical and archaeological (stone tool) evidence for cereal foragers from Toda-1 Cave in the Surkhan Darya, dating to 9200 cal BP. We conclude that early Holocene foragers were processing grains along with nuts and fruits as far north as the rich river valleys of southern Uzbekistan. These data expand the known range that preagricultural cereal foragers covered in the early Holocene, adding to our understanding of the cultural processes that led to farming. Additionally, we present the earliest evidence for people interacting with the progenitors for pistachios and apples (or a close apple relative). The complex foraging behaviors that led to cultivation were being undertaken by people during the early Holocene across a wider area of Eurasia than previously thought.}, archive = {J_PNAS}, author = {Zhou, Xinying and Spengler, Robert N. and Sayfullaev, Bahediyoh and Mutalibjon, Khasanov and Ma, Jian and Liu, Junchi and Shen, Hui and Zhao, Keliang and Chen, Guanhan and Wang, Jian and Stidham, Thomas A. and Xu, Hai and Zhang, Guilin and Yang, Qingjiang and Hou, Yemao and Ma, Jiacheng and Kambarov, Nasibillo and Jiang, Hongen and Maksudov, Farhod and Goldstein, Steven and Wang, Jianxin and Fuller, Dorian Q. and Li, Xiaoqiang}, doi = {10.1073/pnas.2424093122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2424093122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {9,000-year-old barley consumption in the foothills of central asia}, volume = {122}, year = {2025}, }
• (2025). AhR signaling in skin-resident CD207+ cells is involved in UV-B-induced amelioration of neuroinflammation. PNAS, 122(36), e2424009122. (www)

  @article{ , abstract = {Environmental stimuli, including the exposure to ultraviolet (UV)-B light, are known to play a role in the modulation of immune-mediated mechanisms in multiple sclerosis (MS). In experimental autoimmune encephalomyelitis (EAE), we have shown that UV-B irradiation ameliorates disease outcome by regulatory T cells (Treg) expansion. Moreover, the UV-B-mediated induction of Treg numbers was also observed in MS. The aryl hydrocarbon receptor (AhR) can be activated by environmental factors including UV-B-induced photoproducts of tryptophan. Thus, we investigated the role of AhR during the transmission of UV-B irradiation. Therefore, wild-type (WT) and AhR-deficient mice (AhR –/– ) were irradiated with UV-B light and immunized with myelin oligodendrocyte glycoprotein (MOG)-peptide. In WT mice it was shown that UV-B irradiation reduces EAE symptoms by Treg expansion. This effect was abrogated in animals with AhR deficiency. To better understand the underlying mechanisms of AhR regulation, we used mice with a deletion of AhR specifically in different subsets of antigen-presenting cells (APC) that have been shown to mediate the expansion of Treg. Interestingly, we could show that the AhR activation in murine cutaneous APC was sufficient to switch APC from a stimulatory into a regulatory phenotype, and moreover, responsible for APC cell maturation and migration into regional lymph nodes. Thus, our data indicate that AhR activation in APC might be required for UV-B-mediated immunosuppression during MOG-induced EAE. Hence, activation of AHR in tissue-resident APC, potentially by low-dose UV-B irradiation, might be beneficial as an adjuvant treatment in inflammatory or degenerative diseases of the central nervous system.}, archive = {J_PNAS}, author = {Mykicki, Nadine and Eble, Johannes A. and Weighardt, Heike and Gonnelli, Elena and Schneeweiß, Maria and Esser, Charlotte and Weishaupt, Carsten and Rezaei, Maryam and Förster, Irmgard and Schwab, Nicholas and Wiendl, Heinz and Clausen, Björn E. and Meuth, Sven G. and Loser, Karin}, doi = {10.1073/pnas.2424009122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2424009122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {AhR signaling in skin-resident CD207+ cells is involved in UV-B-induced amelioration of neuroinflammation}, volume = {122}, year = {2025}, }
• (2025). Pulsed biogenic methane emissions coupled with episodic warming during the toarcian oceanic anoxic event. PNAS, 122(36), e2423598122. (www)

  @article{ , abstract = {Reconstructing carbon release fluxes during ancient climatic warming events is important for improving predictions of carbon cycle and climate dynamics under future anthropogenic warming scenarios. We investigate the extent of biogenic methane release and its contribution to climate variability across the Toarcian Oceanic Anoxic Event (T-OAE) approximately 183 million years ago. To do this, we developed a global biogeochemical model and applied a Bayesian inversion using Markov Chain Monte Carlo (MCMC) simulations. Based on a high-resolution record of carbon isotope excursions from the Yorkshire section, our results indicate that a release of at least 4,700 Gt carbon from biogenic CH 4 (with a carbon isotopic composition, δ 13 C of −50 to −70‰) is necessary to accurately reproduce the pronounced pulsed shift in the δ 13 C, as well as the inferred changes in atmospheric p CO 2 and global temperature. This massive methane release may have led to a substantial increase in atmospheric p CH 4 and contributed to additional global surface warming, perhaps by more than 2 °C. We further elucidate that the liberation of methane may have been facilitated by an upsurge in methanogenesis alongside a concomitant decline in methane oxidation within organic-rich, sulfate-depleted marine environments. An active CH 4 cycle represents a positive feedback mechanism that exacerbates environmental deterioration during climatic warming events, ultimately contributing to mass extinction of marine life.}, archive = {J_PNAS}, author = {Qiu, Ruoyuan and Yu, Zhichao and Mills, Benjamin J. W. and Huang, Renda and Zhang, Wang and Isson, Terry and Wan, Bo and Zhang, Ruizhen and Zhao, Mingyu and Jin, Zhijun}, doi = {10.1073/pnas.2423598122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2423598122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pulsed biogenic methane emissions coupled with episodic warming during the toarcian oceanic anoxic event}, volume = {122}, year = {2025}, }
• (2025). Integrated ising model with global inhibition for decision-making. PNAS, 122(36), e2423557122. (www)

  @article{ , abstract = {Humans and other organisms make decisions choosing between different options, with the aim of maximizing the reward and minimizing the cost. The main theoretical framework for modeling the decision-making process has been based on the highly successful drift-diffusion model, which is a simple tool for explaining many aspects of this process. However, recent observations challenge this model. It was found that inhibitory tone increases during situations of difficult discrimination tasks, but the origin of this phenomenon is not understood. Motivated by this observation, we extend a recently developed model for directional decision-making of animals moving in real space. We introduce an integrated Ising-type model that includes global inhibition and use it to describe two-choice decision-making. This model can explain how the brain may utilize inhibition to improve its decision-making accuracy. Compared to experimental results, this model suggests that the regime of the brain’s decision-making activity is in proximity to a critical transition line between the ordered and disordered phases. Within the model, this observation can be explained by noting that this critical region has unique dynamics that give rise to advantageous properties for the decision-making process.}, archive = {J_PNAS}, author = {Tapinova, Olga and Finkelman, Tal and Reitich-Stolero, Tamar and Paz, Rony and Tal, Assaf and Gov, Nir S.}, doi = {10.1073/pnas.2423557122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2423557122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Integrated ising model with global inhibition for decision-making}, volume = {122}, year = {2025}, }
• (2025). Capturing the native structure of membrane proteins using vesicles. PNAS, 122(36), e2423407122. (www)

  @article{ , abstract = {Membrane proteins play crucial roles in numerous biological processes and are important drug targets. However, structural studies of membrane proteins often rely on solubilization with detergents, which may not accurately reflect their native states in a cellular context. Additionally, identifying suitable detergents for individual membrane proteins can be a detailed and time-consuming process. Here, we developed a vesicle-based method that preserves the native lipid environment for subsequent structural and functional studies. Using the bacterial multidrug efflux transporter AcrB as an example, we isolated AcrB-containing vesicles and determined its cryo-EM structure with all protomers in a loose (L) state at 3.88 Å by incorporating our micrograph-based sorting strategy. Notably, compared to the L-state AcrB in liposomes and nanoparticles, the exterior transmembrane helices (TMs) in our map exhibited superior quality, featuring a continuous and clear representation of lα, which is positioned horizontally within the lipid bilayer. We further expanded our method by identifying endogenous membrane proteins, including F-ATPase and respiratory complexes, in vesicles generated using mitochondria from pig hearts. The high-resolution structure of respiratory complex III in vesicles revealed a shared subunit nine between two monomers. Briefly, our method presents a promising and straightforward approach for studying the structure and function of membrane proteins in their native environment, eliminating the need for detergent screening and protein purification.}, archive = {J_PNAS}, author = {Liu, Hang and Tse, Chun Mong and Dang, Shangyu}, doi = {10.1073/pnas.2423407122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2423407122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Capturing the native structure of membrane proteins using vesicles}, volume = {122}, year = {2025}, }
• (2025). Migration shapes senescence in a long-lived bird. PNAS, 122(36), e2422882122. (www)

  @article{ , abstract = {Each year, billions of animals migrate across the globe on diverse spatial and temporal scales. Migration behavior thus plays a fundamental role in the life cycle and Darwinian fitness of many organisms. While the influence of migration on early-life survival and reproduction is well documented, its effects on senescence (aging) in advanced age remain largely unexplored. Using a unique 44-y ring-resighting dataset from a long-lived, partially migratory bird species, the Greater Flamingo ( Phoenicopterus roseus ), we demonstrate that migration plays a key role in shaping age-specific trajectories of mortality and reproduction. Resident flamingos exhibit higher early-life demographic performances, with lower baseline mortality than migrants, resulting in longer adult lifespan. Residents also have a higher probability of breeding than migrants, though their breeding success is similar. However, residents seem to pay for their early-life advantages in old age, experiencing accelerated actuarial and reproductive senescence compared to migrants. Overall, our study highlights the critical impact of migration on survival and reproduction throughout life, thereby illustrating the role played by behavioral decisions in the biology of aging in long-lived vertebrates.}, archive = {J_PNAS}, author = {Cayuela, Hugo and Roques, Sébastien and Arnaud, Antoine and Germain, Christophe and Béchet, Arnaud and Champagnon, Jocelyn}, doi = {10.1073/pnas.2422882122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2422882122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Migration shapes senescence in a long-lived bird}, volume = {122}, year = {2025}, }
• (2025). Procollagen IIA mediates positive feedback control of the mouse cardiogenic transcriptional network. PNAS, 122(36), e2422592122. (www)

  @article{ , abstract = {Cardiogenesis relies on the integrated interplay between cardiac transcription factors and signaling pathways. Here, we uncover a role for type IIA procollagen (IIA), an extracellular matrix (ECM) protein encoded by an alternatively spliced Col2a1 transcript, encoding a N-terminal cysteine-rich domain, as a critical regulator in a cardiac gene regulatory feedback loop. The cysteine-rich domain of IIA protein was previously reported to interact with bone morphogenetic proteins (BMPs) and transforming growth factors-beta (TGFβ) in in vitro binding assays and acts as a BMP antagonist in amphibian embryo assays. We show that the Col2a1 gene in mice is activated in the developing heart by core cardiogenic factors (NKX2-5, GATA4, MEF2, and SRF) via cis-regulatory enhancer elements. IIA loss (ΔIIA) in mice results in depletion of Isl1- and Nkx2-5-expressing progenitors, causing outflow tract defects resembling disrupted BMP/TGFβ-SMAD signaling, alongside reduced nuclear pSMAD1/5/8 in cardiac tissues. Compound +/ΔIIA ; Smad4+/− mutants exhibit aggravated malformations. IIA enhances BMP-responsive reporter activity in cells in transactivation assays. We propose that IIA supports a positive functional role on SMAD4-dependent signaling, fine-tuning BMP/TGFβ signaling, thereby regulating GATA4 and NKX2-5 activity during second heart field progenitor specification. These findings position IIA procollagen as a key ECM component that integrates BMP/TGFβ signaling with cardiac transcription factors such as NKX2-5, revealing a feedback loop essential for cardiogenesis. Given its role in cardiac development, IIA emerges as a potential congenital heart disease risk factor.}, archive = {J_PNAS}, author = {Leung, Alan W. and Wong, Sandra Y. and Zhang, Janet C. and Leung, Keith K. H. and Dung, Nelson W. F. and Shang, Catherine A. and Prall, Owen W. and Nim, Hieu T. and See, Michael and Ramialison, Mirana and Chan, Danny and Mohun, Timothy J. and Harvey, Richard P. and Tam, Patrick P. L. and Cheah, Kathryn S. E.}, doi = {10.1073/pnas.2422592122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2422592122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Procollagen IIA mediates positive feedback control of the mouse cardiogenic transcriptional network}, volume = {122}, year = {2025}, }
• (2025). Evolving choice hysteresis in reinforcement learning: Comparing the adaptive value of positivity bias and gradual perseveration. PNAS, 122(36), e2422144122. (www)

  @article{ , abstract = {The tendency to repeat past choices more often than expected from the history of outcomes has been repeatedly empirically observed in reinforcement learning experiments. It can be explained by at least two computational processes: asymmetric update and (gradual) choice perseveration. A recent meta-analysis showed that both mechanisms are detectable in human reinforcement learning. However, while their descriptive value seems to be well established, they have not been compared regarding their possible adaptive value. In this study, we address this gap by simulating reinforcement learning agents in a variety of environments with a variant of an evolutionary algorithm. Our results show that positivity bias (in the form of asymmetric update) is evolutionary stable in many situations, while the emergence of gradual perseveration is less systematic and robust. Overall, our results illustrate that biases can be adaptive and selected by evolution, in an environment-specific manner.}, archive = {J_PNAS}, author = {Hoxha, Isabelle and Sperber, Léo and Palminteri, Stefano}, doi = {10.1073/pnas.2422144122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2422144122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolving choice hysteresis in reinforcement learning: Comparing the adaptive value of positivity bias and gradual perseveration}, volume = {122}, year = {2025}, }
• (2025). Metabolic rewiring of isoniazid sensitivity in mycobacterium tuberculosis. PNAS, 122(36), e2421336122. (www)

  @article{ , abstract = {Isoniazid (INH) inhibits mycolic acid synthesis in Mycobacterium tuberculosis ( Mtb ) and is a cornerstone of treatment regimens against this deadly pathogen. However, over 10% of Mtb infections are INH-resistant. The compound C10 can sensitize clinically relevant INH-resistant mutants to killing by INH. Thus, understanding the mechanism of action for C10 could aid in designing new strategies for circumventing drug resistance. We find that C10 treatment reroutes carbon flux toward valine, drawing carbon away from gluconeogenesis and the TCA cycle. As a result, C10 decreases cell envelope capsule thickness and blocks an accumulation of peptidoglycan precursors that occurs in response to INH treatment in an INH-resistant Mtb katG mutant. In this altered metabolic state induced by C10, INH treatment of the INH-resistant Mtb katG mutant inhibits peptidoglycan synthesis, precipitating collapse of cell envelope integrity. Pyruvate supplementation relieves the C10-induced requirement for carbon flux toward valine, enhancing carbon assimilation into cell envelope precursors and restoring resistance to INH. In addition, we identify the formation of isoniazid-pyruvate in INH-treated katG W328L Mtb , where pyruvate sequesters INH, lowering the concentration of INH available to inhibit Mtb . Together, our findings reveal a bactericidal activity for INH in Mtb that can function in INH-resistant mutants independently of INH-mediated inhibition of mycolic acid synthesis. This activity for INH can be elicited by shifting carbon flux toward valine and away from cell envelope precursor synthesis, highlighting a metabolic vulnerability that can be exploited to kill INH-resistant Mtb .}, archive = {J_PNAS}, author = {Wang, Erin R. and Cho, Kevin and Harrison, Gregory A. and Smelyansky, Stephanie R. and Soni, Vijay and Smirnov, Asya and McKee, Samuel R. and Ghabrial, George S. and Flentie, Kelly N. and Beatty, Wandy and Ofori-Anyinam, Boatema and Sarkar, Souvik and Hurtaux, Thomas and Loza, Liza and Almqvist, Fredrik and Doering, Tamara L. and Yang, Jason H. and Kiessling, Laura L. and Rhee, Kyu Y. and Patti, Gary J. and Stallings, Christina L.}, doi = {10.1073/pnas.2421336122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2421336122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Metabolic rewiring of isoniazid sensitivity in mycobacterium tuberculosis}, volume = {122}, year = {2025}, }
• (2025). Vacuum tunneling of vortices in two-dimensional 4He superfluid films. PNAS, 122(36), e2421273122. (www)

  @article{ , abstract = {At low temperature T we expect vacuum tunneling processes to occur in superfluid 4 He films. We distinguish between extrinsic processes, in which single vortices nucleate by tunneling off boundaries in the system, and intrinsic processes, in which vortex/anti-vortex pairs nucleate far from boundaries. It is crucial to incorporate the varying effective mass of the vortex in tunneling calculations. The intrinsic processes are the superfluid analogue of the Schwinger mechanism in quantum field theory; here they appear as a quantum phase transition at T = 0, driven by an external supercurrent. We calculate the tunneling rate for these processes, and describe a means of testing the predictions using a specific “vortex counting” experiment.}, archive = {J_PNAS}, author = {Desrochers, M. J. and Marchand, D. J. J. and Stamp, P. C. E.}, doi = {10.1073/pnas.2421273122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2421273122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Vacuum tunneling of vortices in two-dimensional 4He superfluid films}, volume = {122}, year = {2025}, }
• (2025). Nonlinear memory in cell-division dynamics across species. PNAS, 122(36), e2417416122. (www)

  @article{ , abstract = {Regulation of cell growth and division is essential to achieve cell-size homeostasis. Recent advances in imaging technologies, such as “mother machines” for bacteria or yeast, have allowed long-term tracking of cell-size dynamics across many generations, and thus have brought major insights into the mechanisms underlying cell-size control. However, understanding the governing rules of cell growth and division within a quantitative dynamical-systems framework remains a major challenge. Here, we implement and apply a framework that makes it possible to infer stochastic-differential-equation models with Poisson noise directly from experimentally measured time series for cellular growth and division. To account for potential nonlinear memory effects, we parameterize the Poisson intensity of stochastic cell-division events in terms of both the cell’s current size and its ancestral history. By applying the algorithm to experimentally measured cell-size trajectories, we are able to quantitatively evaluate the linear one-step memory hypothesis underlying the popular “sizer,” “adder,” and “timer” models of cell homeostasis. For Escherichia coli and Bacillus subtilis bacteria, Schizosaccharomyces pombe yeast and Dictyostelium discoideum amoebae, we find that in many cases, the inferred stochastic models have a substantial nonlinear memory component. This suggests a need to reevaluate and generalize some of the currently prevailing linear-memory paradigms of cell homeostasis. More broadly, the underlying inference framework is directly applicable to identify quantitative models for stochastic jump processes in a wide range of scientific disciplines.}, archive = {J_PNAS}, author = {Zhang, Shijie and Fei, Chenyi and Dunkel, Jörn}, doi = {10.1073/pnas.2417416122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2417416122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nonlinear memory in cell-division dynamics across species}, volume = {122}, year = {2025}, }
• (2025). Surrogate optimization of variational quantum circuits. PNAS, 122(36), e2408530122. (www)

  @article{ , abstract = {Variational quantum eigensolvers are touted as a near-term algorithm capable of impacting many applications. However, the potential has not yet been realized, with few claims of quantum advantage and high resource estimates, especially due to the need for optimization in the presence of noise. Finding algorithms and methods to improve convergence is important to accelerate the capabilities of near-term hardware for variational quantum eigensolver or more broad applications of hybrid methods in which optimization is required. To this goal, we look to use modern approaches developed in circuit simulations and stochastic classical optimization, which can be combined to form a surrogate optimization approach to quantum circuits. Using an approximate (classical central processing unit/graphical processing unit) state vector simulator as a surrogate model, we efficiently calculate an approximate Hessian, which is passed as input for a quantum processing unit or exact circuit simulator. This method will lend itself well to parallelization across quantum processing units. We demonstrate the capabilities of such an approach with and without sampling noise and a proof-of-principle demonstration on a quantum processing unit utilizing 40 qubits.}, archive = {J_PNAS}, author = {Gustafson, Erik J. and Tiihonen, Juha and Chamaki, Diana and Sorourifar, Farshud and Mullinax, J. Wayne and Li, Andy C. Y. and Maciejewski, Filip B. and Sawaya, Nicolas P. D. and Krogel, Jaron T. and Bernal Neira, David E. and Tubman, Norm M.}, doi = {10.1073/pnas.2408530122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2408530122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Surrogate optimization of variational quantum circuits}, volume = {122}, year = {2025}, }
• (2025). Evidence for coopetition at the maternal–fetal interface shaping placental invasion. PNAS, 122(36), e2323038122. (www)

  @article{ , abstract = {Coopetition is a term from game theory that describes a mix of cooperative and competitive behavior. The maternal–fetal interface (MFI) among eutherian mammals presents close interaction of two distinct individuals. These interactions have resulted in a remarkable diversity in MFI structure, often interpreted as the outcome of maternal–fetal conflict. Nevertheless, the fetus and the mother share evolutionary interests since 50% of fetal genes are maternal. In hemochorial species, characterized by invasive placentation, endometrial stromal fibroblasts (ESFs) undergo decidualization to regulate embryo implantation. In great apes, hemochorial placentation is driven by highly invasive extravillous trophoblast cells (EVT). Here, using EVTs differentiated from trophoblast stem cells, term placenta, as well as HTR8/SVneo, we demonstrate that EVTs orchestrate a transformation of the maternal stroma, reducing its resistance to invasion acquired during decidualization. Through paracrine signals, in particular IL-11, trophoblasts transform decidual ESFs from a matrix-producing to a matrix-degrading state. Notably, noninvasive cytotrophoblast cells, do not transform decidual ESFs. We further provide evidence that maternal coadaptation is critical to EVT-induced decidual transformation. Decidual ESFs upregulate expression of Suppressor of Cytokine Signaling 3 in response to EVTs, rewiring downstream IL-11 signaling from JAK/STAT to AP-1 specific transcription. We conclude that the evolution of highly invasive placentation is the outcome of both the evolution of invasive EVTs, as well as the evolution of maternal traits, i.e., the switch from JAK/STAT to AP-1 signaling. We interpret this as evidence for co-opetition (cooperation among competitors).}, archive = {J_PNAS}, author = {Afzal, Junaid and Suhail, Yasir and Du, Wenqiang and Liu, Yamin and Ramasamy, Ramalakshmi and Liu, Zukai and Goyal, Ruchi and Novin, Ashkan and Suhail, Sameera and Maziarz, Jamie and Wali, Khadija and Robson, Paul and Wagner, Günter P. and Kshitiz, null}, doi = {10.1073/pnas.2323038122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {36}, pages = {e2323038122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evidence for coopetition at the maternal–fetal interface shaping placental invasion}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(35), eiti3525122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti3525122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {eiti3525122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Correction for an et al., impact of women’s political empowerment through gender quotas on improved drinking water access in africa. PNAS, 122(35), e2521793122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2521793122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2521793122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for an et al., impact of women’s political empowerment through gender quotas on improved drinking water access in africa}, volume = {122}, year = {2025}, }
• (2025). Correction for soni et al., BIK polymorphism and proteasome regulation unveil host risk factor for severe influenza. PNAS, 122(35), e2521789122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2521789122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2521789122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for soni et al., BIK polymorphism and proteasome regulation unveil host risk factor for severe influenza}, volume = {122}, year = {2025}, }
• (2025). Correction for jankovic et al., wireless arm-worn bioimpedance sensor for continuous assessment of whole-body hydration. PNAS, 122(35), e2521655122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2521655122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2521655122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for jankovic et al., wireless arm-worn bioimpedance sensor for continuous assessment of whole-body hydration}, volume = {122}, year = {2025}, }
• (2025). Correction for sun et al., DNA2 protein destruction dictates DNA hyperexcision, cGAS–STING activation, and innate immune response in CDK12-deregulated cancers. PNAS, 122(35), e2520994122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2520994122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2520994122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for sun et al., DNA2 protein destruction dictates DNA hyperexcision, cGAS–STING activation, and innate immune response in CDK12-deregulated cancers}, volume = {122}, year = {2025}, }
• (2025). Profile of johannes lehmann. PNAS, 122(35), e2520876122. (www)

  @article{ , abstract = {Soil scientist Johannes Lehmann has spent his career examining how to improve soil quality to secure agricultural production, regulate climate, and keep water clean. His work with dark earths in the Brazilian Amazon led to the discovery of the importance of biochar in soil fertility and nutrient recycling from excreta. For more than 24 years, Lehmann has held a faculty position at Cornell University, where his research initially focused on carbon and nutrient cycles and went on to challenge the existence of soil humus and delve into the role of functional complexity in soil management.}, archive = {J_PNAS}, author = {Langlois, Jill}, doi = {10.1073/pnas.2520876122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2520876122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profile of johannes lehmann}, volume = {122}, year = {2025}, }
• (2025). Correction for ma et al., setdb1 ablation in macrophages attenuates fibrosis in heart allografts. PNAS, 122(35), e2520875122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2520875122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2520875122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for ma et al., setdb1 ablation in macrophages attenuates fibrosis in heart allografts}, volume = {122}, year = {2025}, }
• (2025). The US–Israel blavatnik scientific forum on alleviating global water scarcity by desalination and water reuse. PNAS, 122(35), e2519360122. (www)

  @article{ , archive = {J_PNAS}, author = {Walker, Sharon L. and Dagan, Gedeon and Adin, Avner and Alvarez, Pedro J. J. and Elimelech, Menachem and Radian, Adi}, doi = {10.1073/pnas.2519360122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2519360122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The US–Israel blavatnik scientific forum on alleviating global water scarcity by desalination and water reuse}, volume = {122}, year = {2025}, }
• (2025). Cohort mortality forecasts indicate signs of deceleration in life expectancy gains. PNAS, 122(35), e2519179122. (www)

  @article{ , abstract = {The fast-paced improvements in mortality in high-income countries since the early 1900s have led to a sustained increase in life expectancy. However, whether this linear trend will continue or life expectancy gains will decelerate in the near future remains unclear. To answer this question, we apply multiple established and recently developed mortality forecasting methods to estimate cohort life expectancy for individuals born between 1939 and 2000 in 23 high-income countries. Across all forecasting methods, our results robustly and consistently indicate a deceleration in cohort life expectancy. The previously observed pace of improvement, 0.46 y per cohort, declines by 37% to 52%, depending on the method used. Robustness checks suggest that these findings are unlikely to be solely due to downward bias in cohort life expectancy forecasts. Furthermore, an age-decomposition analysis indicates that this deceleration is primarily driven by a slower pace of mortality improvement at very young ages. Over half of the total deceleration is attributable to mortality trends under age 5, while more than two-thirds is explained by mortality trends under age 20. This pattern had already emerged in the observed data for the cohorts included in our analysis. Thus, even if these estimates turned out to be overly pessimistic, it is unlikely that the deceleration will reverse in the near future.}, archive = {J_PNAS}, author = {Andrade, José and Camarda, Carlo Giovanni and Pifarré i Arolas, Héctor}, doi = {10.1073/pnas.2519179122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2519179122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cohort mortality forecasts indicate signs of deceleration in life expectancy gains}, volume = {122}, year = {2025}, }
• (2025). Reply to cummins et al.: GPT reveals cognitive dissonance that is both irrational and alarmingly humanlike. PNAS, 122(35), e2518613122. (www)

  @article{ , archive = {J_PNAS}, author = {Lehr, Steven A. and Saichandran, Ketan S. and Harmon-Jones, Eddie and Vitali, Nykko and Banaji, Mahzarin R.}, doi = {10.1073/pnas.2518613122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2518613122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to cummins et al.: GPT reveals cognitive dissonance that is both irrational and alarmingly humanlike}, volume = {122}, year = {2025}, }
• (2025). Seeding of visceral adipose tissue with perinatally generated regulatory t cells shapes the metabolic tenor in mice. PNAS, 122(35), e2518203122. (www)

  @article{ , abstract = {The Foxp3 + CD4 + regulatory T cells (Tregs) generated around birth are phenotypically and functionally distinct from those engendered during adulthood. That perinatally produced Tregs persist for a protracted period in peripheral lymphoid organs has been well documented, as has their superior ability to protect the organism from many autoimmune diseases. However, their contribution to pools of nonlymphoid-tissue Tregs and their homeostatic functions therein have been little studied. We show that perinatal Tregs preferentially derive from a CD25 + Foxp3 − thymocyte progenitor; that they seed and persist to varying degrees in every nonlymphoid tissue examined; and that transient depletion of perinatally generated Tregs in adults, but not in neonates, is followed by poor reconstitution of Treg numbers and phenotypes in epididymal visceral-adipose tissue (eVAT) and the skin but not in several lymphoid and other nonlymphoid tissues. Potential clinical implications of such a deficiency are highlighted by findings on mice subjected to weight cycling: Imposing a low-fat–high-fat–low-fat diet regimen in adult, but not juvenile, mice results in an impoverished eVAT, but not spleen, Treg compartment, accompanied by normal weight gain and glucose tolerance but profound insulin resistance. These findings point to a layered immune system, the different layers exerting specialized, nonredundant functions.}, archive = {J_PNAS}, author = {Marin-Rodero, Miguel and Jayewickreme, Teshika and Benoist, Christophe and Mathis, Diane}, doi = {10.1073/pnas.2518203122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2518203122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Seeding of visceral adipose tissue with perinatally generated regulatory t cells shapes the metabolic tenor in mice}, volume = {122}, year = {2025}, }
• (2025). Microvilli’s grip on t cell development. PNAS, 122(35), e2518069122. (www)

  @article{ , archive = {J_PNAS}, author = {Ryan, Allison T. and Kim, Minsoo}, doi = {10.1073/pnas.2518069122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2518069122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Microvilli’s grip on t cell development}, volume = {122}, year = {2025}, }
• (2025). Cognitive dissonance in large language models is neither cognitive nor dissonant. PNAS, 122(35), e2517912122. (www)

  @article{ , archive = {J_PNAS}, author = {Cummins, Jamie and Elson, Malte and Hussey, Ian}, doi = {10.1073/pnas.2517912122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2517912122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cognitive dissonance in large language models is neither cognitive nor dissonant}, volume = {122}, year = {2025}, }
• (2025). Correction for kalakonda et al., monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice. PNAS, 122(35), e2517677122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2517677122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2517677122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for kalakonda et al., monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice}, volume = {122}, year = {2025}, }
• (2025). Communication increases cooperation among students in a coordination game. PNAS, 122(35), e2517669122. (www)

  @article{ , abstract = {Cooperation often requires individuals to balance personal risk with mutual gain. The Stag Hunt game provides a well-established paradigm for studying such decision-making. Prior research suggested that verbal communication about the game correlated with participants finding the optimal coordinated solution, but these studies either did not manipulate communication directly or informed participants of the payoff structure in advance. This study examined whether communication improves cooperative decision-making among college students under conditions in which the payoff structure had to be inferred through repeated play. A total of 127 same-sex dyads ( M age = 22.8 y, 51.2% female) played 40 rounds of an online Stag Hunt game, with dyads randomly assigned to either a no communication or communication condition. Participants were not informed about the game’s payoff structure in advance and had to infer it during play. Results showed that coordination on the payoff-dominant outcome (Stag–Stag) increased across trials, but only when communication was possible. No significant sex differences were observed. These findings highlight the central role of communication in fostering cooperation, particularly in environments in which information must be jointly discovered. This is an important consideration for developing and interpreting future research. Moreover, subsequent research should explore how the content, timing, and relevance of communication shape cooperative outcomes over time.}, archive = {J_PNAS}, author = {Hallers-Haalboom, Elizabeth T. and De Jaegher, Kris J. M. and Sterck, Elisabeth H. M. and Brosnan, Sarah F. and Vermande, Marjolijn M.}, doi = {10.1073/pnas.2517669122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2517669122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Communication increases cooperation among students in a coordination game}, volume = {122}, year = {2025}, }
• (2025). The nonadaptive advantage: Why our brains can’t quit gaming. PNAS, 122(35), e2517079122. (www)

  @article{ , archive = {J_PNAS}, author = {Chukoskie, Leanne and Harteveld, Casper}, doi = {10.1073/pnas.2517079122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2517079122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The nonadaptive advantage: Why our brains can’t quit gaming}, volume = {122}, year = {2025}, }
• (2025). Local c-di-GMP signaling, triggered by cross-regulation of cAMP-CRP and c-di-GMP, controls biofilm formation under nutrient limitation. PNAS, 122(35), e2516964122. (www)

  @article{ , abstract = {Bacteria have several nucleotide second messengers, most of which act as global regulators to control a wide range of bacterial physiological processes. Studies usually focus on a single second messenger, and the mechanisms and physiological significance of the cross-regulation between different nucleotide second messengers are often unclear. Here, we show that Shewanella putrefaciens can form biofilms in both nutrient-rich and nutrient-poor media. While both are controlled by c-di-GMP, the regulatory models differ. Under low nutrient conditions, cross-regulation of cAMP-CRP and c-di-GMP occurs at the transcriptional and posttranslational levels, thereby controlling biofilm development. During the early stages of biofilm development, cAMP-CRP directly promotes the transcription of a PDE gene, lrbR , by LrbA. Additionally, cAMP-CRP recruits LrbR to BpfD to suppress early biofilm formation via LrbR-dependent local degradation of c-di-GMP. Finally, as intracellular LrbR levels decrease, cAMP-CRP-BpfD enables a rapid shift to biofilm development and supports biofilm maintenance. Under high nutrient conditions, this cross-regulation does not occur, resulting in a positive correlation between global c-di-GMP levels and biofilm biomass. The identification of distinct modes of biofilm regulation in different nutrients will provide a theoretical basis for future targeted control of biofilm formation in different nutrient environments.}, archive = {J_PNAS}, author = {Sun, Di and Liu, Xiaobo and Zhang, Ying and Shi, Rui and Ru, Yunrui and Zhou, Xuge and Chen, Ying and Yang, Jing and Liu, Jiawen and Zhu, Jingrong and Liu, Cong and Liu, Weijie}, doi = {10.1073/pnas.2516964122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2516964122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Local c-di-GMP signaling, triggered by cross-regulation of cAMP-CRP and c-di-GMP, controls biofilm formation under nutrient limitation}, volume = {122}, year = {2025}, }
• (2025). CRISPR with transcriptional readout reveals influenza transcription is modulated by NELF and can precipitate an interferon response. PNAS, 122(35), e2515564122. (www)

  @article{ , abstract = {Transcription of interferons upon viral infection is critical for cell-intrinsic innate immunity. This process is influenced by many host and viral factors. To identify host factors that modulate interferon induction within cells infected by influenza A virus, we developed CRISPR with Transcriptional Readout using sequencing (CRITR-seq). CRITR-seq is a method linking CRISPR guide sequence to activity at a promoter of interest. Employing this method, we find that depletion of the Negative Elongation Factor (NELF) complex increases both flu transcription and interferon expression. We find that the process of flu transcription, both in the presence and absence of viral replication, is a key contributor to interferon induction. Taken together, our findings highlight innate immune ligand concentration as a limiting factor in triggering an interferon response, identify NELF as an important interface with the flu life cycle, and validate CRITR-seq as a tool for genome-wide screens for phenotypes of gene expression.}, archive = {J_PNAS}, author = {Vicary, Alison C. and Jordan, Sydney N. Z. and Mendes, Marisa and Swaminath, Sharmada and Castro, Lennice K. and Porter, Justin S. and Vo, Kevin D. and Russell, Alistair B.}, doi = {10.1073/pnas.2515564122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2515564122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CRISPR with transcriptional readout reveals influenza transcription is modulated by NELF and can precipitate an interferon response}, volume = {122}, year = {2025}, }
• (2025). Single-strand DNA is the link between neutrophil extracellular traps and thrombin. PNAS, 122(35), e2515545122. (www)

  @article{ , archive = {J_PNAS}, author = {Jenne, Craig and Kubes, Paul}, doi = {10.1073/pnas.2515545122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2515545122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Single-strand DNA is the link between neutrophil extracellular traps and thrombin}, volume = {122}, year = {2025}, }
• (2025). Amyloid β–dependent neuronal silencing through synaptic decoupling. PNAS, 122(35), e2515113122. (www)

  @article{ , abstract = {Amyloid β (Aβ)-dependent circuit dysfunction in Alzheimer’s disease (AD) is determined by a puzzling mix of hyperactive and inactive (“silent”) brain neurons. Recent studies identified excessive glutamate accumulation as a key Aβ-dependent determinant of hyperactivity. The cellular mechanisms underlying neuronal silence depend on both Aβ and tau protein pathologies, with an unknown role of Aβ. Here, by using single-cell-initiated rabies virus (RV) tracing in mouse models of β-amyloidosis, we demonstrate that the presynaptic connectivity of silent, but not that of hyperactive, neurons is severely disrupted. Furthermore, silent neurons display a major spine loss and strongly suppressed synaptic activity. Thus, we suggest that synaptic decoupling is an Aβ-dependent cellular mechanism underlying progressive neuronal silencing and a critical factor for the cognitive impairments encountered in AD.}, archive = {J_PNAS}, author = {Zhang, Yonghai and Chen-Engerer, Hsing-Jung and Zhang, Kuan and Zott, Benedikt and Varga, Zsuzsanna and Chen, Yang and Chen, Xiaowei and Jia, Hongbo and Sakmann, Bert and Nelken, Israel and Konnerth, Arthur}, doi = {10.1073/pnas.2515113122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2515113122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Amyloid β–dependent neuronal silencing through synaptic decoupling}, volume = {122}, year = {2025}, }
• (2025). Evolutionarily conserved grammar rules viral factories of amoeba-infecting members of the hyperdiverse nucleocytoviricota phylum. PNAS, 122(35), e2515074122. (www)

  @article{ , abstract = {Despite sharing fewer than 10 core genes, the hyperdiverse Nucleocytoviricota phylum (ranging from poxviruses to giant viruses) universally assembles viral factories (VFs) resembling biomolecular condensates. Regardless, it is unclear how these viruses achieve such a level of functional conservation without clear conserved genetic information. We demonstrate that the VFs produced by amoeba-infecting viruses have liquid-like properties and identify a conserved molecular grammar governing viral factory scaffold protein: charge-patterned intrinsically disordered regions that drive phase separation independently of sequence homology. This grammar predicts functional scaffold proteins across the 15 viral families, revealing evolutionary constraints invisible to sequence or structural analysis. Strikingly, VFs exhibit subcompartmentalization analogous to nuclei, segregating transcription and mRNA processing (inner condensates) from replication (interphase zones) and translation (host cytoplasm). Our work establishes phase separation as a fundamental organizational principle bridging extreme genomic diversity, explaining how biological complexity emerges without gene conservation. This grammar is likely also conserved in non-amoeba-infecting members of the phylum and thus may represent a primordial solution for organelle-like organization, with broad implications for antiviral targeting.}, archive = {J_PNAS}, author = {Rigou, Sofia and Schmitt, Alain and Moreno, Anaísa B. and Lartigue, Audrey and Danner, Lucile and Mayer, Lotte and Giry, Claire and Trabelsi, Feres and Belmudes, Lucid and Olivero-Deibe, Natalia and Le Guenno, Hugo and Couté, Yohann and Berois, Mabel and Legendre, Matthieu and Jeudy, Sandra and Abergel, Chantal and Bisio, Hugo}, doi = {10.1073/pnas.2515074122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2515074122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolutionarily conserved grammar rules viral factories of amoeba-infecting members of the hyperdiverse nucleocytoviricota phylum}, volume = {122}, year = {2025}, }
• (2025). Multistep catalytic abiotic CO2 conversion to sugars through c1 intermediates. PNAS, 122(35), e2514826122. (www)

  @article{ , abstract = {Carbon dioxide (CO 2 ) to multicarbon (C n ) upgrading for commodity chemicals, fuel production, or artificial food synthesis using renewable energy input is a golden target for researchers in sustainable carbon emission reduction. Here, we explore and analyze a flexible modular roadmap for the task, utilizing sequential electro-, photo-, and organocatalysis to develop a strategy for CO 2 conversion using the key and elusive formaldehyde precursor of interest for sugar generation. We study the electrochemical carbon dioxide reduction reaction to methanol in a flow cell and its discontinuous photooxidation to formaldehyde (PMOR) with excellent selectivity. Utilizing a highly active N- heterocyclic carbene catalyst enables tunable generation of C 4 –C 6 aldoses without undesirable byproducts, with carbon conversion yield reaching 60 to 80% for desired pentose, tetrose, and triose product mixtures and over 20% for hexose. This approach presents a roadmap for CO 2 valorization, aiming to bridge carbon waste streams with sustainable sugar synthesis and opening broad avenues for green chemical production.}, archive = {J_PNAS}, author = {Soland, Nathan and Luo, Jie and Maulana, Arifin Luthfi and Feijoo, Julian and Jo, Hye-Jin and Oddo, Alexander M. and Shan, Yu and Wang, Tianle and Lee, Geonhui and Choi, Jihoon and Huynh, Wei-Shan and Guzman, Maria Fonseca and Jayasinghe, Lihini and Zhu, Cheng and Yang, Yao and Yang, Peidong}, doi = {10.1073/pnas.2514826122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2514826122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multistep catalytic abiotic CO2 conversion to sugars through c1 intermediates}, volume = {122}, year = {2025}, }
• (2025). Candidate denisovan fossils identified through gene regulatory phenotyping. PNAS, 122(35), e2513968122. (www)

  @article{ , abstract = {Denisovans are an extinct group of humans whose morphology is mostly unknown. The scarcity of verified Denisovan fossils makes it challenging to study their anatomy, and how well they were adapted to their environment. We previously developed a genetic phenotyping approach to gain insight into Denisovan anatomy by detecting gene regulatory changes that likely altered Denisovan skeletal morphology. Here, we scan the Middle Pleistocene fossil record for crania matching the predicted Denisovan morphology and might therefore be related to Denisovans. We developed quantitative measures to assess both the proportion and extent of matches. These analyses revealed that the East Asian specimens of Harbin and Dali show an exceptionally high concordance with the Denisovan profile, surpassing all other examined Middle Pleistocene hominin specimens, including Neanderthals. Specifically, 15 out of 18 of Dali ’s features and 16 out of 18 of Harbin ’s matched Denisovan predictions. These findings are robust to overall skull size and to correlations between phenotypes. We also found that Kabwe 1 shows a strong affinity to the Denisovan–Neanderthal clade and might be placed near its root. Our results show that gene regulatory phenotyping may assist in classifying poorly understood specimens.}, archive = {J_PNAS}, author = {Mishol, Nadav and Herzlinger, Gadi and Rak, Yoel and Smilanksy, Uzy and Carmel, Liran and Gokhman, David}, doi = {10.1073/pnas.2513968122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2513968122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Candidate denisovan fossils identified through gene regulatory phenotyping}, volume = {122}, year = {2025}, }
• (2025). Activation of WNK1 signaling through piezo1. PNAS, 122(35), e2513155122. (www)

  @article{ , abstract = {With No lysine (K) 1 (WNK1) is essential for ion and volume homeostasis, sensing osmotic stress and activating pathways that regulate ion transport. Its response to osmotic stress shares similarities with the function of the mechanosensitive ion channel Piezo1. In this study, we show that Yoda1, a Piezo1 agonist, activates WNK1 downstream kinase targets oxidative stress-responsive 1 (OSR1) and STE20/SPS1-related serine, proline-, and alanine-rich kinase (SPAK) in endothelial cells within minutes. Ionophore-induced Ca 2+ influx similarly triggers their activation. Comparable responses were observed in HDMEC, HUVEC, A549, MDA-MB-231, and HeLa cells. Hypotonic stress also enhances SPAK and OSR1 phosphorylation, which is attenuated by WNK1 inhibition or Piezo1 knockdown, whereas hypertonic stress-induced phosphorylation is not affected by Piezo1 knockdown. Chelating Ca 2+ or depleting intracellular stores prevents their activation, while increasing intracellular Ca 2+ via the Na + /Ca 2+ exchanger or thapsigargin enhances it. ER-released Ca 2+ is sufficient to activate SPAK and OSR1 even in the absence of extracellular Ca 2+ , and this effect is diminished by Piezo1 knockdown. Both Yoda1 and ionomycin promote phosphorylation of WNK1 at serine 382, a modification that increases its catalytic activity. These findings identify Piezo1 as an activator of WNK1, linking Ca 2+ dynamics to WNK1-OSR1/SPAK signaling.}, archive = {J_PNAS}, author = {Jung, Ji-Ung and Stippec, Steve and Cobb, Melanie H.}, doi = {10.1073/pnas.2513155122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2513155122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Activation of WNK1 signaling through piezo1}, volume = {122}, year = {2025}, }
• (2025). Ingroup solidarity drives social media engagement after political crises. PNAS, 122(35), e2512765122. (www)

  @article{ , abstract = {Social media are often said to exacerbate polarization by platforming hostility between groups. However, positive social emotions like ingroup solidarity may also drive social media engagement, particularly after major threats such as military invasions or terror attacks. In this preregistered study, we examine the socioemotional drivers of engagement following group threats in the context of the US 2024 presidential campaign trail, where both major political parties faced crises in July of 2024. We test how ingroup solidarity and outgroup hostility predicted social media users’ engagement with 62,118 posts by 484 US partisan accounts before and after the first Trump assassination attempt (July 13) and Biden’s re-election campaign suspension (July 21). We find that, while outgroup hostility is typically the dominant predictor of engagement, interactions with ingroup solidarity surged among Republicans after the Trump shooting and among Democrats after Biden’s withdrawal. We show that negativity toward other groups is not always key to going viral. Rather, positive ingroup emotions appear to play a leading role in times of crisis.}, archive = {J_PNAS}, author = {Marks, Malia and Kyrychenko, Yara and Gärdebo, Johan and Roozenbeek, Jon}, doi = {10.1073/pnas.2512765122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2512765122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ingroup solidarity drives social media engagement after political crises}, volume = {122}, year = {2025}, }
• (2025). ARRDC4-mediated glycolysis enhances innate immunity to influenza a virus through fructose-1,6-bisphosphate. PNAS, 122(35), e2512385122. (www)

  @article{ , abstract = {Glucose metabolism impacts the innate immune response against viral infection. However, the key enzymes or the natural products and mechanisms involved are not well elucidated. Here, we found that arrestin domain containing 4 (ARRDC4), a critical regulator of glucose metabolism, senses influenza A virus (IAV) infection by interacting with viral PA protein. Upregulated ARRDC4 increases the enzymatic activity of phosphofructokinase, muscle type (PFKM) via binding its His298 site to promote the production of the metabolite fructose-1,6-bisphosphate (FBP). Consequently, FBP inhibits the K48-linked ubiquitination degradation of HSP90β, subsequently enhances its interaction with IKKβ and IKKε, and enhances NF-κB- and IRF7-mediated antiviral innate immunity, respectively. Importantly, FBP supplementation enhanced IFN-β-mediated antiviral innate immunity in vitro and in vivo. Our findings highlight a unique immunometabolic regulatory mechanism in which ARRDC4 senses IAV infection and regulates antiviral innate immunity through the PFKM-FBP metabolic axis and provide a strategy for manipulating FBP-related metabolism to treat viral infection.}, archive = {J_PNAS}, author = {Li, Yuhan and Wang, Zhen and Wang, Jie and Jiang, Zhimin and Chen, Mingyue and Ai, Hui and Ma, Chao and Tong, Qi and Liu, Litao and Velkov, Tony and Sun, Honglei and Pu, Juan and Liu, Jinhua and Dai, Chongshan and Sun, Yipeng}, doi = {10.1073/pnas.2512385122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2512385122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ARRDC4-mediated glycolysis enhances innate immunity to influenza a virus through fructose-1,6-bisphosphate}, volume = {122}, year = {2025}, }
• (2025). Using large language models to categorize strategic situations and decipher motivations behind human behaviors. PNAS, 122(35), e2512075122. (www)

  @article{ , abstract = {By varying prompts to a large language model, we can elicit the full range of human behaviors in a variety of different scenarios in classic economic games. By analyzing which prompts elicit which behaviors, we can categorize and compare different strategic situations, which can also help provide insight into what different economic scenarios might induce people to think about. We discuss how this provides a step toward a nonstandard method of inferring (deciphering) the motivations behind the human behaviors. We also show how this deciphering process can be used to categorize differences in the behavioral tendencies of different populations.}, archive = {J_PNAS}, author = {Xie, Yutong and Mei, Qiaozhu and Yuan, Walter and Jackson, Matthew O.}, doi = {10.1073/pnas.2512075122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2512075122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Using large language models to categorize strategic situations and decipher motivations behind human behaviors}, volume = {122}, year = {2025}, }
• (2025). Radiocarbon dating of jerusalem’s siloam dam links climate data and major waterworks. PNAS, 122(35), e2510396122. (www)

  @article{ , abstract = {Using well-established microarchaeological sampling methods, we reached a precise radiocarbon date of 800 BC for the Siloam Pool’s monumental water dam in Jerusalem. This date is a critical link connecting several imposing waterworks constructed at that time. Climate data pointing to droughts and flash floods during the last decades of the 9th century BC provide a logical framework for the reasons behind such endeavors. These included the fortification of the city’s primary water source, the Gihon Spring, and the redirection of the water into the city through a channel to an artificial reservoir created by building the Siloam Dam at the end of the Tyropoeon Valley, which blocked the drainage of rain and redirected spring waters.}, archive = {J_PNAS}, author = {Regev, Johanna and Szanton, Nahshon and Vukosavović, Filip and Berko, Itamar and Shalev, Yiftah and Uziel, Joe and Mintz, Eugenia and Regev, Lior and Boaretto, Elisabetta}, doi = {10.1073/pnas.2510396122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2510396122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Radiocarbon dating of jerusalem’s siloam dam links climate data and major waterworks}, volume = {122}, year = {2025}, }
• (2025). An exploration of basic human values in 38 million obituaries over 30 years. PNAS, 122(35), e2510318122. (www)

  @article{ , abstract = {How societies remember the dead can reveal what people value in life. We analyzed 38 million obituaries from the United States to examine how personal values are encoded in individual and collective legacies. Using Schwartz’s theory of basic human values, we found that tradition and benevolence dominated legacy reflections, while values like power and stimulation appeared less frequently. Major cultural events—the terrorist attacks of September 11th, the 2008 financial crisis, and the COVID-19 pandemic—were systematically linked to changes in legacy reflections about personal values, with security declining after 9/11, achievement declining after the financial crisis, and benevolence declining for years after COVID-19 began and, to date, not yet returning to baseline. Gender and age of the deceased were also linked to differences in legacy: Men were remembered more for achievement , power , and conformity , while women were remembered more for benevolence and hedonism . Older people were remembered more for tradition and conformity than younger people. These patterns shifted dynamically across the lifespan, with obituaries for men showing more age-related variation than legacies for women. Our findings reveal how obituaries serve as psychological and cultural time capsules, preserving not just individual legacies, but also indicating what US society values collectively regarding a life well lived.}, archive = {J_PNAS}, author = {Markowitz, David M. and Mazzuchi, Thomas and Syropoulos, Stylianos and Law, Kyle Fiore and Young, Liane}, doi = {10.1073/pnas.2510318122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2510318122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An exploration of basic human values in 38 million obituaries over 30 years}, volume = {122}, year = {2025}, }
• (2025). A unified model of transient poration induced by antimicrobial peptides. PNAS, 122(35), e2510294122. (www)

  @article{ , abstract = {Membrane active peptides (MAPs) represent a diverse group of agents that disrupt the integrity of lipid membranes. One class of MAPs, antimicrobial peptides (AMPs), destroy bacteria by transiently porating the bacterial membrane causing leakage of cellular contents. Transient leakage is classified as “graded,” where all vesicles in a population leak partially, or “all-or-none,” where some vesicles leak completely. However, the molecular interactions underlying transient leakage have eluded experimental determination. Here, dye leakage experiments with the AMP piscidin 1 (P1) show that graded leakage can be converted to all-or-none by simply adding a defect-promoting lysophospholipid. Molecular dynamics simulations demonstrate that area stress arising from membrane asymmetry decreases the energy of pore formation and is highly lipid dependent. Furthermore, lipids and peptides translocate the bilayer through these pores, leading to area-relaxed states where poration is highly unfavorable. Even pores too small to leak dye relieve area stress; they are the “none” component of all-or-none release. These observations lead to development of a quantitative model where graded and all-or-none leakage are treated as a continuum explained by a single mechanism that accounts for the local peptide concentration and probabilities of different pore sizes. This unified model accurately reproduces the P1 dye leakage data and provides an explanation for varying pore energy, size, and probability within the framework of asymmetry-driven poration. This model is expected to be applicable to other MAPs, including cell-penetrating peptides, and could provide a framework for designing peptides with greater cellular specificity, a long-sought outcome.}, archive = {J_PNAS}, author = {Rice, Amy and Zourou, Andriana C. and Cotten, Myriam L. and Pastor, Richard W.}, doi = {10.1073/pnas.2510294122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2510294122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A unified model of transient poration induced by antimicrobial peptides}, volume = {122}, year = {2025}, }
• (2025). Parallel trade-offs in human cognition and neural networks: The dynamic interplay between in-context and in-weight learning. PNAS, 122(35), e2510270122. (www)

  @article{ , abstract = {Human learning embodies a striking duality: Sometimes, we can rapidly infer and compose logical rules, benefiting from structured curricula (e.g., in formal education), while other times, we rely on an incremental approach or trial-and-error, learning better from curricula that are randomly interleaved. Influential psychological theories explain this seemingly conflicting behavioral evidence by positing two qualitatively different learning systems—one for rapid, rule-based inferences (e.g., in working memory) and another for slow, incremental adaptation (e.g., in long-term and procedural memory). It remains unclear how to reconcile such theories with neural networks, which learn via incremental weight updates and are thus a natural model for the latter, but are not obviously compatible with the former. However, recent evidence suggests that metalearning neural networks and large language models are capable of in-context learning (ICL)—the ability to flexibly infer the structure of a new task from a few examples. In contrast to standard in-weight learning (IWL), which is analogous to synaptic change, ICL is more naturally linked to activation-based dynamics thought to underlie working memory in humans. Here, we show that the interplay between ICL and IWL naturally ties together a broad range of learning phenomena observed in humans, including curriculum effects on category-learning tasks, compositionality, and a trade-off between flexibility and retention in brain and behavior. Our work shows how emergent ICL can equip neural networks with fundamentally different learning properties that can coexist with their native IWL, thus offering an integrative perspective on dual-process theories of human cognition.}, archive = {J_PNAS}, author = {Russin, Jacob and Pavlick, Ellie and Frank, Michael J.}, doi = {10.1073/pnas.2510270122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2510270122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Parallel trade-offs in human cognition and neural networks: The dynamic interplay between in-context and in-weight learning}, volume = {122}, year = {2025}, }
• (2025). Organoid-based neutralization assays reveal a distinctive profile of SARS-CoV-2 antibodies and recapitulate the real-world efficacy. PNAS, 122(35), e2509616122. (www)

  @article{ , abstract = {The efficacy of VIR-7831, a class 3 anti-SARS-CoV-2 monoclonal antibody (mAb), was demonstrated repeatedly in clinical trials; yet, reduced neutralization against Omicron variants in cell-line-based neutralization assays led to its withdrawal from clinical use. We developed organoid-based neutralization assays to measure mAb potency. We found that most class 3 mAbs, especially those not blocking receptor-binding domain-ACE2 binding, including VIR-7831, were substantially underestimated in cell-line-based assays. Nasal organoids adequately recapitulated the real-world effectiveness of VIR-7831 because of biologically relevant low ACE2 expression, and exclusively reproduced the in vivo protection of S2 mAbs due to the high TMPRSS2 expression, reminiscent of native human respiratory epithelial cells. Collectively, the robust organoid culture system and biologically relevant expression profiles of ACE2 and TMPRSS2 make nasal organoids present a correlate of in vivo protection of neutralizing mAbs exclusively. The organoid-based neutralization assays, superior to conventional cell-line-based assays, can recapitulate and predict the real-world efficacy of mAbs.}, archive = {J_PNAS}, author = {Wan, Zhixin and Li, Cun and Zhou, Ying and Yu, Yifei and Chiu, Man Chun and Huang, Jingjing and Zhang, Shuxin and Zhu, Xiaoxin and Lan, Qiaoshuai and Deng, Yanlin and Xue, Wei and Jiang, Chengfan and Wu, Jiali and Zhao, Zijun and Cai, Jian-Piao and Huang, Lin and Zhang, Yong and Liu, Xiaojuan and Zhang, Zheng and Chu, Hin and Zhang, Linqi and Chen, Zhiwei and To, Kelvin Kai-Wang and Yuen, Kwok-Yung and Clevers, Hans and Zhou, Jie}, doi = {10.1073/pnas.2509616122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2509616122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Organoid-based neutralization assays reveal a distinctive profile of SARS-CoV-2 antibodies and recapitulate the real-world efficacy}, volume = {122}, year = {2025}, }
• (2025). Loss of ICOSL expression in the progression to cervical carcinoma. PNAS, 122(35), e2509425122. (www)

  @article{ , abstract = {Human papillomavirus (HPV)–related lesions contain types with benign outcomes and those with a risk of progression to cancer. We addressed the role of immune surveillance in 76 cervical biopsies (normal = 23, HPV+ benign = 16, HPV+ precancer = 37) by studying the infiltration of cytotoxic T cells and the expression of the immune modulators PDL1, ICOSL, and miR-155 and compared the data to 101 cervical squamous cell carcinomas. In the normal cervix, ICOSL expression was restricted to the endocervical epithelia whereas neither miR-155 nor PDL1 were detected. MiR-155 was up-regulated in both the benign (88%) and precancerous (92%) HPV squamous intraepithelial lesions (SIL) and colocalized to cells in the upper part of the lesion that is the area with productive viral infection. Both PDL1 (95%) and ICOSL (89%) were only evident in the precancerous SIL and each localized to squamous cells in the basal aspect that lacked replicating virus. In both microinvasive and invasive cervical squamous cell cancer miR-155 expression remained high (83%) as did PDL1 expression (80%) but ICOSL detection was reduced to 17%. Infiltration by CD8+ T cells was intense in the invasive lesions and these cells were mostly inactive as determined by the lack of granzyme B colocalization. It is concluded that miR-155 expression is a marker of HPV infection in both benign and precancerous lesions, whereas the approximately 10% of the latter lesions that progress to cancer gain PDL1 and lose ICOSL expression, which are important factors in avoiding immune surveillance.}, archive = {J_PNAS}, author = {Nuovo, Gerard J. and Tili, Esmerina and Croce, Carlo M.}, doi = {10.1073/pnas.2509425122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2509425122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Loss of ICOSL expression in the progression to cervical carcinoma}, volume = {122}, year = {2025}, }
• (2025). STAGE: A compact and versatile TnpB-based genome editing toolkit for streptomyces. PNAS, 122(35), e2509146122. (www)

  @article{ , abstract = {Streptomyces are naturally endowed with the capacity to produce a wide array of natural products with biomedical and biotechnological value. They have garnered great interest in synthetic biology applications given the abundance of uncharacterized biosynthetic gene clusters (BGCs). However, progress has been hindered by the limited availability of genetic tools for manipulating these bacteria. Several representative CRISPR-Cas systems have been established in Streptomyces to streamline experimental workflows and improve editing efficiency. Nevertheless, their broader applicability has been constrained by issues such as nuclease activity-related cytotoxicity and the large size of effector proteins. To address these challenges, we present Streptomyces -compatible TnpB-assisted genome editing (STAGE), a genetic toolkit based on ISDra2 TnpB, which is approximately one-third the size of Cas9 and enables precise, site-specific gene editing. We demonstrated that STAGE introduces genetic mutations with high efficiency and minimal off-target effects in two industrially important Streptomyces strains. Building on this platform, we developed STAGE-cBEST and STAGE-McBEST, enabling single and multiplexed C·G-to-T·A base editing, respectively, with editing efficiencies exceeding 75%. To further enhance performance, we engineered the ISDra2 TnpB system using an AI-assisted protein engineering framework, resulting in two variants that achieve nearly 100% genome editing efficiency. Additionally, through sequence homology analysis, we identified a TnpB ortholog from the same biological origin of ISDra2 TnpB, which also functions effectively as a gene editing tool. Our study establishes STAGE as a highly precise, programmable, and versatile genome editing platform for Streptomyces , paving the way for advanced genetic manipulation and synthetic biology applications in these industrially important bacteria.}, archive = {J_PNAS}, author = {Luo, Jing and Chia, Natalie and Qin, Yuxi and Tan, Pan and Zhang, Lingwen and Yang, Sihan and Yuan, Zihan and Hong, Liang and Lee, Sang Yup and Tong, Yaojun}, doi = {10.1073/pnas.2509146122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2509146122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {STAGE: A compact and versatile TnpB-based genome editing toolkit for streptomyces}, volume = {122}, year = {2025}, }
• (2025). Quantum relaxometry for detecting biomolecular interactions with single NV centers. PNAS, 122(35), e2509102122. (www)

  @article{ , abstract = {The investigation of biomolecular interactions at the single-molecule level has emerged as a pivotal research area in life science, particularly through optical, mechanical, and electrochemical approaches. Spins existing widely in biological systems offer a unique degree of freedom for detecting such interactions. However, most previous studies have been largely confined to ensemble-level detection in the spin degree. Here, we developed a molecular interaction analysis method approaching single-molecule level based on relaxometry using the quantum sensor, nitrogen-vacancy (NV) center in diamond. Experiments utilized an optimized diamond surface functionalized with a polyethylenimine nanogel layer, achieving ∼ 10 nm average protein distance and mitigating interfacial steric hindrance. Then we measured the strong interaction between streptavidin and spin-labeled biotin complexes, as well as the weak interaction between bovine serum albumin and biotin complexes, at both the micrometer scale and nanoscale. For the micrometer-scale measurements using ensemble NV centers, we reexamined the often-neglected fast relaxation component and proposed a relaxation rate evaluation method, substantially enhancing the measurement sensitivity. Furthermore, we achieved nanoscale detection approaching single-molecule level using single NV centers. This methodology holds promise for applications in molecular screening, identification, and kinetic studies at the single-molecule level, offering critical insights into molecular function and activity mechanisms.}, archive = {J_PNAS}, author = {Li, Min and Zhang, Qi and Kong, Xi and Zhao, Sheng and Pan, Bin-Bin and Sun, Ziting and Yu, Pei and Wang, Zhecheng and Wang, Mengqi and Ji, Wentao and Kong, Fei and Cheng, Guanglei and Wu, Si and Wang, Ya and Chen, Sanyou and Su, Xun-Cheng and Shi, Fazhan}, doi = {10.1073/pnas.2509102122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2509102122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantum relaxometry for detecting biomolecular interactions with single NV centers}, volume = {122}, year = {2025}, }
• (2025). Specificities of chemosensory receptors in the human gut microbiota. PNAS, 122(35), e2508950122. (www)

  @article{ , abstract = {The human gut is rich in metabolites and harbors a complex microbial community, yet surprisingly little is known about the spectrum of chemical signals detected by the large variety of sensory receptors present in the gut microbiome. Here, we systematically mapped the ligand specificities of selected extracytoplasmic sensory domains from twenty members of the human gut microbiota, with a primary focus on the abundant and physiologically important class of Clostridia. Twenty-five metabolites from different chemical classes—including amino acids, nucleobase derivatives, amines, indole, and carboxylates—were identified as specific ligands for fifteen sensory domains from nine bacterial species, which represent all three major functional classes of transmembrane receptors: chemotaxis receptors, histidine kinases, and enzymatic sensors. We have further characterized the specificity and evolution of ligand binding to Cache superfamily sensors specific for lactate, dicarboxylic acids, and for uracil and short-chain fatty acids (SCFAs). Structural and biochemical analysis of the dCache sensor of uracil and SCFAs revealed that its two different ligand types bind at distinct sensory modules. Overall, combining experimental identification with computational analyses, we were able to assign ligands to approximately half of the Cache-type chemotaxis receptors found in the eleven gut commensal genomes from our set, with carboxylic acids representing the largest ligand class. Among these, the most commonly found ligand specificities were for lactate and formate, indicating a particular importance of these metabolites in the human gut microbiota and consistent with their observed growth-promoting effects on selected bacterial commensals.}, archive = {J_PNAS}, author = {Xu, Wenhao and Jalomo-Khayrova, Ekaterina and Gumerov, Vadim M. and Ross, Patricia A. and Köbel, Tania S. and Schindler, Daniel and Bange, Gert and Zhulin, Igor B. and Sourjik, Victor}, doi = {10.1073/pnas.2508950122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2508950122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Specificities of chemosensory receptors in the human gut microbiota}, volume = {122}, year = {2025}, }
• (2025). CHP1 promotes lipid droplet growth and regulates the localization of key enzymes for triacylglycerol synthesis. PNAS, 122(35), e2508912122. (www)

  @article{ , abstract = {The glycerol-3-phosphate (G-3-P) pathway is central to the synthesis of triacylglycerols (TAGs) and glycerophospholipids, essential for membrane biogenesis and lipid storage. The first and rate-limiting step in this pathway is catalyzed by glycerol-3-phosphate acyltransferases (GPATs), with microsomal GPAT3 and GPAT4 being evolutionarily conserved and predominant in most tissues. While previous studies have implicated Calcineurin B homologous protein 1 (CHP1) as a cofactor for GPAT4, the broader role of CHP1 in regulating microsomal GPATs and TAG biosynthesis remains unclear. Here, we demonstrate that CHP1 is a critical regulator of both GPAT3 and GPAT4, essential for their stability, enzymatic activity, and lipid droplet (LD) localization. Structural modeling and mutational analyses identified key hydrophobic interfaces mediating the CHP1–GPAT interaction, which are required for optimal GPAT activity and LD growth. Loss of CHP1 impairs LD expansion and disrupts the localization of GPAT3/4 and downstream enzymes in the TAG synthesis pathway, including 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) and diacylglycerol O-acyltransferase 2 (DGAT2). Mechanistically, CHP1 helps circumvent seipin-mediated restriction of late LD-targeting enzymes, facilitating their access to mature LDs. Together, our findings reveal CHP1 as a dual-function regulator that stabilizes and activates microsomal GPATs while enabling the coordinated recruitment of TAG biosynthetic enzymes to LDs. This work uncovers a previously unrecognized mechanism for regulating LD growth and glycerolipid metabolism, with broad implications for lipid homeostasis and metabolic diseases.}, archive = {J_PNAS}, author = {Yang, Guang and Du, Ximing and Norris, Dougall and Zadoorian, Armella and Zheng, Yuyuan and Gao, Mingming and Brown, Andrew J. and Grey, Shane T. and Zhou, Chun and Yang, Hongyuan}, doi = {10.1073/pnas.2508912122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2508912122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CHP1 promotes lipid droplet growth and regulates the localization of key enzymes for triacylglycerol synthesis}, volume = {122}, year = {2025}, }
• (2025). Sociohydrodynamics: Data-driven modeling of social behavior. PNAS, 122(35), e2508692122. (www)

  @article{ , abstract = {Living systems display complex behaviors driven by physical forces as well as decision-making. Hydrodynamic theories hold promise for simplified universal descriptions of socially generated collective behaviors. However, the construction of such theories is often divorced from the data they should describe. Here, we develop and apply a data-driven pipeline that links micromotives to macrobehavior by augmenting hydrodynamics with individual preferences that guide motion. We illustrate this pipeline on a case study of residential dynamics in the United States, for which census and sociological data are available. Guided by Census data, sociological surveys, and neural network analysis, we systematically assess standard hydrodynamic assumptions to construct a sociohydrodynamic model. Solving our minimal hydrodynamic model, calibrated using statistical inference, qualitatively captures key features of residential dynamics at the level of individual US counties. We highlight that a social memory, akin to hysteresis in magnets, emerges in the segregation–integration transition even with memory-less agents. While residential segregation is a multifactorial phenomenon, this physics analogy suggests a simple mechanistic explanation for the phenomenon of neighborhood tipping, whereby a small change in a neighborhood’s population leads to a rapid demographic shift. Beyond residential segregation, our work paves the way for systematic investigations of decision-guided motility in real space, from micro-organisms to humans, as well as fitness-mediated motion in more abstract spaces.}, archive = {J_PNAS}, author = {Seara, Daniel S. and Colen, Jonathan and Fruchart, Michel and Avni, Yael and Martin, David G. and Vitelli, Vincenzo}, doi = {10.1073/pnas.2508692122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2508692122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sociohydrodynamics: Data-driven modeling of social behavior}, volume = {122}, year = {2025}, }
• (2025). Coordinated actions of NLR-assembled and glutamate receptor–like calcium channels in plant effector-triggered immunity. PNAS, 122(35), e2508018122. (www)

  @article{ , abstract = {The plant immune system utilizes nucleotide-binding/leucine-rich repeat (NLR) proteins to detect pathogen virulence factors (effectors) inside host cells and transduce recognition to rapid defense. In dicotyledenous plants, pathogen activated Toll-like/interleukin-1 receptor-containing NLRs (TNLs) establish a signaling network of enhanced susceptibility 1 (EDS1)-family dimers with RPW8-type coiled-coil (CC R ) domain NLRs (RNLs) to stimulate transcriptional reprogramming leading to host cell death and pathogen restriction. Evidence suggests that TNL- and EDS1-activated RNLs function as oligomeric Ca 2+ permeable ion channels at the plasma membrane. However, the downstream processes for immunity execution are poorly understood. Here, we studied pathogen effector-triggered immunity conferred by Nicotiana benthamiana TNL (Roq1) which signals almost exclusively through the EDS1-senescence associated gene101 (SAG101)-N required gene 1 (NRG1) RNL module. We identify a pair of glutamate receptor–like Ca 2+ ion channels (GLR2.9a and GLR2.9b) which, unlike most other pathogen-induced GLRs, are highly up-regulated by the EDS1-SAG101-NRG1 module in the TNL immune response. We show that oligomeric NRG1 Ca 2+ channel activity is necessary for GLR2.9a and GLR2.9b induced expression. Consequently, GLR2.9a and GLR2.9b proteins contribute to NRG1 -dependent Ca 2+ accumulation in host cells, and to pathogen resistance and host cell death. We establish that GLR2.9a localizes mainly to the plasma membrane/cytoplasm whereas GLR2.9b accumulates preferentially at the nuclear envelope. The data show that transcriptionally up-regulated canonical Ca 2+ ion channels GLR2.9a and GLR2.9b are a functional output of the EDS1-SAG101-NRG1 module for TNL-triggered immunity.}, archive = {J_PNAS}, author = {Wang, Junli and Sun, Xinhua and Xiong, Fei and Lapin, Dmitry and Lee, Tak and Martin-Ramirez, Sergio and Prakken, Anna and Shen, Qiaochu and Bautor, Jaqueline and Maekawa, Takaki and Parker, Jane E.}, doi = {10.1073/pnas.2508018122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2508018122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Coordinated actions of NLR-assembled and glutamate receptor–like calcium channels in plant effector-triggered immunity}, volume = {122}, year = {2025}, }
• (2025). Ice as a kinetic and mechanistic driver of oxalate-promoted iron oxyhydroxide dissolution. PNAS, 122(35), e2507588122. (www)

  @article{ , abstract = {Ice often mediates unexpected reactions in the Cryosphere, acting as a fascinating geochemical reactor. Mineral–organic interactions in frozen environments, such as soils and permafrost, are crucial for explaining the flux of soluble iron during melting events, yet the mechanisms remain misunderstood. This study elucidates the unique roles of freezing in the dissolution of iron oxyhydroxide nanoparticles (α–FeOOH) by oxalate, a low molecular weight dicarboxylate, under acidic conditions. From time-resolved experiments conducted over 4 d, we demonstrate that soluble iron was released through reactions in minute volumes of liquid water trapped between ice micrograins. Freeze concentration of nanoparticles, oxalate, and protons into this liquid water drove oxalate- and proton-promoted dissolution reactions at temperatures as low as −30 °C. Remarkably, ice at −10 °C dissolved more iron than liquid water at 4 °C under high oxalate loadings, and even more than at 25 °C under low oxalate loadings. In contrast, high salinity subdued dissolution. Also, sequential freeze-thaw cycles enhanced dissolution by releasing unreacted oxalate that was previously locked in ice. By resolving the chemical controls on mineral dissolution in ice, this work can help explain how freeze-thaw events are supplying new fluxes of soluble iron to nature.}, archive = {J_PNAS}, author = {Sebaaly, Angelo P. and van Rijn, Frank and Hanna, Khalil and Boily, Jean-François}, doi = {10.1073/pnas.2507588122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2507588122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ice as a kinetic and mechanistic driver of oxalate-promoted iron oxyhydroxide dissolution}, volume = {122}, year = {2025}, }
• (2025). Reconfigurable photothermal doping filament for selective spin manipulation and addressing. PNAS, 122(35), e2507587122. (www)

  @article{ , abstract = {The room temperature manipulation of solid-state spins provides an opportunity to develop quantum applications under ambient conditions. Local electromagnetic fields, that usually produced by current in micro/nanoscale metal wires, have been employed for the coherent driving and addressing of spin qubit. However, the fixed distribution limits the spatial selectivity and efficiency of qubit manipulation, which is of central importance in a scaled-up quantum system. Here, we report a solution by demonstrating a reconfigurable current with arbitrary shape to engineer microwave and DC magnetic field at microscale. A “photothermal doping” method was proposed to optically control local insulator-to-metal transition in vanadium dioxide. It generates a conducting filament with adjustable position, direction, and width. Universal manipulation and selective addressing of spins at arbitrary sites are realized, by freely changing the filament and electromagnetic field on demand. Our work paves the way for developing quantum devices with large-scale spin qubits.}, archive = {J_PNAS}, author = {Liu, Zhi-Wei and Ma, Meng-Qi and Sun, Bo-Wen and Li, Liang and Jiang, Wang and Zang, Han-Xiang and Bai, Zhe and Dong, Yang and Zhang, Shao-Chun and Chen, Xiang-Dong and Zou, Chong-Wen and Guo, Guang-Can and Sun, Fang-Wen}, doi = {10.1073/pnas.2507587122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2507587122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reconfigurable photothermal doping filament for selective spin manipulation and addressing}, volume = {122}, year = {2025}, }
• (2025). STIM1 transmembrane helix dimerization captured by AI-guided transition path sampling. PNAS, 122(35), e2506516122. (www)

  @article{ , abstract = {Stromal interaction molecule 1 (STIM1) is a Ca 2+ -sensing protein in the endoplasmic reticulum (ER) membrane. The depletion of ER Ca 2+ stores induces a large conformational transition of the cytosolic STIM1 C-terminus, initiated by the dimerization of the transmembrane (TM) domain. We use the AI-guided transition path sampling algorithm aimmd to extensively sample the dimerization of STIM1-TM helices in an ER-mimicking lipid bilayer. In nearly 0.5 ms of all-atom molecular dynamics simulations without bias potentials, we harvest over 170 transition paths, each about 1.2 μs long on average. We find that STIM1 dimerizes into three distinct and coexisting configurations, which reconciles conflicting results from earlier crosslinking studies. The dominant X-shaped bound state centers around contacts supported by the SxxxG TM interfacial motif. Mutating residues in this contact interface allows us to tune the STIM1-dimerization propensity in fluorescence experiments. From the trained model of the committor probability of dimerization, we identify the transition state ensemble for TM-helix dimerization. At the transition state, interhelical contacts in the luminal halves of the two monomers dominate, which likely enables the luminal Ca 2+ -sensing domain in STIM1 to condition the dimerization of the TM helices. Our work demonstrates the unique power of AI-guided simulations to sample rare and slow molecular transitions and to produce detailed atomistic insight into the mechanism of STIM1 TM-helix dimerization as a key step in ER Ca 2+ -sensing.}, archive = {J_PNAS}, author = {Horvath, Ferdinand and Jung, Hendrik and Grabmayr, Herwig and Fahrner, Marc and Romanin, Christoph and Hummer, Gerhard}, doi = {10.1073/pnas.2506516122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2506516122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {STIM1 transmembrane helix dimerization captured by AI-guided transition path sampling}, volume = {122}, year = {2025}, }
• (2025). Chants across seven traditions share acoustic traits that enhance subjective relaxation. PNAS, 122(35), e2506480122. (www)

  @article{ , abstract = {For over 5,000 y, chanting has been practiced across many Western and Eastern traditions. However, there is hardly any empirical research on 1) whether chants from across the globe share common acoustic properties, 2) whether these acoustic features make them distinct from other human vocalizations, and 3) the extent to which they may positively impact listeners’ well-being. Here, we collected 242 chants belonging to seven distinct traditions and associated with a wide range of language families, and compared them acoustically to a large corpus of song (n = 126) and speech (n = 616) samples from across 14 linguistic and 12 geographical regions. We show that, irrespective of language and geographical origin, chants share distinctive acoustic traits, namely relatively flat and slow-changing intonation and steady, unbroken voicing in a comfortable, rather low pitch range with a prevalence of mid-central vowels. Thus, chants are produced in a relaxed vocal tract configuration with minimal articulation. Additionally, playback experiments involving original chants (with a participant pool of 61 listeners), resynthesized chants (with 114 listeners), and fully synthetic chants (with 80 listeners) demonstrate that these acoustic characteristics enhance listeners’ perceived sensations of relaxation. Specifically, relatively flat and slow-changing intonation, combined with vowel production in a relatively relaxed vocal tract configuration, resulted in higher overall relaxation ratings. Together these results hint at a specific function of chants’ acoustic commonalities: the enhancement of well-being through relaxation.}, archive = {J_PNAS}, author = {Canessa-Pollard, Valentina and Anikin, Andrey and Reby, David}, doi = {10.1073/pnas.2506480122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2506480122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chants across seven traditions share acoustic traits that enhance subjective relaxation}, volume = {122}, year = {2025}, }
• (2025). Nucleotide- and metalloid-driven conformational changes in the arsenite efflux ATPase ArsA. PNAS, 122(35), e2506440122. (www)

  @article{ , abstract = {Arsenite (As III ) is toxic to all organisms due to its ability to tightly bind exposed thiols within cells. An important As III resistance mechanism in prokaryotes involves proteins encoded by the ars operon. A central component of the ars operon in many bacteria is the cytoplasmic ATPase, ArsA, which orchestrates a series of nucleotide-dependent handoffs, starting with the capture of As III by the ArsD metallochaperone and culminating in its removal from the cell by the ArsB efflux pump. Although the mechanism of ArsA has been widely studied, the molecular details of how nucleotide hydrolysis modulates these events remain unclear. ArsA is an archetypal member of the intradimeric Walker A (IWA) family of ATPases, implicated in a diversity of complex biological functions. Conformational changes typical of IWA ATPases have been postulated to drive these molecular events but have not been demonstrated. We report cryogenic electron microscopy (cryo-EM) structures of ArsA in MgADP-bound and MgATP-bound open states, as well as a distinct closed MgATP-bound state liganded to As III . X-ray absorption spectroscopy (XAS) confirmed three-coordinate binding of As III to the conserved cysteines at the metalloid-binding site of the closed state. Coupled with biochemical characterization, our cryo-EM structures reveal key conformational changes in the ArsA catalytic cycle consistent with other IWA ATPases and provide the structural basis for allosteric activation of nucleotide hydrolysis by As III . This work establishes how the nucleotide state of ArsA transiently creates a high-affinity binding site that can sequester metalloid within the cell, followed by a nucleotide-driven handoff to ArsB for efflux.}, archive = {J_PNAS}, author = {Mahajan, Shivansh and Pall, Ashley E. and Li, Yancheng E. and Stemmler, Timothy L. and Rees, Douglas C. and Clemons, William M.}, doi = {10.1073/pnas.2506440122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2506440122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nucleotide- and metalloid-driven conformational changes in the arsenite efflux ATPase ArsA}, volume = {122}, year = {2025}, }
• (2025). TIGER: A tdTomato in vivo genome-editing reporter mouse for investigating precision-editor delivery approaches. PNAS, 122(35), e2506257122. (www)

  @article{ , abstract = {In vivo genome editing has the potential to address many inherited and environmental disorders. However, a major hurdle for the clinical translation of genome editing is safe, efficient delivery to disease-relevant tissues. A modality-agnostic reporter animal model that facilitates rapid, precise, and quantifiable assessment of functional delivery and editing could greatly enhance the evaluation and translation of delivery technologies. Here, we present the development of the tdTomato in vivo genome-editing reporter (TIGER) mouse, a reporter strain that harbors an integrated and constitutively expressed mutated tdTomato gene in the Polr2a locus. The mutations (Q115X, Q357X) abolish fluorescence, but successful adenine base editing (ABE) or prime editing (PE) restores tdTomato fluorescence. This mouse model facilitates the tissue- and cell type–specific assessment of genome editing agent delivery. We describe several editing strategies validated in vitro and demonstrate efficient ABE and PE in vivo using viral and nonviral delivery vectors targeting four cell types within the mouse eye: the retinal pigment epithelium, photoreceptors, Müller glia, and the trabecular meshwork. We show direct editing characterization in the ocular tissues via in vivo and ex vivo two-photon confocal microscopy and verify the spectral and fluorescence lifetime properties of tdTomato reporter in other mouse tissues. Additionally, we demonstrate successful adeno-associated virus (AAV)-mediated PE of extraocular tissues, including hepatocytes, skeletal muscle, and brain neurons by intravenous injection. Thus, the TIGER mouse facilitates the direct development, comparison, and optimization of delivery platforms for efficient and productive ABE or PE broadly applicable in vivo across multiple tissues tested in this study.}, archive = {J_PNAS}, author = {Du, Samuel W. and Palczewska, Grazyna and Dong, Zhiqian and Lauterborn, Julie C. and Kaipa, Balasankara Reddy and Yan, Alexander L. and Hołubowicz, Rafał and Ha, Siyoung and Chen, Paul Z. and Gall, Christine M. and Zode, Gulab and Liu, David R. and Palczewski, Krzysztof}, doi = {10.1073/pnas.2506257122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2506257122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TIGER: A tdTomato in vivo genome-editing reporter mouse for investigating precision-editor delivery approaches}, volume = {122}, year = {2025}, }
• (2025). A genome-scale drug discovery pipeline uncovers therapeutic targets and a unique p97 allosteric binding site in schistosoma mansoni. PNAS, 122(35), e2505710122. (www)

  @article{ , abstract = {Schistosomes are parasitic flatworms that infect more than 200 million people globally. However, there is a shortage of molecular tools that enable the discovery of potential drug targets within schistosomes. Thus, praziquantel has remained the frontline treatment for schistosomiasis despite known liabilities. Here, we have conducted a genome-wide study in Schistosoma mansoni using the human druggable genome as a bioinformatic template to identify essential genes within schistosomes bearing similarity to catalogued drug targets. Then, we assessed these candidate targets in silico using a set of unbiased criteria to determine which possess ideal characteristics for a ready-made drug discovery campaign. Following this prioritization, we pursued a parasite p97 ortholog as a bona-fide drug target for the development of therapeutics to treat schistosomiasis. From this effort, we identified a covalent inhibitor series that kills schistosomes through an on-target killing mechanism by disrupting the ubiquitin proteasome system. Fascinatingly, these inhibitors induce a conformational change in the conserved D2 domain P-loop of schistosome p97 upon modification of Cys519. This conformational change reveals an allosteric binding site adjacent to the D2 domain active site reminiscent of the “DFG” flip in protein kinases. This allosteric binding site can potentially be utilized to generate new classes of species-selective p97 inhibitors. Furthermore, these studies provide a resource for the development of alternative therapeutics for schistosomiasis and a workflow to identify potential drug targets in similar systems with few available molecular tools.}, archive = {J_PNAS}, author = {Stephens, Dylon R. and Fung, Ho Yee Joyce and Han, Yan and Liang, Jue and Chen, Zhe and Ready, Joseph and Collins, James J.}, doi = {10.1073/pnas.2505710122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2505710122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A genome-scale drug discovery pipeline uncovers therapeutic targets and a unique p97 allosteric binding site in schistosoma mansoni}, volume = {122}, year = {2025}, }
• (2025). Echoes in AI: Quantifying lack of plot diversity in LLM outputs. PNAS, 122(35), e2504966122. (www)

  @article{ , abstract = {With rapid advances in large language models (LLMs), there has been an increasing application of LLMs in creative content ideation and generation. A critical question emerges: can current LLMs provide ideas that are diverse enough to truly bolster collective creativity? We examine two state-of-the-art LLMs, GPT-4 and LLaMA-3, on story generation and discover that LLM-generated stories often consist of plot elements that are echoed across a number of generations. To quantify this phenomenon, we introduce the Sui Generis score, an automatic metric that measures the uniqueness of a plot element among alternative storylines generated using the same prompt under an LLM. Evaluating on 100 short stories, we find that LLM-generated stories often contain combinations of idiosyncratic plot elements echoed frequently across generations and across different LLMs, while plots from the original human-written stories are rarely recreated or even echoed in pieces. Moreover, our human evaluation shows that the ranking of Sui Generis scores among story segments correlates moderately with human judgment of surprise level, even though score computation is completely automatic without relying on human judgment.}, archive = {J_PNAS}, author = {Xu, Weijia and Jojic, Nebojsa and Rao, Sudha and Brockett, Chris and Dolan, Bill}, doi = {10.1073/pnas.2504966122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2504966122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Echoes in AI: Quantifying lack of plot diversity in LLM outputs}, volume = {122}, year = {2025}, }
• (2025). Hottest year in recorded history compounds global biodiversity risks. PNAS, 122(35), e2504945122. (www)

  @article{ , abstract = {As climate change accelerates, effectively monitoring and managing the growing impacts on biodiversity is an urgent priority. Here, we identify the exposure of species to unprecedented heat to evaluate the potential impact of 2024—the hottest year on record—across >33,000 vertebrate species worldwide. One in six (5,368) species were exposed to unprecedented temperatures across >25% of their range—68% more species than in 2023. Most (81%) species exposed in 2023 were also exposed in 2024, potentially compounding risks. For the first time, widespread species were exposed to extreme temperatures across >10% of their ranges. We propose using these exposure estimates to inform monitoring and mitigation efforts to avoid the worst impacts of climate change.}, archive = {J_PNAS}, author = {Merow, Cory and Maitner, Brian S. and Schwarz Meyer, Andreas and Pigot, Alex L. and Serra-Diaz, Josep M. and Urban, Mark C.}, doi = {10.1073/pnas.2504945122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2504945122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hottest year in recorded history compounds global biodiversity risks}, volume = {122}, year = {2025}, }
• (2025). Unveiling street art: A multimodal and multitechnique approach for analyzing and mapping painting materials on large murals. PNAS, 122(35), e2504918122. (www)

  @article{ , abstract = {Street art murals are increasingly recognized as valuable contemporary artworks, often attaining significant artistic, historical, and social importance. As these murals become integral parts of cultural heritage, finding efficient strategies for their conservation is crucial. However, their typical large surface areas, heterogeneous materials, and high variability in exposure to environmental and pollution factors pose significant challenges in establishing appropriate analytical strategies to obtain the necessary information. This study proposes a multiscale and multitechnique noninvasive approach to investigate and monitor street art murals in situ. By combining portable point techniques—such as external reflection Fourier transform infrared spectroscopy, Raman spectroscopy, visible, near infrared, and short-wave infrared reflectance spectroscopy, and X-ray fluorescence spectroscopy—with visible and near infrared hyperspectral imaging, the mural’s composition across a square meter surface could be analyzed. Additionally, multispectral imaging mounted on a drone provided a global reconstruction and characterization of the overall mural. This method was complemented by microdestructive laboratory analyses of selected samples, using pyrolysis gas chromatography–mass spectrometry and liquid chromatography coupled with diode array detector and tandem mass spectrometry, to further investigate selected samples and support noninvasive results. The approach was applied to the iconic mural “Musica Popolare” (2017) by Orticanoodles in Milan, Italy, revealing detailed information about its pigments, binders, fillers, and degradation. The findings demonstrate the potential of this integrated methodology for the effective material identification, conservation assessment, and short-and long-term monitoring of urban heritage.}, archive = {J_PNAS}, author = {Sabatini, Francesca and Albertin, Fauzia and Doherty, Brenda and Monico, Letizia and Rosi, Francesca and Buti, David and Romani, Aldo and Pecci, Antonio and Abate, Nicodemo and Sileo, Maria and Amodio, Antonio Minervino and Masini, Nicola and Pizzimenti, Silvia and Degano, Ilaria and Modugno, Francesca and Campanella, Beatrice and Legnaioli, Stefano and Cartechini, Laura}, doi = {10.1073/pnas.2504918122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2504918122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unveiling street art: A multimodal and multitechnique approach for analyzing and mapping painting materials on large murals}, volume = {122}, year = {2025}, }
• (2025). Shared metabolism between a bacterial and fungal species that reside in the human gut. PNAS, 122(35), e2504785122. (www)

  @article{ , abstract = {The fungal species Candida albicans and the bacterium Enterococcus faecalis are members of the human gut microbiome. To explore the range of interactions between these two species, we utilized dual RNA-sequencing to transcriptionally profile both C. albicans and E. faecalis during coculture (compared with monoculture controls) under two conditions: 1) an in vitro setting that mimics certain features of the gut environment and 2) a gnotobiotic mouse gut model. RNA-seq analysis revealed a large number of gene expression changes induced by one species in the presence of the other. More specifically, both species highly upregulate citrate-metabolizing genes during coculture: C. albicans upregulates CIT1 (citrate synthase) which produces citrate, while E. faecalis upregulates its cit operon, which breaks down citrate. In vitro analysis showed directly that citrate cross-feeding (production of citrate by C. albicans and breakdown by E. faecalis) enhances growth of E. faecalis . A main byproduct of citrate metabolism in E. faecalis is formate, a short chain fatty acid toxic to fungi. Our RNA profiling revealed that C. albicans upregulates three formate dehydrogenases (FDHs) during coculture; we show that the FDH genes confer a growth advantage to C. albicans when E. faecalis (or simply formate) is present. These findings reveal a metabolically driven cycle between C. albicans and E. faecalis in the mouse gut and in vitro, where cross-feeding of citrate and detoxification of formate facilitates the growth of both species when they are cultured together.}, archive = {J_PNAS}, author = {Gause, Haley and Johnson, Alexander D.}, doi = {10.1073/pnas.2504785122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2504785122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Shared metabolism between a bacterial and fungal species that reside in the human gut}, volume = {122}, year = {2025}, }
• (2025). Flavin-deficient erythrocytes offer protection against malaria parasites. PNAS, 122(35), e2504687122. (www)

  @article{ , abstract = {Studies from the 1980s and 1990s conducted in Italy, where malaria was once endemic, hypothesized that individuals with erythrocytes deficient in flavin mononucleotide and flavin adenine dinucleotide (FAD)—collectively known as flavins—are partially protected against malaria. The condition was reported to be familial, consistent with a genetic element. This hypothesis, however, has never been tested. Using an erythrocyte FAD-dependent glutathione reductase activity assay, we identified individuals with flavin-deficient erythrocytes (FDE) in Ferrara, Italy (23% of 150 individuals screened), and in Huye, Rwanda (13% of 169 individuals). None of the individuals with FDE had a dietary riboflavin deficiency. Importantly, FDE from individuals in Ferrara, as well as erythrocytes depleted of flavins in vitro by riboflavin starvation, inhibited the intraerythrocytic proliferation of Plasmodium falciparum . We provide evidence that these erythrocytes are susceptible to oxidative stress, potentially explaining their inhibitory effect on parasite proliferation. Genetic analysis identified mutations in the FAD synthase gene of three individuals with FDE from Huye, consistent with a potential genetic basis.}, archive = {J_PNAS}, author = {Hemasa, Ayman and van Loon, Welmoed and Fu, Jonathan and Spry, Christina and Jäger, Julia and van Schalkwyk, Donelly A. and Reverberi, Roberto and Ndoli, Jules and Mockenhaupt, Frank P. and Contini, Carlo and Saliba, Kevin J.}, doi = {10.1073/pnas.2504687122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2504687122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Flavin-deficient erythrocytes offer protection against malaria parasites}, volume = {122}, year = {2025}, }
• (2025). Tunable effective diffusion of CO2 in aqueous foam. PNAS, 122(35), e2504617122. (www)

  @article{ , abstract = {Aqueous foams are solid materials composed of gases and liquids, exhibiting a large gas/liquid surface area and enabling dynamic exchanges between their fluid components. The structure of binary-gas foams, whose bubbles consist of a mixture of two gases having different affinities with the liquid, thus offers real potential for the dynamic separation of these gases at low cost. In single-gas foams, the structure evolves under the effect of gas flow induced by Laplace pressure differences, arising from heterogeneities in bubble size. This leads to the well-documented Ostwald ripening. In addition to these capillary effects, the structure of binary-gas foams can evolve under the effect of gas flow induced by partial pressure differences, arising from heterogeneities in bubble composition. We experimentally investigate the shrinking of CO 2 -laden 2D foams exposed to air, observing a crust of tiny bubbles at the front. We derive a nonlinear diffusion model for the gas in the foam and propose a description of the whole foam as an effective, homogeneous medium, the key parameter being the gas permeability ratio across the foam’s soap films (≠1 for CO 2 /air). The effective diffusivity of the gas in the foam emerges from the coupling between foam structure and gas transport across soap films. We extrapolate it for various permeability ratios and show that it can vary continuously between the diffusivity of the gas in the liquid and that of the gas in the atmosphere, enabling tunable gas retention and release by controlling the composition of the atmosphere.}, archive = {J_PNAS}, author = {Aprili, Cécile and Coupier, Gwennou and Lorenceau, Élise and Dollet, Benjamin}, doi = {10.1073/pnas.2504617122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2504617122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tunable effective diffusion of CO2 in aqueous foam}, volume = {122}, year = {2025}, }
• (2025). Thermodynamics of calcium binding to heparin: Implications of solvation and water structuring for polysaccharide biofunctions. PNAS, 122(35), e2504348122. (www)

  @article{ , abstract = {Heparan sulfates are found in all animal tissues and have essential roles in living systems. This family of biomacromolecules modulates binding to calcium ions (Ca 2+ ) in low free energy reactions that influence biochemical processes from cell signaling and anticoagulant efficacy to biomineralization. Despite their ubiquity, the thermodynamic basis for how heparans and similarly functionalized biomolecules regulate Ca 2+ interactions is not yet established. Using heparosan (Control) and heparins with different positions of sulfate groups, we quantify how SO 3 − and COO − content and SO 3 − position modulate Ca 2+ binding by isothermal titration calorimetry. The free energy of all heparin-Ca 2+ interactions (Δ G rxn ) is dominated by entropic contributions due to favorable water release from polar, hydrophilic groups. Heparin with both sulfate esters ( O -SO 3 − ) and sulfamides ( N -SO 3 − ) has the strongest binding to Ca 2+ compared to heparosan and to heparin with only O -SO 3 − groups (~3X). By linking Ca 2+ binding thermodynamics to measurements of the interfacial energy for calcite (CaCO 3 ) crystallization onto polysaccharides, we show molecule-specific differences in nucleation rate can be explained by differences in water structuring during Ca 2+ interactions. A large entropic term (- T Δ S rxn ) upon Ca 2+ –polysaccharide binding correlates with high interfacial energy to CaCO 3 nucleation. Combining our measurements with literature values indicates many Ca 2+ –polysaccharide interactions have a shared thermodynamic signature. The resulting enthalpy–entropy compensation relationship suggests these interactions are generally dominated by water restructuring involving few conformational changes, distinct from Ca 2+ –protein binding. Our findings quantify the thermodynamic origins of heparin-specific interactions with Ca 2+ and demonstrate the contributions of solvation and functional group position during biomacromolecule-mediated ion regulation.}, archive = {J_PNAS}, author = {Knight, Brenna M. and Gallagher, Connor M. B. and Schulz, Michael D. and Edgar, Kevin J. and McNaul, Caylyn D. and McCutchin, Christina A. and Dove, Patricia M.}, doi = {10.1073/pnas.2504348122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2504348122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Thermodynamics of calcium binding to heparin: Implications of solvation and water structuring for polysaccharide biofunctions}, volume = {122}, year = {2025}, }
• (2025). Early-life infectious disease exposure, the “hygiene hypothesis,” and lifespan: Evidence from hookworm disease. PNAS, 122(35), e2504265122. (www)

  @article{ , abstract = {Exposure to infectious disease in early life may have long-term ramifications for health and lifespan. However, reducing pathogen exposure may not be uniformly beneficial. The rise of modern sanitation and reduction of infectious diseases has been implicated in increasing levels of allergy and immune dysregulation: termed, the “hygiene hypothesis.” This study leverages quasi-experimental variation from combining precampaign hookworm exposure with the Rockefeller Sanitary Commission’s deworming campaign in the early 20th century to rigorously examine the impacts of childhood hookworm exposure on adult lifespan and morbidity. Findings show deworming before age five leads to 2.5 additional months of life in a large sample of adult death records. Further, decreasing hookworm exposure is related to improvements in biomarkers for inflammation and skin-tested allergies, in contrast to predictions of the “hygiene hypothesis.” Placebo tests using health outcomes that should not be affected by deworming do not show similar patterns. Overall, childhood deworming leads to improvements in morbidity and lifespan decades later.}, archive = {J_PNAS}, author = {Lawton, Ralph}, doi = {10.1073/pnas.2504265122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2504265122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Early-life infectious disease exposure, the “hygiene hypothesis,” and lifespan: Evidence from hookworm disease}, volume = {122}, year = {2025}, }
• (2025). Color-neutral and reversible tissue transparency enables longitudinal deep-tissue imaging in live mice. PNAS, 122(35), e2504264122. (www)

  @article{ , abstract = {Light scattering in biological tissue presents a significant challenge for deep in vivo imaging. Our previous work demonstrated the ability to achieve optical transparency in live mice using intensely absorbing dye molecules, which created transparency in the red spectrum while blocking shorter-wavelength photons. In this paper, we extend this capability to achieve optical transparency across the entire visible spectrum by employing molecules with strong absorption in the ultraviolet spectrum and sharp absorption edges that rapidly decline upon entering the visible spectrum. This color-neutral and reversible tissue transparency method enables optical transparency for imaging commonly used fluorophores in the green and yellow spectra. Notably, this approach facilitates tissue transparency for structural and functional imaging of the live mouse brain labeled with yellow fluorescent protein and GCaMP through the scalp and skull. We show that this method enables longitudinal imaging of the same brain regions in awake mice over multiple days during development. Histological analyses of the skin and systemic toxicology studies indicate minimal acute or chronic damage to the skin or body using this approach. This color-neutral and reversible tissue transparency technique opens opportunities for noninvasive deep-tissue optical imaging, enabling long-term visualization of cellular structures and dynamic activity with high spatiotemporal resolution and chronic tracking capabilities.}, archive = {J_PNAS}, author = {Keck, Carl H. C. and Schmidt, Elizabeth L. and Roth, Richard H. and Floyd, Brendan M. and Tsai, Andy P. and Garcia, Hassler B. and Cui, Miao and Chen, Xiaoyu and Wang, Chonghe and Park, Andrew and Zhao, Su and Liao, Pinyu A. and Casey, Kerriann M. and Reineking, Wencke and Cai, Sa and Zhang, Ling-Yi and Yang, Qianru and Yuan, Lei and Baghdasaryan, Ani and Lopez, Eduardo R. and Cooper, Lauren and Cui, Han and Esquivel, Daniel and Brinson, Kenneth and Chen, Xiaoke and Wyss-Coray, Tony and Coleman, Todd P. and Brongersma, Mark L. and Bertozzi, Carolyn R. and Wang, Gordon X. and Ding, Jun B. and Hong, Guosong}, doi = {10.1073/pnas.2504264122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2504264122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Color-neutral and reversible tissue transparency enables longitudinal deep-tissue imaging in live mice}, volume = {122}, year = {2025}, }
• (2025). Interfacial electroneutrality controls transport of asymmetric salts through charge-patterned mosaic membranes. PNAS, 122(35), e2504069122. (www)

  @article{ , abstract = {Membranes that selectively enhance target solute permeation while rejecting competing species are essential for precision separations. This study introduces charge-patterned mosaic membranes (CMMs) that selectively transport divalent asymmetric salts by leveraging a net-neutral membrane–solution interface. This mechanism, dictated by the charge ratio of positive and negative domains on the membrane surface and the balance of cations and anions in the salt, is supported by analytical, numerical, and experimental results. Analytical solutions identified cationic domain coverages ( f + ) of 33%, 50%, and 66% as optimal for the selective transport of +2:−1 salts, +1:−1 salts, and +1:−2 salts, respectively, under conditions where the pattern size ( L ) is significantly larger than the Debye length. Numerical simulations and experiments using CMMs with alternating charged-stripes inkjet-printed onto nanostructure copolymer substrates confirmed these findings. By varying stripe widths to control f + , pressure-driven filtration experiments demonstrated selective enrichment of MgCl 2 and K 2 SO 4 at the predicted f + values, with deviations from these values leading to salt rejection. These results highlight the pivotal role of a net-neutral interface in enabling asymmetric salt enrichment. This study positions CMMs as a versatile platform for tuning ion selectivity, addressing challenges in resource recovery, water treatment, and precision separations.}, archive = {J_PNAS}, author = {Gao, Feng and Hoffman, John R. and Xu, Jialing and Ievlev, Anton V. and Whitmer, Jonathan K. and Phillip, William A.}, doi = {10.1073/pnas.2504069122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2504069122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Interfacial electroneutrality controls transport of asymmetric salts through charge-patterned mosaic membranes}, volume = {122}, year = {2025}, }
• (2025). G-quadruplexes as a source of vulnerability in BRCA2-deficient granule cell progenitors and medulloblastoma. PNAS, 122(35), e2503872122. (www)

  @article{ , abstract = {Biallelic pathogenic variants in the essential DNA repair gene BRCA2 cause Fanconi anemia complementation group D1. Patients in this group are highly prone to develop embryonal tumors, most commonly medulloblastoma arising from the cerebellar granule cell progenitors (GCPs). GCPs undergo high proliferation in the postnatal cerebellum under Sonic Hedgehog (SHH) activation, but the type of DNA lesions that require the function of the BRCA2 to prevent tumorigenesis remains unknown. To identify such lesions, we assessed both GCP neurodevelopment and tumor formation using a mouse model with deletion of exons three and four of Brca2 in the central nervous system, coupled with global Trp53 loss. Brca2 Δex3-4 ;Trp53 −/− animals developed SHH subgroup medulloblastomas with complete penetrance. Whole-genome sequencing of the tumors identified structural variants with breakpoints enriched in areas overlapping putative G-quadruplexes (G4s). Brca2 -deficient GCPs exhibited decreased replication speed in the presence of the G4-stabilizer pyridostatin. Pif1 helicase, which resolves G4s during replication, was highly upregulated in tumors, and Pif1 knockout in primary medulloblastoma tumor cells resulted in increased genome instability upon pyridostatin treatment. These data suggest that G4s may represent sites prone to replication stalling in highly proliferative GCPs and without BRCA2, G4s become a source of genome instability. Tumor cells upregulate G4-resolving helicases to facilitate rapid proliferation through G4s highlighting PIF1 helicase as a potential therapeutic target for treatment of BRCA2-deficient medulloblastomas.}, archive = {J_PNAS}, author = {Keahi, Danielle L. and Sanders, Mathijs A. and Paul, Matthew R. and Webster, Andrew L. H. and Fang, Yin and Wiley, Tom F. and Shalaby, Samer and Carroll, Thomas S. and Chandrasekharappa, Settara C. and Sandoval-Garcia, Carolina and MacMillan, Margaret L. and Wagner, John E. and Hatten, Mary E. and Smogorzewska, Agata}, doi = {10.1073/pnas.2503872122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2503872122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {G-quadruplexes as a source of vulnerability in BRCA2-deficient granule cell progenitors and medulloblastoma}, volume = {122}, year = {2025}, }
• (2025). Quantum metric–induced giant and reversible nonreciprocal transport phenomena in chiral loop-current phases of kagome metals. PNAS, 122(35), e2503645122. (www)

  @article{ , abstract = {Emergence of quantum orders with nontrivial quantum geometric properties in metals represent central issues in condensed matter physics. In this context, recently discovered chiral loop-current order in kagome metals has garnered significant attention. Particularly noteworthy is the giant electrical magnetochiral anisotropy (eMChA) observed in CsV 3 Sb 5 , which provides compelling evidence for the simultaneous breaking of time-reversal and inversion symmetries. However, the origin of the eMChA and its fundamental connection to the loop-current remain highly elusive, as the loop-current itself preserves inversion symmetry. Here, we demonstrate that the loop-current phase breaks inversion symmetry in the presence of the experimentally observed stripe charge-density wave, leading to finite eMChA coefficient γ eM . In this mechanism, γ eM is proportional to the product of the loop-current-induced orbital magnetization, M orb 0 , and the lifetime of conduction electrons, τ . Therefore, γ eM is reversible by the magnetic fields, and it takes large value in kagome metals with τ v Fermi ≫ a 0 (=lattice constant). Surprisingly, the quantum metric, which defines a fundamental geometric aspect of Bloch wavefunctions, acquires significant momentum dependence in the loop-current phase, resulting in a dramatic enhancement of eMChA by ∼100 times. This research not only clarifies the fundamental symmetry-breaking states in kagome metals but also opens a path for exploring quantum metric–induced phenomena arising from exotic quantum phase transitions in various metals.}, archive = {J_PNAS}, author = {Tazai, Rina and Yamakawa, Youichi and Morimoto, Takahiro and Kontani, Hiroshi}, doi = {10.1073/pnas.2503645122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2503645122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantum metric–induced giant and reversible nonreciprocal transport phenomena in chiral loop-current phases of kagome metals}, volume = {122}, year = {2025}, }
• (2025). SHP2 genetic variants in NSML-associated RASopathies disrupt the PZR–IRX transcription factor signaling axis. PNAS, 122(35), e2503631122. (www)

  @article{ , abstract = {Noonan syndrome with multiple lentigines (NSML) is a rare autosomal dominant disorder caused by mutations in PTPN11 (protein tyrosine phosphatase nonreceptor type 11) which encodes for the protein tyrosine phosphatase, SHP2. Approximately 85% of NSML patients develop hypertrophic cardiomyopathy (HCM). Here, we show that SHP2 is recruited to tyrosyl phosphorylated protein-zero related (PZR) in NSML mice. This recruitment is required for the Iroquois homeobox (IRX) transcription factors 3 and 5 to suppress BMP10 which negatively regulates postnatal cardiac growth. The protein expression of IRX3 and IRX5 was elevated in hypertrophied NSML hearts. IRX3 and IRX5 upregulation was rescued in NSML mice harboring a knock-in mutation of PZR that fails to become tyrosyl phosphorylated and recruit SHP2. NSML mice treated with low-dose dasatinib also exhibited normalized IRX3 and IRX5 expression levels. Consistent with this, BMP10 expression levels were reduced in NSML mice and rescued in PZR tyrosyl phosphorylation-deficient and low-dose dasatinib-treated NSML mice. A crystal structure of the tandem SH2 domains of SHP2 bound to tyrosyl phosphorylated PZR reveals that recruitment constrains the open SHP2 conformation to facilitate cellular-Src (c-Src) binding. Disruption of c-Src binding to SHP2 abolished IRX activation and failure to suppress BMP10. Hence, NSML-associated SHP2 genetic variants disrupt IRX transcription factor signaling to BMP10, implicating this axis as a target for RASopathy-associated HCM.}, archive = {J_PNAS}, author = {Perla, Sravan and Stiegler, Amy L. and Yi, Jae-Sung and Enyenihi, Liz and Zhang, Lei and Riaz, Muhammad and An, Elvira and Qyang, Yibing and Boggon, Titus J. and Bennett, Anton M.}, doi = {10.1073/pnas.2503631122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2503631122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SHP2 genetic variants in NSML-associated RASopathies disrupt the PZR–IRX transcription factor signaling axis}, volume = {122}, year = {2025}, }
• (2025). Structure of the thomasclavelia ramosa immunoglobulin a protease reveals a modular and minimizable architecture distinct from other immunoglobulin a proteases. PNAS, 122(35), e2503549122. (www)

  @article{ , abstract = {Immunoglobulin A proteases (IgAPs) are a diverse group of enzymes secreted from bacteria that inhabit human mucosal tissues. These enzymes have convergently evolved to cleave human immunoglobulin A as a means of modulating and evading host immunity. Only two of three known IgAP families have been biochemically characterized beyond their initial discovery. Here, we show using solution-scattering, steady-state kinetic, and crystallographic approaches that the protease from Thomasclavelia ramosa , representing the uncharacterized third family, has a truly modular and minimizable protein architecture. This analysis also revealed a unique metal-associated domain that likely functions as a molecular spacer and generated a working hypothesis detailing the structural mechanism behind the enzyme’s high substrate specificity. Our work provides an in-depth biochemical account of this IgAP family, paving the way for advancing clinically relevant IgAP-related research and our understanding of IgAPs as a whole.}, archive = {J_PNAS}, author = {Tran, Norman and Frenette, Aaron and Holyoak, Todd}, doi = {10.1073/pnas.2503549122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2503549122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure of the thomasclavelia ramosa immunoglobulin a protease reveals a modular and minimizable architecture distinct from other immunoglobulin a proteases}, volume = {122}, year = {2025}, }
• (2025). Mass support for conserving 30% of the earth by 2030: Experimental evidence from five continents. PNAS, 122(35), e2503355122. (www)

  @article{ , abstract = {Rapid global expansion of protected areas is critical for safeguarding biodiversity but depends on political action for successful implementation. Following widespread ratification of the Kunming-Montreal Global Biodiversity Framework, an unprecedented increase in area-based conservation is required to reach its target of conserving 30% of land, waters, and seas by 2030. These expansions prompt difficult trade-offs between conservation, social, and economic interests. A key factor in securing legitimacy and practical feasibility for expansion regimes is understanding what factors determine public support for them. Using survey and experimental data, we show that in eight countries across five continents, public opinion is 1) strongly in favor of the “30-by-30”-target and 2) highly consistent regarding policy priorities for the design of international- and domestic-level expansion regimes. We find that for international-level policy regimes, support increases with protection responsibilities equally split between countries, rich countries bearing higher costs, more countries actively cooperating, and placement trade not allowed. For domestic-level policy regimes, support generally increases when nature values are prioritized over social or economic values and, in many countries, decreases when costs are borne by a general tax increase, parks are managed by private companies, and when access to parks is restricted. Together, these results demonstrate how protected area expansion policies can be shaped to facilitate reaching 30% protected areas by 2030.}, archive = {J_PNAS}, author = {Michaelsen, Patrik and Sundström, Aksel and Jagers, Sverker C.}, doi = {10.1073/pnas.2503355122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2503355122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mass support for conserving 30% of the earth by 2030: Experimental evidence from five continents}, volume = {122}, year = {2025}, }
• (2025). Broad neutralizing antibody response of a monomeric spike–based SARS-CoV-2 bivalent vaccine against diverse variants. PNAS, 122(35), e2503254122. (www)

  @article{ , abstract = {severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) bivalent vaccines show potential against variants but lack a full understanding of the immunological mechanisms that drive broadly neutralizing antibodies (bnAbs). This study explored the immunogenicity of a bivalent vaccine in rhesus macaques, containing spike (S) proteins from the prototype (S prototype ) and chimeric S protein (S 1628x ). The vaccine induced bnAbs against multiple variants, including challenging subvariants like EG.1, BA.2.86, and JN.1. The monomeric S protein exposed less accessible regions within the receptor-binding domain (RBD) “inner face” and “NTD face” and subdomains 1, eliciting a diverse array of bnAbs against various Omicron subvariants. Notably, antibodies targeting the conserved RBD inner face, such as 4A5, showed potent neutralization across all tested variants. Structural analyses provide insights into the broad protectiveness of these vaccine-elicited nAbs. This study underscores the potential of bivalent vaccines with monomeric spike proteins to confer broad-spectrum immunity, offering a promising direction for future SARS-CoV-2 universal vaccine design.}, archive = {J_PNAS}, author = {Wang, Siling and Sun, Hui and Wang, Yizhen and Wang, Zikang and Yuan, Lunzhi and Guo, Huilin and Gao, Jiahua and Lan, Miaolin and Wu, Yangtao and Shang, Huixian and Chen, Xiuting and Chen, Zheng and Hu, Jiayi and Tang, Zimin and Wen, Guiping and Ying, Dong and Liu, Chang and Jiang, Yanan and Su, Jinfu and Lin, Min and Wu, Ting and Li, Shaowei and Zhang, Tianying and Zhang, Jun and Guan, Yi and Xia, Ningshao and Yuan, Quan and Zheng, Qingbing and Zhang, Yali and Zheng, Zizheng}, doi = {10.1073/pnas.2503254122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2503254122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Broad neutralizing antibody response of a monomeric spike–based SARS-CoV-2 bivalent vaccine against diverse variants}, volume = {122}, year = {2025}, }
• (2025). An information-theoretic foreshadowing of mathematicians’ sudden insights. PNAS, 122(35), e2502791122. (www)

  @article{ , abstract = {The “eureka” insights that drive progress in science and mathematics remain shrouded in mystery. Sudden, unexpected, appearing like “flashes of lightning”, these insights have the hallmarks of critical transitions in complex systems. Here, zooming in on mathematicians working on proofs in their own departments, we show that sudden insights are anticipated by a system-agnostic, information-theoretic early warning signal. Using dense behavioral recordings of mathematicians’ moment-to-moment activity, we find that their blackboard interactions (e.g., writing, gesturing; N = 4 , 653 ) became increasingly unpredictable before an insight, analogous to the critical fluctuations that anticipate transitions in physical and ecological systems. We explore analytically when this early warning signal applies to varied systems with discrete, symbolic dynamics. While bibliometric analyses offer a zoomed-out perspective on innovation, publications are a coarse-grained record of individuals’ insights. Explaining the sudden insights of innovators, from scientists to sculptors, requires attending to the local, distributed systems of their intellectual activity.}, archive = {J_PNAS}, author = {Tabatabaeian, Shadab and O’bi, Artemisia and Landy, David and Marghetis, Tyler}, doi = {10.1073/pnas.2502791122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2502791122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An information-theoretic foreshadowing of mathematicians’ sudden insights}, volume = {122}, year = {2025}, }
• (2025). CryoEM structure of ALK2:BMP6 reveals distinct mechanism that allow ALK2 to interact with both BMP and activin ligands. PNAS, 122(35), e2502788122. (www)

  @article{ , abstract = {Ligands in the transforming growth factor β (TGF-β) family [activins, Bone Morphogenetic Proteins (BMPs), and TGF-βs] signal by bringing together two type I and two type II receptors. Activin receptor-like kinase-2 (ALK2) is the only type I receptor among the seven TGF-β type I receptors that interacts with both activin and BMP ligands. With BMPs, ALK2 acts as a signaling receptor to activate small mothers against decapentaplegic 1 (SMAD1)/5/8 signaling. Alternatively, with activins, such as Activin A (ActA), ALK2 forms nonsignaling complexes that negatively regulate ALK2 and ActA signaling. To gain insight into how ALK2 interacts with two distinct classes of ligands, we resolved the cryoelectron microscopy structure of ALK2 in complex with the type II receptor, ActRIIB, and the ligand, BMP6, in parallel with the corresponding structure with ALK3 for direct comparison. These structures demonstrate that ALK2 and ALK3 utilize different mechanisms to interact with BMP6 at the wrist interface, with ALK2 relying on BMP6 glycosylation and ALK3 relying on a salt bridge. Modeling of ALK2:ActA reveals that binding relies on ActA’s fingertip region, mirroring the interaction of ActA with its other receptor, ALK4. Our results demonstrate that ALK2 is a “hybrid” receptor that incorporates features of BMP type I receptors such as ALK3 at the wrist interface and an activin type I receptor such as ALK4 at the fingertip.}, archive = {J_PNAS}, author = {Goebel, Erich J. and Aykul, Senem and Hom, Warren W. and Saotome, Kei and Economides, Aris N. and Franklin, Matthew C. and Idone, Vincent J.}, doi = {10.1073/pnas.2502788122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2502788122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CryoEM structure of ALK2:BMP6 reveals distinct mechanism that allow ALK2 to interact with both BMP and activin ligands}, volume = {122}, year = {2025}, }
• (2025). Magnetic decoupling as a proofreading strategy for high-yield, time-efficient microscale self-assembly. PNAS, 122(35), e2502361122. (www)

  @article{ , abstract = {Life thrives due to its remarkable ability to create complex structures through the self-assembly of proteins, nucleic acids, and other biomolecules. Achieving such complex assemblies with the same level of fidelity, reproducibility, and advanced functionality in synthetic systems, however, has remained a grand challenge. One outstanding problem is the presence of parasitic products and long-lived intermediate states that slow the reaction process and limit the yield of the final product. Biology overcomes this challenge by proofreading to recognize and disassemble parasitic products. Such local checks, however, are currently difficult to implement in available self-assembly platforms. Here, we overcome this challenge by implementing a proofreading mechanism in a self-assembly platform. Specifically, we design intermediate states that strongly couple to an external force but a final product that is decoupled and thus highly stable to external driving, such that application of external forces selectively dissociates parasitic products. To implement this idea, we introduce lithographically patterned magnetic dipoles and an applied magnetic field to drive an assembly process similar to thermal self-assembly, but with additional controls. By applying patterns of magnetic driving that selectively destabilize parasitic states, we effectively implement a proofreading strategy to enable high-yield, time-efficient self-assembly. This realization of a general proofreading mechanism bridges the gap between artificial and biological self-assembly, paving the way for advanced self-assembled materials, with applications in next generation responsive materials, biomimetic devices, and microscale machines.}, archive = {J_PNAS}, author = {Liang, Zexi and Lim, Melody Xuan and Zhu, Qian-Ze and Mottes, Francesco and Kim, Jason Z. and Guttieres, Livia and Smart, Conrad and Pearson, Tanner and Du, Chrisy Xiyu and Brenner, Michael and McEuen, Paul and Cohen, Itai}, doi = {10.1073/pnas.2502361122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2502361122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Magnetic decoupling as a proofreading strategy for high-yield, time-efficient microscale self-assembly}, volume = {122}, year = {2025}, }
• (2025). Universal vortex formation time of flapping flight. PNAS, 122(35), e2501511122. (www)

  @article{ , abstract = {Biological flyers periodically flap their appendages to generate aerodynamic forces. Extensive studies have made significant progress in explaining the physics behind their propulsion in cruising by developing scaling laws of their flight kinematics. Notably Strouhal number ( St ; ratio of flapping frequency times stroke amplitude to cruising speed) has been found to fall in a narrow range for animal cruising flights. However, St exhibits strong correlation to flight conditions; as such, its universality has been confined to preferred flight conditions. Since the leading-edge vortices (LEV) on flapping appendages generate the majority of propulsive forces, here we take the perspective of LEV circulation maximization, which generalizes the dimensionless vortex formation time to flapping flight. The generalized vortex formation time scales the duration of vorticity injection with the rate of total vorticity growth inside the LEV and the maximum vorticity allowed inside it. By comparing the new scaling with St of previously reported animal cruising flights of 28 species, we show that the generalized vortex formation time is consistent across different animals and cruising locomotion, independent of flight conditions. This finding advances the fundamental principles underlying the complex wing kinematics of biological flyers and highlights a unifying framework for understanding biolocomotion.}, archive = {J_PNAS}, author = {Sun, Yukun and Palmer, Emily and Dougherty, Christopher and Sbrocco, Cade and Shih, Aspen and Shields, Jena and Roh, Chris}, doi = {10.1073/pnas.2501511122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2501511122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Universal vortex formation time of flapping flight}, volume = {122}, year = {2025}, }
• (2025). Mid-devonian ocean oxygenation enabled the expansion of animals into deeper-water habitats. PNAS, 122(35), e2501342122. (www)

  @article{ , abstract = {The oxygenation history of Earth’s surface environments has had a profound influence on the ecology and evolution of metazoan life. It was traditionally thought that the Neoproterozoic Oxygenation Event enabled the origin of animals in marine environments, followed by their persistence in aerobic marine habitats ever since. However, recent studies of redox proxies (e.g., Fe, Mo, Ce, I) have suggested that low dissolved oxygen levels persisted in the deep ocean until the Late Devonian, when the first heavily wooded ligniophyte forests raised atmospheric O 2 to modern levels. Here, we present a Paleozoic redox proxy record based on selenium enrichments and isotope ratios in fine-grained siliciclastic sediments. Our data reveal transient oxygenation of bottom waters around the Ediacaran–Cambrian boundary, followed by predominantly anoxic deep-water conditions through the Early Devonian (419 to 393 Ma). In the Middle Devonian (393 to 382 Ma), our data document the onset of permanent deep-ocean oxygenation, coincident with the spread of woody biomass across terrestrial landscapes. This episode is concurrent with the ecological occupation and evolutionary radiation of large active invertebrate and vertebrate organisms in deeper oceanic infaunal and epifaunal habitats, suggesting that the burial of recalcitrant wood from the first forests sequestered organic carbon, increased deep marine oxygen levels, and was ultimately responsible for the “mid-Paleozoic marine revolution.”}, archive = {J_PNAS}, author = {Bubphamanee, Kunmanee and Kipp, Michael A. and Meixnerová, Jana and Stüeken, Eva E. and Ivany, Linda C. and Bartholomew, Alexander J. and Algeo, Thomas J. and Brocks, Jochen J. and Dahl, Tais W. and Kinsley, Jordan and Tissot, François L. H. and Buick, Roger}, doi = {10.1073/pnas.2501342122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2501342122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mid-devonian ocean oxygenation enabled the expansion of animals into deeper-water habitats}, volume = {122}, year = {2025}, }
• (2025). Substantial reductions in black carbon from both fossil fuels and biomass burning during china’s clean air action. PNAS, 122(35), e2500843122. (www)

  @article{ , abstract = {Black carbon (BC) aerosols exacerbate air pollution and climate warming, but their climatic impacts and sources are poorly constrained by bottom–up emission inventories (EIs). China’s Clean Air Action (CAA), which was launched in 2013, provides an excellent opportunity for investigating interannual variations in source contributions and validate the accuracy of EIs. Here, we present an 11-y (2008–2018) record of the BC concentration and its source-diagnostic radiocarbon ( 14 C) and stable carbon isotope ( 13 C) signatures at a receptor site in the Pearl River Delta (PRD) region, South China. The results revealed that the implementation of the CAA (2014–2018) led to a 41% reduction in the BC concentration compared with that in the preaction period (2008–2013). There is a large and systemic discrepancy over the whole period in the contribution of biomass burning to BC in South China between predictions from technology-based EIs (4 to 9%) and these source-diagnostic dual-isotopic fingerprints of actual ambient aerosols (21 to 32%). Observational constraints by source-diagnostic δ 13 C/Δ 14 C isotope measurements revealed that the reduction in biomass burning contributed 22% to the decrease in BC associated with the CAA, whereas predictions from EIs assigned a much smaller fraction. These results emphasize the need for observation-based source diagnostics of changing BC emission sources. Detailed source apportionment using independent δ 13 C/Δ 14 C isotope methodology is crucial for refining air pollution control strategies and improving the accuracy of models used for assessing the air quality and climate effects of BC in China and elsewhere.}, archive = {J_PNAS}, author = {Liu, Junwen and Jiang, Fan and Wang, Qiongqiong and Zhang, Gan and Li, Jun and Chen, Weihua and Ding, Ping and Zhu, Sanyuan and Cheng, Zhineng and Zhang, Xiangyun and Sha, Qinge and Huang, Zhijiong and Yuan, Xin and Zheng, Junyu and Zhang, Yanlin and Yan, Caiqing and Tian, Chongguo and Chen, Yingjun and Yu, Jian Zhen and Gustafsson, Örjan}, doi = {10.1073/pnas.2500843122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2500843122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Substantial reductions in black carbon from both fossil fuels and biomass burning during china’s clean air action}, volume = {122}, year = {2025}, }
• (2025). Community detection for directed networks revisited using bimodularity. PNAS, 122(35), e2500571122. (www)

  @article{ , abstract = {Community structure is a key feature omnipresent in real-world network data. Plethora of methods have been proposed to reveal subsets of densely interconnected nodes using criteria such as the modularity index. These approaches have been successful for undirected graphs but directed edge information has not yet been dealt with in a satisfactory way. Here, we revisit the concept of directed communities as a mapping between sending and receiving communities. This translates into a definition that we term bimodularity. Using convex relaxation, bimodularity can be optimized with the singular value decomposition of the directed modularity matrix. Subsequently, we propose an edge-based clustering approach to reveal the directed communities including their mappings. The feasibility of the framework is illustrated on a synthetic model and further applied to the neuronal wiring diagram of the Caenorhabditis elegans , for which it yields meaningful feedforward loops of the head and body motion systems. This framework sets the ground for the understanding and detection of community structures in directed networks.}, archive = {J_PNAS}, author = {Cionca, Alexandre and Chan, Chun Hei Michael and Van De Ville, Dimitri}, doi = {10.1073/pnas.2500571122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2500571122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Community detection for directed networks revisited using bimodularity}, volume = {122}, year = {2025}, }
• (2025). Cellular cartography reveals mouse prostate organization and determinants of castration resistance. PNAS, 122(35), e2427116122. (www)

  @article{ , abstract = {Inadequate response to androgen deprivation therapy (ADT) frequently arises in prostate cancer, driven by cellular mechanisms that remain poorly understood. Here, we integrated single-cell RNA sequencing, single-cell multiomics, and spatial transcriptomics to define the transcriptional, epigenetic, and spatial basis of cell identity and castration response in the mouse prostate. Leveraging these data along with a meta-analysis of human prostates and prostate cancer (PCa), we identified cellular orthologs and key determinants of ADT response and resistance. Our findings reveal that mouse prostates harbor lobe-specific luminal epithelial cell types distinguished by unique gene regulatory modules and anatomically defined androgen-responsive transcriptional programs, indicative of divergent developmental origins. Androgen-insensitive, stem-like epithelial populations—resembling human club and hillock cells—are notably enriched in the urethra and ventral prostate but are rare in other lobes. Within the ventral prostate, we also uncovered two additional androgen-responsive luminal epithelial cell types, marked by Pbsn or Spink1 expression, which align with human luminal subsets and may define the origin of distinct PCa subtypes. Castration profoundly reshaped luminal epithelial transcriptomes, with castration-resistant luminal epithelial cells activating stress-responsive and stemness programs. These transcriptional signatures are enriched in tumor cells from ADT-treated and castration-resistant PCa patients, underscoring their likely role in driving treatment resistance. Temporal tracking of cells will precisely map disease-associated cellular transitions, and our technical framework facilitates such interrogations. Collectively, our comprehensive cellular atlas of the mouse prostate illuminates the importance of lobe-specific contexts for PCa modeling and reveals potential therapeutic targets to counter castration resistance.}, archive = {J_PNAS}, author = {Cho, Hanbyul and Zhang, Yuping and Tien, Jean C. and Mannan, Rahul and Luo, Jie and Narayanan, Sathiya Pandi and Mahapatra, Somnath and Hu, Jing and Shelley, Greg and Cruz, Gabriel and Shahine, Miriam and Wang, Lisha and Su, Fengyun and Wang, Rui and Cao, Xuhong and Dhanasekaran, Saravana Mohan and Keller, Evan T. and Pitchiaya, Sethuramasundaram and Chinnaiyan, Arul M.}, doi = {10.1073/pnas.2427116122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2427116122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cellular cartography reveals mouse prostate organization and determinants of castration resistance}, volume = {122}, year = {2025}, }
• (2025). Rising global temperatures reduce soil microbial diversity over the long term. PNAS, 122(35), e2426200122. (www)

  @article{ , abstract = {Soil microbial diversity is crucial to sustaining ecosystem productivity and improving carbon sequestration. Global temperature continues to rise, but how climate warming affects microbial diversity and its capacity to sequester soil organic carbon (SOC) remains uncertain. Here, by conducting a global meta-analysis with 251 paired observations from 102 studies, we showed that, on average, warming reduced bacterial and fungal diversity (measured by richness and Shannon index) by 16.0 and 19.7%, respectively, and SOC by 18.1%. The negative responses of both soil bacterial and fungal diversity to warming became more pronounced with increasing warming magnitude, experimental duration, and decreasing soil nitrogen availability. Under the worst-case climate warming scenario (2010 to 2070, 3.4 increase in °C), soil bacterial diversity and fungal diversity are projected to reduce by 56% and 81%, respectively, over 60 y. Importantly, in addition to the direct impact of warming on SOC, warming-induced declines in microbial diversity also contributed to SOC losses. We highlight that prolonged warming could substantially reduce soil microbial diversity and decrease SOC sequestration, accelerating future warming and underscoring the urgent need for decisive actions to mitigate global climate change.}, archive = {J_PNAS}, author = {Sun, Yuan and Chen, Han Y. H and Chen, Xin and Hisano, Masumi and Chen, Xinli and Reich, Peter B.}, doi = {10.1073/pnas.2426200122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2426200122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rising global temperatures reduce soil microbial diversity over the long term}, volume = {122}, year = {2025}, }
• (2025). Ovarian germline stem cell dedifferentiation is cytoneme dependent. PNAS, 122(35), e2426145122. (www)

  @article{ , abstract = {Progenitor cell dedifferentiation is important for stem cell maintenance during tissue repair and age-related stem cell decline. Here, we use the Drosophila ovary as a model to study the role of cytonemes in bone morphogenic protein (BMP) signaling–directed germline stem cell (GSC) maintenance and dedifferentiation of germ cells to GSCs. We provide evidence that differentiating germ cell cysts extend longer cytonemes that are more polarized toward the niche during dedifferentiation to reactivate BMP signaling. The presence of additional somatic cells in the niche is associated with a failure of germ cell dedifferentiation, consistent with the formation of a physical barrier to cytoneme–niche contact and outcompetition of germ cells for BMP. Using BMP beads in vitro, we show that these are sufficient to induce cytoneme-dependent contacts in Drosophila tissue culture cells. We demonstrate that the Enabled (Ena) actin polymerase is localized to the tips of germ cell cytonemes and is necessary for robust cytoneme formation, as its mislocalization reduces the frequency, length, and directionality of cytonemes. During homeostasis, specifically perturbing cytoneme function through Ena mislocalization impairs GSC fitness by reducing GSC BMP signaling and niche occupancy. Disrupting cytonemes by targeting Ena during dedifferentiation reduces germ cell BMP responsiveness and the ability of differentiating cysts to dedifferentiate. Overall, our results provide evidence that cytonemes play a fundamental role in establishing polarized signaling and niche occupancy during stem cell maintenance and dedifferentiation.}, archive = {J_PNAS}, author = {Sutcliffe, Catherine and Nandy, Nabarun and Revici, Raluca and Johnson, Heather and Habib, Shukry J. and Ashe, Hilary L. and Wilcockson, Scott G.}, doi = {10.1073/pnas.2426145122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2426145122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ovarian germline stem cell dedifferentiation is cytoneme dependent}, volume = {122}, year = {2025}, }
• (2025). A theoretical framework for scaling ecological niches from individuals to species. PNAS, 122(35), e2425582122. (www)

  @article{ , abstract = {The niche is a key concept that unifies ecology and evolutionary biology. However, empirical and theoretical treatments of the niche are mostly performed at the species level, neglecting individuals as important units of ecological and evolutionary processes. So far, a formal mathematical link between individual-level niches and higher organismal-level niches has been lacking, hampering the unification of ecological theories and more accurate forecasts of biodiversity change. To fill in this gap, we propose a bottom–up approach to derive population and higher organismal-level niches from individual niches. We demonstrate the power of our framework by showing that 1) the statistical properties of higher organismal-level niches (e.g., niche breadth, skewness, etc.) can be partitioned into individual contributions and 2) the species-level niche shifts can be estimated by tracing the responses of individuals. By using individual-level GPS (Global Positioning System) tracking data from three different species, we show that climate change could have contrasting consequences on population-level niche shift depending on individual niche compositions. Our method paves the way for a unifying niche theory and enables mechanistic assessments of organism–environment relationships across organismal scales.}, archive = {J_PNAS}, author = {Lu, Muyang and Yanco, Scott W. and Carlson, Ben S. and Winner, Kevin and Cohen, Jeremy M. and Ellis-Soto, Diego and Sharma, Shubhi and Rogers, Will and Jetz, Walter}, doi = {10.1073/pnas.2425582122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2425582122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A theoretical framework for scaling ecological niches from individuals to species}, volume = {122}, year = {2025}, }
• (2025). De novo rates of a trypanosoma-resistant mutation in two human populations. PNAS, 122(35), e2424538122. (www)

  @article{ , abstract = {Mutation rates have long been measured as averages across many genomic positions. Recently, a method to measure the rates of individual mutations was applied to a narrow region in the human hemoglobin subunit beta ( HBB ) gene containing the site of the hemoglobin S (HbS) mutation as well as to a paralogous hemoglobin subunit delta ( HBD ) region, in sperm samples from sub-Saharan African and northern European donors [Melamed et al ., Genome Res. 32 , 488–498 (2022)]. The HbS mutation, which protects against malaria while causing sickle-cell anemia in homozygotes, originated de novo significantly more frequently in the HBB gene in Africans compared to the other three test cases combined (the European HBB gene and the European and African HBD gene). Here, we apply this approach to the human apolipoprotein L1 ( APOL1 ) gene containing the site of the G1 1024A→G mutation, which protects against African sleeping sickness caused by Trypanosoma brucei gambiense while causing a substantially increased risk of chronic kidney disease in homozygotes. We find that the 1024A→G mutation is the mutation of highest de novo origination rate and deviates most from the genome-wide average rate for its type (A→G) compared to all other observable mutations in the region and that it originates de novo significantly more frequently in Africans than in Europeans—i.e., in the population where it is of adaptive significance. The results are unexpected given the notion that the probability of a specific mutational event is independent of its value to the organism and underscore the importance of studying mutation rates at the individual-mutation resolution.}, archive = {J_PNAS}, author = {Melamed, Daniel and Shemer, Revital and Bolotin, Evgeni and Yakass, Michael B. and Fink-Barkai, Dorit and Hiadzi, Edem K. and Skorecki, Karl L. and Livnat, Adi}, doi = {10.1073/pnas.2424538122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2424538122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {De novo rates of a trypanosoma-resistant mutation in two human populations}, volume = {122}, year = {2025}, }
• (2025). Symbiosis with and mimicry of corals were facilitated by immune gene loss and body remodeling in the pygmy seahorse. PNAS, 122(35), e2423818122. (www)

  @article{ , abstract = {A remarkable example of symbiosis involves the pygmy seahorse ( Hippocampus bargibanti ). It lives obligatorily on gorgonian corals, mimicking their polyps with pink coloration and skin protuberances. Unique for seahorses, pygmy seahorses retain juvenile paedomorphic stunted snouts, resembling the coral’s polyps. We analyzed the tiny seahorse’s genome revealing the genomic bases of several adaptations to their mutualistic life including substantial reductions in conserved noncoding elements that are associated with genes in the vicinity of those CNEs that are known to play a role in growth and metamorphosis-related pathways. Comparative RNA- and ATAC-Seq analyses during their ontogeny suggest that their stunted snout might result from craniofacial remodeling associated with hoxa2b defunctionalization. This is consistent also with findings from in situ hybridization and CRISPR experiments. Their immune system shows extremely low numbers of MHC genes and additional considerable losses of other immune-related genes. This is likely facilitated by the host coral’s antimicrobial metabolites and by the earlier evolution of male pregnancy that requires immunotolerance.}, archive = {J_PNAS}, author = {Qu, Meng and Zhang, Yingyi and Woltering, Joost and Liu, Yali and Liu, Zixuan and Wan, Shiming and Jiang, Han and Yu, Haiyan and Chen, Zelin and Wang, Xin and Zhang, Zhixin and Qin, Geng and Schneider, Ralf and Meyer, Axel and Lin, Qiang}, doi = {10.1073/pnas.2423818122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2423818122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Symbiosis with and mimicry of corals were facilitated by immune gene loss and body remodeling in the pygmy seahorse}, volume = {122}, year = {2025}, }
• (2025). Renormalization group for anderson localization on high-dimensional lattices. PNAS, 122(35), e2423763122. (www)

  @article{ , abstract = {We discuss the dependence of the critical properties of the Anderson model on the dimension d in the language of β -function and renormalization group recently introduced in Vanoni et al. [C. Vanoni et al. , Proc. Natl. Acad. Sci. U.S.A. 121 , e2401955121 (2024)] in the context of Anderson transition on random regular graphs. We show how in the delocalized region, including the transition point, the one-parameter scaling part of the β -function for the fractal dimension D 1 evolves smoothly from its d = 2 form, in which β 2 ≤ 0 , to its β ∞ ≥ 0 form, which is represented by the random regular graph (RRG) result. We show how the ϵ = d − 2 expansion and the 1 / d expansion around the RRG result can be reconciled and how the initial part of a renormalization group trajectory governed by the irrelevant exponent y depends on dimensionality. We also show how the irrelevant exponent emerges out of the high-gradient terms of expansion in the nonlinear sigma model and put forward a conjecture about a lower bound for the fractal dimension. The framework introduced here may serve as a basis for investigations of disordered many-body systems and of more general nonequilibrium quantum systems.}, archive = {J_PNAS}, author = {Altshuler, Boris L. and Kravtsov, Vladimir E. and Scardicchio, Antonello and Sierant, Piotr and Vanoni, Carlo}, doi = {10.1073/pnas.2423763122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2423763122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Renormalization group for anderson localization on high-dimensional lattices}, volume = {122}, year = {2025}, }
• (2025). Abiotic synthesis during the interaction of ferrous chloride–rich silicic fluids with marble under high-grade metamorphic conditions. PNAS, 122(35), e2423043122. (www)

  @article{ , abstract = {Ferrous chloride–rich silicic fluid and melt infiltration led to the decarbonation of dolomitic marble in the Chinese Sulu ultrahigh-pressure metamorphic terrain under temperatures ranging from 670 to 800 °C, pressures from the aragonite + albite to calcite stability fields and the oxygen fugacities between the hematite–magnetite and pyrite–pyrrhotite–magnetite buffers, resulting in the formation of olivine marble and diopsidite. The inclusions in zircons trapped during the decarbonation process suggest that the H 2 -producing reaction 3FeCl 2 (aq) + 3CaCO 3 + H 2 O = Fe 3 O 4 (magnetite) + 3CaCl 2 (aq) + 3CO 2 + H 2 occurred and that it induced magnetite-catalyzed Fischer–Tropsch-type synthesis, as indicated by the presence of whewellite, disordered carbonaceous material, CH 4 , and CO in the inclusions. The results of this study highlight the role of aqueous Fe in generating H 2 and magnetite and have far-reaching implications for carbon speciation and solubility in deep fluids and for endogenic abiotic synthesis, which may be pivotal in the prebiotic occurrence of organic compounds on Earth.}, archive = {J_PNAS}, author = {Fei, Chenhui and Guo, Shun and Li, Yibing and Liu, Jingbo}, doi = {10.1073/pnas.2423043122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2423043122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Abiotic synthesis during the interaction of ferrous chloride–rich silicic fluids with marble under high-grade metamorphic conditions}, volume = {122}, year = {2025}, }
• (2025). Precise antibody delivery to the brain via nanobubble-actuated focused ultrasound alleviates depression. PNAS, 122(35), e2421800122. (www)

  @article{ , abstract = {Precise, noninvasive drug delivery to small but important brain regions is challenging and highly desired given the brain’s inherent complexity and heterogeneous nature. Here, we report an approach utilizing focused ultrasound (FUS) combined with nanobubbles to successfully navigate this challenge. Compared to traditional microbubbles, nanobubbles exhibit superior acoustic properties. The nanobubbles, when exposed to FUS, induce a highly localized and reversible opening of the blood–brain barrier (BBB) with significantly enhanced precision (up to fourfolds compared to microbubbles, as measured by the precision loss metric). Repeated multitarget FUS-NB precisely delivers macromolecular human-derived anti-N-methyl-D-aspartate receptors monoclonal antibodies (HuMAbs) into the small brain region within a 2-h half-life window per opening. Fluorescence images confirm HuMAb retention in the brain parenchyma for at least 10 d postadministration. With this approach, we targeted the lateral habenula, a small but effective brain target for antidepressant treatments, and significantly alleviated depression-like symptoms at least 2 wk in a mouse model (tail suspension test/forced swim test: P < 0.01/0.05). Moreover, minimal red blood cell extravasation (0.9‱ affected area) was observed in the treated region after multiple FUS treatments, indicating the safety and tolerability of FUS-nanobubble-mediated BBB opening. The enhanced delivery precision, coupled with a favorable safety profile, positions our approach as a promising strategy for antibody therapy with significant clinical translation potential.}, archive = {J_PNAS}, author = {Li, Wenjing and Feng, Yifan and Xu, Zhouyang and Xu, Xing and Yang, Kexin and Yao, Xinya and Pan, Jia-Ji and Cui, Hengxiang and Hu, Ji and Cheng, Bingbing}, doi = {10.1073/pnas.2421800122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2421800122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Precise antibody delivery to the brain via nanobubble-actuated focused ultrasound alleviates depression}, volume = {122}, year = {2025}, }
• (2025). Patient stratification reveals the molecular basis of disease co-occurrences. PNAS, 122(35), e2421060122. (www)

  @article{ , abstract = {Epidemiological evidence shows that some diseases tend to co-occur; more exactly, certain groups of patients with a given disease are at a higher risk of developing a specific secondary condition. Here, we develop an approach to generate a disease network that uses the accumulating RNA-seq data on human diseases to significantly match an unprecedented proportion of known comorbidities, providing plausible biological models for such co-occurrences and effectively mirroring the underlying structure of complex disease relationships. Furthermore, 64% of the known disease pairs can be explained by analyzing groups of patients with similar expression profiles, highlighting the importance of patient stratification in the study of comorbidities. These results solidly support the existence of molecular mechanisms behind many of the known comorbidities, with most captured co-occurrences implicating the immune system. Additionally, we identified new and potentially underdiagnosed comorbidities, providing molecular insights that could inform targeted therapeutic strategies. We provide a functional and comprehensive resource to explore diseases, disease co-occurrences, and their underlying molecular processes at different resolution levels at http://disease-perception.bsc.es/rgenexcom/ .}, archive = {J_PNAS}, author = {Urda-García, Beatriz and Sánchez-Valle, Jon and Lepore, Rosalba and Valencia, Alfonso}, doi = {10.1073/pnas.2421060122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2421060122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Patient stratification reveals the molecular basis of disease co-occurrences}, volume = {122}, year = {2025}, }
• (2025). To implement the belém declaration, we need a structured and collaborative approach. PNAS, 122(35), e2420198122. (www)

  @article{ , archive = {J_PNAS}, author = {López-Cubillos, Sofía and Mason, Natalie and Wintle, Brendan and Pacheco, Pablo and Ochoa-Quintero, Jose Manuel and Nascimento, Nathália and Torres, Bolier and Runting, Rebecca K.}, doi = {10.1073/pnas.2420198122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2420198122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {To implement the belém declaration, we need a structured and collaborative approach}, volume = {122}, year = {2025}, }
• (2025). Logging disrupts the ecology of molecules in headwater streams. PNAS, 122(35), e2409104122. (www)

  @article{ , abstract = {Global demand for wood products is increasing forest harvest. One understudied consequence of logging is that it accelerates mobilization of dissolved organic matter (DOM) from soils to aquatic ecosystems where it is more easily rereleased to the atmosphere. Here, we tested how logging changed DOM in headwaters of hardwood-dominated catchments in northern Ontario, Canada. We applied a before-after-control-impact experiment across four catchments for 3 y and measured DOM monthly during ice-free seasons. DOM concentration in streams from logged catchments quadrupled, on average, only for the first 2 mo postharvest, but resulting changes to the molecular composition of DOM persisted for at least 2 y. Ultrahigh-resolution mass spectrometry revealed that DOM composition within logged streams became more available for microbial use and chemically diverse than in controls, with novel highly unsaturated polyphenols, carboxylic-rich alicyclic, and nitrogen-containing formulae. The molecular composition of stream DOM measured fortnightly postharvest was most similar to the DOM composition of surrounding soils, likely due to increased hydrological connectivity. Alongside carbon being more likely to be released into the atmosphere, we estimate that selective logging increased the total flux of dissolved organic carbon in streams by 6.4% of the carbon extracted as timber. Although these estimates are short-lived, they should affect the millions of hectares that are logged annually. Carbon accounting of forestry, including as a natural climate solution, must now consider the transport and fate of DOM from land into water.}, archive = {J_PNAS}, author = {Freeman, Erika C. and Emilson, Erik J. S. and Webster, Kara L. and Dittmar, Thorsten and Tanentzap, Andrew J.}, doi = {10.1073/pnas.2409104122}, journal = {Proceedings of the National Academy of Sciences}, month = {9}, number = {35}, pages = {e2409104122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Logging disrupts the ecology of molecules in headwater streams}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(34), eiti3425122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti3425122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {eiti3425122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Future winters promise less snow, more rain. nobody’s prepared. PNAS, 122(34), e2520764122. (www)

  @article{ , archive = {J_PNAS}, author = {McDermott, Amy}, doi = {10.1073/pnas.2520764122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2520764122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Future winters promise less snow, more rain. nobody’s prepared}, volume = {122}, year = {2025}, }
• (2025). Correction for pan et al., β-catenin regulates myogenesis by relieving I-mfa-mediated suppression of myogenic regulatory factors in p19 cells. PNAS, 122(34), e2520060122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2520060122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2520060122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for pan et al., β-catenin regulates myogenesis by relieving I-mfa-mediated suppression of myogenic regulatory factors in p19 cells}, volume = {122}, year = {2025}, }
• (2025). Correction for kuroda et al., bim and bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. PNAS, 122(34), e2519923122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2519923122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2519923122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for kuroda et al., bim and bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic}, volume = {122}, year = {2025}, }
• (2025). Correction for rege et al., evolution of insulin at the edge of foldability and its medical implications. PNAS, 122(34), e2519221122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2519221122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2519221122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for rege et al., evolution of insulin at the edge of foldability and its medical implications}, volume = {122}, year = {2025}, }
• (2025). Correction for bastani et al., generative AI without guardrails can harm learning: Evidence from high school mathematics. PNAS, 122(34), e2518204122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2518204122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2518204122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for bastani et al., generative AI without guardrails can harm learning: Evidence from high school mathematics}, volume = {122}, year = {2025}, }
• (2025). Rediscovering fire. PNAS, 122(34), e2517596122. (www)

  @article{ , archive = {J_PNAS}, author = {Pyne, Stephen}, doi = {10.1073/pnas.2517596122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2517596122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rediscovering fire}, volume = {122}, year = {2025}, }
• (2025). The nature of ant caste allometry. PNAS, 122(34), e2517077122. (www)

  @article{ , archive = {J_PNAS}, author = {Linksvayer, Timothy A.}, doi = {10.1073/pnas.2517077122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2517077122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The nature of ant caste allometry}, volume = {122}, year = {2025}, }
• (2025). Into the belly of the brainstem: The neurons of the “extended” enteric nervous system. PNAS, 122(34), e2516545122. (www)

  @article{ , archive = {J_PNAS}, author = {Moore, Jeffrey D.}, doi = {10.1073/pnas.2516545122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2516545122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Into the belly of the brainstem: The neurons of the “extended” enteric nervous system}, volume = {122}, year = {2025}, }
• (2025). Reply to michał bogdziewicz et al.: Research on the summer solstice needs falsifiable predictions. PNAS, 122(34), e2516303122. (www)

  @article{ , archive = {J_PNAS}, author = {Van der Meersch, Victor and Wolkovich, E. M.}, doi = {10.1073/pnas.2516303122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2516303122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to michał bogdziewicz et al.: Research on the summer solstice needs falsifiable predictions}, volume = {122}, year = {2025}, }
• (2025). Danicamtiv reduces myosin’s working stroke but activates the thin filament by accelerating actomyosin attachment. PNAS, 122(34), e2515786122. (www)

  @article{ , abstract = {Heart failure is a leading cause of death worldwide, and even with current treatments, the 5-y transplant-free survival rate is only ~50 to 70%. As such, there is a need to develop new treatments for patients that improve survival and quality of life. Recently, there have been efforts to develop small molecules for heart failure that directly target components of the sarcomere, including cardiac myosin. Danicamtiv is one of these molecules; however, its direct effects on myosin’s single molecule mechanics and kinetics are not well understood. Using optical trapping techniques, stopped flow transient kinetics, and in vitro reconstitution assays, we found that danicamtiv reduces the size of cardiac myosin’s working stroke without affecting actomyosin detachment kinetics at the level of individual crossbridges. We demonstrate that danicamtiv accelerates actomyosin association kinetics, leading to increased recruitment of myosin crossbridges and subsequent thin filament activation at physiologically relevant calcium concentrations. We demonstrate important mechanistic differences with another cardiac myosin binding myotrope, omecamtiv mecarbil. Finally, we computationally model how the observed changes in mechanics and kinetics at the level of single crossbridges can contribute to increased cardiac contraction. Taken together, our results have important implications for the design of sarcomeric-targeting compounds for heart failure.}, archive = {J_PNAS}, author = {Scott, Brent and Greenberg, Lina and Squarci, Caterina and Campbell, Kenneth S. and Greenberg, Michael J.}, doi = {10.1073/pnas.2515786122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2515786122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Danicamtiv reduces myosin’s working stroke but activates the thin filament by accelerating actomyosin attachment}, volume = {122}, year = {2025}, }
• (2025). Solstice, selection, and synchrony of seed masting. PNAS, 122(34), e2515264122. (www)

  @article{ , archive = {J_PNAS}, author = {Bogdziewicz, Michał and Hacket-Pain, Andrew and Kelly, Dave and Szymkowiak, Jakub and Foest, Jessie and Journé, Valentin}, doi = {10.1073/pnas.2515264122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2515264122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Solstice, selection, and synchrony of seed masting}, volume = {122}, year = {2025}, }
• (2025). Monoamine-induced diacylglycerol signaling rapidly accumulates unc13 in nanoclusters for fast presynaptic potentiation. PNAS, 122(34), e2514151122. (www)

  @article{ , abstract = {Neuromodulators control mood, arousal, and behavior by inducing synaptic plasticity via G-protein-coupled receptors. While long-term presynaptic potentiation requires structural changes, mechanisms enabling potentiation within minutes remain unclear. Using the Drosophila neuromuscular junction, we show that octopamine, the invertebrate analog of norepinephrine, potentiates evoked neurotransmitter release on the timescale of one minute via a G-protein-coupled pathway involving presynaptic OAMB receptors and phospholipase C. This fast potentiation correlates with elevated signals of the release factor Unc13A and the scaffolding protein Bruchpilot. Live, single-molecule imaging of endogenously tagged Unc13 revealed its instantly reduced motility and increased concentration in synaptic nanoclusters with potentiation. Presynaptic knockdown of Unc13A fully blocked fast potentiation. Moreover, deleting its N-terminal localization sequence mislocalized the protein fragment to the cytosol, but still allowed for rapid plasma membrane recruitment by diacylglycerol (DAG) analog phorbol esters and octopamine, implicating a role of more C-terminal domains. A point mutation of endogenous Unc13 in its DAG-binding C1 domain blocked plasticity-induced nanoscopic enrichment and synaptic potentiation. The mutation increased basal neurotransmission but reduced Unc13 levels, revealing a gain of function and potential homeostatic compensation. The mutation also blocked phorbol ester–induced potentiation, decreased the calcium sensitivity of neurotransmission, and caused short-term synaptic depression. Homeostatic potentiation induced by postsynaptic receptor block mirrored octopamine-induced Unc13 recruitment and required presynaptic OAMB receptors, indicating overlapping machinery. Thus, rapid Unc13 immobilization and nanoscale compaction are salient features of fast presynaptic potentiation.}, archive = {J_PNAS}, author = {Blaum, Natalie and Ghelani, Tina and Götz, Torsten W. B. and Chronister, Keagan S. and Bengochea, Mercedes and Ceresnova, Livia and Christensen, Christian F. and Moulin, Thiago C. and Kern, Hanna and Thomas, Ulrich and Heine, Martin and Sigrist, Stephan J. and Walter, Alexander M.}, doi = {10.1073/pnas.2514151122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2514151122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Monoamine-induced diacylglycerol signaling rapidly accumulates unc13 in nanoclusters for fast presynaptic potentiation}, volume = {122}, year = {2025}, }
• (2025). Elucidating the role of campylobacter concisus–derived indole metabolites in gut inflammation and immune modulation. PNAS, 122(34), e2514071122. (www)

  @article{ , abstract = {The gut microbiota plays a pivotal role in maintaining human health with dysbiosis linked to a variety of diseases. Metagenome sequencing and robust statistical analysis have linked specific strains, including the gut bacterium Campylobacter concisus , to Crohn’s disease and ulcerative colitis, together known as inflammatory bowel disease (IBD). However, the roles of this and other strains in disease progression remain to be investigated. Herein, we assess the contribution of C. concisus secondary metabolites to inflammation. Through untargeted metabolomics, we identified a diverse array of nineteen indole-containing metabolites produced by C. concisus , including trisindoline, previously isolated from a marine bacterium. Collectively, these metabolites modulate inflammatory responses by significantly inducing the release of proinflammatory cytokines interleukin (IL)-1β, IL-6, IL-8, and MCP-1. The metabolites act through the aromatic hydrocarbon receptor arylhydrocarbon receptor and in vivo intravital imaging revealed a marked increase in the recruitment and activation of immune cells, specifically neutrophils and macrophages, following the administration of trisindoline. Several indole metabolites also exhibited antimicrobial activity against commensal strains that facilitate a proper immune response. Our study provides a possible rationale for the association of C. concisus with IBD and underscores the complex interplay between gut bacteria and host immunity. The identification of indole-derived secondary metabolites as key modulators of inflammation offers new avenues for therapeutic intervention.}, archive = {J_PNAS}, author = {Park, Jong-Duk and Lee, Seoung Rak and Dhennezel, Catherine and Taylor, Noel and Dame, Andrea and Kadoki, Motohiko and Pishchany, Gleb and Graham, Daniel B. and Xavier, Ramnik J. and Seyedsayamdost, Mohammad R.}, doi = {10.1073/pnas.2514071122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2514071122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Elucidating the role of campylobacter concisus–derived indole metabolites in gut inflammation and immune modulation}, volume = {122}, year = {2025}, }
• (2025). Efficient neural encoding as revealed by bilingualism. PNAS, 122(34), e2513768122. (www)

  @article{ , abstract = {The remarkable human capacity for bilingual and multilingual acquisition raises fundamental questions about how the brain develops efficient systems for processing multiple languages. In this study, we used neural network models trained on natural speech input to examine how these efficient representations emerge. Our models show that multiple phonological systems can be organized through parallel representations, preserving the unique aspects of each language while maintaining shared articulatory features. This parallel structure scaled effectively from two to three languages without needing additional neural architecture, highlighting the inherent efficiency in multilingual processing. Furthermore, the development of phonological representations varied based on the timing of language exposure, showing how earlier-learned languages shape the acquisition of subsequent ones. These findings imply that the human ability to speak multiple languages may arise from general principles of neural organization that optimize shared resources while maintaining essential distinctions between languages. This work has important implications for language learning, brain plasticity, and cognitive development.}, archive = {J_PNAS}, author = {Moore, Charlotte and Donhauser, Peter W. and Klein, Denise and Byers-Heinlein, Krista}, doi = {10.1073/pnas.2513768122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2513768122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Efficient neural encoding as revealed by bilingualism}, volume = {122}, year = {2025}, }
• (2025). Definition of the components required for selective packaging of coronavirus genomic RNA. PNAS, 122(34), e2513552122. (www)

  @article{ , abstract = {Most cytoplasmic RNA viruses have evolved mechanisms to identify their genomic RNA (gRNA) as the sole RNA species to be packaged into assembled virions. Coronaviruses exhibit highly selective packaging of their gRNA, in spite of the presence of a large excess of subgenomic viral and host RNA in infected cells. Failure to accomplish this selectivity does not impair virion assembly but renders the virus vulnerable to host innate immunity. In the prototype coronavirus mouse hepatitis virus (MHV) packaging selectivity is brought about by a packaging signal (PS), an RNA structure found exclusively in gRNA and absent from subgenomic RNAs. However, it is not well resolved how virion structural proteins participate in the recognition of the PS. Previous studies with virions have shown that the nucleocapsid (N) protein carboxy-terminal RNA-binding domain (CTD) and the carboxy-terminal tail (domain N3) both have roles in PS recognition. Separately, work with a virus-like particle system has implicated the viral membrane (M) protein as the main factor in this process. Here, we pinpoint key amino acids in the CTD and domain N3 that govern selective gRNA packaging into virions, and we provide genetic evidence that the M protein endodomain also plays a required role. We show that the N protein CTD is the primary determinant of PS recognition, and we localize residues in the CTD structure that are critical for specific and nonspecific RNA binding.}, archive = {J_PNAS}, author = {Pata, Janice D. and Stevens, Taína K. and Kuo, Lili and Masters, Paul S.}, doi = {10.1073/pnas.2513552122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2513552122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Definition of the components required for selective packaging of coronavirus genomic RNA}, volume = {122}, year = {2025}, }
• (2025). Protein functional site annotation using local structure embeddings. PNAS, 122(34), e2513219122. (www)

  @article{ , abstract = {The rapid expansion of protein sequence and structure databases has resulted in a significant number of proteins with ambiguous or unknown function. While advances in machine learning techniques hold great potential to fill this annotation gap, current methods for function prediction are unable to associate global function reliably to the specific residues responsible for that function. We address this issue by introducing PARSE (Protein Annotation by Residue-Specific Enrichment), a knowledge-based method which combines pretrained embeddings of local structural environments with traditional statistical techniques to simultaneously predict function and provide residue-level annotations. For the task of predicting the catalytic function of enzymes, PARSE achieves comparable or superior global performance to state-of-the-art machine learning methods (F1 score > 85%) while simultaneously annotating the specific residues involved in each function with much greater precision. Since it does not require supervised training, our method can make one-shot predictions for very rare functions and is not limited to a particular type of functional label (e.g. Enzyme Commission numbers or Gene Ontology codes). Finally, we leverage the AlphaFold Structure Database to perform functional annotation at a proteome scale. By applying PARSE to the dark proteome—predicted structures which cannot be classified into known structural families—we predict several bacterial metalloproteases. Each of these proteins shares a strongly conserved catalytic site despite highly divergent sequences and global folds, illustrating the value of local structure representations for new function discovery.}, archive = {J_PNAS}, author = {Derry, Alexander and Tartici, Alp and Altman, Russ B.}, doi = {10.1073/pnas.2513219122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2513219122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Protein functional site annotation using local structure embeddings}, volume = {122}, year = {2025}, }
• (2025). CO2 upgrading into bioproducts using a two-step abiotic–biotic system. PNAS, 122(34), e2512565122. (www)

  @article{ , abstract = {The valorization of CO 2 to chemicals beyond C 1-2 products is receiving significant interest; however, the direct electrosynthesis of C n molecules (n > 4) remains a challenge. Here, we present a two-step abiotic–biotic system for upgrading CO 2 into the biopolymer, poly(3-hydroxybutyrate). In the electrolysis system, CO 2 is converted into C 2 oxygenates using a Cu–Ag tandem electrocatalyst. The electrolysis process generates a liquid stream containing ~ 200 mM acetate in a bio-compatible electrolyte. This electrosynthesized acetate is then fed to a bioreactor, where the substrate is upgraded by Cupriavidus necator to biopolymer with a maximum rate of 32 ± 3.5 mg L −1 h −1 . We further demonstrate the purification of the resulting biopolymer into a powder. The high productivity of the abiotic–biotic system demonstrates its feasibility for sustainable chemical manufacturing.}, archive = {J_PNAS}, author = {Lee, Geonhui and Jo, Hye-Jin and Choi, Jihoon and Guzman, Maria Fonseca and Shan, Yu and Le, Han K. D. and Feijoo, Julian and Soland, Nathan and Clark, Douglas S. and Yang, Peidong}, doi = {10.1073/pnas.2512565122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2512565122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CO2 upgrading into bioproducts using a two-step abiotic–biotic system}, volume = {122}, year = {2025}, }
• (2025). Diverse thioether macrocyclized peptides through a radical SAM maturase. PNAS, 122(34), e2512563122. (www)

  @article{ , abstract = {Disulfide bonds stabilize many bioactive peptides, but their susceptibility to reduction under physiological conditions limits broad applicability in biotechnology. PapB is a promiscuous radical S -adenosyl-L-methionine enzyme that is involved in the maturation of PapA, which is a ribosomally produced and posttranslationally modified polypeptide. PapB introduces six thioether linkages between internal Cys residues and carbon atom that is α to the side-chain carboxylate of Asp/Glu residues C-terminal to the Cys residues. Herein, we show that PapB also efficiently couples an internal Cys thiol to the C-terminal carboxylate of peptides terminating in D- or β-amino acids, forming α- or β-thioether macrocycles. Moreover, PapB tolerates β- and N-methyl amino acids within the peptide, resulting in the formation of macrocycles that are comprised entirely of unnatural amino acids, such as peptides containing all β-residues. These findings establish PapB as a sequence-agnostic thioether ligase for efficient C-terminal macrocyclization. Our work expands the enzymatic toolbox for constructing conformationally constrained peptides for therapeutics and chemical biology.}, archive = {J_PNAS}, author = {Eastman, Karsten A. S. and Roberts, Andrew G. and Bandarian, Vahe}, doi = {10.1073/pnas.2512563122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2512563122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Diverse thioether macrocyclized peptides through a radical SAM maturase}, volume = {122}, year = {2025}, }
• (2025). FliO is an evolutionarily conserved yet diversified core component of the bacterial flagellar type III secretion system. PNAS, 122(34), e2512476122. (www)

  @article{ , abstract = {The bacterial flagellum is a complex nanomachine essential for motility, environmental sensing, and host colonization. While many of its core components have been well characterized, the relevance of proteins such as FliO, which are inconsistently annotated and poorly conserved at the sequence level, has remained ambiguous in their evolutionary and functional status. Here, we present a comprehensive phylogenomic and structural analysis of FliO across >30,000 representative genomes spanning >100 bacterial phyla. Additionally, during this analysis, we found that approximately 40% of bacterial genomes contain flagellar genes—significantly fewer than previously reported. Using a custom pipeline combining low-threshold Hidden Markov models searches, operon context analysis, and structural information, we demonstrate that FliO is present in ~95% of genomes encoding the core flagellar components FliP, FliQ, and FliR. This suggests that FliO is a nearly ubiquitous and ancestral core component of the flagellar type III secretion system (fT3SS). FliO exhibits considerable structural diversity, including lineage-specific acquisitions of LysM and AMIN domains. We identify FliO homologs not only in canonical flagellar systems but also in some virulence-associated T3SS and even some nonflagellated organisms, suggesting functional repurposing and highlighting its functional plasticity. Functional studies in Campylobacter jejuni reveal that FliO and its AMIN domain are critical for efficient amphitrichous flagellation, membrane stability of the export gate component FlhB, and colonization of the host. These findings establish FliO as a core, yet evolutionarily dynamic, component of flagella and provide insights into the evolution and diversification of bacterial secretion systems.}, archive = {J_PNAS}, author = {Andrianova, Ekaterina P. and Dobbins, Amanda L. and Erhardt, Marc and Hendrixson, David R. and Zhulin, Igor B.}, doi = {10.1073/pnas.2512476122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2512476122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {FliO is an evolutionarily conserved yet diversified core component of the bacterial flagellar type III secretion system}, volume = {122}, year = {2025}, }
• (2025). Systemic kras ablation disrupts myeloid cell homeostasis in adult mice. PNAS, 122(34), e2512404122. (www)

  @article{ , abstract = {The KRAS oncogene has been associated with many types of cancer, including pancreatic, lung, and colorectal. For decades, its gene products were thought to be undruggable. However, during the last decade, a large battery of KRAS inhibitors selective against specific mutations (KRAS G12C and KRAS G12D ), panKRAS inhibitors active against all KRAS isoforms, or even panRAS inhibitors, capable of inhibiting the three members of the RAS family, have been developed. In mice, the Kras locus is essential for embryonic development and can sustain adult homeostasis in the absence of Hras and Nras expression. Thus, we considered of interest to interrogate the role of the Kras locus in an experimental system to generate potentially relevant information regarding the use of panKRAS or panRAS inhibitors in the clinic. Here, we report that systemic ablation of Kras expression in adult mice does not induce significant changes in overall survival, body weight, glucose levels, metabolic profile, or heart function. In contrast, flow cytometry and histopathological analyses of organs such as blood, bone marrow, and spleen showed a significant increase of the myeloid lineage leading to myelomonocytic metaplasia. In this context, replacement of the KRAS isoforms by HRAS is sufficient to maintain adult homeostasis, suggesting that the unique properties of the Kras locus are primarily due to its pattern of expression rather than to the activity of its gene products.}, archive = {J_PNAS}, author = {Zamorano-Dominguez, Elena and Morales-Cacho, Lucía and Barrero, Rebeca and Jiménez-Parrado, Silvia and Dhawahir, Alma and Hernández-Porras, Isabel and Simón-Carrasco, Lucía and Barrambana, Sara and Sun, Pian and Galván-del-Rey, Ana and Rosas-Perez, Blanca and Liaki, Vasiliki and Drosten, Matthias and Musteanu, Mónica and Virga, Federico and Santos, Eugenio and Mulero, Francisca and Caleiras, Eduardo and Guerra, Carmen and Barbacid, Mariano}, doi = {10.1073/pnas.2512404122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2512404122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Systemic kras ablation disrupts myeloid cell homeostasis in adult mice}, volume = {122}, year = {2025}, }
• (2025). ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability. PNAS, 122(34), e2512154122. (www)

  @article{ , abstract = {Toll-like receptor 4 (TLR4), a pattern-recognition receptor located on the plasma membrane, senses extracellular danger signals to initiate inflammatory immune responses. It is initially synthesized in the endoplasmic reticulum (ER), undergoes N-linked glycosylation, and is subsequently transported to the Golgi before ultimately reaching the plasma membrane. However, the mechanisms underlying the processing and maturation of TLR4 in the ER remain elusive. Through whole genome-wide CRISPR screening, CCDC134 was identified as a critical and essential factor for TLR4-dependent inflammatory response. Localization of CCDC134 in the ER lumen rather than its exosome-mediated secretion is required for its role in TLR4 signaling. Loss of CCDC134 results in the retention of TLR4 in the ER for subsequent ER-associated degradation, and thus blockade of TLR4 maturation and plasma membrane trafficking. Defects in TLR4 processing and maturation in the ER in CCDC134-depleted cells are caused by aberrant hyperglycosylation and destabilization of glycoprotein 96 (gp96), a key chaperone of TLR4. These results suggest that CCDC134 controls gp96 glycosylation to facilitate TLR4 maturation in the ER.}, archive = {J_PNAS}, author = {Bai, Yang and Zhang, Chao and Liu, Hao and Deng, Fan and Wu, Zeyu and Deng, Wanyan and Zheng, Zengzhang and Min, Rui and Mei, Shenglin and Kang, He and Yu, Huiqing and Pan, Youdong and Lieberman, Judy and Zhao, Jingxia and Liu, Xing}, doi = {10.1073/pnas.2512154122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2512154122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability}, volume = {122}, year = {2025}, }
• (2025). Asymmetric development and function of paired sperm-storage organs in drosophila melanogaster. PNAS, 122(34), e2512096122. (www)

  @article{ , abstract = {Paired structures often have similar forms and functions, but the processes underlying their formation can differ. They may originate from a common source or from parallel sources, or arise from distinct precursors that follow separate developmental pathways, ultimately converging on comparable structures and roles. When asymmetries emerge and persist through development, members of the pair can specialize in ways that might increase fitness. Here, we report that the Drosophila melanogaster female’s pair of spermathecae, which appear similar and have the common role of sperm storage, derive from different developmental compartments defined by expression of lineage-tracing markers corresponding, respectively, to the key patterning genes engrailed and wingless . We further find that the two spermathecae show significant differences in size, secretory activity, and calcium levels and, perhaps as a consequence, sperm retention dynamics. These results open broad avenues for understanding how developmental, physiological, and behavioral asymmetries arise and impact reproductive success.}, archive = {J_PNAS}, author = {Chen, Dawn S. and Marrero, Kianairy and Sanchez-Lopez, Javier Arturo and Belenky, Michael and Thomalla, Jonathon M. and Buehner, Norene A. and Apel, Ido and Levi, Yarin and Hafezi, Yassi and Wang, Shuran and Clark, Andrew G. and Heifetz, Yael and Siegal, Mark L. and Wolfner, Mariana F.}, doi = {10.1073/pnas.2512096122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2512096122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Asymmetric development and function of paired sperm-storage organs in drosophila melanogaster}, volume = {122}, year = {2025}, }
• (2025). Nano-biochar regulates phage–host interactions, reducing antibiotic resistance genes in vermicomposting systems. PNAS, 122(34), e2511986122. (www)

  @article{ , abstract = {Biochar amendment reshapes microbial community dynamics in vermicomposting, but the mechanism of how phages respond to this anthropogenic intervention and regulate the dissemination of antibiotic resistance genes (ARGs) remains unclear. In this study, we used metagenomics, viromics, and laboratory validation to explore how nano-biochar affects phage–host interactions and ARGs dissemination in vermicomposting. Our results revealed distinct niche-specific phage life strategies. In vermicompost, lytic phages dominated and used a “kill-the-winner” strategy to suppress antibiotic-resistant bacteria (ARB). In contrast, lysogenic phages prevailed in the earthworm gut, adopting a “piggyback-the-winner” strategy that promoted ARGs transduction through mutualistic host interactions. Nano-biochar induced the conversion of lysogenic to lytic phages in the earthworm gut, while concurrently reducing the abundance of lysogenic phages and their encoded auxiliary metabolic genes carried by ARB. This shift disrupted phage–host mutualism and inhibited ARGs transmission via a “phage shunting” mechanism. In vitro validation with batch culture experiments further confirmed that lysogenic phages increased transduction of ARGs in the earthworm gut, while nano-biochar reduced the spread of ARGs by enhancing lysis infectivity. Our study constructs a mechanistic framework linking nano-biochar induced shifts in phage lifestyles that suppress ARG spread, offering insights into phage–host coadaptation and resistance mitigation strategies in organic waste treatment ecosystems.}, archive = {J_PNAS}, author = {Xie, Ting and Lin, Da and Cai, Xing-Da and Ma, Li-Juan and Wang, Lu and Cai, Tian-Gui and Ye, Yu-Qiu and Shen, Luo-Qin and Sun, Ming-Ming and Ye, Mao and Neilson, Roy and Zhu, Dong}, doi = {10.1073/pnas.2511986122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2511986122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nano-biochar regulates phage–host interactions, reducing antibiotic resistance genes in vermicomposting systems}, volume = {122}, year = {2025}, }
• (2025). Melanocyte-dependent macrophage redistribution enhances skin immunity upon acute stress. PNAS, 122(34), e2511358122. (www)

  @article{ , abstract = {It is well established that stress generally suppresses immunity. However, under certain conditions, acute stress has been shown to stimulate the immune system, particularly those at barrier surfaces like the skin. The cellular and molecular mechanisms underlying this effect remain poorly understood. In the present study, we have identified an immune-enhancing effect of stress using zebrafish larvae. The use of this animal model allowed us to visualize the redistribution of macrophages to the skin upon exposure to an acute stressor, which appeared to be dependent on the increased levels of cortisol. Through real-time imaging of fluorescently labeled leukocytes, we observed that this cortisol-driven redistribution was mediated by both the mineralocorticoid and the glucocorticoid receptor, which upregulated the chemokine receptor Cxcr4. Strikingly, this stress-induced macrophage migration required the presence of melanocytes in the skin, which increased the expression of the gene encoding Cxcl12, the ligand for Cxcr4. This result indicates a pivotal role for pigment cells in immune regulation under stress. Functional assays further revealed that the redistributed macrophages actively increased antigen uptake from the external environment, suggesting an elevated state of immune readiness. Together, we demonstrate that acute stress triggers a coordinated, cortisol-mediated response that enhances immune surveillance at the skin barrier. This stress-induced enhancement of barrier immunity potentially prepares the organism for increased pathogen exposure under challenging conditions.}, archive = {J_PNAS}, author = {Faught, Erin and Schaaf, Marcel J. M.}, doi = {10.1073/pnas.2511358122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2511358122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Melanocyte-dependent macrophage redistribution enhances skin immunity upon acute stress}, volume = {122}, year = {2025}, }
• (2025). Efficiently quantifying dependence in massive scientific datasets using InterDependence scores. PNAS, 122(34), e2509860122. (www)

  @article{ , abstract = {Large-scale scientific datasets today contain tens of thousands of random variables across millions of samples (for example, the RNA expression levels of 20,000 protein-coding genes across 30 million single cells). Being able to quantify dependencies between these variables would help us discover novel relationships between variables of interest. Simple measures of dependence, such as Pearson correlation, are fast to compute, but limited in that they are designed to detect linear relationships between variables. Complex measures are known with the ability to detect any kind of dependence, but they do not readily scale to many modern datasets of interest. We introduce the InterDependence Score (IDS), a scalable measure of dependence that captures linear and various nonlinear dependencies between random variables. Our IDS algorithm is motivated by a dependence measure defined in infinite-dimensional Hilbert spaces, capable of capturing any type of dependence, and a fast (linear time) algorithm that neural networks natively implement to compute dependencies between random variables. We apply IDS to identify 1) relevant variables for predictive modeling tasks, 2) sets of words forming topics from millions of documents, and 3) sets of genes related to “gene-expression programs” in tens of millions of cells. We provide an efficient implementation that computes IDS between billions of pairs of variables across millions of samples in several hours on a single GPU. Given its speed and effectiveness in identifying nonlinear dependencies, we envision IDS will be a valuable tool for uncovering insights from scientific data.}, archive = {J_PNAS}, author = {Radhakrishnan, Adityanarayanan and Jain, Yajit and Uhler, Caroline and Lander, Eric S.}, doi = {10.1073/pnas.2509860122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2509860122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Efficiently quantifying dependence in massive scientific datasets using InterDependence scores}, volume = {122}, year = {2025}, }
• (2025). The likelihood of sympatric speciation and morphological divergence in plants. PNAS, 122(34), e2508958122. (www)

  @article{ , abstract = {Sympatric speciation is considered rare, but oceanic Howea palms, crater lake cichlids, and parasitic indigobirds provide compelling evidence that it occurs. Still, the frequency of sympatric speciation and its relationship to morphological divergence in plants remains poorly understood, especially in plants. Here, we analyze the geographic distributions, traits, and divergence times of palm and conifer sister species (740 species from 108 genera) to determine the dominant geographic mode and role of morphological divergence in plant speciation. We show that allopatric speciation is dominant, and while frequent sympatric speciation cannot be discounted, the most likely scenario is that zero (conifers) or 10% (palms) of speciation events occur in sympatry. Our models show that the incidence of sympatry among sister pairs rises rapidly within the first million years after speciation and then declines, suggesting that species failing to attain sympatry early tend to remain allopatric. Finally, we find no evidence for morphological divergence in allopatric or sympatric palms. Our findings question the link between speciation and morphological divergence and suggest that while plants and animals share similar modes of speciation, plants exhibit a complex spatiotemporal dynamic, challenging the typical vertebrate pattern of steadily increasing sympatry.}, archive = {J_PNAS}, author = {Olivares, Ingrid and Faurby, Søren and Cámara-Leret, Rodrigo and Pigot, Alex L.}, doi = {10.1073/pnas.2508958122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2508958122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The likelihood of sympatric speciation and morphological divergence in plants}, volume = {122}, year = {2025}, }
• (2025). Underappreciated role of canopy nitrogen deposition for forest productivity. PNAS, 122(34), e2508925122. (www)

  @article{ , abstract = {Atmospheric nitrogen (N) deposition is generally expected to stimulate plant carbon (C) sequestration and promote tree growth, thereby mitigating atmospheric CO 2 accumulation. Yet, the magnitude of N deposition contribution to forest productivity remains contentious. While correlative studies suggest substantial plant growth enhancement, controlled fertilization experiments typically demonstrate a limited impact. This discrepancy may arise from whether or not to consider canopy N uptake processes. Here, we conducted a 10-y field experiment comparing canopy addition of N (CAN) with understory addition of N (UAN) at the rate of 0, 25, and 50 kg N ha –1 y –1 in a temperate deciduous forest in central China. We show that CAN significantly enhanced net primary productivity by 37.0% over control, driven by enhanced leaf litterfall, wood and fine root production, whereas UAN effects were marginal (8%). 15 N isotopic tracing revealed that CAN, through enhanced plant N uptake and increased ecosystem N retention, yielded a 3.5-fold higher C sequestration efficiency (∆C/∆N) of 54.5 ± 7.7 kg C kg –1 N, than UAN (12.2 ± 3.4 kg C kg –1 N) resulted from greater N loss through leaching. Physiological measurements indicated CAN enhanced leaf photosynthetic rates, modified leaf morphology, and extended leaf lifespan via delayed senescence. These findings provide robust empirical evidence that canopy N uptake is crucial for maximizing N-induced forest productivity, thereby holding significant implications for refining global C models and urging modelers to incorporate canopy processes for more accurate projections of future C sinks and climate change mitigation strategies.}, archive = {J_PNAS}, author = {Li, Xiaowei and Zhang, Chenlu and Zhang, Beibei and Jiang, Li and Tang, Shengqi and Sun, Chenhui and Bai, Yulong and Wang, Yubang and Shi, Yifei and Ma, Lei and Zhang, Wei and Ye, Qing and Yan, Junhua and Wang, Keya and Fu, Juemin and Du, Wenzhi and Ha, Denglong and Ju, Yuxi and Wan, Shiqiang and Hong, Liang and Fang, Yunting and Siemann, Evan and Luo, Yiqi and Reich, Peter B. and Fu, Shenglei}, doi = {10.1073/pnas.2508925122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2508925122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Underappreciated role of canopy nitrogen deposition for forest productivity}, volume = {122}, year = {2025}, }
• (2025). Identification of broadly inhibitory anti-PfEMP1 antibodies by mass spectrometry sequencing of plasma IgG from a malaria-exposed child. PNAS, 122(34), e2508744122. (www)

  @article{ , abstract = {Plasmodium falciparum pathology is driven by the accumulation of parasite-infected erythrocytes in blood capillaries. This sequestration process is mediated by the parasite’s P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesins, which bind select endothelial cell receptors. A subset of PfEMP1 binding human endothelial protein C receptor (EPCR) through their cysteine-rich interdomain region alpha 1 (CIDRα1) domains drives the pathogenesis to severe malaria. Despite high sequence diversity among CIDRα1 domains, individuals living in malaria-endemic regions become immune to severe disease in part through acquisition of antibodies inhibiting the PfEMP1–EPCR interaction. Here, we demonstrate an approach to identify pathogen-specific human monoclonal antibodies from plasma, combining mass spectrometry analysis of antigen-purified polyclonal plasma IgG and Ig transcript sequencing. We identified a clonal family of broadly reactive and EPCR binding-inhibitory human monoclonal antibodies against CIDRα1. The antibodies, isolated from a 9-y-old child, exhibited potent inhibition of EPCR binding broadly across CIDRα1 domains as well as binding of infected erythrocytes to EPCR. Structural analysis of one antibody variant complexed with CIDRα1 revealed a shared epitope of the clonal antibody family overlapping the EPCR binding site and the epitopes of two previously identified monoclonal antibodies, C7 and C74, with similar functional patterns. However, although C7, C74, and 110-3 antibodies all depend on the same few residues conserved in CIDRα1 to retain EPCR binding, the 110-3 antibodies contact additional variable residues, reducing their breadth of reactivity across the CIDRα1 family. These data bolster the hypothesis that broadly inhibitory antibodies against severe malaria-associated PfEMP1 target similar epitopes and are commonly developed in malaria-exposed individuals.}, archive = {J_PNAS}, author = {Turner, Louise and Nunez de Villavicencio Diaz, Teresa and Raghavan, Sai Sundar Rajan and Kana, Ikhlaq Hussain and Lyimo, Eric and Reitzel, Chelsea and Wang, Christian W. and Berube, Ewen and Jensen, Rasmus W. and Loeffler, Johannes R. and Fernández-Quintero, Monica Lisa and Theander, Thor G. and Lusingu, John P. A. and Le Bihan, Thierry and Han, Xiaobing and Minja, Daniel T. R. and Ward, Andrew B. and Ma, Bin and Lavstsen, Thomas}, doi = {10.1073/pnas.2508744122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2508744122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identification of broadly inhibitory anti-PfEMP1 antibodies by mass spectrometry sequencing of plasma IgG from a malaria-exposed child}, volume = {122}, year = {2025}, }
• (2025). N6-methyladenine modification of DNA enhances RecA-mediated homologous recombination. PNAS, 122(34), e2508652122. (www)

  @article{ , abstract = {Both DNA methylation and homologous recombination (HR) are extensively studied. In bacteria, Dam methylation is the most studied DNA modification, while RecA-mediated HR is a primary mechanism to repair DNA damages including double-stranded breaks, single-stranded gaps, and stalled replication forks. While HR regulation by proteins is extensively studied, whether methylation of DNA itself directly affects the functions of RecA and HR remains unclear. Mainly by single-molecule experiments, we report that Dam methylation of single-stranded DNA (ssDNA) promotes RecA assembly, partially by reducing the effective charge of ssDNA under counterion screening. Furthermore, Dam methylation of double-stranded DNA promotes homologous pairing, joint molecule growth, and strand exchange. In cellular experiments, dam deletion impairs HR, whereas hypermethylation of the adenines in the genome enhances HR in P1 transduction assays and DNA-damage sensitivity tests without significantly upregulated HR-related genes. In addition, the preference of RecA for Dam-methylated DNA in RecA assembly and homologous pairing is conserved across divergent species covering a gram-negative bacterium Klebsiella pneumoniae , a gram-positive bacterium Bacillus subtilis, and a flowering plant Arabidopsis thaliana . Dam methylation of ssDNA increases the ATPase activity of molecular motors such as RecQ helicase that containing RecA-like domains. These findings reveal effects of DNA methylation and mechanisms regulating RecA-mediated HR and molecular motors.}, archive = {J_PNAS}, author = {Zhao, Xiao-Cong and Wu, Bin and Yang, Ya-Jun and Li, Ying and Qiu, Qi-Yuan and Wang, Liu and Xu, Ya-Peng and Gong, Han and Song, Lun and Wang, Xue-Jie and Shi, Jing-Yao and Chen, Xue-Feng and Zhang, Shao-Ran and Zong, Qi and Dai, Liang and Du, Shi-Shen and Zhang, Yan and Wu, Wen-Qiang and Zhang, Xing-Hua}, doi = {10.1073/pnas.2508652122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2508652122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {N6-methyladenine modification of DNA enhances RecA-mediated homologous recombination}, volume = {122}, year = {2025}, }
• (2025). Profitable third-party punishment destabilizes cooperation. PNAS, 122(34), e2508479122. (www)

  @article{ , abstract = {Third-party punishment is theorized by some scholars to be essential to the evolution of large-scale cooperation, but empirically, it often fails to bring about its desired effects. Here, we suggest that third-party punishment destabilizes cooperation when third parties have profit motives to punish. Across nine economic games and judgment experiments (including four preregistered studies), we find that when third-party punishment is profitable, rates of cooperation decrease immediately and remain lower even when punishment outcomes are optimized to support cooperative behavior. Profitable third-party punishment causes targets of punishment to anticipate antisocial punishment and perceive social norms in terms of self-interest, suggesting that the introduction of payment degrades the communicative signals that punishment is meant to convey about punishers’ intentions and social norms. Critically, participants who would benefit from increased cooperation inadvertently reduce their own monetary compensation by opting in to experimental conditions that pay punishers, suggesting that they intuitively fail to consider the signaling consequences of profit motives to punish. Implications for systems of punishment and cooperation in real-world contexts are discussed.}, archive = {J_PNAS}, author = {Alam, Raihan and Rai, Tage S.}, doi = {10.1073/pnas.2508479122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2508479122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profitable third-party punishment destabilizes cooperation}, volume = {122}, year = {2025}, }
• (2025). Programmable immunoprobiotics orchestrate antitumor immune response with pin1 inhibition for pancreatic cancer treatment. PNAS, 122(34), e2507711122. (www)

  @article{ , abstract = {Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options due to its desmoplastic and immunosuppressive tumor microenvironment (TME), which impedes drug delivery and limits T cell infiltration. Immune checkpoint blockade (ICB) has shown poor efficacy in PDAC, partly due to the desmoplastic stroma and low immunogenicity. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) promotes both fibrosis and immune evasion, making it a compelling target for TME remodeling. Here, we develop a dual-action, programmable immunoprobiotic delivery system (EcN@Nbs-NP@API-1) that combines Pin1 inhibition with PD-L1 blockade to enhance immunotherapy. This system uses Escherichia coli Nissle 1917 (EcN) to selectively deliver nanoparticles encapsulating the Pin1 inhibitor API-1 to PDAC, enabling sustained release to degrade the fibrotic stroma and upregulate PD-L1 on tumor cells, promoting immune infiltration. Engineered EcN also produces anti-PD-L1 nanobodies in situ, synergizing with API-1 to boost CD8 + T cell–mediated immunity. In orthotopic PDAC mouse models, this strategy remodels the TME, enhances immune cell infiltration, and improves antitumor response while minimizing systemic toxicity. Moreover, it shows efficacy in other ECM-rich tumors, such as triple-negative breast cancer, highlighting its broader potential. This work presents a promising platform to overcome immunotherapy resistance in solid tumors.}, archive = {J_PNAS}, author = {Yuan, Sichen and Yang, Xicheng and Bremmer, Alexa M. and Wang, Yixin and Li, Sherry and Chen, Yu and You, Yawen and Hu, Quanyin}, doi = {10.1073/pnas.2507711122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2507711122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Programmable immunoprobiotics orchestrate antitumor immune response with pin1 inhibition for pancreatic cancer treatment}, volume = {122}, year = {2025}, }
• (2025). Evolution of developmental bias explains divergent patterns of phenotypic evolution in two nematode clades. PNAS, 122(34), e2507529122. (www)

  @article{ , abstract = {Rates of phenotypic evolution vary across traits, and these evolutionary patterns themselves evolve. Understanding how development contributes to such patterns remains a challenge because it requires large-scale measurement of phenotypic variation resulting from random mutations across multiple species. Using the experimentally tractable system of nematode vulval development, we quantified the evolution and mutational sensitivity of six cell fates across two clades. First, we find that the cell whose fate evolves fastest is distinct for each clade: P3.p in Caenorhabditis and P4.p in Oscheius . Second, we show that this evolutionary pattern matches the pattern of variation within species of each clade. Third, we find that within each clade, the differential effect on each cell of random mutation, quantified as their mutational phenotypic variance, is sufficient to explain the observed phenotypic evolution. Finally, we propose that the difference between clades is explained by a simple spatial shift across cells of the sensitive region in a Wnt dose–response curve. These findings underscore the importance of integrating the evolving structure of the genotype–phenotype map and measures of developmental sensitivity into the understanding of phenotypic change at both micro- and macroevolutionary scales.}, archive = {J_PNAS}, author = {Picao-Osorio, Joao and Bouleau, Charlotte and Gonzalez de la Rosa, Pablo M. and Stevens, Lewis and Fekonja, Nina and Blaxter, Mark and Braendle, Christian and Félix, Marie-Anne}, doi = {10.1073/pnas.2507529122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2507529122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolution of developmental bias explains divergent patterns of phenotypic evolution in two nematode clades}, volume = {122}, year = {2025}, }
• (2025). Replay in the human visual cortex during brief task pauses is linked to implicit learning of successor representations. PNAS, 122(34), e2507516122. (www)

  @article{ , abstract = {Humans can implicitly learn about multistep sequential relationships between events in the environment from their statistical co-occurrence. Theoretical work has suggested that neural replay is a candidate mechanism that aids such learning. Here, we used functional MRI (fMRI) to test whether replay is related to implicit learning of higher-order sequential relationships. Human participants viewed sequences of images that followed probabilistic transitions determined by ring-like graph structures. Behavioral modeling of response times revealed that participants acquired multistep transition knowledge in a manner consistent with gradual updating of an internal successor representation (SR) model. Yet, half of participants did not report being aware of any sequential task structure, and most participants failed to provide meaningful transition probability ratings in a posttask test. Analyses of temporal dynamics of multivariate fMRI patterns during brief 10 s pauses from the ongoing statistical learning task indicated backward sequential replay of multistep sequences in visual cortical areas. Variations in model parameters between participants that captured response time patterns related to strength of neural replay. No corresponding relations between replay and measures of explicit awareness were found. These findings indicate that implicit learning of higher-order relationships establishes an internal SR-based map of the task and is accompanied by cortical on-task replay.}, archive = {J_PNAS}, author = {Wittkuhn, Lennart and Krippner, Lena M. and Koch, Christoph and Schuck, Nicolas W.}, doi = {10.1073/pnas.2507516122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2507516122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Replay in the human visual cortex during brief task pauses is linked to implicit learning of successor representations}, volume = {122}, year = {2025}, }
• (2025). Climate variability amplifies the need for vector-borne disease outbreak preparedness. PNAS, 122(34), e2507311122. (www)

  @article{ , abstract = {In locations that do not currently experience vector-borne disease (VBD) outbreaks but may be at risk under climate change, modeling future climate suitability for transmission is important for outbreak preparedness. Uncertainty in the future climate arises from three sources—differences in emissions scenarios, structural uncertainty across climate models, and internal climate variability (ICV)—but ICV is rarely considered in climate-VBD studies. Here, we demonstrate that ICV is a key source of uncertainty in climate suitability for VBD transmission, even decades into the future. Because of ICV, suitable climate conditions for transmission may arise in many locations sooner than expected under climate change alone.}, archive = {J_PNAS}, author = {Hart, William S. and Hurrell, James W. and Kaye, Alexander R. and Chand, Meera and Keeling, Matt J. and Thompson, Robin N.}, doi = {10.1073/pnas.2507311122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2507311122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Climate variability amplifies the need for vector-borne disease outbreak preparedness}, volume = {122}, year = {2025}, }
• (2025). A β-cap on the FliPQR protein-export channel acts as the cap for initial flagellar rod assembly. PNAS, 122(34), e2507221122. (www)

  @article{ , abstract = {The FliPQR complex constitutes a channel for export of the flagellar proteins involved in axial structure assembly. It also serves as a template for the assembly of the rod structure, which consists of FliE, FlgB, FlgC, FlgF, and FlgG. FliP, FliQ, and FliR assemble into a right-handed helical structure within the central pore of the flagellar basal body MS-ring, and the complex has two gates on the cytoplasmic and periplasmic sides. The periplasmic gate, formed by the N-terminal α-helices of FliP and FliR, remains closed until six FliE subunits assemble onto FliP and FliR to form the first layer of the rod, but it has remained unclear how each FliE subunit opens the gate and assembles in the absence of the rod cap required for efficient assembly of other rod proteins. Here, we present a cryoelectron microscopy structure of the FliPQR complex in closed form at 3.0 Å resolution. A β-cap, formed by the N-terminal β-strands of FliP and FliR, is located at the top of the FliPQR complex and tightly seals the closed gate. The β-cap has a narrow pore that efficiently and accurately leads the first FliE subunit to its assembly site. Interactions of FliE with FliP and FliR induce a conformational change in FliP and FliR, with their N-terminal α-helices move up and outward to open the gate. Consequently, each of the N-terminal β-strands of FliP and FliR detaches from the β-cap one after another, thereby creating a docking site for the next FliE subunit to efficiently assemble.}, archive = {J_PNAS}, author = {Kinoshita, Miki and Miyata, Tomoko and Makino, Fumiaki and Imada, Katsumi and Namba, Keiichi and Minamino, Tohru}, doi = {10.1073/pnas.2507221122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2507221122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A β-cap on the FliPQR protein-export channel acts as the cap for initial flagellar rod assembly}, volume = {122}, year = {2025}, }
• (2025). A tubulin–MAPKKK pathway engages tubulin isotype interaction for neuroprotection. PNAS, 122(34), e2507208122. (www)

  @article{ , abstract = {The microtubule (MT) cytoskeleton is essential for neuronal morphology, neurite growth, synapse formation and maintenance, as well as regulation of signal transduction. Most cells express multiple isotypes of α- and β-tubulin that can coassemble into MTs. While a variety of signaling pathways regulate MT integrity and homeostasis, little is known about how tubulin isotypes interact in vivo. Here, we report a mechanism in which altered function of a neuronal β-tubulin in Caenorhabditis elegans activates the conserved kinase DLK-1 and its downstream signal transduction, which in turn upregulates expression of an α-tubulin isotype to ensure MT integrity. We find that alteration in the T7 loop of the β-tubulin/BEN-1 causes the formation of BEN-1-enriched islands along MTs in neurites. Combining genome editing with cellular imaging, we identified amino acid residues in α-tubulin/TBA-2 that are necessary for formation of BEN-1 islands. Activation of DLK-1 signaling in ben-1 mutants promotes TBA-2 transcription and protects axon and synapse morphology. These data uncover a positive feedback loop between DLK-1 and regulation of tubulin isotype interaction that maintains neuronal resilience.}, archive = {J_PNAS}, author = {Zhou, Junxiang and Feng, Chihin and Sun, Yue and Noma, Kentaro and Jin, Yishi}, doi = {10.1073/pnas.2507208122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2507208122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A tubulin–MAPKKK pathway engages tubulin isotype interaction for neuroprotection}, volume = {122}, year = {2025}, }
• (2025). G-quadruplex stabilization induces DNA breaks in pericentromeric repetitive DNA sequences in b lymphocytes. PNAS, 122(34), e2506939122. (www)

  @article{ , abstract = {DNA secondary G-quadruplex (G4) structures can impair and even obstruct DNA replication. Defects in processing G4 structures are associated with replication stress, a common property of both B cell cancers and hyperproliferative premalignant cells. Genome instability arising from replication stress is a hallmark of cancer and strongly contributes to the chromosome rearrangements in B cell cancers. Here, we define the impact of G4-stabilizing ligands on generating genome instability in primary and malignant B cells. Treatment with the G4-stabilizing compound pyridostatin (PDS) causes breaks and chromosome rearrangements at ribosomal DNA and pericentromeric major satellite regions in both mouse primary B cell culture and CH12 lymphoma cells. PDS also causes extensive pericentromeric DNA damage in immortalized human B cell lines. Remarkably, PDS causes high level of tetraploid metaphase cells correlated with high level of dicentric chromosomes specifically in primary but not in CH12 B cells. Unlike primary B cells, CH12 cells undergo checkpoint activation and strong G2/M arrest in response to PDS treatment thus preventing tetraploid appearance. Altogether, these results highlight the difference between primary and malignant B cells in response to PDS, revealing the therapeutic potential of G4-stabilizing drugs to selectively suppress tumor cell growth and proliferation.}, archive = {J_PNAS}, author = {Waisertreiger, Irina and Ayele, Kalkidan and Elshaikh, Mehad Hilal and Barlow, Jacqueline H.}, doi = {10.1073/pnas.2506939122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2506939122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {G-quadruplex stabilization induces DNA breaks in pericentromeric repetitive DNA sequences in b lymphocytes}, volume = {122}, year = {2025}, }
• (2025). Reduced gas accretion onto galaxies due to effects of external giant radio lobes. PNAS, 122(34), e2506790122. (www)

  @article{ , abstract = {Suppression effects of giant radio lobes from supermassive black holes on gas accretion onto galaxies in the surrounding regions are quantified using cosmological magneto-hydrodynamic simulations. With an appropriate amount of radio jet energy injected into the intergalactic medium following the formation peak of supermassive black holes at redshift two, we find that galaxies in the greater neighborhood of the jet-launching massive galaxies subsequently experience a significant reduction in the amount of accreted gas. The distribution of the resulting magnetic field in the intergalactic medium is highly inhomogeneous, due to the highly biased nature of the most massive supermassive black holes. In regions with magnetic field strength B > 10 − 2 μ G, the baryon fraction is on average reduced by 17%, 14%, and 12%, respectively, for halos of mass in the range of [ 10 11 , 10 12 ) M ⊙ , [ 10 12 , 10 13 ) M ⊙ , and [ 10 13 , 10 14 ) M ⊙ . A proper inclusion of this new, external, global, preventive feedback mechanism from active galactic nuclei (AGN) in the next generation of cosmological simulation may be necessary.}, archive = {J_PNAS}, author = {Qiu, Yu and Cen, Renyue}, doi = {10.1073/pnas.2506790122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2506790122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reduced gas accretion onto galaxies due to effects of external giant radio lobes}, volume = {122}, year = {2025}, }
• (2025). Scaling and mechanical optimality of bristled wings in microinsects. PNAS, 122(34), e2506403122. (www)

  @article{ , abstract = {It is crucial for both animal evolution and engineering to optimize the relative size of structures. Animal wings are no exception, every structural design having its limits in terms of achievable size and performance. For instance, many microinsects have bristled wings, which are more efficient at small scales than the membranous wings common in larger insects. However, the limitations and the optimal characteristics of bristled wings remain largely underinvestigated. We collected morphological and kinematic data on a variety of beetles ranging between 0.3 and 5 mm in wing length. This was followed by a theoretical analysis to explain from the mechanical standpoint the morphological traits and allometric scalings observed in the data. We derived functional dependencies for parameters such as the number of bristles, bristle length and diameter, size of the wing blade, etc., from considerations of wing inertia minimization under the aerodynamic and structural stiffness constraints. The solution of the optimization problem reveals scaling relationships aligning with empirical trends, which suggests that the reduction of wing membrane during miniaturization can be explained by mechanical optimality. Thus, scaling of the number of bristles and the average gap width between bristles follows directly from the aerodynamic condition of maintaining low permeability, while the bristle diameter and length are determined mainly by the structural stiffness requirement. Similar mechanical arguments are likely applicable to other miniature animals that propel through fluids.}, archive = {J_PNAS}, author = {Kolomenskiy, Dmitry and Farisenkov, Sergey E. and Petrov, Pyotr N. and Polilov, Alexey A.}, doi = {10.1073/pnas.2506403122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2506403122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Scaling and mechanical optimality of bristled wings in microinsects}, volume = {122}, year = {2025}, }
• (2025). Sparse autoencoders uncover biologically interpretable features in protein language model representations. PNAS, 122(34), e2506316122. (www)

  @article{ , abstract = {Foundation models in biology—particularly protein language models (PLMs)—have enabled ground-breaking predictions in protein structure, function, and beyond. However, the “black-box” nature of these representations limits transparency and explainability, posing challenges for human–AI collaboration and leaving open questions about their human-interpretable features. Here, we leverage sparse autoencoders (SAEs) and a variant, transcoders, from natural language processing to extract, in a completely unsupervised fashion, interpretable sparse features present in both protein-level and amino acid (AA)-level representations from ESM2, a popular PLM. Unlike other approaches such as training probes for features, the extraction of features by the SAE is performed without any supervision. We find that many sparse features extracted from SAEs trained on protein-level representations are tightly associated with Gene Ontology (GO) terms across all levels of the GO hierarchy. We also use Anthropic’s Claude to automate the interpretation of sparse features for both protein-level and AA-level representations and find that many of these features correspond to specific protein families and functions such as the NAD Kinase, IUNH, and the PTH family, as well as proteins involved in methyltransferase activity and in olfactory and gustatory sensory perception. We show that sparse features are more interpretable than ESM2 neurons across all our trained SAEs and transcoders. These findings demonstrate that SAEs offer a promising unsupervised approach for disentangling biologically relevant information present in PLM representations, thus aiding interpretability. This work opens the door to safety, trust, and explainability of PLMs and their applications, and paves the way to extracting meaningful biological insights across increasingly powerful models in the life sciences.}, archive = {J_PNAS}, author = {Gujral, Onkar and Bafna, Mihir and Alm, Eric and Berger, Bonnie}, doi = {10.1073/pnas.2506316122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2506316122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sparse autoencoders uncover biologically interpretable features in protein language model representations}, volume = {122}, year = {2025}, }
• (2025). Tuning water dissociation at oxide–electrolyte interfaces with electric fields. PNAS, 122(34), e2505929122. (www)

  @article{ , abstract = {Understanding how electric fields influence water dissociation at heterogeneous interfaces is crucial for controlling interfacial chemical reactions and advancing next-generation energy technologies. Herein, ab initio–based machine learning simulations show that even small electric field changes can significantly alter the water dissociation fraction at planar TiO 2 –electrolyte interfaces. The resulting free energy difference between undissociated and dissociated interfacial water exhibits a linear dependence on the field change with a slope of 1.97 e Å, which far exceeds the dissociation-induced dipole change of a water molecule. Employing a machine-learned collective variable to investigate the reaction statistics of thousands of water dissociation/recombination events, we find that small electric field changes exert minor effects on individual reaction energy barriers but significantly influence the populations of local configurations associated with initial states that are most favorable for reactions. These findings elucidate the pronounced impact of electric fields on interfacial water dissociation and reveal a mechanism for electric-field-controlled chemical reactions.}, archive = {J_PNAS}, author = {Zhang, Chunyi and Yu, Zheng and Car, Roberto and Selloni, Annabella}, doi = {10.1073/pnas.2505929122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2505929122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tuning water dissociation at oxide–electrolyte interfaces with electric fields}, volume = {122}, year = {2025}, }
• (2025). Germline variants in UHRF1 are associated with multilocus imprinting disturbance in humans and mice. PNAS, 122(34), e2505884122. (www)

  @article{ , abstract = {The investigation of congenital imprinting disorders (CIDs) provides opportunities to elucidate the molecular mechanisms and role of genomic imprinting in development and human disease. Beckwith–Wiedemann spectrum (BWSp) is a prototypic CID resulting from genetic and epigenetic alterations of imprinted genes at chromosome 11p15.5. In up to a quarter of individuals with BWSp, the epigenetic alterations are not confined to 11p15.5 imprinting control regions but also involve other imprinted gene clusters (multilocus imprinting disturbance; MLID). In a consanguineous family with two children diagnosed with BWSp and MLID, the affected individuals were homozygous for a missense variant in UHRF1 , a gene previously implicated in the maintenance of DNA methylation. To investigate whether the UHRF1 c. 2001G>C, p.(Lys667Asn) missense substitution predisposes to abnormal establishment/maintenance of genomic imprinting patterns, a genetically engineered mouse model with a Uhrf1 p.(Lys661Asn) variant was developed. Mice homozygous for the variant born to heterozygous mothers did not display an abnormal phenotype, but homozygotes born to healthy homozygous mothers displayed a range of phenotypes including prenatal lethality. Also, MLID was observed in affected mouse embryos. These findings are consistent with biallelic UHRF1 variants in affected individuals resulting in an autosomal recessively inherited cause of MLID in humans and expand the range of epigenetic disorders associated with UHRF1.}, archive = {J_PNAS}, author = {Ochoa, Eguzkine and Zvetkova, Ilona and Liv Lee, Sunwoo and Takahashi, Nozomi and Lan-Leung, Benoit and Hobson, Emma and Issa, Mahmoud and Yngvadottir, Bryndis and Docquier, France and Rodger, Fay and Foster-Hall, Dounia and Clark, Graeme and Toribio, Ana and Martin, Ezequiel and Bottolo, Leonardo and Ferguson-Smith, Anne C. and Fischle, Wolfgang and Constancia, Miguel and Maher, Eamonn R.}, doi = {10.1073/pnas.2505884122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2505884122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Germline variants in UHRF1 are associated with multilocus imprinting disturbance in humans and mice}, volume = {122}, year = {2025}, }
• (2025). Soil eDNA reflects regionally dominant species rather than local composition of tropical tree communities. PNAS, 122(34), e2505772122. (www)

  @article{ , abstract = {Environmental DNA (eDNA) is increasingly used for biodiversity monitoring, but validation of the spatial scale(s) at which eDNA reflects extant communities is scarce, particularly in tropical forests: the terrestrial biome with the most concentrated diversity on earth. We leveraged spatially explicit tree inventory data from the 16-ha Luquillo Forest Dynamics Plot (LFDP) in Puerto Rico to validate soil eDNA as a spatially explicit indicator of tree diversity/composition. Using a comprehensive local chloroplast trnL -P6 reference library, we analyzed soil samples at multiple scales through eDNA trnL -P6 metabarcoding. We compared eDNA taxonomic diversity/composition, considering several bioinformatic thresholds, with inventory data across a range of spatial scales, as well as random points to compare observed correlations with random expectations. Despite considerable fine-scale heterogeneity in soil plant eDNA composition, we detected 53 tree Operational Taxonomic Units (OTUs) across the LFDP, corresponding to 68% of tree OTUs from the census data. Encouragingly, this equated to 98% of the total basal area (and 98% of the total stems). An initial confusion matrix evaluation suggested a highly localized eDNA signal (within 5 m of the sampled locations). However, comparison with random expectations revealed a lack of support for a fine-scale spatial signal due to misclassification (i.e., eDNA false presence or/and false absence) of relatively common taxa. Our study shows that “universal” PCR primer metabarcoding of tree eDNA in tropical soils may be useful for assessing dominant taxa at landscape scales, but not for spatially explicit characterization of rare species and community composition at local scales.}, archive = {J_PNAS}, author = {Borràs Sayas, Francesc and Iacovino, Ottavia and Uriarte, María and Zimmerman, Jess K. and Nytch, Christopher J. and Dunshea, Glenn and Muscarella, Robert}, doi = {10.1073/pnas.2505772122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2505772122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Soil eDNA reflects regionally dominant species rather than local composition of tropical tree communities}, volume = {122}, year = {2025}, }
• (2025). Metabolomics navigates natural variation in pathogen-induced secondary metabolism across soybean cultivar populations. PNAS, 122(34), e2505532122. (www)

  @article{ , abstract = {Phytophthora soja e-induced root rot poses a major threat to soybean production. While the molecular mechanisms underlying soybean– P. sojae interactions have been extensively studied, their biochemical basis remains largely unexplored. Previous research has identified key metabolic modules involved in pathogen defense, but structural diversity has largely been constrained by studies on single soybean accessions. Here, we broadened the chemical search space to a diverse soybean germplasm collection using high-throughput metabolomics as a powerful tool for comprehensive metabolic profiling. Chemical classes of lipids and phenylpropanoids again retrieved the most pronounced responses upon P. sojae infection in general. A two-layer analytical strategy further finely resolved metabolites into pathogenesis-, resistance-, and tolerance-type accumulation patterns, leading to the identification of cinnamaldehyde and coumestrol as potent defense metabolites. Bioassays validated cinnamaldehyde directly and strongly inhibited cyst germination and mycelial growth, and coumestrol, a benzofuran-type metabolite, exhibited broad-spectrum activity against spore germination as an identified phytoalexin. Multiomics analyses nailed down the candidate of coumestrol biosynthesis genes, and genetically overexpression of regulatory genes ( Dir2a/4a/4b ) in hairy root systems increased coumestrol accumulation thus positively correlating with improved host resistance. Interestingly, tolerance-type compounds may serve distinct ecological roles, as exemplified by daidzein, which, despite being classified as a tolerance-type metabolite, recruits more zoospores facilitating secondary infection in fact. This study highlights a systematic approach for population-level investigations and emphasizes the necessity of integrating bioinformatics with experimental validation to accurately predict metabolite or gene ecological functions.}, archive = {J_PNAS}, author = {Tian, Mengjun and Sun, Yaru and Zhang, Guodong and Xu, Yufei and Zhu, Jiang and Huang, Wenwen and Wang, Yizhan and Zhang, Bingcui and Li, Zhiyuan and Lin, Shaoyan and Zhang, Fang and Ma, Zhenchuan and Gan, Xiangchao and Tan, Junjie and Chen, Yu and Li, Suhua and Gai, Junyi and Xing, Guangnan and Wang, Ming and Wang, Yuanchao}, doi = {10.1073/pnas.2505532122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2505532122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Metabolomics navigates natural variation in pathogen-induced secondary metabolism across soybean cultivar populations}, volume = {122}, year = {2025}, }
• (2025). Identifying fish populations prone to abrupt shifts via dynamical footprint analysis. PNAS, 122(34), e2505461122. (www)

  @article{ , abstract = {Fish population biomass fluctuates through time in ways that may be either gradual or abrupt. While abrupt shifts in fish population productivity have been shown to be common, they are rarely integrated into stock assessment or fishery management, in part because of the difficulty of predicting when abrupt shifts may occur and which stocks are prone to such shifts. In this study, we address the latter challenge by designing a mechanism-agnostic context-specific approach that is based on exploiting the dynamical properties of fish population fluctuations for detecting potential abrupt shifts. We use time series of fish population biomass from three global datasets, first, to classify their shapes into abrupt and nonabrupt (linear, quadratic, or no change) classes, and, second, to predict classified shapes based only on their dynamical footprint (a set of metrics such as variance, autocorrelation, etc, of the time series). We find that populations prone to abrupt shifts can be detected with moderate accuracy in the three datasets in spite of data limitations. In total, we identified 50 populations at risk of future abrupt shifts across 11 different Large Marine Ecosystem regions. Our context-specific approach offers critical insights into population stability and enables the identification of stocks whose dynamical properties suggest that they would benefit from more precautionary management.}, archive = {J_PNAS}, author = {Cano, Alejandro V. and Jensen, Olaf P. and Dakos, Vasilis}, doi = {10.1073/pnas.2505461122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2505461122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identifying fish populations prone to abrupt shifts via dynamical footprint analysis}, volume = {122}, year = {2025}, }
• (2025). Transient oxygenation of the mediterranean after the zanclean megaflood. PNAS, 122(34), e2505429122. (www)

  @article{ , abstract = {The Mediterranean basin reconnected to the Atlantic Ocean ~5.33 Myr ago, following its partial desiccation during the preceding Messinian salinity crisis (5.97 to 5.33 Myr). While the extent of terminal Messinian drawdown and abruptness of reconnection are debated, recent work inferred that an anomalously long-lasting eastern Mediterranean organic-rich “mystery sapropel” layer was deposited due to salinity-stratification and anoxia following catastrophic flooding that refilled the basin. However, independent evidence is required to test this hypothesis. Here, we present extensive proxy data and numerical model results to show that irrespective of the largely hypersaline or oligohaline conditions proposed for the terminal Messinian, the eastern Mediterranean became oxygenated due to the ~1.5-km-high, turbulent and aerated cascade that refilled the basin, which created a salinity-stratified but oxygenated water column that allowed preservation of only the most recalcitrant organic components. Next, oxygen was gradually depleted over a period of up to 12,000 y due to remineralization of sinking organic matter, culminating in a stratified, anoxic basin. It took 33,000 y after flooding (7,000 y longer than suggested previously) for turbulent diffusion to weaken the stratification and allow resumption of convective deep-water renewal, which marked the final return of normal oxygenated marine conditions throughout the Mediterranean.}, archive = {J_PNAS}, author = {Amarathunga, Udara and Brocks, Jochen J. and Meijer, Paul Th. and Hope, Janet M. and Zachariasse, Willem-Jan and Hennekam, Rick and van der Hoeven, Isabel and Roehl, Ursula and Rule, Susan and Troitzsch, Ulrike and Haberle, Simon and Sluijs, Appy and Grant, Katharine M. and Krijgsman, Wout and Garcia-Castellanos, Daniel and Hogg, Andrew McC. and Reichart, Gert-Jan and Roberts, Andrew P. and Rohling, Eelco J.}, doi = {10.1073/pnas.2505429122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2505429122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transient oxygenation of the mediterranean after the zanclean megaflood}, volume = {122}, year = {2025}, }
• (2025). Interhemispheric resting-state functional connectivity correlates with spontaneous neural interactions. PNAS, 122(34), e2505294122. (www)

  @article{ , abstract = {Functional connectivity (FC), a statistical correlation of pair-wise brain signals from resting-state (RS) functional MRI (fMRI), is a widely used concept for mapping large-scale functional networks in both humans and animals. However, its underlying causal mechanism remains poorly understood, particularly for strong interhemispheric connectivity (e.g., homotopic connections) consistently observed in FC. In this study, we investigated the neural basis of RS FC in mice using fMRI with anatomically defined patterned optogenetic activation and inhibition of excitatory neurons in six cortical regions. Unlike commonly used optogenetic activation, optogenetic silencing suppresses spontaneous neural activity in a localized region, reducing RS synaptic inputs to downstream networked areas. Consequently, fMRI can track spontaneous functional connections without the neural perturbations associated with excitation. While conventional optogenetic activation of excitatory neurons in the targeted cortical areas predominantly elicited their ipsilateral functional responses in both cortical and subcortical regions, optogenetic silencing induced both intra- and interhemispheric cortical responses, which were stronger than cortical-subcortical connections. These effects more closely resembled statistically defined RS FC patterns, providing insight into the underlying mechanisms of intrinsic FC. By modeling synaptic path length-dependent connectivity patterns based on structural connectivity (SC), we found that spontaneous functional connections can be explained by polysynaptic propagation, whereas evoked activity is largely restricted to monosynaptic pathways. These findings highlight the critical role of polysynaptic pathways in shaping spontaneous connectivity, suggesting that RS FC arises from causal interactions of spontaneous ongoing neural activity.}, archive = {J_PNAS}, author = {Moon, Hyun Seok and Vo, Thanh Tan and Ho Im, Geun and Hong, Seok-Jun and Kim, Seong-Gi}, doi = {10.1073/pnas.2505294122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2505294122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Interhemispheric resting-state functional connectivity correlates with spontaneous neural interactions}, volume = {122}, year = {2025}, }
• (2025). Loss of sialic acid side-chain O-acetylation exacerbates colitis. PNAS, 122(34), e2505249122. (www)

  @article{ , abstract = {Sialic acids (Sias) are a diverse family of nine-carbon backbone monosaccharides occupying terminal positions on cell surface and secreted glycans and are abundant at mucosal surfaces. Sias can be modified with O -acetyl esters on the side chain (C7 to C9) hydroxyls. Structural analysis and functional studies of these modifications are challenging due to chemical lability and variable resistance to sialidases. For in-depth analysis of the expression and functions of O -acetyl Sia modifications, we used a unique set of sialoglycan-recognizing probes, HPLC analysis of DMB-derivatized Sias and mice lacking the first known sialate O -acetyltransferase, CASD1. C7/C9- O -acetylated Sias are most abundant in the colon, with lower levels in the heart, brain, and spleen, and minimal levels in other digestive organs of wild-type mice. CASD1 deficiency led to a marked loss of C9/C7- O -acetylated Sias in the colon and other tissues. No differences were observed in colonic O -acetylated Sias from conventional and germ-free wild-type mice, indicating that Sia O -acetylation is independent of the commensal microbiota. Nonetheless, CASD1 deficiency caused subtle changes in microbial gene repertoire consistent with potential exploitation of Sias by subsets of intestinal microbes. Furthermore, CASD1-deficient mice exhibited more severe inflammation and ulceration upon colitis induction compared to controls. Reduced Sia O -acetylation was observed in mice during acute colitis and in colon biopsies from patients with inflammatory bowel disease. Together, our findings suggest CASD1 is the primary physiologically relevant enzyme to add C7/C8/C9- O -acetyl ester groups to Sias and that these Sia modifications exert important gut-protective functions, perhaps by preventing microbial Sia release and metabolism.}, archive = {J_PNAS}, author = {Ji, Yang and Parashar, Shubham and Miyamoto, Yukiko and Srivastava, Saurabh and Lewis, Amanda L. and Varki, Nissi and Varki, Ajit and Eckmann, Lars}, doi = {10.1073/pnas.2505249122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2505249122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Loss of sialic acid side-chain O-acetylation exacerbates colitis}, volume = {122}, year = {2025}, }
• (2025). Reply to xiao et al.: A wet or dry martian mid-crust, that is only part of the question. PNAS, 122(34), e2505168122. (www)

  @article{ , archive = {J_PNAS}, author = {Wright, Vashan and Morzfeld, Matthias and Manga, Michael}, doi = {10.1073/pnas.2505168122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2505168122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to xiao et al.: A wet or dry martian mid-crust, that is only part of the question}, volume = {122}, year = {2025}, }
• (2025). Life’s homochirality: Across a prebiotic network. PNAS, 122(34), e2505126122. (www)

  @article{ , abstract = {For centuries, scientists have been puzzled by the mystery of life’s biomolecular homochirality—the single-handedness of biological compounds. Sugars and nucleic acids are right-handed, while amino acids are left-handed in biological systems. Likewise, certain metabolites are homochiral, though their handedness varies. However, efforts to address the homochirality problem have often focused on a single compound, a single molecular class, or invoke an extraterrestrial origin. Here, we emphasize the importance of achieving homochirality across an entire prebiotic chemical network and explore a terrestrial pathway for its emergence. This pathway is supported by recent experimental results from several independent studies, as well as analyses of pristine asteroid materials. Our analysis identifies the genome as a key site for achieving network-scale homochirality on early Earth and addresses the opposite handedness of D -nucleic acids and L -peptides in biology through nonenzymatic, stereoselective coded peptide synthesis.}, archive = {J_PNAS}, author = {Ozturk, S. Furkan and Sasselov, Dimitar D.}, doi = {10.1073/pnas.2505126122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2505126122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Life’s homochirality: Across a prebiotic network}, volume = {122}, year = {2025}, }
• (2025). Cancer cells subvert the primate-specific KRAB zinc finger protein ZNF93 to control APOBEC3B. PNAS, 122(34), e2505021122. (www)

  @article{ , abstract = {ZNF93 is a primate-restricted Krüppel-associated box zinc finger protein responsible for repressing 20- to 12-My-old L1 transposable elements. Here, we reveal that ZNF93 also regulates the key cancer driver APOBEC3B—a mutagenic enzyme linked to tumorigenesis and cancer progression. ZNF93 depletion impairs DNA synthesis, activates replication and DNA damage checkpoints, and triggers proinflammatory phenotypes. Conversely, its overexpression enhances resistance to exogenous genotoxic stress, mirroring the effects observed with APOBEC3B depletion. ZNF93 expression correlates with cell proliferation rates and is overexpressed in many cancer types. These findings suggest that ZNF93 serves as a critical guardian of genome integrity, co-opted by cancer cells to counterbalance APOBEC3B-induced and L1-derived genomic instability and inflammation.}, archive = {J_PNAS}, author = {Forey, Romain and Raclot, Charlène and Pulver, Cyril and Rosspopoff, Olga and Offner, Sandra and Duc, Julien and Planet, Evarist and Martins, Filipe and Turelli, Priscilla and Trono, Didier}, doi = {10.1073/pnas.2505021122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2505021122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cancer cells subvert the primate-specific KRAB zinc finger protein ZNF93 to control APOBEC3B}, volume = {122}, year = {2025}, }
• (2025). A FRET assay to monitor different structural states of human β-cardiac myosin including the interacting-heads motif. PNAS, 122(34), e2504562122. (www)

  @article{ , abstract = {In cardiac muscle, myosin molecules exist in multiple structural states as they transit through their ATPase cycle, including an off-cycle resting or OFF-state with their catalytic heads in a folded structure known as the interacting-heads motif (IHM). The blocked head configuration (BHC) of the IHM is unusual because its light chain binding region is held in an exaggerated prestroke angle stabilized by interactions with its own S2 tail. An additional partial OFF-state, where the second head of the IHM is not folded back onto the blocked head, has been proposed, which still has the blocked head interacting with S2. Many mutations in the human β-cardiac myosin gene that cause hypertrophic cardiomyopathy are thought to destabilize (decrease the population of) the OFF-states. The effects of pathogenic mutations on the folded back structural states are often studied using indirect assays, including a single-ATP turnover assay that detects the biochemical state of myosin functionally. Here, we use a fluorescence resonance energy transfer (FRET) based sensor for direct quantification in solution of the myosin BHC state. Using the FRET sensor, we provide evidence that the myosin tail acts as an activator of the recovery stroke transition after ATP binding to poststroke state apomyosin and that BHC formation is rapid after ATP binding and depends on formation of the prestroke state. We propose that the positively charged loop 2 of the prestroke state head interacts with the Ring 2 cluster of negatively charged residues on the S2 tail to form a preBHC state that facilitates BHC state formation.}, archive = {J_PNAS}, author = {Goluguri, Rama Reddy and Guhathakurta, Piyali and Nandwani, Neha and Dawood, Aminah and Yokota, Seiji and Roopnarine, Osha and Thomas, David D. and Ruppel, Kathleen M. and Spudich, James A.}, doi = {10.1073/pnas.2504562122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2504562122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A FRET assay to monitor different structural states of human β-cardiac myosin including the interacting-heads motif}, volume = {122}, year = {2025}, }
• (2025). Synergistic action of specialized metabolites from divergent biosynthesis in the human oral microbiome. PNAS, 122(34), e2504492122. (www)

  @article{ , abstract = {Despite extensive efforts, our understanding of the virulence factors contributing to oral biofilm formation—a hallmark of dental caries—remains incomplete. We present evidence that the specialized metabolism of the oral microbiome is a critical yet underexplored factor in oral biofilm formation. Through microbiome analysis, we identified a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) encoding biosynthetic gene cluster that correlates with dental caries and is widely represented in oral pathogens, including Streptococcus mutans . This gene cluster produces two major mutanoclumpin metabolites, MC-584 and MC-586, which feature molecular scaffolds differing in a C–C macrocyclic linkage. Both metabolites synergistically promote robust biofilm formation of S. mutans through a rare dual-metabolite mode of action. Further, each metabolite binds uniquely to the S. mutans cell surface, resulting in distinct multicellular morphologies. The biosynthesis of mutanoclumpins employs a unique chemical logic that produces two major products, rare within PKS-NRPS assembly lines. This study underscores the importance of characterizing genes implicated in human diseases through microbiome analysis and lays the foundation for exploring strategies to inhibit streptococci-induced dental caries.}, archive = {J_PNAS}, author = {Loop Yao, McKenna and Zill, Nicholas A. and Barber, Colin Charles and Du, Yongle and Lin, Peijun and Zhai, Rui and Yoon, Eunice and Al Marzooqi, Dunya and Zhang, Wenjun}, doi = {10.1073/pnas.2504492122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2504492122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synergistic action of specialized metabolites from divergent biosynthesis in the human oral microbiome}, volume = {122}, year = {2025}, }
• (2025). Aspartic acid residues in BBE-like enzymes from morus alba promote a function shift from oxidative cyclization to dehydrogenation. PNAS, 122(34), e2504346122. (www)

  @article{ , abstract = {Berberine bridge enzyme (BBE)-like enzymes catalyze various oxidative cyclization and dehydrogenation reactions in natural product biosynthesis, but the molecular mechanism underlying the selectivity remains unknown. Here, we elucidated the catalytic mechanism of BBE-like oxidases from Morus alba involved in the oxidative cyclization and dehydrogenation of moracin C. X-ray crystal structures of a functionally promiscuous flavin adenine dinucleotide (FAD)–bound oxidase, MaDS1, with and without an oxidative dehydrogenation product were determined at 2.03 Å and 2.21 Å resolution, respectively. Structure-guided mutagenesis and sequence analysis have identified a conserved aspartic acid that directs the reaction toward the oxidative dehydrogenation pathway. A combination of density functional theory (DFT) calculations and molecular dynamics (MD) simulations has revealed that aspartic acid acts as the catalytic base to deprotonate the carbon-cation intermediate to generate the dehydrogenated product, which otherwise undergoes a spontaneous 6π electrocyclization in the oxidative cyclization pathway to furnish the 2H-benzopyran product.}, archive = {J_PNAS}, author = {Guo, Nianxin and Gu, Jun and Zhou, Qingyang and Liu, Fang and Dong, Haoran and Ding, Qi and Wang, Qixuan and Wu, Dongshan and Yang, Jun and Fan, Junping and Gao, Lei and Houk, Kendall N. and Lei, Xiaoguang}, doi = {10.1073/pnas.2504346122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2504346122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Aspartic acid residues in BBE-like enzymes from morus alba promote a function shift from oxidative cyclization to dehydrogenation}, volume = {122}, year = {2025}, }
• (2025). Self-generated chemotaxis of mixed cell populations. PNAS, 122(34), e2504064122. (www)

  @article{ , abstract = {Cell and tissue movement in development, cancer invasion, and immune response relies on chemical or mechanical guidance cues. In many systems, this behavior is locally directed by self-generated signaling gradients rather than long-range, prepatterned cues. However, how heterogeneous mixtures of cells interact nonreciprocally and navigate through self-generated gradients remains largely unexplored. Here, we introduce a theoretical framework for the self-organized chemotaxis of heterogeneous cell populations. We find that the relative chemotactic sensitivities of different cell populations control their long-time coupling and comigration dynamics, with boundary conditions such as external cell and attractant reservoirs substantially influencing the migration patterns. Our model predicts an optimal parameter regime that enables robust and colocalized migration. We test our theoretical predictions with in vitro experiments demonstrating the comigration of distinct immune cell populations, and quantitatively reproduce observed migration patterns under wild-type and perturbed conditions. Interestingly, immune cell comigration occurs close to the predicted optimal regime. Finally, we incorporate mechanical interactions into our framework, revealing a nontrivial interplay between chemotactic and mechanical nonreciprocity in driving collective migration. Together, our findings suggest that self-generated chemotaxis is a robust strategy for the navigation of mixed cell populations.}, archive = {J_PNAS}, author = {Uçar, Mehmet Can and Alsberga, Zane and Alanko, Jonna and Sixt, Michael and Hannezo, Edouard}, doi = {10.1073/pnas.2504064122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2504064122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Self-generated chemotaxis of mixed cell populations}, volume = {122}, year = {2025}, }
• (2025). Negative interplay between HIV-1 gag and amyloid precursor protein centers around competition for VPS4A and TSG101. PNAS, 122(34), e2503988122. (www)

  @article{ , abstract = {Intracellular multivesicular bodies (MVBs) act as sites of assembly and release of HIV type 1 (HIV-1) in macrophages and microglia. Recent work has shown that processing of amyloid precursor protein (APP) into a C-terminal fragment (CTF), termed C99, inhibits HIV-1 access to CD63+ MVBs and to counteract this, HIV-1 Group-specific antigen (Gag) increases C99 processing into toxic amyloids. However, the underlying reasons for this negative interplay between Gag and C99 remain unclear. Here, we show that HIV-1 Gag polyprotein and APP processing pathways intersect and compete, relying in different ways on two vesicular trafficking components: the endosomal sorting complexes required for transport protein, TSG101, and vacuolar protein sorting (VPS) subunit, VPS4A. VPS4A plays a complex role in infection by both directly regulating virion production and the abundance of distinct CTFs with differing subcellular localizations and effects on infection. Meanwhile, APP and C99’s use of TSG101 for insertion into vesicles limits Gag access to MVBs. Depletion of TSG101 resulted in impaired Gag localization to MVBs and processing into mature virions, and this could be partially reversed by codepletion of APP. By contrast, modulation of TSG101 or APP levels had no effect on the localization patterns of a Gag-P6 mutant that is unable to bind TSG101, while this mutant also failed to promote C99 degradation. Our findings reveal how CTF processing and HIV-1 maturation at MVBs converge in complex ways around VPS4A and TSG101, which in turn underlies how these processes negatively influence one another during virus replication in microglia.}, archive = {J_PNAS}, author = {Gu, Feng and Naghavi, Mojgan H.}, doi = {10.1073/pnas.2503988122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2503988122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Negative interplay between HIV-1 gag and amyloid precursor protein centers around competition for VPS4A and TSG101}, volume = {122}, year = {2025}, }
• (2025). Svalbard’s 2024 record summer: An early view of arctic glacier meltdown?. PNAS, 122(34), e2503806122. (www)

  @article{ , abstract = {A record-breaking melt season affected the Arctic glaciers of Svalbard in summer 2024 by a substantial margin. Across the entire archipelago, glacier melting corresponded to an anomaly of up to four SD and exceeded any previous observation. The pan-Svalbard mass loss in summer 2024 amounts to ~61.7 ± 11.1 Gt and corresponds to 1% of the total ice volume on Svalbard and is comparable to that of the Greenland ice sheet (55 ± 35 Gt), which occupies an area about 50 times larger. Altogether, Svalbard and other glacier regions surrounding the Barents Sea lost 102.1 ± 22.9 Gt of ice in a single year and contributed 0.27 ± 0.06 mm (of which 0.16 mm alone is due to Svalbard) to global sea-level, putting the circum-Barents region among the strongest contributors to global sea-level rise in 2024. Most of the 2024 glacier melt occurred during a 6-wk period of persistent atmospheric circulation pattern causing record-high air temperatures, an event with an extremely low recurrence interval under current climate conditions. However, future climate projections suggest that such temperature levels will become increasingly commonplace by the end of the 21st century, potentially even surpassing those of 2024. Svalbard’s summer of 2024 serves as a forecast for future glacier meltdown in the Arctic, offering a glimpse into conditions 70 y ahead.}, archive = {J_PNAS}, author = {Schuler, Thomas Vikhamar and Benestad, Rasmus Emil and Isaksen, Ketil and Kierulf, Halfdan Pascal and Kohler, Jack and Moholdt, Geir and Schmidt, Louise Steffensen}, doi = {10.1073/pnas.2503806122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2503806122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Svalbard’s 2024 record summer: An early view of arctic glacier meltdown?}, volume = {122}, year = {2025}, }
• (2025). Unraveling the neuroimmune mechanisms in cancer-induced bone pain: New horizons for therapeutic intervention of the two-phase paradigm. PNAS, 122(34), e2503779122. (www)

  @article{ , abstract = {Cancer-induced bone pain (CIBP) is a severely painful condition that profoundly impacts patients’ quality of life. However, the neuroimmune mechanisms underlying CIBP remain largely elusive. Substance P (SP), which is known to play a pivotal role in pain perception, became the focal point of our study. To this end, we adopted a comprehensive approach combining behavioral and physiological methods to investigate its role in neuroimmune interactions in CIBP. The results showed that SP released by dorsal root ganglion (DRG) neurons via exocytosis initiates CIBP, with its release peaking on the 14th day and correlating with pain behavior. Macrophages were found to infiltrate the DRGs and the sciatic nerves. Notably, in mice with CIBP, the population of macrophage type I was significantly augmented. Significantly, we found that the deletion of macrophages led to a notable alleviation of CIBP, while the blockade of the SP-neurokinin 1 receptor pathway effectively mitigated the infiltration of macrophages and alleviated CIBP. In the advanced phase, DRGs released C-C Motif Chemokine Ligand 3 and C-C Motif Chemokine Ligand 2 to recruit macrophages. A two-phase model for CIBP progression in mice was proposed, with SP-induced macrophage infiltration in the primary phase and chemokine-mediated macrophage recruitment in the advanced phase. Our investigation has unearthed a previously unrecognized mechanism governing the neuroimmune interaction in CIBP, which highlights a critical target for impeding the progression of this debilitating pain, potentially opening up broad avenues for the development of effective therapeutic interventions at different stages of CIBP with cancer development.}, archive = {J_PNAS}, author = {Wang, Changming and Ji, Haiwang and Wang, Hanwen and Chen, Ziyun and Zhou, Lan and Yang, Yan and Jiang, Yucui and Yu, Guang and Jiang, Ling and Tang, Zongxiang}, doi = {10.1073/pnas.2503779122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2503779122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unraveling the neuroimmune mechanisms in cancer-induced bone pain: New horizons for therapeutic intervention of the two-phase paradigm}, volume = {122}, year = {2025}, }
• (2025). Hippocampal mismatch signals are based on episodic memories and not schematic knowledge. PNAS, 122(34), e2503535122. (www)

  @article{ , abstract = {Prediction errors drive learning by signaling mismatches between expectations and reality, but the neural systems supporting these computations remain debated. The hippocampus is implicated in mismatch detection, yet it is not known whether it signals mismatches with episodic memories or generalized knowledge. Across three functional Magnetic Resonance Imaging (fMRI) experiments, we show that the hippocampus selectively responds to mismatches with episodic memories of specific events. In contrast, schematic mismatches engage Semantic Control and Multiple Demand Networks, as well as subcortical regions linked to prediction error signaling. Episodic mismatches also recruit the Default Mode Network. These findings challenge accounts that propose the hippocampus is a domain-general mismatch detector. Instead, the findings support a more specialized role for the hippocampus in learning that is underpinned by its well-established importance in processing episodic memories.}, archive = {J_PNAS}, author = {Varga, Dominika K. and Raykov, Petar P. and Jefferies, Elizabeth and Ben-Yakov, Aya and Bird, Chris M.}, doi = {10.1073/pnas.2503535122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2503535122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hippocampal mismatch signals are based on episodic memories and not schematic knowledge}, volume = {122}, year = {2025}, }
• (2025). Factors underlying a latitudinal gradient in the S/G lignin monomer ratio in natural poplar variants. PNAS, 122(34), e2503491122. (www)

  @article{ , abstract = {The chemical composition of wood plays a pivotal role in the adaptability and structural integrity of trees. However, few studies have investigated the environmental factors that determine lignin composition and its biological significance in plants. Here, we examined the lignin syringyl-to-guaiacyl (S/G) ratio in members of a Populus trichocarpa population sourced from their native habitat and conducted a genome wide association study to identify genes linked to lignin formation. Our results revealed many significant associations, suggesting that lignin biosynthesis is a complex polygenic trait. Additionally, we found an increase in the S/G ratio from northern to southern geographic origin of the trees sampled, along with a corresponding metabolic and transcriptional reprogramming of xylem cell wall biosynthesis. Further molecular analysis identified a mutation in a cell wall laccase genetically associated with higher S/G ratios that predominate in trees from warmer lower latitudes. Collectively, our findings suggest that lignin heterogeneity arises from an evolutionary process enabling poplar adaptation to different climatic challenges.}, archive = {J_PNAS}, author = {Zhu, Weiwei and Zhang, Jin and Prabhakar, Pradeep Kumar and Chan, Yen On and Weber, Rachel A. and Shu, Mengjun and Panzade, Ganesh and Cooper, Connor J. and Davidson, Russell B. and Parks, Jerry M. and Urbanowicz, Breeanna R. and Tuskan, Gerald A. and Joshi, Trupti and Dixon, Richard A. and Muchero, Wellington and Barros, Jaime}, doi = {10.1073/pnas.2503491122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2503491122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Factors underlying a latitudinal gradient in the S/G lignin monomer ratio in natural poplar variants}, volume = {122}, year = {2025}, }
• (2025). Landscape changes elevate the risk of avian influenza virus diversification and emergence in the east Asian–Australasian flyway. PNAS, 122(34), e2503427122. (www)

  @article{ , abstract = {Highly pathogenic avian influenza viruses (HPAIV) persistently threaten wild waterfowl, domestic poultry, and public health. The East Asian–Australasian Flyway plays a crucial role in HPAIV dynamics due to its large populations of migratory waterfowl and poultry. Over recent decades, this flyway has undergone substantial landscape changes, including both losses and gains of waterfowl habitats. These changes can affect waterfowl distributions, increase contact with poultry, and consequently alter ecological conditions that favor avian influenza virus (AIV) evolution. However, limited research has assessed these likely impacts. Here, we integrated empirical data and an individual-based model to simulate AIV transmission in migratory waterfowl and domestic poultry, including wild-to-poultry spillover and reassortment dynamics in poultry, across landscapes representing the years 2000 and 2015. We used the reassortment incidence as a proxy for ecological and transmission conditions that support viral diversification and the emergence of novel subtypes. Our simulations show that landscape change reshaped the waterfowl distribution, facilitated bird aggregation at improved habitats, increased coinfection, and raised reassortment rate by 1,593%, indicating a substantially higher potential for viral diversification and emergence. Model-generated risk maps show expanded and increased reassortment risk in southeastern China, the Yellow River Basin, and northeastern China. These findings suggest the importance of landscape change as a driver of potential AIV diversification and subtype emergence. This underscores the need for interdisciplinary approaches that integrate landscape dynamics, host movement, and viral evolution to better assess and mitigate future risk.}, archive = {J_PNAS}, author = {Yin, Shenglai and Zhang, Chenchen and Teitelbaum, Claire S. and Si, Yali and Zhang, Geli and Wang, Xinxin and Mao, Dehua and Huang, Zheng Y.X. and Frederik de Boer, Willem and Takekawa, John and Prosser, Diann J. and Xiao, Xiangming}, doi = {10.1073/pnas.2503427122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2503427122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Landscape changes elevate the risk of avian influenza virus diversification and emergence in the east Asian–Australasian flyway}, volume = {122}, year = {2025}, }
• (2025). Action-type mapping principles extend beyond evolutionarily conserved actions, even in people born without hands. PNAS, 122(34), e2503188122. (www)

  @article{ , abstract = {How are actions represented in the motor system? Although the sensorimotor system is broadly organized somatotopically, higher-level sensorimotor areas encode action-type information for reaching and grasping actions—regardless of the acting body part. Does the brain similarly support generalization across acting body parts for more evolutionarily recent actions, such as tool-use? We tested whether there is a body-part-independent action-type organization in sensorimotor areas by examining fMRI responses for tool-use actions that participants performed with their hands or feet. We additionally included individuals born without hands to test whether hand sensorimotor experience is necessary for the development of this action-type organization. Across analyses, we found a consistent dissociation in the motor system. The primary sensorimotor cortices encoded concrete, body-part specific information in both groups. In contrast, higher-level motor areas within the tool-use network represent abstract, action-type information independent of the body part for both groups. Together, our results suggest that the hierarchical organization of the motor system is not dependent on a long evolutionary history of an action. Further, this organization is not dependent on an individual’s manual sensorimotor experience. Our results also show that the functional reorganization in congenital handlessness follows the hierarchical organization of the intact cortex, revealing the limitations of brain plasticity. Finally, the results support using a readout of a more abstract code for hierarchical brain–computer interfaces.}, archive = {J_PNAS}, author = {Martinez-Addiego, Florencia and Liu, Yuqi and Moon, Kyungji and Shytle, Elizabeth and Amaral, Lénia and O’Brien, Caroline and Sen, Sriparna and Riesenhuber, Maximilian and Culham, Jody C. and Striem-Amit, Ella}, doi = {10.1073/pnas.2503188122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2503188122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Action-type mapping principles extend beyond evolutionarily conserved actions, even in people born without hands}, volume = {122}, year = {2025}, }
• (2025). Liquid water might not be the only answer: Evaluating pore-filling materials in the martian crust. PNAS, 122(34), e2503071122. (www)

  @article{ , archive = {J_PNAS}, author = {Xiao, Wanbo and Pan, Lu and Wang, Yanbin and Li, Jiaqi}, doi = {10.1073/pnas.2503071122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2503071122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Liquid water might not be the only answer: Evaluating pore-filling materials in the martian crust}, volume = {122}, year = {2025}, }
• (2025). Aphid herbivory on macrophytes drives adaptive evolution in an aquatic community via indirect effects. PNAS, 122(34), e2502742122. (www)

  @article{ , abstract = {Indirect ecological effects occur when the impact of one species on another is mediated by a third species or the shared environment. Although indirect effects are ubiquitous in nature, we know remarkably little about how they may drive ecoevolutionary processes across community boundaries. Here, we show that insect (aphid) herbivory on macrophytes (duckweed) drove the adaptive evolution of a planktonic crustacean ( Daphnia magna ) in large outdoor aquatic mesocosms via indirect ecological effects. Aphid herbivory reduced duckweed growth and increased the nutrient and light availability in the water column, which promoted phytoplankton growth and boosted the abundance of D. magna that feed on phytoplankton. Whole-genome pool-sequencing and phenotypic assays revealed aphid-herbivory-mediated evolutionary changes to Daphnia population. Transplant experiments indicated that these evolutionary changes were adaptive. Furthermore, aphid-herbivory-mediated biotic and abiotic changes in the aquatic community increased the performance of the macrophytes and aphids. These results demonstrate that indirect ecological effects can shape ecoevolutionary interactions between seemingly independent species in natural communities.}, archive = {J_PNAS}, author = {Schäfer, Martin and Malacrinò, Antonino and Walcher, Christoph and Spaak, Piet and Serwaty-Sárazová, Marie and Käser, Silvana and Bulas, Thea and Dambone-Bösch, Christine and Dexter, Eric and Hottinger, Jürgen and Böttner, Laura and Vorburger, Christoph and Ebert, Dieter and Xu, Shuqing}, doi = {10.1073/pnas.2502742122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2502742122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Aphid herbivory on macrophytes drives adaptive evolution in an aquatic community via indirect effects}, volume = {122}, year = {2025}, }
• (2025). CO2 hydration at the air–water interface: A surface-mediated “in-and-out” mechanism. PNAS, 122(34), e2502684122. (www)

  @article{ , abstract = {An understanding of the CO 2 + H 2 O hydration reaction is crucial for modeling the effects of ocean acidification, for enabling novel carbon storage solutions, and as a model process in the geosciences. While the mechanism of this reaction has been investigated extensively in the condensed phase, its mechanism at the air–water interface remains elusive, leaving uncertain the contribution that surface-adsorbed CO 2 makes to the overall acidification reaction. In this study, we employ machine-learned potentials trained to various levels of theory to provide a molecular-level understanding of CO 2 hydration at the air–water interface. We show that reaction at the interface follows a surface-mediated “in-and-out” mechanism: CO 2 diffuses into the aqueous surface layer, reacts to form carbonic acid, and is subsequently expelled from solution. We show that this surface layer provides a bulk-like solvation environment, engendering similar modes of reactivity and near-identical free energy profiles for the bulk and interfacial processes. Our study unveils an unconventional reaction mechanism that underscores the dynamic nature of the molecular reaction site at the air–water interface. The similarity between bulk and interfacial profiles shows that CO 2 hydration is equally as feasible under these two solvation environments and that acidification rates are likely enhanced by this additional surface contribution.}, archive = {J_PNAS}, author = {Brookes, Samuel G. H. and Kapil, Venkat and Michaelides, Angelos and Schran, Christoph}, doi = {10.1073/pnas.2502684122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2502684122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CO2 hydration at the air–water interface: A surface-mediated “in-and-out” mechanism}, volume = {122}, year = {2025}, }
• (2025). Cognitive bridge between geometric and numerical learning in monkeys. PNAS, 122(34), e2502101122. (www)

  @article{ , abstract = {Educational research highlights strong developmental links between numerical and spatial cognition in humans, often shaped by cultural tools like the number line. However, emerging evidence suggests that these number–space connections may reflect our evolutionary history and emerge even in the absence of cultural tools. We examined how task-naïve monkeys learn spatial and numerical concepts over time. Monkeys’ learning trajectories revealed successful learning of both numerical and geometric concepts. Discriminability effects showed that abstract quantitative features were stronger predictors of accuracy on both tasks than low-level visual similarity, reflecting abstract processing of both tasks. Cross-lagged analyses revealed that learning in the geometry task significantly predicted future gains in numerosity performance, even after controlling session-level trends, within-task stability, and general performance factors. Together, these findings provide evidence that spatial and numerical learning in primates rely on mutual cognitive processes. Such representations could form the evolutionary foundation for the well-documented “cognitive bridge” between numerical and spatial reasoning in human development.}, archive = {J_PNAS}, author = {Cantlon, Jessica F. and Brownell, Logan R. and Li, Jialin and DeLong, Caroline M.}, doi = {10.1073/pnas.2502101122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2502101122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cognitive bridge between geometric and numerical learning in monkeys}, volume = {122}, year = {2025}, }
• (2025). Nitric oxide promotes cysteine N-degron proteolysis through control of oxygen availability. PNAS, 122(34), e2501796122. (www)

  @article{ , abstract = {Selected proteins containing an N-terminal cysteine (Nt-Cys) are subjected to rapid, O 2 -dependent proteolysis via the Cys/Arg-branch of the N-degron pathway. Cysteine dioxygenation is catalyzed in mammalian cells by 2-aminoethanethiol dioxygenase (ADO), an enzyme that manifests extreme O 2 sensitivity. The canonical substrates of this pathway in mammalia are the regulators of G-protein signaling 4, 5, and 16, as well as interleukin-32. In addition to operating as an O 2 -sensing mechanism, this pathway has previously been described as a sensor of nitric oxide (NO), with robust effects on substrate stability upon modulation of NO bioavailability being widely demonstrated. Despite this, no mechanism to describe the action of NO on the Cys/Arg N-degron pathway has yet been substantiated. We demonstrate that NO can regulate the stability of Cys N-degron substrates indirectly via the regulation of ADO cosubstrate availability. Through competitive, O 2 -dependent inhibition of cytochrome C oxidase, NO can substantially modify cellular O 2 consumption rate and, in doing so, alter the availability of O 2 for Nt-Cys dioxygenation. We show that this increase in O 2 availability in response to NO exposure is sufficient to alter both dynamic and steady-state ADO substrate levels. It is likely that this mechanism operates to couple O 2 supply and mitochondrial respiration with responses to G-protein-coupled receptor stimulation.}, archive = {J_PNAS}, author = {Kim, Haeun and Tian, Ya-Min and Ratcliffe, Peter J. and Keeley, Thomas P.}, doi = {10.1073/pnas.2501796122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2501796122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nitric oxide promotes cysteine N-degron proteolysis through control of oxygen availability}, volume = {122}, year = {2025}, }
• (2025). Inbreeding reduces fitness in spatially structured populations of a threatened rattlesnake. PNAS, 122(34), e2501745122. (www)

  @article{ , abstract = {Small and fragmented populations are at high risk of local extinction, in part because of elevated inbreeding and subsequent inbreeding depression. A major conservation priority is to identify the mechanisms and extent of inbreeding depression in small populations. The eastern massasauga ( Sistrurus catenatus ) rattlesnake is listed as Federally Threatened in the United States, having experienced significant habitat fragmentation and concomitant population declines over the past 200 years. Here, we use long-term monitoring of two wild populations of eastern massasaugas in Michigan to estimate the extent of inbreeding in each population, identify mechanisms that generate inbreeding, and test for the impact of inbreeding on fitness. Using targeted genomic data and spatial coordinates of capture locations from over 1000 individuals, we find evidence of inbreeding and link inbreeding to spatial kinship structure within populations, possibly driven by limited dispersal. We reconstruct multigenerational pedigrees for each population to measure reproductive output and use long-term capture–recapture data to estimate individual survival (i.e., the two major components of fitness). We find evidence of inbreeding depression in both fitness metrics. The 5% most inbred individuals are 13.5% less likely to have any surviving offspring and have 11.6% lower annual survival compared to all less inbred individuals. By combining genomics and long-term monitoring data, we are able to link the life history of eastern massasaugas to inbreeding and detect relationships between fitness and inbreeding. These insights provide important conservation context for future management and for understanding how spatial structure can generate inbreeding depression even at fine spatial scales.}, archive = {J_PNAS}, author = {Clark, Meaghan I. and Hileman, Eric T. and Moore, Jennifer A. and Faust, Lisa J. and Junge, Randall E. and Reid, Brendan N. and Bradke, Danielle R. and Bradburd, Gideon S. and Fitzpatrick, Sarah W.}, doi = {10.1073/pnas.2501745122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2501745122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inbreeding reduces fitness in spatially structured populations of a threatened rattlesnake}, volume = {122}, year = {2025}, }
• (2025). RyR1-mediated ca2+-induced ca2+ release plays a negligible role in excitation–contraction coupling of normal skeletal muscle. PNAS, 122(34), e2500449122. (www)

  @article{ , abstract = {Type 1 ryanodine receptor (RyR1) is a Ca 2+ release channel in the sarcoplasmic reticulum in skeletal muscle. In excitation–contraction (E-C) coupling, RyR1 opens by depolarization of transverse tubule membrane via physical interaction with dihydropyridine receptor, which is referred to as depolarization-induced Ca 2+ release (DICR). RyR1 can also be gated via Ca 2+ -induced Ca 2+ release (CICR), in which binding of Ca 2+ directly opens the channel. Thus, RyR1 has two Ca 2+ release modes; DICR and CICR, but the physiological role of CICR has been a matter of debate: whether CICR can amplify Ca 2+ signals in E-C coupling. To address this issue, we created a mouse model carrying a mutation in the Ca 2+ -binding site in RyR1 (RyR1-E3896A), which selectively inhibits CICR. Surprisingly, the homozygous RyR1-E3896A mice show no appreciable changes in E-C coupling, ex vivo muscle contraction, in vivo muscle performance, or muscle fiber type. Gain-of-function mutations in RyR1 cause malignant hyperthermia (MH), which is a lethal disease triggered by inhalational anesthetics. The E3896A mutation conferred resistance to isoflurane-induced MH episodes and severe heat stroke triggered by environmental heat stress. Our data suggest that RyR1-mediated CICR plays a negligible role in E-C coupling of normal skeletal muscle but may increase the risk for muscle diseases when excessively activated.}, archive = {J_PNAS}, author = {Kobayashi, Takuya and Yamazawa, Toshiko and Kurebayashi, Nagomi and Konishi, Masato and Tanihata, Jun and Sugihara, Masami and Miki, Yoshifumi and Noguchi, Satoru and Inoue, Yukiko U. and Inoue, Takayoshi and Sakurai, Takashi and Murayama, Takashi}, doi = {10.1073/pnas.2500449122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2500449122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RyR1-mediated ca2+-induced ca2+ release plays a negligible role in excitation–contraction coupling of normal skeletal muscle}, volume = {122}, year = {2025}, }
• (2025). The functional dynamics of FicD’s TPR domain are modulated by the interaction with ATP and BiP. PNAS, 122(34), e2500079122. (www)

  @article{ , abstract = {The human Fic enzyme FicD plays an important role in regulating the Hsp70 homolog BiP in the endoplasmic reticulum: FicD reversibly modulates BiP’s activity through attaching an adenosine monophosphate to the substrate binding domain. This reduces BiP’s chaperone activity by shifting it into a conformation with reduced substrate affinity. Crystal structures of FicD in the apo, adenosine triphosphate (ATP)-bound, and BiP-bound states suggested significant conformational variability in the tetratricopeptide repeat (TPR) motifs. However, nothing is known about the underlying dynamics. In this study, we investigate the conformational dynamics of FicD’s TPR motifs using two-color, single-molecule Förster resonance energy transfer (smFRET) experiments. We demonstrate that the TPR motifs exhibit conformational dynamics between a TPR-out and a TPR-in conformation on timescales ranging from microseconds to milliseconds. In addition, we extend our investigation on multiple labeling positions within FicD, revealing how conformational dynamics vary depending on the location within the TPR motif. We quantify the motions with dynamic photon distribution analysis for the FRET constructs and generate an ensemble of structures for the different states consistent with the smFRET data using molecular dynamic simulations. We propose a conformational landscape model for FicD where the TPR-in/out states exist in equilibrium and the fraction of dynamic population is altered due to the presence of ATP and BiP. These results indicate that not only is FicD dynamic, but the dynamics are linked to the functionality and interactions of FicD with BiP.}, archive = {J_PNAS}, author = {Runge, Svenja and Bilgen, Ecenaz and Magni, Andrea and Bonollo, Giorgio and Colombo, Giorgio and Itzen, Aymelt and Lamb, Don C.}, doi = {10.1073/pnas.2500079122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2500079122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The functional dynamics of FicD’s TPR domain are modulated by the interaction with ATP and BiP}, volume = {122}, year = {2025}, }
• (2025). Indigenous fire stewardship shaped north american great lakes forests. PNAS, 122(34), e2500024122. (www)

  @article{ , abstract = {Interest in bringing Traditional Ecological Knowledge (TEK) and Western Science together to enhance climate and landscape resilience is growing rapidly, particularly for engagement with pyrogenic communities around the world. For these systems, Indigenous Knowledge offers unique insights that reflect millennia of intimate engagement with local landscapes, while Western Science can offer additional understanding of the emergence of climates and ecological conditions that are novel at evolutionary timescales. Here, we weave Indigenous Knowledge together with a multicentury history of fire, landuse, and forest development derived from tree rings to retell a more complete history of human engagement with the places commonly referred to as Wisconsin and Minnesota Points at the head of Lake Superior in the Laurentian Great Lakes. Our aim in this work is to create mutual reciprocal benefits for those involved in this work to disrupt a long history of extractive research and to honor the knowledge shared with us by reducing barriers to the revitalization of traditional cultural and landuse practices. This intensely local study, contextualized by substantial bodies of Indigenous Knowledge and Western Science, illustrates the importance of place-based and community-based research for understanding the role of Indigenous fire stewardship in shaping pine barrens sites and demonstrates how these fine-scale relationships are linked to regional landscape diversity yet may be invisible to other proxy-based studies. These results help (re)center Indigenous Knowledge and traditional fire-use practices in the process of ecocultural fire restoration for the creation of diverse, resilient, and just socioecological systems that continue to transition toward a warmer future.}, archive = {J_PNAS}, author = {Larson, Evan R. and Montano, Nisogaabokwe Melonee and Lockling, Emily and Ojibway, Ashla and Reynolds, Mocha B. and Zhaawendaagozikwe, Valerie Ross and Johnson, Lane B. and Kipfmueller, Kurt F. and Dockry, Michael J. and Northrup, Vern and Savage, Jeff and Kimmerer, Robin Wall}, doi = {10.1073/pnas.2500024122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2500024122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Indigenous fire stewardship shaped north american great lakes forests}, volume = {122}, year = {2025}, }
• (2025). GATA3 promotes ferroptosis resistance by repressing integrin β1 signaling. PNAS, 122(34), e2427304122. (www)

  @article{ , abstract = {Understanding mechanisms that determine the response of cells to ferroptotic stress is a timely issue that has significant ramifications for biology and pathology. We investigated these mechanisms in the context of breast cancer where tumors are composed of diverse populations of cancer cells that differ in their ferroptosis sensitivity. Using single-cell RNA-sequencing, we determined that cancer cell populations with luminal differentiation are more resistant to ferroptosis than other cells within a heterogeneous tumor. Subsequent bioinformatic analysis and experimentation revealed that GATA3, a transcription factor that promotes luminal differentiation, has a causal role in ferroptosis resistance in luminal breast cancer cells. In pursuit of the mechanism involved, we found that GATA3 represses the expression of integrin β1 and its downstream signaling cascade. This observation led us to demonstrate that integrin β1 signaling is necessary for sensitivity to ferroptosis in basal breast cancer cells because it regulates a FAK/ROCK pathway that sustains the expression of ACSL4, a lipid-modifying enzyme that is essential for ferroptosis. The repression of integrin β1 by GATA3 inhibits this signaling pathway, rendering cells ferroptosis resistant. Together, these data provide insight into mechanisms of ferroptosis sensitivity and resistance that are linked to the cell biology and signaling pathways of the diverse types of cells present in breast tumors.}, archive = {J_PNAS}, author = {Karner, Emmet R. and Wang, Mengdie and Goel, Hira Lal and Mercurio, Arthur M.}, doi = {10.1073/pnas.2427304122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2427304122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {GATA3 promotes ferroptosis resistance by repressing integrin β1 signaling}, volume = {122}, year = {2025}, }
• (2025). Pervasive and recurrent hybridization prevents inbreeding in europe’s most threatened seabird. PNAS, 122(34), e2427223122. (www)

  @article{ , abstract = {Hybridization is a double-edged sword: While it can erode distinct evolutionary lineages, it can also introduce genetic diversity and adaptive potential into dwindling populations. In the Critically Endangered Balearic shearwater ( Puffinus mauretanicus ), this dilemma is exacerbated by a limited understanding of the extent and consequences of hybridization with the Yelkouan shearwater ( Puffinus yelkouan ). This knowledge gap has limited the scope of science-based conservation strategies to avoid the Balearic shearwater’s imminent extinction. Here, we investigate shearwater hybridization dynamics and their effect on genome-wide diversity in the Balearic shearwater. Divergence dating, demographic modeling, and admixture analyses suggest that these two poorly differentiated shearwater lineages have experienced recurrent episodes of divergence and widespread hybridization during glacial cycles. Selection scans reveal a 500 kb region hosting an adaptive haplotype that potentially underpins interspecific differences in migratory behavior and which has been repeatedly introgressed between the two taxa. Moreover, we show that interspecific gene flow has prevented increases in homozygosity and genetic load, and through forward simulations, we illustrate how it can buffer the negative effects of future population bottlenecks in the Balearic shearwater. Our findings illustrate how introgression can be crucial for maintaining genetic diversity in threatened taxa and highlight the need for considering the protection of hybridization in conservation plans.}, archive = {J_PNAS}, author = {Izquierdo-Arànega, Guillem and Cuevas-Caballé, Cristian and Giannelli, Francesco and Paris, Josephine R. and Bourgeois, Karen and Trucchi, Emiliano and González-Solís, Jacob and Riutort, Marta and Obiol, Joan Ferrer and Rozas, Julio}, doi = {10.1073/pnas.2427223122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2427223122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pervasive and recurrent hybridization prevents inbreeding in europe’s most threatened seabird}, volume = {122}, year = {2025}, }
• (2025). Fragmentation signatures in cancer patients resemble those of patients with vascular or autoimmune diseases. PNAS, 122(34), e2426890122. (www)

  @article{ , abstract = {Multiple case-controlled studies have shown that analyzing fragmentation patterns in plasma cell-free DNA (cfDNA) can distinguish individuals with cancer from healthy controls. However, there have been few studies that investigate various types of cfDNA fragmentomics patterns in individuals with other diseases. We therefore developed a comprehensive statistic, called fragmentation signatures, that integrates the distributions of fragment positioning, fragment length, and fragment end-motifs in cfDNA. We found that individuals with venous thromboembolism, systemic lupus erythematosus, dermatomyositis, or scleroderma have cfDNA fragmentation signatures that closely resemble those found in individuals with advanced cancers. Furthermore, these signatures were highly correlated with increases in inflammatory markers in the blood. We demonstrate that these similarities in fragmentation signatures lead to high rates of false positives in individuals with autoimmune or vascular disease when evaluated using conventional binary classification approaches for multicancer earlier detection (MCED). To address this issue, we introduced a multiclass approach for MCED that integrates fragmentation signatures with protein biomarkers and achieves improved specificity in individuals with autoimmune or vascular disease while maintaining high sensitivity. Though these data put substantial limitations on the specificity of fragmentomics-based tests for cancer diagnostics, they also offer ways to improve the interpretability of such tests. Moreover, we expect these results will lead to a better understanding of the process—most likely inflammatory—from which abnormal fragmentation signatures are derived.}, archive = {J_PNAS}, author = {Curtis, Samuel D. and Liu, Tingshan and Bai, Yuxin and Wang, Yuxuan and Panda, Sambit and Li, Adam and Xu, Haoyin and O’Reilly, Eliza and Dobbyn, Lisa and Popoli, Maria and Ptak, Janine and Silliman, Natalie and Thoburn, Chris and Tie, Jeanne and Gibbs, Peter and Ho-Pham, Lan T. and Tran, Bich N. H. and Tran, Thach S. and Nguyen, Tuan V. and Konig, Maximilian F. and Petri, Michelle and Rosen, Antony and Mecoli, Christopher A. and Shah, Ami A. and Mulder, Frits and van Es, Nick and null, null and Bettegowda, Chetan and Kinzler, Kenneth W. and Papadopoulos, Nickolas and Vogelstein, Joshua T. and Vogelstein, Bert and Douville, Christopher and Klok, Frederikus A. and Beyer-Westendorf, Jan and Jara-Palomares, Luis and Ageno, Walter and Peters, Mike J.L. and Delluc, Aurélien and Best, Myron and Guman, Noori and Otten, Hans-Martin}, doi = {10.1073/pnas.2426890122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2426890122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fragmentation signatures in cancer patients resemble those of patients with vascular or autoimmune diseases}, volume = {122}, year = {2025}, }
• (2025). Laser-emitting aqueous bioreactors for ultrasensitive bioactivity analysis. PNAS, 122(34), e2425829122. (www)

  @article{ , abstract = {Water droplets, acting as natural bioreactors and optical whispering-gallery-mode (WGM) resonators, hold the potential for laser-assisted analysis. However, water/aqueous droplet lasers can only survive in air with a limited lifespan (<100 s) due to rapid evaporation, restricting their applications in bioreactions. To address this challenge, we introduce laser-emitting aqueous bioreactors (LEABs) in fluorocarbon oils. These LEABs enable stable laser emission and extend a droplet lifespan over 1,000-fold. LEABs enable the encapsulation of bioactive materials for long-term analysis with unique lasing characteristic fingerprints. The reactions within LEAB can interact with the most resonating light, enhancing detection sensitivity by over 100-fold compared to conventional WGM sensors. By integrating LEABs with microfluidic droplet technology, we demonstrated their application in monitoring enzyme activity and cellular metabolism at single-cell and multicellular levels. Furthermore, we showed the laser threshold-gated screening of single yeast. This platform can bridge the gap between laser technology and biochemical applications, broadening the scope of laser-based analysis.}, archive = {J_PNAS}, author = {Fang, Guocheng and Tseng, Po-Hao and Liao, Jie and Zhu, Song and Zhou, Tian and Liu, Hangrui and Zhu, Hui and Jin, Dayong and Yang, Lan and Chen, Yu-Cheng}, doi = {10.1073/pnas.2425829122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2425829122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Laser-emitting aqueous bioreactors for ultrasensitive bioactivity analysis}, volume = {122}, year = {2025}, }
• (2025). FADDDED filaments coordinate complex IIa assembly during TNF-induced apoptosis. PNAS, 122(34), e2425802122. (www)

  @article{ , abstract = {Extrinsic apoptosis is initiated by signaling from death receptors, leading to the assembly of RIPK1, FADD, and caspase-8 complex. Subsequently, caspase-8 forms a filamentous structure through the oligomerization of its tandem death effector domain (tDED), resulting in caspase activation and cell death. Although the DED of FADD ( FADD DED) is homologous to the tDEDs of caspase-8 ( casp8 tDED) and both oligomerize to function, the functional form of FADD DED oligomer in extrinsic apoptosis remains unclear. Here, using cryogenic-electron microscopy, we elucidate the structure of FADD DED filaments comprising three helical chains assembled through three types of iterative interactions. Mutations disrupting FADD DED filament formation impair the recruitment of RIPK1 and caspase-8, and abrogate the cell death response, suggesting that FADD DED filamentation represents an important mechanistic step in the initiation of TNF-induced extrinsic apoptosis. Contrary to the belief that the homotypic death domains of RIPK1 and FADD are solely responsible for their interaction, we here show this interaction requires FADD DED filamentation. Furthermore, cFLIP can disrupt FADD DED filaments, uncovering an additional antiapoptotic mechanism of cFLIP beyond its disruption of caspase-8 filament. Molecular dynamics simulations reveal that FADD DED filament thermodynamically favors casp8 tDED monomer over FADD DED monomer, thus explaining the hierarchy and stoichiometry of FADD/caspase-8 complex assembly. These findings highlight the hitherto unappreciated roles of FADD DED filament formation in extrinsic apoptosis.}, archive = {J_PNAS}, author = {Chen, Ying and Huynh, Vinh Thang and Lai, Lihua and Liu, Ping and Li, Tongyang and Tan, Yaw Bia and Chew, Che Shin and Velazquez, Amhed Missael Vargas and Samsudin, Firdaus and Marzinek, Jan K. and Bond, Peter J. and Wu, Bin and Luo, Dahai and Tergaonkar, Vinay}, doi = {10.1073/pnas.2425802122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2425802122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {FADDDED filaments coordinate complex IIa assembly during TNF-induced apoptosis}, volume = {122}, year = {2025}, }
• (2025). Amazonian and andean tree communities are not tracking current climate warming. PNAS, 122(34), e2425619122. (www)

  @article{ , abstract = {Climate change is shifting species distributions, leading to changes in community composition and novel species assemblages worldwide. However, the responses of tropical forests to climate change across large-scale environmental gradients remain largely unexplored. Using long-term data over 66,000 trees of more than 2,500 species occurring over 3,500 m elevation along the hyperdiverse Amazon-to-Andes elevational gradients in Peru and Bolivia, we assessed community-level shifts in species composition over a 40+ y time span. We tested the thermophilization hypothesis, which predicts an increase in the relative abundances of species from warmer climates through time. Additionally, we examined the relative contributions of tree mortality, recruitment, and growth to the observed compositional changes. Mean thermophilization rates (TR) across the Amazon-to-Andes gradient were slow relative to regional temperature change. TR were positive and more variable among Andean forest plots compared to Amazonian plots but were highest at midelevations around the cloud base. Across all elevations, TR were driven primarily by tree mortality and decreased growth of highland (cool-adapted) species rather than an influx of lowland species with higher thermal optima. Given the high variability of community-level responses to warming along the elevational gradients, the high tree mortality, and the slower-than-warming rates of compositional change, we conclude that most tropical tree species, and especially lowland Amazonian tree species, will not be able to escape current or future climate change through upward range shifts, causing fundamental changes to composition and function in Earth’s highest diversity forests.}, archive = {J_PNAS}, author = {Farfan-Rios, William and Feeley, Kenneth J. and Myers, Jonathan A. and Tello, Sebastian and Sallo-Bravo, Jhonatan and Malhi, Yadvinder and Phillips, Oliver L. and Baker, Timothy R. and Nina-Quispe, Alex and Garcia-Cabrera, Karina and Saatchi, Sasan S. and Terborgh, John W. and Pitman, Nigel C. A. and Monteagudo Mendoza, Abel Lorenzo and Vasquez, Rodolfo and Salinas, Norma and Cayola, Leslie and Fuentes Claros, Alfredo and Loza, Maria I. and Nuñez Vargas, Percy and Silman, Miles R.}, doi = {10.1073/pnas.2425619122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2425619122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Amazonian and andean tree communities are not tracking current climate warming}, volume = {122}, year = {2025}, }
• (2025). A universal of speech timing: Intonation units form low-frequency rhythms. PNAS, 122(34), e2425166122. (www)

  @article{ , abstract = {Intonation units (IUs) are a hypothesized universal building block of human speech [W. Chafe, Discourse, Consciousness and Time: The Flow and Displacement of Conscious Experience in Speaking and Writing (1994); N. P. Himmelmann et al. , Phonology 35 , 207–245 (2018)). Linguistic research suggests they are found across languages and that they fulfill important communicative functions such as the pacing of ideas in discourse and swift turn-taking. We study the rate of IUs in 48 languages from every continent and from 27 distinct language families. Using an analytic method to annotate natural speech recordings, we identify a low-frequency rate of IUs across the sample, with a peak at 0.6 Hz, and little variation between sexes or across the life span. We find that IU rate is only weakly related to speech rate quantified at the syllable level, and crucially, that cross-linguistic variation in IU rate does not stem from cross-linguistic variation in syllable rate.}, archive = {J_PNAS}, author = {Inbar, Maya and Grossman, Eitan and Landau, Ayelet N.}, doi = {10.1073/pnas.2425166122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2425166122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A universal of speech timing: Intonation units form low-frequency rhythms}, volume = {122}, year = {2025}, }
• (2025). The medicago truncatula lncRNA ENOD40 is a mediator of microRNA169-controlled NF-YA activity in nodule initiation. PNAS, 122(34), e2424231122. (www)

  @article{ , abstract = {The hallmark of the legume lncRNA EARLY NODULIN40 ( ENOD40 ), involved in rhizobium-induced nodulation, is the presence of a highly conserved stretch of 24 nucleotides, designated box2, preceded by a small open-reading-frame (sORF) coding for a peptide of 12 to 13 amino acids. Although there is a well-established link between ENOD40 and nodulation, it is not fully clear by which mechanism ENOD40 functions in this process. Here, we show that a region harboring box2 can complement nodule formation in an ENOD40 knock-out mutant ( enod40-1-2/1 ). The sequence of box2 bears the characteristics of a miR169 target mimic. We show that the artificial target mimic MIM169defg can indeed complement the reduced capability of nodule formation in enod40-1-2/1 , and that box2 exhibits target mimic activity in a transient luciferase assay. In addition, the introduction of a miR169 -resistant form of MtNF-YA1 also elevates the capacity to form nodules in enod40-1-2/1. We conclude that ENOD40 effectuates nodule initiation by posttranscriptional upregulation of the miR169 target NF-YA1 , which encodes an essential transcription factor in this step of the nodulation process.}, archive = {J_PNAS}, author = {Wijsman, Tristan and Mohd-Radzman, Nadia A. and Liu, Jieyu and Oldroyd, Giles E. D. and Kohlen, Wouter and Kulikova, Olga and Heidstra, Renze and Scheres, Ben and Franssen, Henk J.}, doi = {10.1073/pnas.2424231122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2424231122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The medicago truncatula lncRNA ENOD40 is a mediator of microRNA169-controlled NF-YA activity in nodule initiation}, volume = {122}, year = {2025}, }
• (2025). Minimizing and quantifying uncertainty in AI-informed decisions: Applications in medicine. PNAS, 122(34), e2424203122. (www)

  @article{ , abstract = {AI is now a cornerstone of modern dataset analysis. In many real world applications, practitioners are concerned with controlling specific kinds of errors, rather than minimizing the overall number of errors. For example, biomedical screening assays may primarily be concerned with mitigating the number of false positives rather than false negatives. Quantifying uncertainty in AI-based predictions, and in particular those controlling specific kinds of errors, remains theoretically and practically challenging. We develop a strategy called multidimensional informed generalized hypothesis testing (MIGHT) which we prove accurately quantifies uncertainty and confidence given sufficient data, and concomitantly controls for particular error types. Our key insight was that it is possible to integrate canonical cross-validation and parametric calibration procedures within a nonparametric ensemble method. Simulations demonstrate that while typical AI based-approaches cannot be trusted to obtain the truth, MIGHT can be. We apply MIGHT to answer an open question in liquid biopsies using circulating cell-free DNA (ccfDNA) in individuals with or without cancer: Which biomarkers, or combinations thereof, can we trust? Performance estimates produced by MIGHT on ccfDNA data have coefficients of variation that are often orders of magnitude lower than other state of the art algorithms such as support vector machines, random forests, and Transformers, while often also achieving higher sensitivity. We find that combinations of variable sets often decrease rather than increase sensitivity over the optimal single variable set because some variable sets add more noise than signal. This work demonstrates the importance of quantifying uncertainty and confidence—with theoretical guarantees—for the interpretation of real-world data.}, archive = {J_PNAS}, author = {Curtis, Samuel D. and Panda, Sambit and Li, Adam and Xu, Haoyin and Bai, Yuxin and Ogihara, Itsuki and O’Reilly, Eliza and Wang, Yuxuan and Dobbyn, Lisa and Popoli, Maria and Ptak, Janine and Nehme, Nadine and Silliman, Natalie and Tie, Jeanne and Gibbs, Peter and Ho-Pham, Lan T. and Tran, Bich N. H. and Tran, Thach S. and Nguyen, Tuan V. and Irajizad, Ehsan and Goggins, Michael and Wolfgang, Christopher L. and Wang, Tian-Li and Shih, Ie-Ming and Fader, Amanda and Lennon, Anne Marie and Hruban, Ralph H. and Bettegowda, Chetan and Gilbert, Lucy and Kinzler, Kenneth W. and Papadopoulos, Nickolas and Vogelstein, Bert and Vogelstein, Joshua T. and Douville, Christopher}, doi = {10.1073/pnas.2424203122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2424203122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Minimizing and quantifying uncertainty in AI-informed decisions: Applications in medicine}, volume = {122}, year = {2025}, }
• (2025). Opposing action of photosystem II assembly factors RBD1 and HCF136 underlies light-regulated psbA translation in plant chloroplasts. PNAS, 122(34), e2423694122. (www)

  @article{ , abstract = {The D1 subunit of photosystem II (PSII) is subject to light-induced damage. In plants, D1 photodamage activates translation of chloroplast psbA mRNA encoding D1, providing D1 for PSII repair. Three D1 assembly factors have been implicated in the regulatory mechanism: HCF244 and RBD1 activate psbA translation, whereas HCF136 represses psbA translation in the dark. To clarify the regulatory circuit, we analyzed psbA ribosome occupancy in dark-adapted and illuminated rbd1 and rbd1;hcf136 double mutants in Arabidopsis and in Zm- hcf244 and Zm- hcf244; Zm- hcf136 double mutants in maize. The results show that RBD1 is required for light-induced psbA translation but has only a small effect on psbA ribosome occupancy in the dark. RBD1 is not required for psbA translation when HCF136 is absent, indicating that RBD1 activates psbA translation in the light by inhibiting HCF136’s repressive effect. By contrast, HCF244 is required to recruit ribosomes to psbA mRNA in light, dark, and in the absence of HCF136. We demonstrate further that HCF244 is not required for the translational activator HCF173 to bind the psbA 5’UTR. These results show that RBD1 is central to the perception of the D1 photodamage that triggers D1 synthesis and that it activates psbA translation by relieving repression by an HCF136-dependent assembly intermediate. HCF244 activates downstream of those events without impacting HCF173’s binding to psbA mRNA. The results implicate a feature of nascent D1 that is affected by both HCF136 and RBD1 as the signal that reports D1 photodamage to regulate psbA translation rate as needed for PSII repair.}, archive = {J_PNAS}, author = {Rojas, Margarita and Williams-Carrier, Rosalind and Chotewutmontri, Prakitchai and Belcher, Susan and Boyce, Emily and Barkan, Alice}, doi = {10.1073/pnas.2423694122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2423694122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Opposing action of photosystem II assembly factors RBD1 and HCF136 underlies light-regulated psbA translation in plant chloroplasts}, volume = {122}, year = {2025}, }
• (2025). Multisensory feedback makes swimming circuits robust against spinal transection and enables terrestrial crawling in elongate fish. PNAS, 122(34), e2422248122. (www)

  @article{ , abstract = {Vertebrate locomotion is due to the interplay of neural oscillators and sensory feedback loops in the spinal cord that interact with the body and the environment. Here, we study these circuits with a focus on undulatory locomotion as produced by elongated fish such as eels and lampreys. We address three questions: i) How do proprioception (stretch feedback) and exteroception (pressure on skin) interact with local oscillators to generate stable swimming patterns? ii) Can these feedback loops also contribute to dry ground locomotion? iii) Can they explain the remarkable robustness of eels against spinal cord transections? To address these questions, we developed abstract models of the locomotion circuits based on coupled phase oscillators, local stretch and pressure feedback loops, and simulated muscle models that were tested both in simulation and with a real undulatory robot. We also performed swimming experiments with eels before and after spinal cord transections. We found that stretch and pressure feedback work well together in swimming, as they contribute to rapid pattern generation and can, in principle, both replace direct couplings between oscillators. Interestingly, the swimming controllers could generate good ground locomotion when placed in an arena with pegs. For ground locomotion, the stretch feedback is more beneficial than pressure feedback. Finally, our models could replicate the remarkable ability of eels to keep swimming shortly after a full spinal cord transection. We found that stretch feedback and the ability of oscillators to spontaneously oscillate are likely explanations for keeping the neural oscillators active and coordinated below the transection.}, archive = {J_PNAS}, author = {Yasui, Kotaro and Gupta, Astha and Fu, Qiyuan and Suzuki, Shura and Hainer, Jeffrey and Paez, Laura and Lutek, Keegan and Arreguit, Jonathan and Kano, Takeshi and Standen, Emily M. and Ijspeert, Auke J. and Ishiguro, Akio}, doi = {10.1073/pnas.2422248122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2422248122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multisensory feedback makes swimming circuits robust against spinal transection and enables terrestrial crawling in elongate fish}, volume = {122}, year = {2025}, }
• (2025). Altricial brains and the evolution of infant vocal learning. PNAS, 122(34), e2421095122. (www)

  @article{ , abstract = {Vocal development in human infants is strongly influenced by interactions with caregivers who reinforce more speech-like sounds. This trajectory of vocal development in humans is radically different from those of our close phylogenetic relatives, cercopithecoid monkeys and apes. In these primates, social feedback seems to play no significant role in their vocal development. Oddly,marmoset monkeys, a more distantly related primate species, do exhibit socially guided vocal learning. How can this be? We hypothesized that the evolution of human and marmoset vocal learning in early infancy is facilitated by their neurally altricial births (relative to other primates) and their cooperative breeding social environment. Our analysis found that, indeed, both human and marmoset brains are growing faster at birth when compared with chimpanzees and rhesus macaques, making humans and marmoset monkeys altricial relative to these other primates. The time interval of this faster brain growth overlaps with important vocal learning milestones. We formalized our hypothesis using a simple model showing that if vocal learning is influenced by the timing of brain growth and social stimuli, it benefits from an altricial brain and a cooperative breeding environment. Our data support the idea that the evolution of socially guided vocal learning during early infancy in humans and marmosets was afforded by infants with an altricial brain embedded in a vocally rich environment.}, archive = {J_PNAS}, author = {Biazzi, Renata B. and Takahashi, Daniel Y. and Ghazanfar, Asif A.}, doi = {10.1073/pnas.2421095122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2421095122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Altricial brains and the evolution of infant vocal learning}, volume = {122}, year = {2025}, }
• (2025). Warming climate and water withdrawals threaten river flow connectivity in china. PNAS, 122(34), e2421046122. (www)

  @article{ , abstract = {River flow connectivity, the continuity of fluvial discharge in space and time, provides a crucial lifeline for most biotic communities on Earth. Yet there is still limited understanding of the impacts of climate change and human water withdrawal on river connectivity. Here, we assess the river flow connectivity of 217,001 river reaches in mainland China from 1961 to 2020 and the impact of different climate warming trends and water withdrawals for different sectors. We estimate that naturally intermittent rivers represent about 13% of all river reaches, with a large contrast between northern and southern China (12% vs. 1%, respectively). Although river intermittency decreased slightly during this period (i.e., river connectivity lengthened due to increasing precipitation), warming temperatures offset this decrease by reducing surface water persistence, causing the decrease (−476 vs. −233 km/y) to double when removing the long-term temperature trend. Critically, the length of intermittent rivers increased remarkably from 13 to 50% when considering human water withdrawal by agricultural, domestic, and industrial sectors, in addition to environmental flow requirements. Our findings highlight the urgent need to maintain sustainable water resources in a warming climate in which unregulated water abstractions increasingly threaten river flow connectivity, particularly in drying regions.}, archive = {J_PNAS}, author = {Gou, Jiaojiao and Miao, Chiyuan and Ni, Jinren and Sorooshian, Soroosh and Duan, Qingyun and Yan, Denghua and Slater, Louise and Xu, Zongxue and Borthwick, Alistair G. L. and Su, Lu and Zhang, Qi and Wada, Yoshihide}, doi = {10.1073/pnas.2421046122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2421046122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Warming climate and water withdrawals threaten river flow connectivity in china}, volume = {122}, year = {2025}, }
• (2025). Object-directed action representations are componentially built in parietal cortex. PNAS, 122(34), e2421032122. (www)

  @article{ , abstract = {The inferior parietal lobule supports action representations that are necessary to grasp and use objects in a functionally appropriate manner [S. H. Johnson-Frey, Trends Cogn. Sci. 8 , 71–78 (2004)]. The supramarginal gyrus (SMG) is a structure within the inferior parietal lobule that specifically processes object-directed patterns of manipulation during functional object use. Here, we demonstrate that neural representations of complex object-directed actions in the SMG can be predicted by a linear encoding model that componentially builds complex actions from an empirically defined set of kinematic synergies. Each kinematic synergy represents a unique combination of finger, hand, wrist, and arm postures and movements. Control analyses demonstrate that models based on image-computable similarity (AlexNet, ResNet50, VGG16) robustly predict variance in visual areas, but not in the SMG. We also show that SMG activity is specifically modulated by kinematic (as opposed to visual) properties of object-directed actions. The action-relevant, as opposed to visually relevant, nature of the representations supported by the SMG aligns with findings from neuropsychological studies of upper limb apraxia. These findings support a model in which kinematic synergies are the basic unit of representation, out of which the SMG componentially builds object-directed actions. In combination with other findings [Q. Chen et al., Cereb. Cortex 28 , 2162–2174 (2018)], we suggest that kinematic synergies are related to complex object-directed actions in a similar way to how articulatory and voicing features combine to form phonological segments in spoken language production.}, archive = {J_PNAS}, author = {Caglar, Leyla Roksan and Walbrin, Jon and Akwayena, Emefa and Almeida, Jorge and Mahon, Bradford Z.}, doi = {10.1073/pnas.2421032122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2421032122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Object-directed action representations are componentially built in parietal cortex}, volume = {122}, year = {2025}, }
• (2025). Macrophage TBK1 signaling drives the development and outgrowth of breast cancer brain metastasis. PNAS, 122(34), e2420793122. (www)

  @article{ , abstract = {Tumor-associated macrophages (TAMs) are the predominant immune cells in the tumor microenvironment that promote breast cancer brain metastasis (BCBM). Here, we identify TANK-binding kinase (TBK1) as a critical signaling molecule enriched and activated in TAMs of BCBM tumors, playing an indispensable role in BCBM development and metastatic outgrowth in the brain. Mechanistically, BCBM cell-secreted matrix metalloproteinase 1 binds to protease-activated receptor 1 and integrin αVβ5 on macrophages, leading to TBK1 activation mediated by the nuclear factor-kappa B pathway. Reciprocally, TBK1-regulated TAMs produce granulocyte-macrophage colony-stimulating factor (GM-CSF) to drive breast cancer cell epithelial–mesenchymal transition, migration, and invasion, ultimately contributing to BCBM development and brain metastatic outgrowth. Inhibition of TBK1 signaling in TAMs or GM-CSF receptor in cancer cells impedes BCBM development and brain metastatic outgrowth. Correspondingly, the TBK1–GM-CSF signaling axis correlates with lower overall survival in patients with BCBM. Thus, TBK1-mediated tumor-TAM symbiotic interaction provides a promising therapeutic target for patients with BCBM.}, archive = {J_PNAS}, author = {Khan, Fatima and Liu, Yang and Whitfield, Donovan and Pang, Lizhi and Ali, Heba and Huang, Yuyun and Zhou, Fei and Hagan, Robert S. and Frenis, Katie and Rowe, R. Grant and Chen, Peiwen}, doi = {10.1073/pnas.2420793122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2420793122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Macrophage TBK1 signaling drives the development and outgrowth of breast cancer brain metastasis}, volume = {122}, year = {2025}, }
• (2025). Long-term climate warming weakens positive plant biomass responses globally. PNAS, 122(34), e2420379122. (www)

  @article{ , abstract = {Carbon sequestration through plant biomass responses to global warming plays a vital role in mitigating climate change, but recent evidence suggests that this effect diminishes in the long term. To investigate the effect of warming duration on plant biomass responses, we analyzed a global dataset of 2,291 paired observations, revealing that warming increased overall aboveground plant biomass by 9.4% and belowground biomass by 2.6%. However, as the warming duration increased, the positive plant biomass response shifted to neutral or negative, with great biomass reductions in regions where mean annual temperatures exceeded 10 °C. Global aboveground biomass is projected to decline by 4 to 16% under a 2 °C increase in climate warming. Our study suggests that long-term climate warming will significantly weaken plant carbon storage, even if temperature increases remain within the targets of the Paris Agreement, and offers empirical constraints for global biomass–climate models.}, archive = {J_PNAS}, author = {Dang, Pengfei and Ciais, Philippe and Gao, Jiaxin and Zhu, Yunxiao and Xue, Jiquan and Qin, Xiaoliang and Ros, Gerard H.}, doi = {10.1073/pnas.2420379122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2420379122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Long-term climate warming weakens positive plant biomass responses globally}, volume = {122}, year = {2025}, }
• (2025). Synaptic transmission is dispensable for selecting the winner input but is crucial for the subsequent events of synapse elimination. PNAS, 122(34), e2416797122. (www)

  @article{ , abstract = {Synaptic transmission has long been thought to regulate neuronal wiring during postnatal development, but this assumption remains largely untested. Selective strengthening of a single “winner” climbing fiber (CF) afferent to each Purkinje cell (PC) and elimination of the other “loser” CF axons in the cerebellum has been a representative model of neural circuit refinement. Here, we examined the role of neurotransmission at CF-PC synapses in their postnatal development. We labeled a subset of CFs in neonatal mice with fluorescent markers and the tetanus toxin light chain to ablate neurotransmitter release from these CFs. Surprisingly, we found that such neurotransmitter release–deficient CFs were able to become the winners. However, synaptic transmission was crucial for the winning CF to extend its synaptic territory along the PC dendritic arbor and eliminate the loser CFs. These findings reveal how synaptic transmission governs multiple steps of synapse elimination but not the selection of the winner input that persists throughout life.}, archive = {J_PNAS}, author = {Kao, Tzu-Huei and Okuno, Yuto and Matsuyama, Kyoko and Watanabe, Takaki and Uesaka, Naofumi and Kano, Masanobu}, doi = {10.1073/pnas.2416797122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2416797122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synaptic transmission is dispensable for selecting the winner input but is crucial for the subsequent events of synapse elimination}, volume = {122}, year = {2025}, }
• (2025). The rise of diversity terminology in biomedical research. PNAS, 122(34), e2401805122. (www)

  @article{ , abstract = {Recent scholarship has highlighted the rise of “diversity projects” across various educational and business contexts, but few studies have explored the meaning of diversity in biomedical research. In this paper, we employ a computationally driven matching technique to examine quantitative trends in the use of various forms of diversity and population terminology in a sample of nearly two million biomedical abstracts spanning a 30-y period. The curated dictionaries we leverage to detect these trends were formalized into open-source software that are publicly available for other researchers to use. Our analyses demonstrate marked growth in diversity, sex, gender, life course, and socioeconomic terms while terms relating to race and ethnicity largely plateaued or declined in usage, beginning in the mid-2000s. In addition, the use of national, continental, and subcontinental population labels increased dramatically over the same period. We also present logistic regression analyses to investigate what may be fueling the rise in use of diversity terminology. We argue that the use of diversity has grown to encompass concepts beyond its historical origins in race-based programs as it has in fields like higher education and employment. Despite some critics’ claims regarding the role of diversity in research, we do not find evidence that its use signals retreat from or commitment to equity and inclusion efforts.}, archive = {J_PNAS}, author = {Kramer, Brandon L. and Lee, Catherine}, doi = {10.1073/pnas.2401805122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {34}, pages = {e2401805122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The rise of diversity terminology in biomedical research}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(33), eiti3325122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti3325122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {eiti3325122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Correction for kuo et al., a proteomic signature of healthspan. PNAS, 122(33), e2520058122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2520058122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2520058122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for kuo et al., a proteomic signature of healthspan}, volume = {122}, year = {2025}, }
• (2025). Correction for jeong et al., tumor-promoting UBR4 coordinates impaired mitophagy–associated senescence and lung adenocarcinoma pathogenesis. PNAS, 122(33), e2519796122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2519796122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2519796122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for jeong et al., tumor-promoting UBR4 coordinates impaired mitophagy–associated senescence and lung adenocarcinoma pathogenesis}, volume = {122}, year = {2025}, }
• (2025). Correction for ota et al., engineering a protease-stable, oral single-domain antibody to inhibit IL-23 signaling. PNAS, 122(33), e2519793122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2519793122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2519793122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for ota et al., engineering a protease-stable, oral single-domain antibody to inhibit IL-23 signaling}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for rei et al., basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway. PNAS, 122(33), e2519784122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2519784122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2519784122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for rei et al., basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway}, volume = {122}, year = {2025}, }
• (2025). Retraction for jaijyan et al., new intranasal and injectable gene therapy for healthy life extension. PNAS, 122(33), e2519570122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2519570122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2519570122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Retraction for jaijyan et al., new intranasal and injectable gene therapy for healthy life extension}, volume = {122}, year = {2025}, }
• (2025). Étienne-Émile baulieu (1929–2025): Scientist of steroids and champion of women’s reproductive rights. PNAS, 122(33), e2517065122. (www)

  @article{ , abstract = {Having trained as a physician, Étienne-Émile Baulieu soon turned his focus to research, as early as his medical internship. He went on to make major contributions on ketosteroids and other steroids, such as estrogen, and how they act on target organs through receptors to which the hormones bind and activate physiological responses. Later, he consulted with a French pharmaceutical company, encouraging them to pursue his concept for an antigestational agent, which became the iconic RU-486 (Mifepristone). For this, he was applauded by many and criticized by others. He died at his home in a suburb of Paris on May 30, 2025, at the age of 98. To his last days, he vigorously maintained his support for women’s reproductive rights.}, archive = {J_PNAS}, author = {Pederson, Thoru}, doi = {10.1073/pnas.2517065122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2517065122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Étienne-Émile baulieu (1929–2025): Scientist of steroids and champion of women’s reproductive rights}, volume = {122}, year = {2025}, }
• (2025). Predictability and the pleasure of music. PNAS, 122(33), e2516635122. (www)

  @article{ , archive = {J_PNAS}, author = {Belfi, Amy M.}, doi = {10.1073/pnas.2516635122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2516635122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Predictability and the pleasure of music}, volume = {122}, year = {2025}, }
• (2025). Trends in coastal storm impacts are not only about changes in hurricanes. PNAS, 122(33), e2516546122. (www)

  @article{ , archive = {J_PNAS}, author = {Broccoli, Anthony J.}, doi = {10.1073/pnas.2516546122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2516546122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Trends in coastal storm impacts are not only about changes in hurricanes}, volume = {122}, year = {2025}, }
• (2025). Stress granule–mediated ZBP1 activation drives necroptotic cell death in non-obstructive azoospermia and testicular aging. PNAS, 122(33), e2514837122. (www)

  @article{ , abstract = {Male infertility remains a major unmet medical challenge, with poorly defined molecular mechanisms and no effective therapies. Here, we identify a stress granule–mediated necroptotic pathway as a key driver of non-obstructive azoospermia, a severe form of male infertility marked by the loss of spermatogenesis. Environmental or physiological stress activates eIF2α kinases, inducing stress granule formation and the recruitment of ZBP1 and RIPK3 into a cytoplasmic complex. This assembly triggers RIPK3 activation, MLKL phosphorylation, and necroptotic death of spermatogonia and Sertoli cells. Genetic ablation of Zbp1 or Ripk3 protects mice from heat-induced testicular degeneration, establishing their essential role in stress-induced testicular damage. Importantly, activation of this pathway is also observed in aged human testes, linking stress-responsive necroptosis to both pathological infertility and the broader process of reproductive aging. These findings reveal an unrecognized mechanism that couples cellular stress responses to regulated cell death in the male reproductive system.}, archive = {J_PNAS}, author = {Lei, Hongen and Li, Dianrong and Chen, Jie and Du, Baowen and Jiang, Kaiju and Xu, Tao and Han, Hu and Fan, Weiliang and Tian, Long and Wang, Xiaodong}, doi = {10.1073/pnas.2514837122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2514837122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stress granule–mediated ZBP1 activation drives necroptotic cell death in non-obstructive azoospermia and testicular aging}, volume = {122}, year = {2025}, }
• (2025). The 2025 mw7.7 mandalay, myanmar, earthquake reveals a complex earthquake cycle with clustering and variable segmentation on the sagaing fault. PNAS, 122(33), e2514378122. (www)

  @article{ , abstract = {We use remote sensing observations to document surface deformation caused by the 2025 M w 7.7 Mandalay earthquake. This event is a unique case of an extremely long (~510 km) and sustained supershear rupture probably favored by the rather smooth and continuous geometry of this section of the structurally mature Sagaing Fault. The seismic rupture involved the locked portion of the fault over its entire depth extent (0 to 13 km) with a remarkably uniform slip distribution that averages 3.3 m, and an average stress drop of 4.7 MPa. No shallow-slip deficit is observed. The rupture extent challenges usual scaling laws relating earthquake magnitude, fault length, and slip. The fault ruptured along a known seismic gap that last ruptured in 1839 and tailed off into sections that ruptured during large earthquakes in 1930 and 1946. The amplitude and spatial distribution of fault slip in the 2025 event conform only approximatively to the slip-predictable model and the segmentation inferred from the fault geometry and past ruptures. Plausible sequences of earthquakes with variable magnitude, segmentation, and return periods, including events similar to the 2025 earthquake are produced in quasidynamic simulations using a simplified but nonplanar fault geometry. Based on this simulation, M w >7.5 events return irregularly with an interevent time of ~141 y on average and a SD of ~40 y. The simulation is consistent with the historical seismicity and with the maximum magnitude ~M w 7.9 and return period (~250 y) derived from moment conservation. Data assimilation into such simulations could provide a way for time-dependent hazard assessment in the future.}, archive = {J_PNAS}, author = {Antoine, Solene L. and Shrestha, Rajani and Milliner, Chris and Im, Kyungjae and Rollins, Chris and Wang, Kang and Chen, Kejie and Avouac, Jean-Philippe}, doi = {10.1073/pnas.2514378122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2514378122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The 2025 mw7.7 mandalay, myanmar, earthquake reveals a complex earthquake cycle with clustering and variable segmentation on the sagaing fault}, volume = {122}, year = {2025}, }
• (2025). Remembrance of phytoplankton’s past. PNAS, 122(33), e2513874122. (www)

  @article{ , archive = {J_PNAS}, author = {Savage, Van M.}, doi = {10.1073/pnas.2513874122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2513874122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Remembrance of phytoplankton’s past}, volume = {122}, year = {2025}, }
• (2025). Maintenance suppression enhances subsequent associative learning. PNAS, 122(33), e2512322122. (www)

  @article{ , abstract = {Removing irrelevant information from working memory (WM) can free cognitive resources and reduce interference with current task goals. Beyond these immediate benefits, removal may also support long-term memory processes. We tested this hypothesis using an associative memory paradigm with directed forgetting instructions and characterized the underlying neural mechanisms. In complementary behavioral (N = 22) and fMRI (N = 17) experiments, participants completed an ABC associative memory task using pictures of objects, faces, and scenes. Each A item was sequentially paired with B and C items. Our key manipulation targeted the B items: following B encoding, participants were instructed either to maintain or suppress B. We hypothesized that suppression would impair AB memory but enhance AC memory, and this is precisely what we found. Suppression cues elicited distributed activations across frontoparietal control regions, as expected. Critically, multivoxel pattern analyses revealed enhanced encoding fidelity for C items in hippocampal subregion CA1 following suppression compared to maintenance. During subsequent associative memory tests cued by A items, reactivation of suppressed B items was significantly reduced relative to C items, reflecting diminished competition from B items during retrieval. Together, these findings demonstrate that suppression of unwanted information in WM benefits the formation of new memories by enhancing their encoding fidelity and biasing subsequent memory retrieval away from the suppressed associations.}, archive = {J_PNAS}, author = {Zhang, Ziyao and Lewis-Peacock, Jarrod A.}, doi = {10.1073/pnas.2512322122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2512322122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Maintenance suppression enhances subsequent associative learning}, volume = {122}, year = {2025}, }
• (2025). Solution spillover: Pairing issues with ideological solutions fuels polarization. PNAS, 122(33), e2512064122. (www)

  @article{ , abstract = {Recent research has focused on understanding ideological and affective political polarization in the United States; however, the polarization of issue salience—defined as personal beliefs about how important or concerning an issue is, and how much attention or priority it deserves—has garnered less attention, especially regarding its underlying causes. We propose that issue salience polarization, particularly that of ideologically neutral issues, is driven in part by two psychological processes: solution aversion (denying problem severity when solutions are introduced that conflict with political beliefs) and solution attraction (exaggerating problem severity when solutions are introduced that align with political beliefs). If this is so, we should be able to observe issues that are nonpolarized at baseline become suddenly polarized when paired with solutions that are consistent with a specific ideological position (liberal or conservative). Consistent with this prediction, four experimental studies demonstrate the emergence of issue salience polarization arising from solution aversion and solution attraction (Studies 1–4). Results also demonstrate support for the role of zero-sum beliefs, or the belief that one political party’s gains must come at the expense of the other party, in driving this process (Study 3).}, archive = {J_PNAS}, author = {Kafka, Adrienne M. and Campbell, Troy H. and Kay, Aaron C.}, doi = {10.1073/pnas.2512064122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2512064122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Solution spillover: Pairing issues with ideological solutions fuels polarization}, volume = {122}, year = {2025}, }
• (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. PNAS, 122(33), e2511037122. (www)

  @article{ , abstract = {Transient Receptor Potential Canonical 4 (TRPC4) channels have been implicated in multiple neurological functions, including anxiety and sociability. TRPC4 variants were also found in patients with autism. However, the contributions of TRPC4 to neurodevelopment remain undefined. Here, we show that neurobehavioral deficits appear early in young TRPC4 knockout ( Trpc4 −/− ) mice immediately after weaning, manifesting as alterations in multiple, limbic-related behaviors, such as nesting, marble burying, burrowing, self-grooming, and social interactions. Hippocampal neurons of Trpc4 −/− mice exhibit reduced dendritic arborization both in vivo and in vitro. Mechanistically, we found that TRPC4 expression in dendrites surged at the same time when glutamate exerted its stimulatory effect on dendritic branching. In live-cell imaging assays, glutamate induced the formation of new dendrite branches in both wild-type and Trpc4 −/− neurons. However, many of the new and preexisting branches retracted in the mutant neurons. Furthermore, TRPC4 mediated Ca 2+ entry in dendrites downstream from metabotropic glutamate receptors, leading to phosphorylation of nonmuscle myosin light chain (MLC) by the Ca 2+ -dependent myosin light chain kinase (MLCK), which in turn supported integrin activation in dendrite branches. Our findings underscore the essential role of TRPC4 channels in both dendrite morphogenesis and modulation of motivation-related behaviors. The mechanistic underpinning elucidated for the impaired dendritic development and abnormal behaviors in juvenile Trpc4 −/− mice provides insights into the understanding of neurodevelopmental disorders, particularly autism spectrum disorder, opening potential avenues for targeted therapeutic interventions against TRPC4.}, archive = {J_PNAS}, author = {Jeon, Jaepyo and Moore, Travis I. and So, Insuk and Freichel, Marc and Flockerzi, Veit and Birnbaumer, Lutz and Zhu, Michael X.}, doi = {10.1073/pnas.2511037122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2511037122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation}, volume = {122}, year = {2025}, }
• (2025). Ludwig–Soret microscopy with the vibrational photothermal effect. PNAS, 122(33), e2510703122. (www)

  @article{ , abstract = {Vibrational microscopy provides label-free, bond-selective chemical contrast by detecting molecular vibrations, making it invaluable for biomedical research. While conventional methods rely on the direct detection of Raman scattering or infrared absorption, recently developed vibrational photothermal (ViP) microscopy achieves chemical contrast indirectly through refractive index (RI) changes. This indirect approach enables unique imaging capabilities beyond traditional chemical imaging. Here, we introduce an application of ViP microscopy: Label-free intracellular thermophoretic (Soret) imaging, which visualizes biomolecular transport driven by temperature gradients. ViP-induced Soret (ViPS) imaging leverages a steady-state temperature distribution generated by optical heating through vibrational photothermal effect, combined with time-resolved RI imaging via optical diffraction tomography. Using ViPS imaging, we measured thermophoretic behavior in living COS7 cells, determining intracellular diffusion and Soret coefficients. Notably, we observed a reversed direction of molecular transport (negative Soret effect) in the cytoplasm compared to the nucleus, possibly driven by thermophoresis-induced diffusiophoresis. Furthermore, time-lapse imaging under CO 2 -depleted conditions revealed a remarkable reduction in thermophoretic activity, suggesting glass formation during the dying process, likely due to polymer aggregation. ViPS imaging represents a frontier in intracellular thermophoretic studies, expanding the capabilities of vibrational microscopy.}, archive = {J_PNAS}, author = {Toda, Keiichiro and Ideguchi, Takuro}, doi = {10.1073/pnas.2510703122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2510703122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ludwig–Soret microscopy with the vibrational photothermal effect}, volume = {122}, year = {2025}, }
• (2025). Sox11 genes affect neuronal differentiation in the developing zebrafish enteric nervous system. PNAS, 122(33), e2510548122. (www)

  @article{ , abstract = {The vertebrate enteric nervous system (ENS) is derived from vagal neural crest cells, which enter the foregut as progenitors that migrate from rostral to caudal to populate the entire length of the gut. Here, we show that transcription factors sox11a and sox11b , zebrafish orthologs of the human SOX11 gene, are highly expressed in neural crest cells transitioning from progenitors to differentiating neuronal subtypes. Accordingly, CRISPR-Cas9 depletion shows that loss of sox11 paralogs reduces the number of neurons that express the inhibitory motor neuron marker adcyap1b without affecting cell proliferation or death. Transcription factor footprinting analysis of open chromatin regions identified by ATAC-seq reveals Sox11 binding sites in the adcyap1b enhancer. Furthermore, mutational analysis shows these binding sites are required for mediating enhancer-driven reporter expression. Taken together, our results demonstrate an important and previously unrecognized role for sox11a and sox11b in neuronal subtype specification in the developing zebrafish ENS.}, archive = {J_PNAS}, author = {Huang, Yuanyun and Li, Can and Desingu Rajan, Ayyappa Raja and Bronner, Marianne E.}, doi = {10.1073/pnas.2510548122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2510548122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sox11 genes affect neuronal differentiation in the developing zebrafish enteric nervous system}, volume = {122}, year = {2025}, }
• (2025). Structural insights into VRC01-class bnAb precursors with diverse light chains elicited in the IAVI g001 human vaccine trial. PNAS, 122(33), e2510163122. (www)

  @article{ , abstract = {The development of germline-targeting vaccines represents a potentially transformative strategy to elicit broadly neutralizing antibodies (bnAbs) against HIV and other antigenically diverse pathogens. Here, we report on structural characterization of vaccine-elicited VRC01-class bnAb precursors in the IAVI G001 Phase 1 clinical trial with the eOD-GT8 60mer nanoparticle as immunogen. High-resolution X-ray structures of eOD-GT8 monomer complexed with Fabs of five VRC01-class bnAb precursors with >90% germline identity revealed a conserved mode of binding to the HIV CD4-binding site via IGHV1-2-encoded heavy chains, mirroring mature bnAb interactions. The light-chain V-gene diversity emulated VRC01 bnAbs and stabilized antigen engagement, while their conserved five-residue LCDR3 motifs prevented steric clashes. Notably, the VRC01-class bnAb precursors accommodated the N276 glycan, a key barrier in HIV Env recognition, through structural rearrangements in HCDR3 or LCDR1, despite its absence in the immunogen. Surface plasmon resonance analysis showed that 87% of elicited antibodies retained glycan binding capacity, albeit with reduced affinity. These findings validate the ability of eOD-GT8 60mer nanoparticles to prime VRC01-class bnAb precursors with native-like paratopes but with intrinsic glycan adaptability. Structural mimicry of mature bnAbs was observed even with limited somatic hypermutation, indicating that critical features are encoded in the germline repertoire. The structures highlight how germline-encoded features drive bnAb-like recognition at early stages. This work provides molecular evidence supporting germline targeting in humans and provides guidance for designing booster immunogens to shepherd affinity maturation toward broad neutralization.}, archive = {J_PNAS}, author = {Lin, Xiaohe and Cottrell, Christopher A. and Kalyuzhniy, Oleksandr and Tingle, Ryan and Kubitz, Michael and Lu, Danny and Yuan, Meng and Schief, William R. and Wilson, Ian A.}, doi = {10.1073/pnas.2510163122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2510163122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural insights into VRC01-class bnAb precursors with diverse light chains elicited in the IAVI g001 human vaccine trial}, volume = {122}, year = {2025}, }
• (2025). Sustained benefits of long-term biochar application for food security and climate change mitigation. PNAS, 122(33), e2509237122. (www)

  @article{ , abstract = {Biochar application offers significant potential to enhance food security and mitigate climate change. However, most evidence stems from short-term field experiments (≤3 y), leaving uncertainty about the long-term sustainability of these benefits, especially with annual biochar additions to soils. To address this knowledge gap, we analyzed a global dataset from 438 studies (3,229 observations) and found that long-term annual biochar application (≥4 y) not only sustains but often enhances its benefits. These include improved crop yields (+10.8%), reductions in CH 4 (–13.5%) and N 2 O (–21.4%) emissions, and increased soil organic carbon content (+52.5%). In contrast, these benefits tend to diminish over time with single biochar applications due to the aging effect of biochar. Results from 29 global long-term experiments (4 to 12 y) confirm these sustained benefits for crop yield and greenhouse gas mitigation, although the magnitude of effects varies with soil properties, climate, and management practices. To maximize biochar’s long-term benefits for global food security and climate change mitigation, it is essential to develop viable strategies, such as applying biochar at intervals of several years while tailoring practices to local soil, climate, and cropping conditions.}, archive = {J_PNAS}, author = {Yang, Jingrui and Xia, Longlong and van Groenigen, Kees Jan and Zhao, Xu and Ti, Chaopu and Wang, Weilu and Du, Zhangliu and Fan, Mingsheng and Zhuang, Minghao and Smith, Pete and Lal, Rattan and Butterbach-Bahl, Klaus and Han, Xiaori and Meng, Jun and Liu, Jia and Cai, Hongguang and Cheng, Yanhong and Liu, Xingren and Shu, Xiangyang and Jiao, Xiaoyan and Pan, Zhandong and Tang, Guangmu and Yan, Xiaoyuan}, doi = {10.1073/pnas.2509237122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2509237122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sustained benefits of long-term biochar application for food security and climate change mitigation}, volume = {122}, year = {2025}, }
• (2025). Client–scaffold interactions suppress aggregation of a client protein in model condensates. PNAS, 122(33), e2508403122. (www)

  @article{ , abstract = {Many studies have shown that sequestration of client proteins into condensates locally increases their concentrations and/or modulates their conformational landscapes to promote aberrant aggregation. Far fewer examples have emerged where the proteinaceous condensed phase environment protects clients from aggregation. Here, we show that a condensate scaffolded by the C-terminal disordered region of Cell Cycle Associated Protein 1 (CAPRIN1) suppresses aggregation of the Fused in Sarcoma (FUS) RNA Recognition Motif (RRM) client, both components of stress granules. Although FUS RRM aggregation is mediated through the unfolded ensemble, comparative NMR studies of the FUS RRM outside and within the condensate establish that CAPRIN1 condensates attenuate FUS RRM aggregation despite locally increasing its concentration by twofold and significantly unfolding the domain. Regions of transient intermolecular contacts between unfolded FUS RRM protomers that could drive aggregation have been identified, including the hydrophobic segments spanning I287-I308 and G335-A369. Intermolecular NOE experiments recorded on the FUS RRM:CAPRIN1 condensate indicate that CAPRIN1 interacts with much of the unfolded FUS RRM, with regions of stronger contacts including the RRM sequences 287 IFVQ 290 , 296 VTIES 300 , 322 INLY 325 , and 351 IDWFDG 356 . These interactions collectively outcompete the homotypic contacts between unfolded FUS RRM clients driving aggregation. Our results demonstrate that condensate scaffold molecules can, in some cases, shield client interprotomer interactions, delaying or completely suppressing their aggregation.}, archive = {J_PNAS}, author = {Ahmed, Rashik and Hudson, Rhea P. and Forman-Kay, Julie D. and Kay, Lewis E.}, doi = {10.1073/pnas.2508403122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2508403122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Client–scaffold interactions suppress aggregation of a client protein in model condensates}, volume = {122}, year = {2025}, }
• (2025). Analytical solutions for light propagation of LED. PNAS, 122(33), e2508163122. (www)

  @article{ , abstract = {Analytical solutions of diffusion theory for light propagation in turbid media are essential for optical diagnostics and therapeutic applications, including cerebral oximetry, hemodynamic monitoring, and photostimulation. While existing solutions work reasonably well for collimated light sources—lasers and optical fibers—analytical solutions for LEDs remain missing, despite the growing use of LEDs in wearable and implantable bioelectronics. We present a method to solve the diffusion theory and derive analytical solutions for two biomedically relevant configurations: 1) surface-mounted LEDs on semi-infinite media (e.g., wearable devices) and 2) embedded LEDs in infinite media (e.g., implantable devices). Beyond a distance of 4 times the scattering length of the medium to the LED source, our analytical solutions are reasonably accurate, within 6% error for 1) and 3% for 2). This represents significant improvements over existing analytical solutions, characterized by 26% and 15% error, respectively. Using our analytical solutions, we derive tissue optical properties ( μ a and μ s ′ ) from diffuse reflectance results with <7% error, and we determine the irradiance threshold for photostimulation, aligned with experimental optogenetic activation data. Our analytical solutions are readily adaptable to various biomedical applications, offering a rigorous theoretical foundation for next-generation LED-based bioelectronics, to enable more accurate optical diagnostics and therapies in clinical applications.}, archive = {J_PNAS}, author = {Zhang, Haohui and Zhang, Kaiqing and Wu, Mingzheng and Li, Shupeng and Bodkin, Kevin L. and Kozorovitskiy, Yevgenia and Rogers, John A. and Huang, Yonggang}, doi = {10.1073/pnas.2508163122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2508163122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Analytical solutions for light propagation of LED}, volume = {122}, year = {2025}, }
• (2025). TRIM24 as a therapeutic target in endocrine treatment–resistant breast cancer. PNAS, 122(33), e2507571122. (www)

  @article{ , abstract = {While Estrogen receptor alpha (ERα)+ breast cancer treatment is considered effective, resistance to endocrine therapy is common. Since ERα is still the main driver in most therapy-resistant tumors, alternative therapeutic strategies are needed to disrupt ERα transcriptional activity. In this work, we position TRIM24 as a therapeutic target in endocrine resistance, given its role as a key component of the ERα transcriptional complex. TRIM24 interacts with ERα and other well-known ERα cofactors to facilitate ERα chromatin interactions and allows for maintenance of active histone marks including H3K23ac and H3K27ac. Consequently, genetic perturbation of TRIM24 abrogates ERα-driven transcriptional programs and reduces tumor cell proliferation capacity. Using a recently developed degrader targeting TRIM24, ERα-driven transcriptional output and growth were blocked, effectively treating not only endocrine-responsive cell lines but also drug-resistant derivatives thereof as well as cell line models bearing activating ESR1 point mutations. Finally, using human tumor-derived organoid models, we could show the efficacy of TRIM24 degrader in the endocrine-responsive and -resistant setting. Overall, our study positions TRIM24 as a central component for the integrity and activity of the ERα transcriptional complex, with degradation-mediated perturbation of TRIM24 as a promising therapeutic avenue in the treatment of primary and endocrine resistance breast cancer.}, archive = {J_PNAS}, author = {Padrão, Nuno and Gregoricchio, Sebastian and Eickhoff, Nils and Dong, Jing and Luzietti, Lara and Bossi, Daniela and Severson, Tesa M. and Siefert, Joseph and Calcinotto, Arianna and Buluwela, Laki and Donaldson Collier, Maria and Ali, Simak and Young, Leonie and Theurillat, Jean-Philippe and Varešlija, Damir and Zwart, Wilbert}, doi = {10.1073/pnas.2507571122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2507571122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TRIM24 as a therapeutic target in endocrine treatment–resistant breast cancer}, volume = {122}, year = {2025}, }
• (2025). Geographical diversity of peer reviewers shapes author success. PNAS, 122(33), e2507394122. (www)

  @article{ , abstract = {Scientific institutions like funding agencies and journals rely on peer reviewers to select among competing submissions. How does the geographical diversity of reviewers affect which authors are selected? If reviewers typically favor submissions from their own countries, but reviewers from only some countries are well represented in the reviewer pool, this can create a “geographical representation bias” favoring authors from those well-represented countries. Using administrative data on 204,718 submissions to 60 STEM journals from the Institute of Physics Publishing, we find support for representation bias. Reviewers from the same country as the corresponding author are 4.78 percentage points more likely to review positively compared to other reviewers of the same manuscript. Authors from the United States of America, China, and India are 8 to 9 times more likely to be evaluated by same-country reviewers compared to less-represented countries with similar incomes. Furthermore, an instrumental variables analysis of an anonymization policy shock shows that anonymizing submissions does not significantly reduce same-country homophily. Thus, investments in reviewer diversification may be necessary to mitigate the structural advantage of authors from major science-producing countries and avoid blind spots in collective knowledge.}, archive = {J_PNAS}, author = {Zumel Dumlao, James M. and Teplitskiy, Misha}, doi = {10.1073/pnas.2507394122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2507394122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Geographical diversity of peer reviewers shapes author success}, volume = {122}, year = {2025}, }
• (2025). Circulating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome. PNAS, 122(33), e2507345122. (www)

  @article{ , abstract = {People living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience heterogeneous and debilitating symptoms that lack sufficient biological explanation, compounded by the absence of accurate, noninvasive diagnostic tools. To address these challenges, we explored circulating cell-free RNA (cfRNA) as a blood-borne bioanalyte to monitor ME/CFS. cfRNA is released into the bloodstream during cellular turnover and reflects dynamic changes in gene expression, cellular signaling, and tissue-specific processes. We profiled cfRNA in plasma by RNA sequencing for 93 ME/CFS cases and 75 healthy sedentary controls, then applied machine learning to develop diagnostic models and advance our understanding of ME/CFS pathobiology. A generalized linear model with least absolute shrinkage selector operator regression trained on condition-specific signatures achieved a test-set AUC of 0.81 and an accuracy of 77%. Immune cfRNA deconvolution revealed differences in platelet-derived cfRNA between cases and controls, as well as elevated levels of plasmacytoid dendritic, monocyte, and T cell–derived cfRNA in ME/CFS. Biological network analysis further implicated immune dysfunction in ME/CFS, with signatures of cytokine signaling and T cell exhaustion. These findings demonstrate the utility of RNA liquid biopsy as a minimally invasive tool for unraveling the complex biology behind chronic illnesses.}, archive = {J_PNAS}, author = {Gardella, Anne E. and Eweis-LaBolle, Daniel and Loy, Conor J. and Belcher, Emma D. and Lenz, Joan S. and Franconi, Carl J. and Scofield, Sally Y. and Grimson, Andrew and Hanson, Maureen R. and De Vlaminck, Iwijn}, doi = {10.1073/pnas.2507345122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2507345122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Circulating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome}, volume = {122}, year = {2025}, }
• (2025). Genomes of nitrogen-fixing eukaryotes reveal an alternate path for organellogenesis. PNAS, 122(33), e2507237122. (www)

  @article{ , abstract = {Endosymbiotic gene transfer (EGT) and import of host-encoded proteins have been considered hallmarks of organelles necessary for stable integration of two cells. However, newer endosymbiotic models have challenged the origin and timing of such genetic integration during organellogenesis. Epithemia diatoms contain diazoplasts, obligate endosymbionts derived from cyanobacteria that are closely phylogenetically related to UCYN-A, a recently described nitrogen-fixing organelle. Diazoplasts function as permanent membrane compartments in Epithemia hosts, but it is unknown if genetic integration has occurred. We report genomic analyses of two Epithemia diatom species, freshwater Epithemia clementina and marine E. pelagica , which are highly divergent but share a common ancestor at the origin of the endosymbiosis <35Mya. We find minimal evidence for genetic integration. Segments of fragmented and rearranged DNA from the diazoplast were detected integrated into the E. clementina nuclear genome, but the transfers that have occurred so far are nonfunctional. No DNA or gene transfers were detected in E. pelagica. In E. clementina , 6 host-encoded proteins of unknown function were identified in the diazoplast proteome, far fewer than detected in recently acquired endosymbiotic organelles. Overall, Epithemia diazoplasts are a valuable counterpoint to existing organelle models, demonstrating that endosymbionts can function as integral compartments—maintained over millions of years of host speciation—absent significant genetic integration. The minimal genetic integration makes diazoplasts valuable blueprints for bioengineering endosymbiotic compartments de novo.}, archive = {J_PNAS}, author = {Frail, Sarah and Steele-Ogus, Melissa and Doenier, Jon and Moulin, Solène L. Y. and Braukmann, Tom and Xu, Shouling and Yeh, Ellen}, doi = {10.1073/pnas.2507237122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2507237122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genomes of nitrogen-fixing eukaryotes reveal an alternate path for organellogenesis}, volume = {122}, year = {2025}, }
• (2025). DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons. PNAS, 122(33), e2506846122. (www)

  @article{ , abstract = {Somatic mutations in cortical neurons have been implicated in psychiatric disorders. While endogenous DNA damage and repair errors are potential contributors to these mutations during development, the underlying mutagenic mechanism remains unclear. Here, we investigated somatic mutations in immature cortical neurons using mouse somatic cell nuclear transfer-derived embryonic stem cells and whole-genome sequencing. Insertions and deletions (indels) were commonly observed in both repeat and nonrepeat sequences in wild-type cells. The loss of DNA polymerase β (Polβ), an enzyme involved in gap-filling during base excision repair and Ten-Eleven Translocation (TET)-mediated active DNA demethylation, in neural progenitor cells increased indel frequency by ~ninefold at cytosine-phosphate-guanine (CpG) dinucleotides and raised the frequency of structural variants by ~fivefold. These mutations were enriched in neuronal genes, leading to frameshift mutations, amino acid insertions/deletions, and the gain and loss of CpG sites in regulatory regions. Our findings suggest that Polβ preferentially repairs DNA lesions generated at CpG sites by TET-mediated active demethylation, thereby suppressing the mutagenesis that accompanies neuronal gene activation during cortical development.}, archive = {J_PNAS}, author = {Sugo, Noriyuki and Uchimura, Arikuni and Matsumoto, Risa and Nakayama, Hiro and Fujimoto, Shota and Mizuno, Saya and Higuchi, Mayumi and Toshishige, Masaaki and Satoh, Yasunari and Wakayama, Sayaka and Wakayama, Teruhiko and Yagi, Takeshi}, doi = {10.1073/pnas.2506846122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2506846122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons}, volume = {122}, year = {2025}, }
• (2025). Structural basis and affinity improvement for an ATP-binding DNA aptamer. PNAS, 122(33), e2506491122. (www)

  @article{ , abstract = {DNA aptamers that bind small molecules with high affinity have revolutionized the fields of biosensing and bioimaging. Recently, a DNA aptamer named 1301b has been identified as the most potent DNA aptamer for the binding of adenosine triphosphate (ATP) with a dissociation constant ( K D ) of ~2.7 µM. However, the structural basis and recognition mechanism remain unclear, hindering further development of this DNA aptamer. In this study, we first design a shortened DNA aptamer namely 1301b_v1 that retains a good affinity for ATP and then determine the tertiary structure of 1:1 1301b_v1-ATP binding complex using solution NMR spectroscopy. The overall complex structure shows an “L” shape architecture with the binding pocket formed by two internal loops. The ATP intercalates into the binding pocket through forming hydrogen bond with G14 and stacking with T8·A28 and G9. We also reveal an adaptive binding mechanism where the DNA aptamer switches from a semifolded state to a stable tertiary structure upon ATP binding. Based on the structure–function relationship, we introduce 2′-O-methyl modification to residues in the central junction and obtain a DNA aptamer named 9/10/16 OMe with a K D of ~0.7 µM for the binding of ATP. These results underscore the ability of DNA molecules to form intricate three-dimensional folds with sophisticated functionality, opening up avenues for designing novel DNA-based molecular tools.}, archive = {J_PNAS}, author = {Jiang, Yan and Zhang, Yuchao and Wan, Liqi and Cui, Cheng and Guo, Pei and Han, Da and Tan, Weihong}, doi = {10.1073/pnas.2506491122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2506491122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis and affinity improvement for an ATP-binding DNA aptamer}, volume = {122}, year = {2025}, }
• (2025). ITAF45 is a pervasive trans-acting factor for picornavirus type II IRES elements. PNAS, 122(33), e2506281122. (www)

  @article{ , abstract = {Viruses have evolved elaborate mechanisms to hijack the host mRNA translation machinery to direct viral protein synthesis. Picornaviruses, whose RNA genome lacks a cap structure, inhibit cap-dependent mRNA translation, and utilize an internal ribosome entry site (IRES) in the RNA 5′ untranslated region to recruit the 40S ribosomal subunit. IRES activity is stimulated by a set of host proteins termed IRES trans -acting factors (ITAFs). The cellular protein ITAF 45 (also known as PA2G4 or EBP1) was documented as an essential ITAF for foot-and-mouth disease virus (FMDV), with no apparent role in cell-free systems for encephalomyocarditis virus (EMCV) and Theiler’s murine encephalomyelitis virus (TMEV), which are closely related viruses harboring similar IRES elements. Here, we demonstrate that ITAF 45 is a pervasive host factor for picornaviruses containing a Type II IRES. CRISPR/Cas9 knockout of ITAF 45 in several human cell lines conferred resistance to infection with FMDV, EMCV, TMEV, and equine rhinitis A virus (ERAV). We show that ITAF 45 enhances initiation of translation on Type II IRESs in cell line models. This is mediated by the C-terminal lysine-rich region of ITAF 45 known to enable binding to viral RNA. These findings challenge previous reports of a restricted role for ITAF 45 in FMDV infection, thus positioning ITAF 45 as a potential antiviral target for various animal viruses and emerging human cardioviruses.}, archive = {J_PNAS}, author = {Bellucci, Michael A. and Amiri, Mehdi and Berryman, Stephen and Moshari, Andia and Owino, Collins Oduor and Luteijn, Rutger D. and Tuthill, Tobias J. and Svitkin, Yuri and Belsham, Graham J. and van Kuppeveld, Frank J. M. and Sonenberg, Nahum}, doi = {10.1073/pnas.2506281122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2506281122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ITAF45 is a pervasive trans-acting factor for picornavirus type II IRES elements}, volume = {122}, year = {2025}, }
• (2025). Remote analysis and management of sweat biomarkers using a wearable microfluidic sticker in adult cystic fibrosis patients. PNAS, 122(33), e2506137122. (www)

  @article{ , abstract = {Sweat parameters such as volume and chloride concentration may offer invaluable clinical insights for people with CF (PwCF). Pilocarpine-induced sweat collection for chloridometry measurement is the gold standard for a CF diagnosis, but this technique is cumbersome and not suitable for remote settings or repeat measurements. We have previously reported the utility of a skin-interfaced microfluidic device (CF Patch) in conjunction with a smartphone image processing platform that enables real-time measurement of sweating rates and sodium chloride loss in laboratory and remote settings. Here, we conducted clinical studies assessing the accuracy of the CF Patch compared to chloridometry when using pilocarpine to induce sweat. We also tested the feasibility and accuracy of exercise-induced sweat chloride measurements in PwCF and healthy volunteers (HV). In the laboratory, using either pilocarpine or exercise to induce sweat, the CF Patch demonstrated strong correlations with sweat chloride measured by pilocarpine-induced chloridometry. In remote settings, exercise-induced sweat chlorides measured using the CF patch were strongly correlated with in-laboratory exercise-induced CF patch sweat chlorides in HV but had a weaker correlation in PwCF. For PwCF on CFTR modulators, there was greater day-to-day variability in sweat chloride compared to HV, which highlights the limitations of assessing CFTR modulator efficacy and pharmacodynamics based on a single in-laboratory chloridometry measurement. Moreover, these findings demonstrate that the CF Patch is suitable as a remote management device capable of measuring serial sweat chloride concentrations and offers the potential of monitoring the efficacy of CF medication regimens but should not replace pilocarpine-based chloridometry for making a CF diagnosis.}, archive = {J_PNAS}, author = {Nelson, Rachel S. and Grossman, Margaret G. and Klug, Zasu M. and Calamari, Mia and Donayre, Alvaro and Cybulski, Thaddeus and Schooley, Jared and Griffith, Garett J. and Corcos, Daniel M. and Wright, Donald E. and Wallace, Jessica C. and Yang, Da Som and Wright, John A. and Rogers, John A. and Lee, Stephen P. and Ghaffari, Roozbeh and Aranyosi, A. J. and Jain, Manu}, doi = {10.1073/pnas.2506137122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2506137122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Remote analysis and management of sweat biomarkers using a wearable microfluidic sticker in adult cystic fibrosis patients}, volume = {122}, year = {2025}, }
• (2025). Decoding memory function through naturalistic gaze patterns. PNAS, 122(33), e2505879122. (www)

  @article{ , abstract = {Eye movements are closely linked to encoding and retrieval processes, with changes in viewing behavior reflecting age- and pathology-related memory decline. In the current study, we leveraged this relationship to explore possible gaze-based indicators of memory function. Across two task-free viewing experiments, we investigated changes in naturalistic viewing behavior across five participant groups spanning a broad spectrum of memory function, from healthy young adults to amnesic cases. We show that memory decline is associated with an underlying reduction in explorative, adaptive, and differentiated visual sampling of the environment. Our results provide compelling evidence that naturalistic gaze patterns can serve as a sensitive marker of cognitive decline.}, archive = {J_PNAS}, author = {Wynn, Jordana S. and Khosla, Anisha and Kacollja, Arber and Shahmiri, Elaheh and Anderson, Nicole D. and Shen, Kelly and Ryan, Jennifer D.}, doi = {10.1073/pnas.2505879122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2505879122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Decoding memory function through naturalistic gaze patterns}, volume = {122}, year = {2025}, }
• (2025). Measuring the selective packaging of RNA molecules by viral coat proteins in cells. PNAS, 122(33), e2505190122. (www)

  @article{ , abstract = {Some RNA viruses package their genomes with extraordinary selectivity, assembling protein capsids around their own viral RNA while excluding nearly all host RNA. How the assembling proteins distinguish viral RNA from host RNA is not fully understood, but RNA structure is thought to play a key role. To test this idea, we perform in-cellulo packaging experiments using bacteriophage MS2 coat proteins and a variety of RNA molecules in Escherichia coli . In each experiment, plasmid-derived RNA molecules with a specified sequence compete against the cellular transcriptome for packaging by plasmid-derived coat proteins. Following this competition, we quantify the total amount and relative composition of the packaged RNA using electron microscopy, interferometric scattering microscopy, and high-throughput sequencing. By systematically varying the input RNA sequence and measuring changes in packaging outcomes, we are able to directly test competing models of selective packaging. Our results rule out a longstanding model in which selective packaging requires the well-known translational repressor (TR) stem-loop, and instead support more recent models in which selectivity emerges from the collective interactions of multiple coat proteins and multiple stem-loops distributed across the RNA molecule. These findings establish a framework for studying and understanding selective packaging in a range of natural viruses and virus-like particles, and lay the groundwork for engineering synthetic systems that package specific RNA cargoes.}, archive = {J_PNAS}, author = {Rastandeh, Amineh and Makasarashvili, Nino and Dhaliwal, Herman K. and Baker, Sherry and Subramanian, Sundharraman and Villarreal, Daniel A. and Gamez, Elmer I. and Parent, Kristin N. and Garmann, Rees F.}, doi = {10.1073/pnas.2505190122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2505190122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Measuring the selective packaging of RNA molecules by viral coat proteins in cells}, volume = {122}, year = {2025}, }
• (2025). Repeated polyploidization shapes divergence in floral morphology in lithophragma bolanderi (Saxifragaceae). PNAS, 122(33), e2505119122. (www)

  @article{ , abstract = {Polyploidization is an important driver of evolution and diversification in flowering plants. Here, we assess how repeated polyploidization may have shaped diversification of floral morphology in Lithophragma bolanderi (Saxifragaceae). This species comprises multiple cytotypes and varies geographically in its interactions with specialized pollinating moths in the genus Greya (Prodoxidae). Past studies have shown that coevolution with these moths has favored particular suites of floral characters but does not fully explain local and regional floral diversification. We combined phenotypic and genomic data from more than 1,800 individuals from 40 L. bolanderi populations spread across its entire range. Flow-cytometric analyses revealed a geographic mosaic of populations comprising one to four of three dominant (diploid, tetraploid, hexaploid) and three rare (triploid, pentaploid, octoploid) cytotypes. Whole-genome resequencing of a subset of populations suggested that polyploids arose from multiple autopolyploidization events, rather than a single event and/or through hybridization, albeit with some signals consistent with low levels of introgression from the congener Lithophragma glabrum . Quantification of flower traits from plants grown in a common garden showed that cytotype explained more than 15% of the variation in floral morphology, with polyploids showing more variability than diploids. Experimental induction of neopolyploids directly induced phenotypic changes but also indicated that local selection may have favored subsequent convergence in floral morphology among cytotypes in natural populations. Collectively, this comprehensive and integrative approach provides insights into how variability generating processes, such as polyploidization integrates with selection from species interactions to shape local floral diversification.}, archive = {J_PNAS}, author = {Gross, Karin and Yazdi, Homa Papoli and Schlager, Elisabeth and Lilley, Jodie and Romero-Bravo, Andrés and Runemark, Anna and Thompson, John N. and Friberg, Magne}, doi = {10.1073/pnas.2505119122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2505119122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Repeated polyploidization shapes divergence in floral morphology in lithophragma bolanderi (Saxifragaceae)}, volume = {122}, year = {2025}, }
• (2025). Plant-specific mitochondrial fission machinery connects mitochondrial dynamics and mitophagosome formation for piecemeal mitophagy. PNAS, 122(33), e2504921122. (www)

  @article{ , abstract = {As the energy center of the cell, mitochondria display enormous metabolic plasticity to meet the cellular demand for plant growth and development, which is tightly linked to their structural and dynamic plasticity. Mitochondrial number and morphology are coordinated through the actions of the mitochondrial division and fusion. Meanwhile, damaged mitochondrial contents are removed to avoid excess toxicity to the plant cells. Mitophagy, a selective degradation pathway of mitochondria through a double-membrane sac named autophagosome (also known as mitophagosome), plays a crucial role in maintaining mitochondrial homeostasis. Typically, wholesale mitophagy requires the elongation of a cup-shaped phagophore along the entire mitochondrion, which finally seals and closes as a mitophagosome. How plant mitophagosome formation and mitochondria sequestration are coordinated remains incompletely understood. In this work, we report an unappreciated role of the plant-specific mitochondrial fission regulator ELM1, together with the dynamin-related protein family DRP3 and the autophagic regulator SH3P2, to coordinate mitochondria segregation for piecemeal mitophagy under heat stress conditions. Dysfunction in mitochondrial fission activity impairs heat-induced mitophagy, leading to an accumulation of interconnected megamitochondria which are partially sequestered by the ATG8-positive phagophore. Furthermore, we show that the ELM1-mediated piecemeal mitophagy also engages the plant archetypal selective autophagic receptor NBR1. Using 3D tomography analysis, we illustrate the morphological features and spatial relationship of the megamitochondria and phagophore intermediates in connection with the mitochondrial fission sites. Collectively, our study provides an updated model of mitophagosome formation for piecemeal mitophagy mediated by the plant-unique mitochondrial fission machinery.}, archive = {J_PNAS}, author = {Ma, Juncai and Li, Chaorui and Ren, Kaike and Zhang, Kaiyan and Feng, Lanlan and Law, Kai Ching and Chung, Ka Kit and Bing, Yizhou and Gao, Caiji and Kang, Byung-Ho and Zhuang, Xiaohong}, doi = {10.1073/pnas.2504921122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2504921122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Plant-specific mitochondrial fission machinery connects mitochondrial dynamics and mitophagosome formation for piecemeal mitophagy}, volume = {122}, year = {2025}, }
• (2025). Keys to the global treeline formation: Thermal limit for its position and moisture for the taxon-specific variation. PNAS, 122(33), e2504685122. (www)

  @article{ , abstract = {Alpine treeline is a prominent biogeographic feature worldwide, determined by the physiological limit of tree life form. There are considerable variations in the various dimensions of physiological limit among tree taxa; thus, varied environmental drivers and spatial patterns are expected for different tree taxa at treelines. However, such taxonomic variability of treeline is often overlooked in large-scale studies. Here, we assembled, to our knowledge, the most comprehensive dataset of tree species at alpine treelines, drawing from research conducted over the past half-century, encompassing over 2,000 records across 38 mountain regions and 43 countries. Using this extensive global dataset, we examined the spatial patterns and environmental drivers shaping different tree taxa at treelines worldwide. The highest tree richness at treelines was found in mid-latitude mountains of the Northern Hemisphere, reflecting floristic differentiation caused by continental isolation. Moisture and climatic variability, particularly seasonal fluctuations, determine the turnover of tree taxa at treelines. Heat limitations appear to restrict the establishment of all genera, effectively defining treeline positions. Heat conditions at treeline positions tend to be about 35% below the genus- and species- level thermal optima. This thermal threshold can effectively explain the global pattern of uppermost tree elevation. Our findings highlight the synergic effects between heat and moisture in determining the taxonomic variation in treeline formation, offering insights for alpine treeline studies under climate change.}, archive = {J_PNAS}, author = {Xie, Yuyang and Shen, Zehao and Camarero, J. Julio and Peñuelas, Josep and Wang, Xuejing and Li, Jitang and Rao, Wenge and Chen, Xiangwu and Zhao, Fu and Feng, Xiao}, doi = {10.1073/pnas.2504685122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2504685122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Keys to the global treeline formation: Thermal limit for its position and moisture for the taxon-specific variation}, volume = {122}, year = {2025}, }
• (2025). Mesozoic atmospheric CO2 concentrations reconstructed from dinosaur tooth enamel. PNAS, 122(33), e2504324122. (www)

  @article{ , abstract = {Air-breathing vertebrates incorporate a fraction of isotopically anomalous air O 2 in their body water. The 17 O isotope anomaly of air O 2 (expressed as Δ’ 17 O air ) is related to atmospheric CO 2 concentrations ( p CO 2 ) and gross primary production (GPP). Tooth enamel records the Δ’ 17 O of body water and can thus preserve such paleo- p CO 2 or paleo-GPP information over geological time periods. Here, we demonstrate the potential of respective reconstructions of atmospheric p CO 2 or GPP from the triple oxygen isotope composition of fossil dinosaur tooth enamel. The data from unaltered enamel samples, along with an assumed modern GPP t /GPP 0 ratio of 1 for the Mesozoic, suggest a mean Late Jurassic p CO 2 = 1,200 ± 150 ppmv and Late Cretaceous p CO 2 = 750 ± 200 ppmv. These estimates are in good agreement with other p CO 2 proxy data for the same time intervals. When utilizing a p CO 2 inferred from other proxies, tooth enamel Δ’ 17 O PO4 may also serve as a proxy for GPP. Using published p CO 2 data, we reconstructed GPP t /GPP 0 ratios with 1.20 ± 0.17 for the Late Jurassic and 2.24 ± 0.96 for the Late Cretaceous, which would imply a 20 to 120% higher GPP in the Mesozoic than today. Overall, triple oxygen isotope analysis of fossil teeth of terrestrial amniotes can provide insights into past atmospheric greenhouse gas content and global primary productivity.}, archive = {J_PNAS}, author = {Feng, Dingsu and Tütken, Thomas and Griebeler, Eva Maria and Herwartz, Daniel and Pack, Andreas}, doi = {10.1073/pnas.2504324122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2504324122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mesozoic atmospheric CO2 concentrations reconstructed from dinosaur tooth enamel}, volume = {122}, year = {2025}, }
• (2025). Mechanistic insights into the small-molecule inhibition of influenza a virus entry. PNAS, 122(33), e2503899122. (www)

  @article{ , abstract = {Influenza A virus (IAV) is a zoonotic pathogen responsible for seasonal and pandemic flu. The extensive genetic and antigenic diversity within and between IAV phylogenetic groups presents major challenges for developing universal vaccines and broad-spectrum antiviral therapies. Current interventions provide limited protection due to the virus’s high mutation rate and capacity for immune evasion. Recent advancements in viral hemagglutinin (HA)-targeting small-molecule entry inhibitors offer a promising avenue to overcome these limitations. Here, we present structural and functional analyses of two group 2 HA-specific small-molecule inhibitors recently identified by our team. Cryogenic electron microscopy (cryo-EM) structures revealed that these inhibitors bind a conserved pocket within the HA stalk, likely interfering with the conformational rearrangements necessary for membrane fusion and viral entry. Structure-guided mutagenesis confirmed the critical roles of key interacting residues and uncovered distinct resistance profiles between the two compounds, as well as in comparison to Arbidol, a previously reported HA inhibitor. Notably, our structural analysis highlights intrinsic barriers to achieving cross-group inhibition with current small-molecule designs. To address this, we propose an alternative strategy for broadening antiviral coverage. Together, these findings provide mechanistic insights into IAV entry inhibition and a foundation for the rational design of next-generation anti-influenza therapeutics.}, archive = {J_PNAS}, author = {Xu, Yan and Anirudhan, Varada and Gaisina, Irina N. and Du, Haijuan and Alqarni, Saad and Moore, Terry W. and Caffrey, Michael and Manicassamy, Balaji and Zhou, Tongqing and Rong, Lijun and Xu, Kai}, doi = {10.1073/pnas.2503899122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2503899122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mechanistic insights into the small-molecule inhibition of influenza a virus entry}, volume = {122}, year = {2025}, }
• (2025). Our current climate already merits serious research and policy attention. PNAS, 122(33), e2503892122. (www)

  @article{ , archive = {J_PNAS}, author = {Obradovich, Nick and Lawrance, Emma L. and Minor, Kelton}, doi = {10.1073/pnas.2503892122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2503892122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Our current climate already merits serious research and policy attention}, volume = {122}, year = {2025}, }
• (2025). The fetal hydrops–associated single-residue mutation L322P disrupts mechanical but not chemical activation of the PIEZO1 ion channel. PNAS, 122(33), e2503793122. (www)

  @article{ , abstract = {The mechanically activated PIEZO1 ion channel is genetically linked to numerous physiological and pathophysiological processes. For example, deleting PIEZO1 in mice leads to defective lymphatic vessel development, while nonsense mutations in humans are associated with autosomal recessive generalized lymphatic dysplasia (GLD) and nonimmune hydrops fetalis. However, it remains unclear whether PIEZO1-dependent biological processes are directly mediated by its intrinsic mechanosensitivity. Here, we identified a human fetal hydrops–associated single-residue mutation, L322P (corresponding to L329P in mouse PIEZO1). The mutant failed to show mechanically activated currents in response to poking or stretch of the cell membrane, but preserved normal plasma membrane expression and responsiveness to its chemical activators such as Yoda1 and Jedi1. Remarkably, the mechanical response of the mutant can be restored by Yoda1. These findings demonstrate a direct link between the loss of PIEZO1’s mechanosensitivity and the pathophysiological phenotype of fetal hydrops and raise the therapeutic potential of using PIEZO1 chemical activators to restore the mechanosensitivity of PIEZO1 missense mutants that are associated with genetic diseases such as GLD and hydrops fetalis.}, archive = {J_PNAS}, author = {Jiang, Jinghui and Guo, Wei and Chen, Xudong and He, Qijing and Wang, Yubo and Zhu, Xiaohui and Yan, Liying and Qiao, Jie and Xiao, Bailong}, doi = {10.1073/pnas.2503793122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2503793122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The fetal hydrops–associated single-residue mutation L322P disrupts mechanical but not chemical activation of the PIEZO1 ion channel}, volume = {122}, year = {2025}, }
• (2025). Biochar in the circular bionutrient economy. PNAS, 122(33), e2503668122. (www)

  @article{ , abstract = {The circular bionutrient economy is defined here as the circular economy of nutrients in managed organic residues. Here, we posit that biochar technology can stimulate the circular bionutrient economy by meeting the following three requirements: 1) nutrients are captured in a dry form, increasing market value and lowering transportation cost; 2) individual nutrients can be captured separately and combined as needed for particular plants and soils; 3) all pathogens and most pollutants can be removed with the notable exception of heavy metals. Pyrolysis and associated moisture removal enabled by the energy released during pyrolysis decreases weight of solid excreta by 85 to 90% and volume by 74 to 90%. This will lower storage and transport costs allowing redistribution of nutrients from production to processing and consumption of food. Incorporating liquid organic residues into nutrient recovery processes is crucial to the circular bionutrient economy. For example, N fertilizer from human feces would only generate about 2% (2.0 to 2.4 Tg N y −1 ) of current global N application, whereas including urine could increase this fraction to 16 to 17% (15.7 to 16.9 Tg N y −1 ). Nutrient acquisition by plants can be increased by biochar through nutrient retention and pH buffering in soil. We posit that leveraging biochar to close the nutrient circle requires public–private partnerships in forms of a community of practice and green alliances. These must develop a marketable product that incentivizes private investment. Such products may only be cost competitive with established fertilizer products by internalizing external environmental costs possibly through market mechanisms including but not limited to carbon credits.}, archive = {J_PNAS}, author = {Lehmann, Johannes and Barrios, Edmundo and Devault, Mariana and Li, Lucinda and Nelson, Rebecca and Six, Johan and Trimmer, John}, doi = {10.1073/pnas.2503668122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2503668122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biochar in the circular bionutrient economy}, volume = {122}, year = {2025}, }
• (2025). Layer 1 NDNF interneurons form distinct subpopulations with opposite activation patterns during sleep in freely behaving mice. PNAS, 122(33), e2503139122. (www)

  @article{ , abstract = {Non–rapid eye movement (NREM) sleep facilitates memory consolidation by transferring information from the hippocampus to the neocortex. This transfer is thought to occur primarily when hippocampal sharp-wave ripples (SWRs) and thalamocortical spindles are synchronized. However, the mechanisms underlying this synchronization remain unknown. In this study, we investigated the role of cortical layer 1 neuron-derived neurotrophic factor (NDNF)-expressing (L1 NDNF) interneurons in gating information transfer during SWR-spindle synchronization in NREM sleep. Using simultaneous cell-type specific calcium imaging with a head-mounted microscope and local field potential recordings in freely moving mice, we compared the activity of L1 NDNF and L2/3 neurons across vigilance states and during NREM-specific oscillations. Our findings reveal that L1 NDNF neurons form three distinct populations, assembling into cell networks tuned to specific sleep stages. REM active L1 NDNF and L2/3 neurons exhibit opposite activation patterns during spindles. While L2/3 cells are mostly inactive during SWR, NREM and REM active L1 NDNF cells inhibit the network upon SWR onset depending on their coupling with spindles. L1 NDNF neurons mediate slow inhibition primarily via GABA B receptors. Systemic application of a GABA B receptor antagonist resulted in decreased neuronal coupling of pyramidal cells but did not change the responses during SWRs. Overall, these findings highlight the potential role of L1 NDNF neuron-mediated inhibition in the response to synchronized sleep oscillations, with possible implications for memory consolidation.}, archive = {J_PNAS}, author = {Brécier, Aurélie and Mailhos, Gaëlle and Jarzebowski, Przemyslaw and Li, Yuqi and Paulsen, Ole and Hay, Y. Audrey}, doi = {10.1073/pnas.2503139122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2503139122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Layer 1 NDNF interneurons form distinct subpopulations with opposite activation patterns during sleep in freely behaving mice}, volume = {122}, year = {2025}, }
• (2025). Gene regulatory logic of the interferon-β enhancer is characterized by two selectively deployed modes of transcription factor synergy. PNAS, 122(33), e2502800122. (www)

  @article{ , abstract = {Type I interferon IFNβ is a key immune response cytokine, and when its expression is dysregulated, it causes disease. The regulation of IFNβ enhancer has been a touchpoint of mammalian gene control research since the discovery of functional synergy between two stimulus-responsive transcription factors (TFs), nuclear factor kappa B (NFκB) and interferon regulatory factors (IRF). However, subsequent gene knockout studies revealed that in some conditions either NFκB or IRF activation can be dispensable, leaving the precise regulatory logic of IFNβ transcription an open question. Here, we developed a series of quantitative enhancer states models of IFNβ expression control and evaluated them with stimulus–response data from TF knockouts. Of these, our analysis reveals that two modes of TF synergy account for the available data and neither is based on binding cooperativity. The first involves two adjacent IRF dimers, with a sigmoidal binding curve at the distal site rendering it ultrasensitive and restricting it to conditions of high IRF activity upon viral infection. The second is driven by the proximal site, which has high affinity and synergizes with NFκB to enable about half-maximal expression in response to bacterial exposure. Its accessibility is controlled by the competitive repressor p50:p50, which prevents basal IRF from binding, such that NFκB-only stimuli do not induce IFNβ expression and may allow for prior-exposure-dependent tuning. The model explains how the regulatory logic of the IFNβ enhancer ensures invariant IFNβ expression in response to viral exposure, while providing tunable, context-dependent expression in response to bacterial exposure.}, archive = {J_PNAS}, author = {Schiffman, Allison and Cheng, Zhang and Ourthiague, Diana and Hoffmann, Alexander}, doi = {10.1073/pnas.2502800122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2502800122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Gene regulatory logic of the interferon-β enhancer is characterized by two selectively deployed modes of transcription factor synergy}, volume = {122}, year = {2025}, }
• (2025). The distortion–push mechanism for the γ subunit rotation in f1-ATPase. PNAS, 122(33), e2502642122. (www)

  @article{ , abstract = {F 1 -ATPase comprises the stator ring consisting of α 3 β 3 subunits and the rotor γ subunit. The γ subunit rotation mechanism has been extensively investigated by biochemical analyses, structural studies, single-molecule measurements, and computational studies. Recent cryoelectron microscopy (cryo-EM) structures of F 1 -ATPase from the thermophilic bacterium Bacillus PS3 (TF 1 ) provide us with further possibilities for a better understanding of the γ-rotation mechanisms. Using cryo-EM structures having the γ-rotation angles close to the binding dwell and catalytic dwell states, we investigate the relationships between the γ subunit rotation, conformational changes of the stator α 3 β 3 subunits, and the nucleotide-binding and release. We performed targeted molecular dynamics (MD) simulations with external forces on the α 3 β 3 subunits and observed 80° substep rotations of the γ subunit. Then, we optimized the most probable transition pathway through the mean-force string method simulations with 64 images. Finally, using umbrella sampling, we calculated the potential of mean forces along the minimum free energy pathway during the 80° substep rotation. Our MD simulations suggest that 80° substep rotation is divided into the first rotation, resting, and the second rotation. Notably, the first rotation is driven by the distortion of the stator α 3 β 3 subunits, and the second rotation is induced mainly by direct β/γ subunit interactions. This model, which we call the distortion–push mechanism, is consistent with the residue-level experimental analysis on F 1 -ATPase and the atomic structures determined by X-ray crystallography and cryo-EM.}, archive = {J_PNAS}, author = {Motohashi, Masahiro and Oide, Mao and Kobayashi, Chigusa and Jung, Jaewoon and Muneyuki, Eiro and Sugita, Yuji}, doi = {10.1073/pnas.2502642122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2502642122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The distortion–push mechanism for the γ subunit rotation in f1-ATPase}, volume = {122}, year = {2025}, }
• (2025). Suppressing mechanical property variability in recycled plastics via bioinspired design. PNAS, 122(33), e2502613122. (www)

  @article{ , abstract = {Over 350 million metric tons of plastic waste are generated annually, with most ending up in landfills, dumps, or the environment, posing significant risks. Mechanical recycling remains underutilized, largely due to the high variability in the mechanical properties of recycled plastics (recyclates). This variability undermines performance reliability and hinders the adoption of recyclates in demanding industrial applications. Inspired by natural materials, known for their mechanical robustness despite microstructural stochasticity, we propose a universal, chemistry-agnostic, brick-and-mortar design tailored for recycled polymers. In this design, stiff recycled plastic platelets (bricks) are embedded in a soft virgin polymer matrix (mortar), which accommodates deformation and redistributes stress. To predict the effective modulus, strength, and property variability of such structures, we developed an uncertainty-aware tension-shear-chain model, combining Monte Carlo simulations with literature-based distributions of recyclates’ stiffness and conservative interfacial parameter stochasticity assumptions. We validated our model using nacre-inspired composites fabricated from recycled high-density polyethylene (rHDPE) platelets and polydimethylsiloxane (PDMS) mortar. The experimental results matched model predictions, confirming significant suppression of variability. In a case study on industrial HDPE stretch film, our design reduced modulus variability by up to 93% and maximum permissible strain variability by at least 68% compared to input rHDPE, while matching the modulus of virgin HDPE film. This work introduces a design-enabled variability-suppression strategy for recycled plastics, able to transform highly heterogenous materials into structurally robust products. By supporting virgin-plastic substitution and circular design strategies, our approach can enable the broader adoption of recyclates by several industries.}, archive = {J_PNAS}, author = {Georgiou, Dimitrios and Sun, Danqi and Liu, Xing and Athanasiou, Christos E.}, doi = {10.1073/pnas.2502613122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2502613122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Suppressing mechanical property variability in recycled plastics via bioinspired design}, volume = {122}, year = {2025}, }
• (2025). Observed declines in leaf nitrogen explained by photosynthetic acclimation to CO2. PNAS, 122(33), e2501958122. (www)

  @article{ , abstract = {Widespread evidence of decreasing leaf nutrients has raised concerns about ecosystem productivity under global change. Interpreting trends in leaf nutrients has important implications for the fate of ecosystem services, particularly the role of forests in mitigating climate change and sustaining quality food sources. Here, we challenge the common interpretation that decreasing leaf nitrogen concentration ( LNC ) is evidence of increasing nutrient limitations on ecosystem primary productivity. Instead, we show that declines in LNC (4% decrease per 50 ppm CO 2 increase), observed across 409 European forest plots over 22 y, can be explained by reduced photosynthetic nitrogen demand. This regional trend is consistent with leaf acclimation to increasing atmospheric CO 2 according to optimality theory. This finding suggests that enhanced photosynthetic nitrogen use efficiency due to CO 2 fertilization may lead to less nitrogen uptake and/or reallocation of nitrogen for plant growth and other functions. Our results have large implications for understanding and simulating interactions between ecosystem nitrogen and carbon cycles and suggest nitrogen requirements for terrestrial carbon uptake under elevated CO 2 may be lower than previously thought.}, archive = {J_PNAS}, author = {Bassiouni, Maoya and G. Smith, Nicholas and Reu, Jacqueline C. and Peñuelas, Josep and Keenan, Trevor F.}, doi = {10.1073/pnas.2501958122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2501958122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Observed declines in leaf nitrogen explained by photosynthetic acclimation to CO2}, volume = {122}, year = {2025}, }
• (2025). Scalable high-voltage Zn||MnO2 batteries achieved by mild amphiphilic hydrogel electrolytes. PNAS, 122(33), e2501935122. (www)

  @article{ , abstract = {The practical applications of aqueous Zn||MnO 2 batteries are limited by their small areal capacity, low discharging plateau, and clumsy packing device. Currently, the high potential MnO 2 /Mn 2+ redox conversion can only be well activated in electrolytes with a very low pH value, which is not friendly to the Zn metal anode. To overcome these limitations, we have designed mild amphiphilic hydrogel electrolytes (AHEs) with a wide electrochemical stability window (ESW) and high ionic activity. The design is based on the mechanism that trace amounts of hydrophobic moieties enhance the hydrogen bonding between hydrophilic groups and water molecules in the hydrogel electrolytes. The developed AHE possesses an ESW up to ~3.0 V even at a high water content of ~76 wt%. The assembled Zn||MnO 2 pouch cells using the hydrogel electrolytes demonstrated a large areal capacity of ~5 mAh cm −2 at 1 mA cm −2 and a high-voltage and flat discharging plateau of ~1.9 V. Furthermore, a pouch cell with an area of 40 cm 2 was fabricated, exhibiting a capacity of ~125 mAh at 2 mA cm −2 . Two pouch cells (25 cm 2 ) in series were used to drive a 3.7 V-powerable electric fan. This work highlights the rational design of wide-ESW AHEs with high ionic activity as a promising approach to achieving portable and scalable applications of aqueous high-voltage Zn||MnO 2 batteries.}, archive = {J_PNAS}, author = {Li, Chuan and Liang, Bochun and Chen, Ze and Zhang, Rong and Cui, Huilin and Wang, Yanbo and Li, Qing and Peng, Chao and Fan, Jun and Pei, Zengxia and Zhi, Chunyi}, doi = {10.1073/pnas.2501935122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2501935122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Scalable high-voltage Zn||MnO2 batteries achieved by mild amphiphilic hydrogel electrolytes}, volume = {122}, year = {2025}, }
• (2025). Global profiling of N-terminal cysteine–dependent degradation mechanisms. PNAS, 122(33), e2501681122. (www)

  @article{ , abstract = {Hypoxia, a condition characterized by insufficient oxygen supply, challenges cellular homeostasis and energy production, triggering adaptive responses to promote survival under these stressful conditions. One key strategy involves enzymatic oxidation of N-terminal cysteine residues coupled with proteolysis through the Cys-Arg/N-degron pathway. Despite hundreds of human proteins possessing N-terminal cysteine, very few have been identified as substrates of this pathway, and its substrate selectivity remains unclear. Moreover, the biological role of this pathway in the cellular response to hypoxia is not well defined. Here, by systematically screening protein stability using an N-terminome library, we reveal a broad set of cysteine-initiating proteins regulated by this pathway. Mutagenesis experiments further revealed the specificity of Cys-Arg/N-degron pathway, showing a preference for hydrophobic and positively charged residues following cysteine. Additionally, we uncovered full-length substrates that are regulated by this pathway during hypoxia, including IP6K1. Loss of IP6K1 impaired glucose uptake, glycolytic ATP production, and overall mitochondrial function. Consequently, IP6K1-deficient cells exhibited disrupted metabolic adaptation under hypoxic conditions and reduced survival under stress. These findings underscore the importance of the Cys-Arg/N-degron pathway in regulating metabolic responses and highlight its potential importance in hypoxia-related disorders.}, archive = {J_PNAS}, author = {Bekturova, Aizat and Makaros, Yaara and Ben-David, Shahar and Koren, Itay}, doi = {10.1073/pnas.2501681122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2501681122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global profiling of N-terminal cysteine–dependent degradation mechanisms}, volume = {122}, year = {2025}, }
• (2025). Embolism resistance supports the contribution of dry-season precipitation to transpiration in eastern amazon forests. PNAS, 122(33), e2501585122. (www)

  @article{ , abstract = {Transpiration drives most of the local rainfall during the dry season in the Amazon forests by recycling moisture into the atmosphere. However, the source, temporal origin of transpiration, and spatial distribution of transpiration water sources remain unclear. Here, we quantify transpiration sources across a topographic gradient in the eastern Amazon. We show that on hills, dry-season transpiration sources are mostly shallow soil water recharged by dry-season rainfall. This is different in valleys, where tree water sources include both shallow and deep soil layers, with both dry- and wet-season contributions. We show that species embolism resistance largely explains this pattern in tree water use but with contrasting trade-offs between topographic positions. The significant relationship between embolism resistance and depth of water uptake in both hill and valley species may merit incorporation into process-based models to understand changes in vegetation and land surface fluxes.}, archive = {J_PNAS}, author = {Nehemy, Magali F. and Mattos, Caio R. C. and Oliveira, Rafael S. and Hirota, Marina and Fan, Ying and Schlickmann, Monique B. and Penha, Deliane and Giacomin, Leandro L. and Silva, Julliene S. G. M. and Rocha, Mayda and Rodrigues, Gleicy A. and McDonnell, Jeffrey J.}, doi = {10.1073/pnas.2501585122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2501585122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Embolism resistance supports the contribution of dry-season precipitation to transpiration in eastern amazon forests}, volume = {122}, year = {2025}, }
• (2025). Locusts employ neuronal sensory prioritization to reconcile two conflicting olfactory signals while aggregating. PNAS, 122(33), e2501490122. (www)

  @article{ , abstract = {Migratory locusts ( Locusta migratoria ) emit two key odorants during aggregation: 4-vinylanisole (4VA), which serves as an aggregation pheromone attracting conspecifics to form swarms, and phenylacetonitrile (PAN), which acts as an aposematic signal and a precursor of a defense toxin, deterring conspecifics from cannibalism and protecting against predators. However, how locusts reconcile these two conflicting olfactory signals while aggregating is not yet understood. Our study addresses this by examining the release dynamics of the two signals, their behavioral effects, and the neural mechanisms underlying their perception. 4VA is released earlier and at lower locust densities than PAN, with PAN’s release increasing as aggregation progresses. Although PAN’s emission levels eventually exceed those of 4VA, locusts consistently exhibit a preference for the emitted blend, regardless of variations in proportions and concentrations. Notably, increasing amounts of 4VA added to PAN can counteract PAN’s repellent effects, but this is not the case when PAN is added to 4VA. Mechanistically, we found that antennal neurons responsive to 4VA suppress the activity of neurons responsive to PAN. In the antennal lobe, it is the conduction velocities of projection neurons, rather than other neural properties, that are responsible for the observed behavioral pattern, leading to an overall attractive response. Collectively, our findings imply that insects are capable of harmonizing the effects of two distinct pheromones to optimize both social cohesion and chemical defense.}, archive = {J_PNAS}, author = {Yu, Qiaoqiao and Yang, Jing and Yu, Jia and Lei, Hong and Kang, Le and Guo, Xiaojiao}, doi = {10.1073/pnas.2501490122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2501490122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Locusts employ neuronal sensory prioritization to reconcile two conflicting olfactory signals while aggregating}, volume = {122}, year = {2025}, }
• (2025). Three decades of declines restructure butterfly communities in the midwestern united states. PNAS, 122(33), e2501340122. (www)

  @article{ , abstract = {Insects are declining worldwide. These declines have been documented across taxonomic groups and are worrisome given ecosystem services provided by insects. Long-term data have illuminated butterfly declines across geographic regions. However, critical questions remain on how butterfly declines are distributed across species and functional groups, limiting effective conservation. Here, we show unprecedented changes in butterfly biodiversity resulting from 32 y of species levels declines throughout the Midwestern United States. No species increased over the three-decade study period and abundance declined across every functional group (e.g., rare, common, migratory, resident; annual mean trend: −0.9 to −2.3% per year). Species richness declined across all but one functional group, with concomitant increases in evenness (e.g., abundance among species) in several groups resulting from steeper losses in abundance for common species (abundance: −1.9% per year; richness: −0.04% per year) as compared to rare species (abundance: −0.9% per year; richness: −1.33% per year). Our results paint a bleaker picture than other butterfly studies likely due to our long time series of data and ability to include rare species. Such widespread declines undoubtedly affect other trophic levels and ecosystem services. Focusing risk assessments and management interventions only on rare species is likely to be insufficient given broad declines across species, which have fundamentally restructured butterfly communities in the region. As such, conservation efforts should shift focus to species assemblages and entire communities when possible.}, archive = {J_PNAS}, author = {Leuenberger, Wendy and Doser, Jeffrey W. and Belitz, Michael W. and Ries, Leslie and Haddad, Nick M. and Thogmartin, Wayne E. and Zipkin, Elise F.}, doi = {10.1073/pnas.2501340122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2501340122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Three decades of declines restructure butterfly communities in the midwestern united states}, volume = {122}, year = {2025}, }
• (2025). A stochastic theory of urban metabolism. PNAS, 122(33), e2501224122. (www)

  @article{ , abstract = {A current tenet in the science of cities is the emergence of power-law relations between population size and a variety of urban indicators, echoing allometric scaling in living organisms akin to Kleiber’s law. However fascinating, existing scaling theories suffer from biases related to the ad-hoc definition of city boundaries and to their neglect of intraurban variability of city properties. Here, to deal rigorously with biases, we explore the hypothesis that the empirical statistics of intracity variations in population counts, road networks, and carbon emissions-across various cities and spatial scales-can be interpreted as resulting from the joint fluctuations of spatially dependent random variables. Rather than relating urban characteristics to overall city size, we focus on how intraurban properties and local population patterns vary together across space. We find that the marginal and joint probability distributions are characterized by finite-size scaling functions which, upon suitable rescaling, collapse onto a set of universal curves. These results are analogous to those relating intraspecies variability in living organisms where the scaling of mean body mass with a characteristic metabolic rate clouds the effects of the variance of both traits. Our findings lay the foundations for a generalized theory of urban metabolism, linking city-scale quantities to the covariation of intraurban characteristics. This also opens up opportunities for a full exploitation of available urban data allowing the integration of biologically inspired theories into the modeling and planning of cities.}, archive = {J_PNAS}, author = {Hendrick, Martin and Rinaldo, Andrea and Manoli, Gabriele}, doi = {10.1073/pnas.2501224122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2501224122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A stochastic theory of urban metabolism}, volume = {122}, year = {2025}, }
• (2025). Therapeutic CD8+ t cell tissue retention and immunomodulation during ART interruption fail to prevent SIV rebound. PNAS, 122(33), e2501037122. (www)

  @article{ , abstract = {A primary obstacle for HIV elimination is the long-term viral reservoir in lymphoid tissues (LT) that can cause rebound viremia if therapy is stopped. Cytotoxic CD8 + T cells are critical for control of HIV and Simian immunodeficiency virus (SIV) viremia; however, CD8 + T cells that migrate to LT are primarily noncytotoxic, calling into question whether these cells could reduce the viral reservoir on antiretroviral therapy (ART) or control viral replication when therapy is halted. To determine whether CD8 + T cells can inhibit viral replication when retained in LT, we inhibited lymphocyte egress from LTs in ART-treated SIV-infected rhesus macaques (RMs) during analytic treatment interruption (ATI) using the S1PR modulator FTY720 alone or in combination with anti-PD1 antibody (αPD1) and the IL-15 receptor superagonist N-803 to increase cytolytic function. FTY720 retained migrating CD4 + and CD8 + T cells in LT, whereas cytotoxic CD8 + T cells remained in the vasculature. After ATI and viral rebound, activated SIV-specific CD8 + T cells increased in frequency in LT of FTY720-treated RMs but failed to become cytotoxic or control plasma viremia compared to controls, even when combined with αPD1 and N-803. These findings indicate that LT-localized CD8 + T cells alone may be insufficient to delay or prevent plasma viral rebound during ATI.}, archive = {J_PNAS}, author = {Pampena, M. Betina and Samer, Sadia and Viox, Elise G. and Nguyen, Kevin and Deleage, Claire and Kuri-Cervantes, Leticia and Regan, James and Wu, Vincent H. and Docken, Steffen and Safrit, Jeffrey T. and Bar, Katharine J. and Keele, Brandon F. and Davenport, Miles P. and Paiardini, Mirko and Betts, Michael R.}, doi = {10.1073/pnas.2501037122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2501037122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Therapeutic CD8+ t cell tissue retention and immunomodulation during ART interruption fail to prevent SIV rebound}, volume = {122}, year = {2025}, }
• (2025). Evolutionarily divergent nidovirus with an exceptionally large genome identified in pacific oysters undergoing mass mortality. PNAS, 122(33), e2426923122. (www)

  @article{ , abstract = {Metatranscriptomic data from a mass-mortality event of adult Pacific Oysters, Crassostrea ( Magallana ) gigas , the most widely cultivated shellfish globally, revealed a nidovirus shown to replicate in a bivalve, Pacific Oyster Nidovirus 1 (PONV1). At 64,331 bp of linear bisegmented, positive-sense single-stranded RNA, PONV1 has one of the largest genomes reported for an RNA virus. Moreover, transcriptomic data reveal that many conspecific viruses of PONV1 occur in Pacific oysters from Europe and the Pacific coasts of Asia and North America. PONV1 (tentative species Megarnavirus gigas ) and its conspecific viruses represent a putative family, Megarnaviridae , that is widely divergent from other families of nidoviruses, and encodes protein domains likely involved in virus–host interaction that are undescribed for other nidoviruses. Given that PONV1 occurs in diseased Pacific oysters undergoing mass mortality, and that close relatives of PONV1 are widespread globally, it emphasizes the need for caution in the translocation of Pacific oyster spat that routinely occurs.}, archive = {J_PNAS}, author = {Zhong, Kevin Xu and Chan, Amy M. and Miller, Kristina M. and Saunders, Rob and Suttle, Curtis A.}, doi = {10.1073/pnas.2426923122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2426923122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolutionarily divergent nidovirus with an exceptionally large genome identified in pacific oysters undergoing mass mortality}, volume = {122}, year = {2025}, }
• (2025). Anyon superconductivity from topological criticality in a Hofstadter–Hubbard model. PNAS, 122(33), e2426680122. (www)

  @article{ , abstract = {We argue that the combination of strong repulsive interactions and high magnetic fields can generate electron pairing and superconductivity. Inspired by the large lattice constants of moiré materials, which make large flux per unit cell accessible at laboratory fields, we study the triangular lattice Hofstadter–Hubbard model at one-quarter flux quantum per plaquette, where previous literature has argued that a chiral spin liquid separates a weak-coupling integer quantum Hall phase and a strong-coupling topologically trivial antiferromagnetic insulator at a density of one electron per site. We argue that topological superconductivity emerges upon doping in the vicinity of the integer quantum Hall to chiral spin liquid transition. We employ exact diagonalization and density matrix renormalization group methods to examine this theoretical scenario and find that electronic pairing indeed occurs on both sides of criticality over a remarkably broad range of interaction strengths. On the chiral spin liquid side, our results provide a concrete model realization of the long-hypothesized mechanism of anyon superconductivity. Our study thus establishes a beyond-Bardeen-Cooper-Schrieffer route to electron pairing in a well-controlled limit, relying crucially on the interplay between electron correlations and band topology.}, archive = {J_PNAS}, author = {Divic, Stefan and Crépel, Valentin and Soejima, Tomohiro and Song, Xue-Yang and Millis, Andrew J. and Zaletel, Michael P. and Vishwanath, Ashvin}, doi = {10.1073/pnas.2426680122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2426680122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Anyon superconductivity from topological criticality in a Hofstadter–Hubbard model}, volume = {122}, year = {2025}, }
• (2025). A critical role for vibrio parahaemolyticus LPS to mediate evasion of host immune response during infection. PNAS, 122(33), e2426547122. (www)

  @article{ , abstract = {Vibrio parahaemolyticus ( V. para ), a Gram-negative halophilic bacterium, is the leading cause of seafood-borne gastroenteritis. While the cytotoxic and enterotoxic capabilities of this bacterium have been previously investigated, the strategies it employs to circumvent innate immune detection by the host remain poorly understood. Bacterial lipopolysaccharide (LPS) serves as the major pathogen-associated molecular pattern that triggers host inflammatory responses, and its lipid A structure contributes to the degree of innate immune system activation. We sought to define the structure of the lipid A component of LPS in V. para and probe its role in host innate immunity. Free living V. para synthesizes a predominantly hepta-acylated lipid A structure, while also producing a minor subset of hexa-acylated lipid A. This altered acylated lipid A elicits a weakened TLR4 immune response as compared to Escherichia coli , allowing V. para entry and replication inside host cells. Deletion of the V. para lipid A biosynthesis enzyme lpxM (VP0213) leads to a mutant strain with altered lipid A secondary acylation, enhanced immune response, and impaired replication within epithelial cells. This study provides evidence that the unique LPS structure synthesized by V. para plays a crucial role in evading host innate immunity, facilitating the bacterium’s survival and replication within host cells.}, archive = {J_PNAS}, author = {Jaishankar, Jananee and Yang, Hyojik and O’Keefe, Ian P. and Tenaglia, Brandon M. and Kinch, Lisa N. and Ernst, Robert K. and Orth, Kim}, doi = {10.1073/pnas.2426547122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2426547122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A critical role for vibrio parahaemolyticus LPS to mediate evasion of host immune response during infection}, volume = {122}, year = {2025}, }
• (2025). Keldysh tuning of photoluminescence in a lead halide perovskite crystal. PNAS, 122(33), e2426253122. (www)

  @article{ , abstract = {In 1964, Keldysh laid the groundwork for strong-field physics in atomic, molecular, and solid-state systems by delineating a ubiquitous transition from multiphoton absorption to classical field-driven electron tunneling under intense electromagnetic waves. While both processes in semiconductors can generate carriers and result in photon emission through electron–hole recombination, the low quantum yields in most materials have hindered direct observation of the Keldysh crossover. Leveraging the large quantum yields of photoluminescence in lead halide perovskites, we show that we can not only induce bright light emission from extreme subbandgap excitation but also distinguish between photon-induced and electric-field-induced processes. Our results span the transition between quantum-mechanical and classical field effects of the light and provide generalizable insights into the nonequilibrium dynamics that result from strong-field light–matter interactions. The findings also open avenues for light upconversion and subbandgap photon detection, highlighting the potential of lead halide perovskites in advanced optoelectronic applications.}, archive = {J_PNAS}, author = {Zhang, Zhuquan and Ning, Honglie and Liu, Zi-Jie and Hou, Jin and Mohite, Aditya D. and Baldini, Edoardo and Gedik, Nuh and Nelson, Keith A.}, doi = {10.1073/pnas.2426253122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2426253122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Keldysh tuning of photoluminescence in a lead halide perovskite crystal}, volume = {122}, year = {2025}, }
• (2025). Quantum spin liquid from electron–phonon coupling. PNAS, 122(33), e2426111122. (www)

  @article{ , abstract = {A quantum spin liquid (QSL) is an exotic insulating phase with emergent gauge fields and fractionalized excitations. However, the unambiguous demonstration of the existence of a QSL in a “nonengineered” microscopic model (or in any material) remains challenging. Here, using numerically exact sign-problem-free quantum Monte Carlo simulations, we show that a QSL arises in a nonengineered electron–phonon model. Specifically, we investigate the ground-state phase diagram of the bond Su–Schrieffer–Heeger model on a 2D triangular lattice at (one electron per site), which we show includes a QSL phase which is fully gapped, exhibits no symmetry-breaking order, and supports deconfined fractionalized holon excitations. This suggests promising routes for finding QSLs in realistic materials and high- T c superconductivity by lightly doping them.}, archive = {J_PNAS}, author = {Cai, Xun and Han, Zhaoyu and Li, Zi-Xiang and Kivelson, Steven A. and Yao, Hong}, doi = {10.1073/pnas.2426111122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2426111122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantum spin liquid from electron–phonon coupling}, volume = {122}, year = {2025}, }
• (2025). Dynamic GLUT trafficking at high glucose levels enhances insulin secretion: Dysregulation leads to decreased insulin secretion during type 2 diabetes. PNAS, 122(33), e2425955122. (www)

  @article{ , abstract = {Glucose transporters (GLUT1/2) facilitate glucose uptake in pancreatic β cells, triggering insulin secretion. The availability of GLUTs at the plasma membrane (PM) is governed by its expression, delivery to the membrane, and endocytosis. Little is known about the dynamics of GLUT trafficking in response to glucose that triggers glucose-stimulated insulin secretion. In our study, we found that the recruitment of GLUTs to the PM of β cells correlates with increasing glucose concentrations. The recruitment of GLUTs to PM is coupled with endocytosis driven by clathrin. During endocytosis, GLUT actively translocated to clathrin pits, triggering internalization. Disruption of endocytosis with dominant negative dynamin2-K44A or pitstop2 leads to altered GLUT dynamics in response to high glucose levels, resulting in reduced glucose uptake. Augmenting this finding, GLUT distribution and endocytosis in response to glucose are impaired in human islets from type 2 diabetes (T2D) donors, further confirmed by single-cell RNA-seq from β cells of nondiabetic and T2D donors. This leads to limited availability of insulin granules at higher glucose concentrations in T2D islets. Moreover, our data suggest that the glucose-dependent spatial association between GLUT and a subset of insulin granules which are primed via Munc-13.1. In line with this, we see our results highlight the importance of GLUTs delivery to the PM and clathrin-mediated endocytosis, leading to sustained availability of GLUTs for glucose uptake and subsequent insulin secretion in response to glucose. Notably, impaired insulin secretion during T2D might be reversible by modulating GLUT trafficking.}, archive = {J_PNAS}, author = {Pallavi, Anuma and Sinha, Neha and ArunKumar, Nagapriya K. and Kothegala, Lakshmi and Gandasi, Nikhil R.}, doi = {10.1073/pnas.2425955122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2425955122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic GLUT trafficking at high glucose levels enhances insulin secretion: Dysregulation leads to decreased insulin secretion during type 2 diabetes}, volume = {122}, year = {2025}, }
• (2025). Spatiotemporal distribution of the glycoprotein pherophorin II reveals stochastic geometry of the growing ECM of volvox carteri. PNAS, 122(33), e2425759122. (www)

  @article{ , abstract = {The evolution of multicellularity involved the transformation of a simple cell wall of unicellular ancestors into a complex, multifunctional extracellular matrix (ECM). A suitable model organism to study the formation and expansion of an ECM during ontogenesis is the multicellular green alga Volvox carteri , which, along with the related volvocine algae, produces a complex, self-organized ECM composed of multiple substructures. These self-assembled structures primarily consist of hydroxyproline-rich glycoproteins, a major component of which is pherophorins. To investigate the geometry of the growing ECM, we fused the yfp gene with the gene for pherophorin II (PhII) in V. carteri . Confocal microscopy reveals PhII:YFP localization at key ECM structures, including the boundaries of compartments surrounding each somatic cell and the outer surface of the organism. Image analysis during the life cycle allows the stochastic geometry of growing compartments to be quantified; their areas and aspect ratios exhibit robust gamma distributions and exhibit a structural transition from a tight polygonal to a looser acircular packing geometry with stable eccentricity over time, evoking parallels and distinctions with the behavior of hydrated foams. These results provide quantitative insight into a general, open question in biology: how do cells collectively produce a complex structure external to themselves in a robust and accurate manner?}, archive = {J_PNAS}, author = {von der Heyde, Benjamin and Srinivasan, Anand and Birwa, Sumit Kumar and von der Heyde, Eva Laura and Höhn, Steph S. M. H. and Goldstein, Raymond E. and Hallmann, Armin}, doi = {10.1073/pnas.2425759122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2425759122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatiotemporal distribution of the glycoprotein pherophorin II reveals stochastic geometry of the growing ECM of volvox carteri}, volume = {122}, year = {2025}, }
• (2025). Warm, water-depleted rocky exoplanets with surface ionic liquids: A proposed class for planetary habitability. PNAS, 122(33), e2425520122. (www)

  @article{ , abstract = {The discovery of thousands of exoplanets and the emergence of telescopes capable of exoplanet atmospheric characterization have intensified the search for habitable worlds. Due to selection biases, many exoplanets under study are planets deemed inhospitable because their surfaces are too warm to support liquid water. We propose that such planets could still support life through ionic liquids: Liquid salts with negligible vapor pressure that can persist on warm planets with thin atmospheres, where liquid water cannot. Ionic liquids have not previously been considered as naturally occurring substances, and thus have not been discussed in planetary science. We demonstrate in laboratory experiments that ionic liquids can form from planetary materials: Sulfuric acid combined with nitrogen-containing organic molecules. Sulfuric acid can be volcanic in origin, and organic compounds are commonly found on planetary bodies. The required planetary surface is water-depleted and must support sulfuric acid transiently in liquid phase to dissolve organics, followed by evaporation of excess liquid—conditions spanning approximately 300 K at 10 −7 atm to 350—470 K at 0.01 atm. Because ionic liquids have extremely low vapor pressures, they are not prone to evaporation, allowing small droplets or pools to persist without ocean-like reservoirs. Ionic liquids’ minuscule vapor pressure at room temperature suggests possible stability on planets with negligible atmospheres, shielded by magnetic fields or rock crevices against harsh cosmic radiation. Ionic liquids can stably dissolve enzymes and other biomolecules, enabling biocatalysis and offering a plausible solvent for life—broadening the definition of habitable worlds.}, archive = {J_PNAS}, author = {Agrawal, Rachana and Seager, Sara and Iakubivskyi, Iaroslav and Buchanan, Weston P. and Glidden, Ana and Seager, Maxwell D. and Bains, William and Huang, Jingcheng and Petkowski, Janusz J.}, doi = {10.1073/pnas.2425520122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2425520122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Warm, water-depleted rocky exoplanets with surface ionic liquids: A proposed class for planetary habitability}, volume = {122}, year = {2025}, }
• (2025). Atomistic mechanisms of calcium permeation modulated by Q/R editing and selectivity filter mutations in GluA2 AMPA receptors. PNAS, 122(33), e2425172122. (www)

  @article{ , abstract = {GluA2 is a key subunit of α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) ion channels that is abundantly expressed in the vertebrate brain. Posttranscriptional Q/R editing of GluA2 renders AMPARs nearly impermeable to calcium ions, which is crucial for their normal function. Although previous studies have characterized conductivity and selectivity differences between edited and unedited GluA2 variants and heteromeric receptors incorporating GluA2, the consequences of pore editing have not been studied in all-atom simulations, which leave the atomistic mechanisms unclear. In this study, we investigate ion permeation in the context of multiple Ca 2+ binding sites along the pore predicted from molecular dynamics (MD) simulations, considering both mutations and co-permeating monovalent ions. Patch clamp electrophysiology recordings confirmed a binding site at the intracellular mouth of the selectivity filter that confers selectivity for calcium over monovalent ions. A patient mutation at the same site has been previously shown to cause neurodevelopmental abnormalities. Furthermore, MD simulations of GluA2 with different arginine copy number at the Q/R site show that Ca 2+ conduction is blocked in the presence of two arginines, whereas K + is only blocked by four arginines, in explaining the results from decades of electrophysiological work. Finally, MD simulations revealed that Ca 2+ reduces K + conduction by preferentially occupying the intracellular selectivity filter binding site, whereas Na + does not. This result is consistent with electrophysiological results from the D590 mutants and suggests that divalent binding in the selectivity filter is a major determinant of AMPAR conductance.}, archive = {J_PNAS}, author = {Heiser, Florian and Biedermann, Johann and Kuru, Ece and Plested, Andrew J. R. and Sun, Han}, doi = {10.1073/pnas.2425172122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2425172122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Atomistic mechanisms of calcium permeation modulated by Q/R editing and selectivity filter mutations in GluA2 AMPA receptors}, volume = {122}, year = {2025}, }
• (2025). Dural ectopic lymphatic structures accumulate during aging and exhibit dysregulation in neurodegenerative diseases. PNAS, 122(33), e2425081122. (www)

  @article{ , abstract = {The meninges serve as a critical interface between the peripheral immune system and the central nervous system, playing a crucial role in maintaining parenchymal homeostasis. Neurodegenerative disorders, such as amyloidosis and tauopathies, are marked by the accumulation of extracellular neurotoxic amyloid-β (Aβ) plaques and intracellular tau tangles, respectively, leading to neuronal cell death and cognitive decline. The role of the adaptive immune response in these pathologies remains under debate. Adaptive immune cells can manifest as ectopic lymphoid structures (ELS), which resemble secondary lymphoid organs, and form at sites of inflammation or pathology. While ELSs can support immune responses against infections or tumors, they may also have detrimental effects in certain pathological conditions. To explore whether meningeal ELS are implicated in aging and neurodegeneration, we analyzed the meninges of aged wild-type mice and mouse models of early-onset Alzheimer’s disease, tauopathy, and Down syndrome-related neurodegenerative disorders. Our findings suggest that the accumulation of dural ELS varies according to age, brain pathology, and sex. Meningeal myeloid cells may contribute to the initiation and maintenance of ELS during aging. These results demonstrate the potential contribution of meningeal ELS to healthy aging and neurodegenerative conditions, offering directions for future research.}, archive = {J_PNAS}, author = {Fruitman Davidi, Amit and Shirenova, Sophie and Michaelovich, Dolev and Benedetti, Giulio and Shtrasberg, Hadar and Shoval, Irit and Hauschner, Hagit and Oz, Gal and Vardy, Karin and Hirsh, Tamir and Madar, Ravit and Stern, Edward A. and Rosenmann, Hanna and Biragyn, Arya and Okun, Eitan}, doi = {10.1073/pnas.2425081122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2425081122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dural ectopic lymphatic structures accumulate during aging and exhibit dysregulation in neurodegenerative diseases}, volume = {122}, year = {2025}, }
• (2025). The edge-averaging process on graphs with random initial opinions. PNAS, 122(33), e2423947122. (www)

  @article{ , abstract = {In several settings (e.g., sensor networks and social networks), nodes of a graph are equipped with initial opinions, and the goal is to estimate the average of these opinions using local operations. A natural algorithm to achieve this is the edge-averaging process, where edges are repeatedly selected at random (according to independent Poisson clocks) and the opinions on the nodes of each selected edge are replaced by their average. The effectiveness of this algorithm is determined by its convergence rate. It is known that on a finite graph of n nodes, the opinions reach approximate consensus in polynomial time. We prove that the convergence is much faster when the initial opinions are disordered (independent identically distributed): The time to reach approximate consensus is O ( log 2 n ) , and this bound is sharp. For infinite graphs, we show that for every p ≥ 1 , if the initial opinions are in L p , then the opinion at each vertex converges to the mean in L p , and if p > 4 , then almost sure convergence holds as well.}, archive = {J_PNAS}, author = {Elboim, Dor and Peres, Yuval and Peretz, Ron}, doi = {10.1073/pnas.2423947122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2423947122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The edge-averaging process on graphs with random initial opinions}, volume = {122}, year = {2025}, }
• (2025). Blood–labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus. PNAS, 122(33), e2423240122. (www)

  @article{ , abstract = {Hearing loss (HL) in patients with systemic lupus erythematosus (SLE) has been widely reported, though the underlying mechanisms remain unclear. In this study, we demonstrate significant HL in an imiquimod-induced mouse model of SLE, accompanied by blood–labyrinth barrier (BLB) damage in the stria vascularis (SV). We found that cytotoxic CD8 + T lymphocytes and natural killer cells mediate BLB disruption, with granzyme b (Gzmb) acting as the primary factor inducing cell death of the cochlear capillary endothelial cells. Remarkably, inhibiting Gzmb by Serpinb9 significantly alleviates the elevations of hearing thresholds in imiquimod-induced SLE model mice, suggesting a therapeutic target for autoimmune-related HL. Our findings provide insights into the pathogenesis of SLE-related HL and propose Gzmb inhibition as a potential therapeutic strategy.}, archive = {J_PNAS}, author = {Zhao, Zihe and Li, Ao and Zhu, Yan and Cen, Shaoqin and Liu, Qing and Zhang, Yuan and Fan, Hanqi and Hou, Zhenxing and Ma, Dengbin and Liu, Dingding and Duan, Maoli and Qian, Xiaoyun and Chai, Renjie and Wan, Guoqiang and Gao, Xia}, doi = {10.1073/pnas.2423240122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2423240122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Blood–labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus}, volume = {122}, year = {2025}, }
• (2025). A 65-kb deletion survey identifies a distal cis-regulatory region for red-light induction of ghd7, a key rice floral repressor. PNAS, 122(33), e2423119122. (www)

  @article{ , abstract = {The Ghd7 ( Grain number, plant height, and heading date 7 ) gene integrates red light signals and circadian rhythms to control floral repression under long-day conditions in rice. CRISPR/Cas9 systems were employed to create a series of deletion mutant lines in the upstream regions of Ghd7 , covering a 65-kb genomic region from its transcription start site (TSS). These deletions ranged from 2 to 25 kb in size. Three deletion lines, those from 0 to −3 kb (0/−3 K), −20 to −40 kb (−20/−40 K), and −26 to −30 kb (−26/−30 K) from the TSS, resulted in early flowering, similar to Ghd7 knockout lines. The −20/−40 and −26/−30 K lines exhibited a loss of acute Ghd7 morning induction. Night-break experiments consistently supported these findings, suggesting that the key cis- regulatory region for red light responses was located within the 3.7-kb region in −26/−30 K. In seedlings of the 0/−3 K deletion line, which retains the −29 to −86 bp region, Ghd7 showed a diurnal pattern similar to wild type. This suggests that the deleted region in 0/−3 K is dispensable for both circadian rhythms and red-light responses. Further analyses of two deletion lines within the −26/−30 K region allowed us to narrow down the core cis- regulatory elements, responsive to morning-light signals, within a 228-bp segment located at 28-kb upstream of the TSS in Ghd7 .}, archive = {J_PNAS}, author = {Ogo, Yuko and Kawauchi, Takumi and Mimura, Manaki and Naito, Ken and Itoh, Hironori and Izawa, Takeshi}, doi = {10.1073/pnas.2423119122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2423119122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A 65-kb deletion survey identifies a distal cis-regulatory region for red-light induction of ghd7, a key rice floral repressor}, volume = {122}, year = {2025}, }
• (2025). Ensemble approaches for short-term dengue fever forecasts: A global evaluation study. PNAS, 122(33), e2422335122. (www)

  @article{ , abstract = {Dengue fever, a tropical vector-borne disease, is a leading cause of hospitalization and death in many parts of the world, especially in Asia and Latin America. Where timely dengue surveillance exists, decision-makers can better implement public health measures and allocate resources. Reliable near-term forecasts may help anticipate healthcare demands and promote preparedness. We propose ensemble modeling approaches combining mechanistic, statistical, and machine learning models to forecast dengue cases 1 to 3 mo ahead at the province level across multiple countries. We assess these models’ predictive ability out-of-sample and retrospectively in over 180 locations worldwide, including provinces in Brazil, Colombia, Malaysia, Mexico, Thailand, plus Iquitos, Peru, and San Juan, Puerto Rico, during at least 2 to 3 y. We also evaluate ensemble approaches in a real-time, prospective dengue forecasting platform during 2022–2023, considering data availability limitations. Our ensemble modeling leads to an improvement to previous efforts that may help decision-making in the context of large uncertainties. This contrasts with the variable performance of individual component models across locations and time. No single model achieves optimal predictions across all scenarios, but while ensemble models may not always perform best in specific locations, they consistently rank among the top 3 performing models both retrospectively and prospectively.}, archive = {J_PNAS}, author = {Wu, Skyler and Meyer, Austin G. and Clemente, Leonardo and Stolerman, Lucas M. and Lu, Fred and Majumder, Atreyee and Verbeeck, Rudi and Masyn, Serge and Santillana, Mauricio}, doi = {10.1073/pnas.2422335122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2422335122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ensemble approaches for short-term dengue fever forecasts: A global evaluation study}, volume = {122}, year = {2025}, }
• (2025). Familial transmission of neural representations for mental arithmetic across two generations. PNAS, 122(33), e2421528122. (www)

  @article{ , abstract = {Parental skills are among the most powerful predictors of children’s outcomes. While distal genetic and environmental pathways likely contribute to skill transmission within families, much less is known about the proximal neural markers that support the transmission of cognitive functioning from parents to children. It is also unclear whether brain similarity between parents and children predicts similarity in cognitive skills. In this study, we used fMRI to measure brain activity associated with mental arithmetic—a task for which intergenerational transmission is consistently observed—in 37 familial dyads of 8-y-old children and their mothers. Regardless of familial ties, multivariate searchlight representational similarity analyses revealed remarkable adult–child similarity in the neural representations of a signature of arithmetic processing, the problem-size effect, within a broad occipito-parieto-frontal system. Comparing familial to nonfamilial adult–child dyads, family-specific transmission of neural representations was identified in the bilateral anterior insula and left precentral gyrus, key regions of the arithmetic processing network. Mother–child neural similarity in the insula and precentral gyrus interacted with maternal skillto predict mother–child similarity in math and working memory skills, such that neural similarity was more positively related to behavioral similarity in dyads with lower-skilled than higher-skilled mothers. Therefore, increased parent–child neural similarity may particularly predict shared cognitive abilities among dyads where parents experience greater difficulties. Our findings demonstrate that task-related intergenerational neuroimaging can identify brain regions involved in the intergenerational transmission of cognitive skills. They may have relevance for identifying neural markers of learning disabilities through familial transmission.}, archive = {J_PNAS}, author = {Constant-Varlet, Charlotte and Nakai, Tomoya and Longo, Léa and Bouchet, Honorine and Prado, Jérôme}, doi = {10.1073/pnas.2421528122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2421528122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Familial transmission of neural representations for mental arithmetic across two generations}, volume = {122}, year = {2025}, }
• (2025). Keystone predator and keystone intransitivity and the rescue of a competitively subdominant species. PNAS, 122(33), e2421005122. (www)

  @article{ , abstract = {Two significant complications in the structure of ecological communities are its dimensionality (many species interacting) and its network diversity (many ways to “wire” the interactions). Two classic concepts, the competitive exclusion principle and the keystone predator hypothesis, may frequently be embedded elements within that community structure and partially responsible for generating it. Other less-venerable concepts may be involved. In particular, for the current work, a keystone intransitivity and a behavioral higher-order effect are involved. We employ a strategic intersection of several particular network modalities—competitive hierarchy, keystone predator, keystone intransitivity, and higher-order trait-mediated effect—to examine the population dynamics of a real system, exploring the nature of its persistence (or extinction) based on the qualitative nature of its network structure. Because two of the dynamic structures, predation and intransitive competition, are both fundamentally oscillatory, the theoretical framework of coupled oscillators comes into play, a mathematical structure well known to be a major source of chaos. We use a set of natural history observations and measurements of a five-dimensional system, common in the coffee agroecosystems of Puerto Rico, to show how the unexpected persistence of a subdominant competitor in a competitive hierarchy may be contingent on a particular wiring of the system. It is notable that all five species are non-native and all are involved in a complex system of potential biological control of two significant pests.}, archive = {J_PNAS}, author = {Vandermeer, John and Perfecto, Ivette}, doi = {10.1073/pnas.2421005122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2421005122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Keystone predator and keystone intransitivity and the rescue of a competitively subdominant species}, volume = {122}, year = {2025}, }
• (2025). Climate change and vibrio: Environmental determinants for predictive risk assessment. PNAS, 122(33), e2420423122. (www)

  @article{ , abstract = {Climate change significantly impacts the incidence and abundance of microorganisms, including those essential for environmental cycles and those pathogenic to humans and animals. Shifts in conditions favorable for microbial growth have expanded the geographic range of many pathogens, contributing to the emergence and reemergence of infectious diseases. Waterborne diseases pose severe risks in regions where adverse climate conditions intersect with population vulnerabilities, especially inadequate water, sanitation, and hygiene infrastructure. Since many waterborne pathogens play crucial roles in the environment, such as in carbon and nitrogen cycling, their eradication is not possible. However, predictive intelligence models that identify environmental heuristics conducive to the growth of pathogenic strains, integrating microbiological, sociological, and weather data, can offer anticipatory decision-making capabilities, reducing infection risks. Here, the objective was to analyze data from studies since the 1960s to identify environmental determinants driving the occurrence and distribution of pathogenic Vibrio spp ., enabling predictive modeling of the effects of climate change on cholera and noncholera vibriosis. The proliferation of Vibrio spp. in aquatic ecosystems has been linked to climate change and, concomitantly, with increased environmental disease transmission, notably cholera in Southeast Asia and parts of Africa and noncholera vibriosis in Northern Europe and along the Eastern seaboard of North America. Global predictive risk models for Vibrio cholerae have contributed to reduction in case fatality rates when coupled with individual and large-scale intervention early in outbreaks. These models, when appropriately modified, hold the potential to predict disease caused by all clinically relevant Vibrio spp . and other waterborne pathogens.}, archive = {J_PNAS}, author = {Brumfield, Kyle D. and Usmani, Moiz and Long, Daniel M. and Lupari, Henry A. and Pope, Robert K. and Jutla, Antarpreet S. and Huq, Anwar and Colwell, Rita R.}, doi = {10.1073/pnas.2420423122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2420423122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Climate change and vibrio: Environmental determinants for predictive risk assessment}, volume = {122}, year = {2025}, }
• (2025). Targeted deletions of large syntenic regions in arabidopsis thaliana. PNAS, 122(33), e2419744122. (www)

  @article{ , abstract = {Plant genomes have undergone multiple rounds of whole-genome duplication (WGD) throughout their evolutionary history. As a result, many species, including Arabidopsis thaliana , retain duplicated genomic segments, or syntenic regions, which harbor large numbers of paralogous genes preserved from these ancient WGD events. We deleted four large, duplicated blocks, ranging from ~115 kb to ~684 kb using Staphylococcus aureus Cas9 to explore the effects of knocking out these blocks in Arabidopsis . Large deletions like these remain rare, especially in small and gene-dense plant genomes. Deletions were subsequently verified using whole-genome sequencing, which revealed minimal off-target effects. The number of deleted genes ranged from 16 to 60, and transposable elements ranged from 4 to 112 among the four deleted blocks. Two deletion lines showed distinct phenotypes resulting from the loss of many genes, while two others displayed no obvious defects, including for flowering time or hypocotyl elongation. Moreover, RNA-sequencing revealed that expression compensation, where deletions of paralogous genes lead to the upregulation of intact paralogues, was not a general response to the deleted regions under the conditions tested. Thus, it is possible to obtain viable plants when deleting large fragments that may be redundant or that contain nonessential genes. These results demonstrate that large chromosomal deletions can be used as a tool for genome engineering approaches, such as genome minimization in plants and allele replacement using homology-directed repair and other precision editing methods. Targeted deletions of large chromosome fragments will be a valuable tool for research and biotechnology applications.}, archive = {J_PNAS}, author = {Papikian, Ashot and Rattner, Rachel J. and Kao, Jenni and Hauser, Neil and Allsing, Nicholas and Mamerto, Allen and Hartwick, Nolan T. and Colt, Kelly and Michael, Todd P.}, doi = {10.1073/pnas.2419744122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2419744122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Targeted deletions of large syntenic regions in arabidopsis thaliana}, volume = {122}, year = {2025}, }
• (2025). Increased microbial carbon use efficiency upon abrupt permafrost thaw. PNAS, 122(33), e2419206122. (www)

  @article{ , abstract = {Soil carbon (C) dynamics upon permafrost thaw represents a major uncertainty in climate projections. Both soil C loss and formation in permafrost regions are mediated by microorganisms, and the balance of these two processes could be characterized by a synthetic metric termed microbial carbon use efficiency (CUE, defined as the ratio of C used for growth over C uptake). However, how microbial CUE responds to permafrost thaw remains unclear due to the lack of direct experimental evidence. Here, based on an ~27 y permafrost thaw sequence and five additional thermokarst-impacted sites across the northeastern Tibetan Plateau, we investigate the response of microbial CUE to abrupt permafrost thaw using a substrate-independent 18 O tracing approach. Results from the thaw sequence and additional sites at the regional scale consistently reveal that topsoil (0 to 10 cm) microbial CUE increases after permafrost collapse as a consequence of accelerated growth. The elevated microbial growth and CUE are driven by the alterations in microbial communities with larger ratio of fungal to bacterial biomass and more copiotrophs. In addition, the increased soil phosphorus availability could also promote microbial growth and CUE. These results highlight that the higher microbial CUE upon abrupt permafrost thaw would potentially enhance soil C stability by promoting the deposition of microbial-derived C into soil. Earth system models should thus explicitly characterize microbial CUE and its drivers to accurately predict permafrost C-climate feedback.}, archive = {J_PNAS}, author = {Qin, Shuqi and Wang, Guanqin and Zhang, Dianye and Yang, Yuanhe}, doi = {10.1073/pnas.2419206122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {33}, pages = {e2419206122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Increased microbial carbon use efficiency upon abrupt permafrost thaw}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(32), eiti3225122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti3225122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {eiti3225122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Saturn’s moon mimas may have a vast hidden ocean. PNAS, 122(32), e2519269122. (www)

  @article{ , archive = {J_PNAS}, author = {Tillman, Nola Taylor}, doi = {10.1073/pnas.2519269122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2519269122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Saturn’s moon mimas may have a vast hidden ocean}, volume = {122}, year = {2025}, }
• (2025). Profile of chris h. greene. PNAS, 122(32), e2519256122. (www)

  @article{ , abstract = {Chris Greene grew up with an early interest in science. During his undergraduate studies at the University of Nebraska in Lincoln, he realized he wanted to focus on theoretical atomic, molecular, and optical (AMO) physics. With help from influential mentors such as his PhD advisor Ugo Fano, Greene went on to have a long and distinguished career as a theorist working in AMO physics and chemical physics. Over his career, he helped develop theories of few-body systems, particularly in ultracold gases, and in his Inaugural Article, he describes his latest work on developing the theory of a five-body collision.}, archive = {J_PNAS}, author = {Ravindran, Sandeep}, doi = {10.1073/pnas.2519256122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2519256122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profile of chris h. greene}, volume = {122}, year = {2025}, }
• (2025). Correction for mellya et al., natural dispersal is better than translocation for reducing risks of inbreeding depression in eastern black rhinoceros (Diceros bicornis michaeli). PNAS, 122(32), e2519110122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2519110122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2519110122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for mellya et al., natural dispersal is better than translocation for reducing risks of inbreeding depression in eastern black rhinoceros (Diceros bicornis michaeli)}, volume = {122}, year = {2025}, }
• (2025). Correction for brill et al., dissociation of SYNGAP1 enzymatic and structural roles: Intrinsic excitability and seizure susceptibility. PNAS, 122(32), e2518853122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2518853122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2518853122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for brill et al., dissociation of SYNGAP1 enzymatic and structural roles: Intrinsic excitability and seizure susceptibility}, volume = {122}, year = {2025}, }
• (2025). Correction for schaumann and alastrué de asenjo, weakening AMOC reduces ocean carbon uptake and increases the social cost of carbon. PNAS, 122(32), e2518618122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2518618122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2518618122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for schaumann and alastrué de asenjo, weakening AMOC reduces ocean carbon uptake and increases the social cost of carbon}, volume = {122}, year = {2025}, }
• (2025). Retraction for martinez et al., microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. PNAS, 122(32), e2518460122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2518460122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2518460122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Retraction for martinez et al., microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells}, volume = {122}, year = {2025}, }
• (2025). Derailed degradation: LRRK2-dependent exocytosis in parkinson’s disease. PNAS, 122(32), e2515758122. (www)

  @article{ , archive = {J_PNAS}, author = {Ferguson, Shawn M.}, doi = {10.1073/pnas.2515758122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2515758122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Derailed degradation: LRRK2-dependent exocytosis in parkinson’s disease}, volume = {122}, year = {2025}, }
• (2025). Toward a molecular logic of lipid droplet heterogeneity?. PNAS, 122(32), e2515548122. (www)

  @article{ , archive = {J_PNAS}, author = {Vanni, Stefano}, doi = {10.1073/pnas.2515548122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2515548122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Toward a molecular logic of lipid droplet heterogeneity?}, volume = {122}, year = {2025}, }
• (2025). VPS29C: Adding complexity to the retromer complex. PNAS, 122(32), e2515546122. (www)

  @article{ , archive = {J_PNAS}, author = {Chen, Baoyu and Burstein, Ezra and Billadeau, Daniel D.}, doi = {10.1073/pnas.2515546122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2515546122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {VPS29C: Adding complexity to the retromer complex}, volume = {122}, year = {2025}, }
• (2025). Detecting chirality-induced spin selectivity in chromophore-linked DNA hairpins using photogenerated radical pairs. PNAS, 122(32), e2515120122. (www)

  @article{ , abstract = {Chirality-induced spin selectivity (CISS) results in spin polarization of electrons transmitted through chiral molecules and materials. Since CISS results in spin polarization even at room temperature, it affords the possibility of using it to develop quantum technologies that can operate under ambient conditions. We have shown previously that photo-driven hole transfer within DNA hairpins provides a facile route to generate spin-correlated radical pairs (SCRPs). To study the effect of CISS on the spin dynamics of SCRPs in DNA hairpins, we prepared a series of electron donor—chiral bridge—acceptor molecules where the chiral bridge is a B-form DNA helix consisting of 4 to 6 base pairs. Naphthalene-1,8:4,5-bis(dicarboximide) (NDI) serves as the hairpin linker chromophore and electron acceptor. Photoexcitation of NDI results in rapid hole transfer through the π-stacked purine bases of the DNA and trapping of the hole on a terminal stilbene diether (Sd) to generate the NDI •− - Sd •+ SCRP. Time-resolved electron paramagnetic resonance spectra of the SCRPs at X- (9.6 GHz), Q- (34 GHz), and W- (94 GHz) bands show that the CISS effect imparts significant triplet character to the SCRP. We do not observe a significant dependence of CISS on DNA length, likely resulting from hole delocalization over the guanine bases in the G-tract. Interestingly, we find that the CISS contribution significantly increases with magnetic field strength. These findings should be considered in any future modeling of CISS.}, archive = {J_PNAS}, author = {Latawiec, Elisabeth I. and Chiesa, Alessandro and Qiu, Yunfan and Tcyrulnikov, Nikolai A. and Young, Ryan M. and Carretta, Stefano and Krzyaniak, Matthew D. and Wasielewski, Michael R.}, doi = {10.1073/pnas.2515120122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2515120122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Detecting chirality-induced spin selectivity in chromophore-linked DNA hairpins using photogenerated radical pairs}, volume = {122}, year = {2025}, }
• (2025). Small lakes are suffocating as winters warm. PNAS, 122(32), e2514621122. (www)

  @article{ , archive = {J_PNAS}, author = {Elser, James J. and Klip, Helena C. L.}, doi = {10.1073/pnas.2514621122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2514621122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Small lakes are suffocating as winters warm}, volume = {122}, year = {2025}, }
• (2025). NIPBL and STAG1 enable loop extrusion by providing differential DNA–cohesin affinity. PNAS, 122(32), e2514190122. (www)

  @article{ , abstract = {DNA loop extrusion by cohesin has emerged as a critical pathway for chromosome organization. In vitro single-molecule experiments indicate that loop extrusion requires the assembly of a heteropentameric complex consisting of the SMC1/SMC3 heterodimer, STAG1, NIPBL, and the kleisin SCC1. The complexity of the complete extrusion machinery, consisting of multiple subunits, DNA binding sites, and ATPases poses substantial challenges for revealing the underlying biomolecular mechanism. As a result, a number of different models have been proposed, many of which do not agree on key mechanistic aspects, such as the details of DNA loading, holoenzyme assembly, or the consequences of ATP binding and hydrolysis. Here, we use mass photometry to comprehensively quantify all the key biomolecular interactions required for DNA loop extrusion. We find that STAG1 binds tightly to the trimeric complex formed by the SMC1/SMC3 heterodimer and SCC1, and together they weakly, but cooperatively, bind the DNA. Full-length NIPBL tightly binds DNA, acting as a DNA anchor during the mechanochemical loop extrusion cycle. Cohesin mutants incapable of head engagement, and those lacking DNA-binding domains in the ATPase heads show negligible differences in overall DNA-affinity, suggesting a minor role of these features for DNA binding. Instead, we find an ATP-modulated DNA binding site created by the interaction of STAG1 with SMC1/SMC3/SCC1, important for repeated grabbing and release of DNA critical to extrusion. Our results call for a careful reexamination of the proposed mechanisms and set energetic boundaries for future proposals.}, archive = {J_PNAS}, author = {van Wee, Raman and Asor, Roi and Li, Yiwen and Drechsel, David and Popova, Mariia and Litos, Gabriele and Davidson, Iain F. and Peters, Jan-Michael and Kukura, Philipp}, doi = {10.1073/pnas.2514190122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2514190122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {NIPBL and STAG1 enable loop extrusion by providing differential DNA–cohesin affinity}, volume = {122}, year = {2025}, }
• (2025). Controlling transient and coupled diffusion with pseudoconformal mapping. PNAS, 122(32), e2511708122. (www)

  @article{ , abstract = {Diffusion in physical, chemical, and biological systems often occurs under transient conditions and involves coupling across multiple physical fields, challenging conventional control methods limited to steady-state, single-field settings. Here, we present a general geometric framework for regulating diffusion in time-dependent and multiphysics-coupled environments based on pseudoconformal mapping. This method preserves material isotropy and ensures smooth interface matching, enabling robust and flexible modulation of diffusion governed by Fick’s second law and beyond. We apply this framework to radiative–conductive, advective–conductive, and thermoelectric systems, achieving precise spatial and temporal control of temperature, flux, and voltage distributions. The proposed strategy is validated through simulations and experiments, demonstrating its broad applicability and scalability. Our findings provide a geometry-driven paradigm to programmable diffusion control, with potential impact across thermal management, energy conversion, and biomedical transport systems.}, archive = {J_PNAS}, author = {Dai, Gaole and Qu, Teng and Lei, Min and Li, Zhuo and Yang, Fubao and Zhang, Ziwei and Wang, Yuanyuan and Xie, Huaqing and Huang, Jiping and Wang, Jun}, doi = {10.1073/pnas.2511708122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2511708122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Controlling transient and coupled diffusion with pseudoconformal mapping}, volume = {122}, year = {2025}, }
• (2025). A common denominator: PTSD, rapid eye movements, and fear extinction. PNAS, 122(32), e2511191122. (www)

  @article{ , archive = {J_PNAS}, author = {Uzoigwe, Chika Edward}, doi = {10.1073/pnas.2511191122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2511191122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A common denominator: PTSD, rapid eye movements, and fear extinction}, volume = {122}, year = {2025}, }
• (2025). Structural insights into proteolysis-dependent and -independent suppression of the master regulator DELLA by the gibberellin receptor. PNAS, 122(32), e2511012122. (www)

  @article{ , abstract = {The perception of the phytohormone gibberellin (GA) by its nuclear receptor GIBBERELLIN INSENSITIVE DWARF1 (GID1) triggers polyubiquitination and proteasomal degradation of master growth regulators—DELLA proteins—mediated by the SCF SLY1/GID2 E3 ubiquitin ligase complex. DELLA-encoding genes are known as ‘Green Revolution’ genes, as their dominant mutations lead to semidwarf cereal varieties with significantly higher yields due to reduced GA response. DELLAs function as central signaling hubs, coordinating diverse physiological responses by interacting with key transcription factors across multiple cellular pathways. While the DELLA domain mediates GA-GID1 binding, the mechanism of SCF SLY1/GID2 recruitment remained unknown. Additionally, GA-GID1 binding can inhibit DELLA protein activity independently of its proteolysis, although the underlying mechanism was unclear. Here, we present the cryo-EM structures of GA 3 -GID1A complexed with a full-length DELLA protein in Arabidopsis , RGA (REPRESSOR OF ga1-3 ), and the GA 3 -GID1A-RGA-SLY1-ASK1 complex. We show that the DELLA domain of RGA functions as a molecular bridge to enhance its GRAS domain binding to GID1A through direct interactions with both the GRAS domain and GID1A. Disrupting either intramolecular (DELLA-GRAS) or intermolecular (GRAS-GID1A) interactions weakens RGA-GID1 binding. Contrary to prior models, SLY1 binds the GRAS domain’s concave surface without inducing conformational changes. Combining AlphaFold modeling and yeast three-hybrid assays, we demonstrate that GID1 binding to the RGA GRAS domain blocks its interactions with INDETERMINATE DOMAIN (IDD) transcription factors, explaining how GA-GID1 relieves growth suppression independently of DELLA degradation.}, archive = {J_PNAS}, author = {Dahal, Pawan and Wang, Yan and Hu, Jianhong and Park, Jeongmoo and Forker, Karly and Zhang, Zhong-Lin and Sharma, Kedar and Borgnia, Mario J. and Sun, Tai-ping and Zhou, Pei}, doi = {10.1073/pnas.2511012122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2511012122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural insights into proteolysis-dependent and -independent suppression of the master regulator DELLA by the gibberellin receptor}, volume = {122}, year = {2025}, }
• (2025). Structural basis for anaerobic alkane activation by a multisubunit glycyl radical enzyme. PNAS, 122(32), e2510389122. (www)

  @article{ , abstract = {X-succinate synthases (XSSs) are glycyl radical enzymes (GREs) that catalyze the addition of hydrocarbons to fumarate via radical chemistry, thereby activating them for microbial metabolism. To date, the only structurally characterized XSS is benzylsuccinate synthase (BSS), which functionalizes toluene. A distinct subclass of XSSs acts on saturated hydrocarbons, which possess much stronger C(sp 3 )–H bonds than toluene, suggesting mechanistic and structural differences from BSS. Here, we use cryogenic electron microscopy to determine the structure of one such enzyme, (1-methylalkyl)succinate synthase (MASS) from Azoarcus strain HxN1, which functionalizes n -alkanes (C6–C8). The structure reveals an asymmetric dimer in which both sides contain a catalytic α-subunit and accessory γ-subunit. One α-subunit also binds two additional subunits, β and δ. The β-subunit binds a [4Fe–4S] cluster and adopts a fold similar to BSSβ. The β-subunit appears to regulate the flexibility of the α-subunit to enable opening of the active site, affording the binding of n -alkane substrates. The δ-subunit, which lacks homology to known GRE subunits, adopts a rubredoxin-like fold that binds a single Fe ion, an architecture not previously reported for GREs. MASSδ occupies the same region of the α-subunit as the activating enzyme (AE) and may regulate the conformational changes required for glycyl radical installation. Structural comparisons between MASS and BSS reveal differences in how fumarate is bound and show amino acid substitutions that could account for the binding of alkanes versus toluene. Together, this structure offers insight into anaerobic alkane activation via fumarate addition.}, archive = {J_PNAS}, author = {Andorfer, Mary C. and Levitz, Talya S. and Liu, Jian and Chakraborty, Ankush and King-Roberts, Devin T. and Nweneka, Delight and Imrich, Christa N. and Drennan, Catherine L.}, doi = {10.1073/pnas.2510389122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2510389122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis for anaerobic alkane activation by a multisubunit glycyl radical enzyme}, volume = {122}, year = {2025}, }
• (2025). Critical role of extracellular loops in differential modulations of TTX-sensitive and TTX-resistant nav channels. PNAS, 122(32), e2510355122. (www)

  @article{ , abstract = {The cardiac voltage-gated sodium channel Na v 1.5 is resistant to tetrodotoxin (TTXr). Here, we report a cryo-electron microscopy (cryo-EM) structure of wild-type human Na v 1.5, coexpressed with the β1 auxiliary subunit and treated with high-concentration TTX, at 3.4 Å resolution. Structural comparison reveals the molecular determinants for the distinct responses to TTX as well as β subunits between TTXr and TTX-sensitive (TTXs) Na v channels. A conserved cation–π interaction between the guanidinium group of TTX and Tyr or Phe on the P2 I helix in TTXs Na v channels is lost in all TTXr subtypes owing to the replacement by Cys/Ser at the corresponding locus, explaining their differential TTX sensitivities. The β1 subunit is invisible in the EM map. Comparison of Na v 1.5 with Na v 1.7 and Na v 1.8, which are, respectively, TTXs and TTXr, identifies four sites on the extracellular loops (ECLs) that may account for their different β1-binding abilities. When the corresponding residues in TTXs Na v 1.7 are replaced with those from Na v 1.5, the modulatory effects of β1 on channel activation and inactivation are diminished. Consistently, β1 is absent in the 3D EM reconstruction of this Na v 1.7 mutant. Together with our previous structure-guided discovery that TTXr channels lack a Cys on the ECL II for disulfide bond formation with β2 or β4, the structure–function relationship studies underscore the importance of the ECLs in the mechanistic distinctions between TTXs and TTXr Na v channels. The ECLs may be further explored for the development of subtype-specific drugs.}, archive = {J_PNAS}, author = {Wu, Tong and Yang, Xinyu and Jin, Xueqin and Yan, Nieng and Li, Zhangqiang}, doi = {10.1073/pnas.2510355122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2510355122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Critical role of extracellular loops in differential modulations of TTX-sensitive and TTX-resistant nav channels}, volume = {122}, year = {2025}, }
• (2025). Progressively greater biological carbon storage in the deep atlantic during glacial inception. PNAS, 122(32), e2510171122. (www)

  @article{ , abstract = {Changes in oceanic circulation and carbon storage have been implicated as important drivers of atmospheric pCO 2 variability during the last glacial cycle (0 to 150 ka), though consensus on the mechanisms responsible remains elusive due to sparse marine carbonate chemistry reconstructions. Here, we present vertical profiles of carbonate ion concentration ([CO 3 2 − ]) from the Southwest Atlantic to investigate oceanic carbon sequestration during key intervals of atmospheric CO 2 change. During the first major decline in atmospheric CO 2 (115 to 109 ka), enhanced carbon storage occurred in the abyssal Atlantic (>3,500 m water depth). During the second decline in CO 2 (72 to 68 ka), enhanced carbon storage occurred throughout the deep Atlantic (>2,000 m water depth). Paired with δ 13 C and δ 18 O vertical profiles from the same locations, the [CO 3 2 − ] results suggest progressively greater sequestration of biological carbon occurred in the South Atlantic as the volume of Southern Source Water expanded during glacial inception. Shoaling of the carbonate ion saturation horizon during the second decline in pCO 2 resulted in seafloor calcium carbonate dissolution and enhanced alkalinity, likely contributing to further draw down of atmospheric CO 2 . We also document carbon release from the deep South Atlantic during glacial Terminations I and II when atmospheric CO 2 was rising. Overall, our results highlight the tight linkage between pCO 2 and deep Atlantic carbon storage over the last glacial cycle.}, archive = {J_PNAS}, author = {Garity, Monica and Lund, David and Jerris, Hope and McBride, Jacquelyn}, doi = {10.1073/pnas.2510171122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2510171122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Progressively greater biological carbon storage in the deep atlantic during glacial inception}, volume = {122}, year = {2025}, }
• (2025). A recurrent de novo damaging variant in EMP2 causes progressive symmetric erythrokeratoderma. PNAS, 122(32), e2509896122. (www)

  @article{ , abstract = {Genetic investigation in Mendelian skin disorders featuring generalized or localized skin scaling and redness, known as the ichthyoses, has revealed novel pathways relevant to epidermal integrity, barrier function, and desquamation. Here, we show that a recurrent de novo missense variant in EMP2 (epithelial membrane protein 2), which encodes a cell surface tetraspan protein in the growth-arrest specific 3 (GAS3)/peripheral myelin protein 22 (PMP22) family, is associated with a Mendelian skin disorder in the progressive symmetric erythrokeratoderma spectrum. The disorder features severely thickened, red, and scaly skin at sites of wound healing or repetitive movement including on the face, genitals, flexural areas, and the palms and soles. EMP2 has previously been shown to directly associate with focal adhesion kinase, which links cell junction forces to signaling pathways relevant to proliferation, migration, and wound healing. Using single-cell spatial transcriptomics in affected tissue, we found ectopic suprabasal activation of signaling pathways downstream of receptor tyrosine kinases including epidermal growth factor receptor (EGFR), which we confirmed with western blotting in affected cells, supporting a gain-of-function mechanism for mutant EMP2. Remarkably, treatment with erlotinib, an EGFR inhibitor, led to marked clinical improvement underscoring the key role of EMP2 in epidermal differentiation and proliferation.}, archive = {J_PNAS}, author = {Jiang, Xingyuan and Mortlock, Ryland D. and Pironon, Nathalie and Zhou, Jing and Hu, Ronghua and Liu, William and Acosta, Agustina and Shwayder, Tor A. and Hovnanian, Alain and Lifton, Richard P. and Choate, Keith A.}, doi = {10.1073/pnas.2509896122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2509896122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A recurrent de novo damaging variant in EMP2 causes progressive symmetric erythrokeratoderma}, volume = {122}, year = {2025}, }
• (2025). Computational investigation of water glasses using machine-learning potentials. PNAS, 122(32), e2509609122. (www)

  @article{ , abstract = {The molecular origins of water’s anomalous properties have long been a subject of scientific inquiry. The liquid–liquid phase transition hypothesis, which posits the existence of distinct low-density and high-density liquid states separated by a first-order phase transition terminating at a critical point, has gained increasing experimental and computational support and offers a thermodynamically consistent framework for many of water’s anomalies. However, experimental challenges in avoiding crystallization near the postulated liquid–liquid critical point have focused attention to water’s canonical glassy states: low-density and high-density amorphous ice. Here, we use two Deep Potential machine-learning models, trained on the Strongly Constrained and Appropriately Normed density functional and the highly accurate Many-Body Polarizable potential, to conduct an investigation of water’s glassy phenomenology based on quantum mechanical calculations. Despite not being explicitly trained on amorphous ices, both models accurately capture the structure and transformation of the water glasses, including their interconversion along different thermodynamic paths. Isobaric quenching of liquid water at various pressures generates a continuum of intermediate amorphous ices and density fluctuations increase near the liquid–liquid critical pressure. The glass transition temperatures of the amorphous ices produced at different pressures exhibit two distinct branches, corresponding to low-density and high-density amorphous ice behaviors, consistent with experiment and the liquid–liquid transition hypothesis. Extrapolating transformation pressures from isothermal compressions to experimental compression rates brings our simulations into excellent agreement with data. Our findings demonstrate that machine-learning potentials trained on equilibrium phases can effectively model nonequilibrium glassy behavior and pave the way for studying long-timescale, out-of-equilibrium processes with quantum mechanical accuracy.}, archive = {J_PNAS}, author = {Szukalo, Ryan J. and Giovambattista, Nicolas and Debenedetti, Pablo G.}, doi = {10.1073/pnas.2509609122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2509609122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Computational investigation of water glasses using machine-learning potentials}, volume = {122}, year = {2025}, }
• (2025). 20E-induced kr-h1 expression facilitates developmental transitions depending on chromosome accessibility of BR-C enhancers. PNAS, 122(32), e2509608122. (www)

  @article{ , abstract = {Transcription factors and histone modification-mediated chromatin accessibility coordinately regulate spatiotemporal expression of genes that control growth and development. It is well documented that juvenile hormone-activated Kr-h1 antagonizes 20-hydroxyecdysone (20E)-induced expression of the pupal specifier BR-C to sustain larval status in holometabolous insects. Here, we revealed that during the larval–prepupal transition in Drosophila melanogaster , the 20E-activated Kr-h1-BR-C axis is a prerequisite for wing disc morphogenesis. Mechanistically, 20E-EcR/USP-Met-Tai directly activates Kr-h1 that upregulates BR-C expression via the positive Kr-h1 binding sites (PKBS) in the BR-C enhancers. Furthermore, we showed that 20E-induced H3K27 acetylation increases chromatin accessibility of the PKBS-containing enhancers, facilitating the maximum of BR-C expression that promotes developmental transitions. Collectively, in response to different hormone stimuli, a single transcription factor either negatively or positively regulates the expression of the same target gene depending on chromatin accessibility of its different enhancer regions, thus manipulating distinct developmental events.}, archive = {J_PNAS}, author = {Long, Shihui and Qiu, Yongyu and Lin, Tong and Huang, Shumin and Zhang, Wenhao and Liu, Suning and Tian, Ling and Palli, Subba R. and Li, Sheng and Li, Kang}, doi = {10.1073/pnas.2509608122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2509608122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {20E-induced kr-h1 expression facilitates developmental transitions depending on chromosome accessibility of BR-C enhancers}, volume = {122}, year = {2025}, }
• (2025). Dense suspensions as trainable rheological metafluids. PNAS, 122(32), e2509525122. (www)

  @article{ , abstract = {In materials, the ability to retain the memory of applied stresses or strains opens up new opportunities for enhancing their performance adaptively via training. In dense suspensions, a stress-adaptive response is enabled by non-Newtonian rheology; however, typical suspensions have little memory, which implies rapid cessation of any adapted behavior. Here, we show how multiple adaptive responses can be achieved by designing suspensions where different stress levels trigger different memories. This is achieved through the interplay of particle interactions based on frictional contact and dynamic chemical bridging. These two interactions give rise to stress-activated memories associated with opposite time-dependent trends. As a result, a suspension can be trained to adapt to applied stress either by softening or stiffening, exhibiting targeted viscosity and energy dissipation in response to low-velocity impact. Such behavior, usually associated with mechanical metamaterials, suggests that dense suspensions with multiple memories can be viewed as trainable rheological metafluids.}, archive = {J_PNAS}, author = {Kim, Hojin and Livermore, Samantha M. and Rowan, Stuart J. and Jaeger, Heinrich M.}, doi = {10.1073/pnas.2509525122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2509525122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dense suspensions as trainable rheological metafluids}, volume = {122}, year = {2025}, }
• (2025). Tree rings reveal persistent western apache (Ndee) fire stewardship and niche construction in the american southwest. PNAS, 122(32), e2509169122. (www)

  @article{ , abstract = {Identifying the influence of low-density Indigenous populations in paleofire records has been methodologically challenging. In the Southwest United States, well-replicated fire histories suggest that abundant lightning and suitable climate conditions drove frequent low-severity wildfires in dry pine forests independent of human activities even as ethnography provided hints that highly mobile indigenous populations used fire in myriad land use contexts. Here, we leverage published and unpublished tree-ring fire history records from pine forests in Western Apache (Ndee) traditional territory in central and eastern Arizona (N = 34 sites, N = 649 trees) to demonstrate that historical fire regimes were overwhelmingly influenced by Ndee cultural burning. Our tree-ring synthesis shows significantly more frequent fires in Ndee territory than elsewhere in the region for centuries before the establishment of reservations (1600–1870 CE). Despite the heightened fire activity, fires were largely small and asynchronous, occurred disproportionately in late April and May, when Ndee invested significant subsistence activities in these pine forests, and occurred independent of climate drivers. This suggests that Ndee fire stewardship created a patchwork of nearly annual small, spring fires that inhibited natural fire spread and limited the influence of drought on fire activity. Our work shows that even relatively small, highly mobile populations of forager-gardeners had significant influence on some pre-Euroamerican fire regimes despite abundant natural ignitions. Our study shows clearly that Indigenous fire management impacted fire-size distributions, fire frequencies, and fire seasonality in ways that cannot be explained by seasonal and annual lightning densities.}, archive = {J_PNAS}, author = {Roos, Christopher I. and Kaib, J. Mark and Laluk, Nicholas C. and Adams, Melinda M. and Guiterman, Christopher H. and Baisan, Christopher H. and Morino, Kiyomi and Swetnam, Thomas W.}, doi = {10.1073/pnas.2509169122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2509169122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tree rings reveal persistent western apache (Ndee) fire stewardship and niche construction in the american southwest}, volume = {122}, year = {2025}, }
• (2025). The activity and expression of adenylosuccinate lyase were reduced during modern human evolution, affecting brain and behavior. PNAS, 122(32), e2508540122. (www)

  @article{ , abstract = {Adenylosuccinate lyase (ADSL), an enzyme that is crucial for purine biosynthesis, carries an amino acid substitution that is present in almost all humans today but absent in Neandertals and Denisovans. This substitution reduces the stability of the enzyme, but what functional consequences it has are unknown. Here, we show that when introduced into mice, this substitution causes substrates of the enzyme to accumulate in amounts that correlate negatively with ADSL expression levels. In the brain, where the expression of the enzyme is low, the substitution results in particularly high substrate levels. When the behavior of the mice is analyzed, female mice expressing the modern human-like version of ADSL access water more efficiently for drinking than their wild-type littermates. In addition to the amino acid substitution, a haplotype in the ADSL gene occurs at a carrier frequency of >97% in present-day humans and exhibits evidence of positive selection. It is associated with less ADSL expression as well as with increased concentrations of succinyladenosine, one of the substrates of the enzyme, in cerebrospinal fluid. Thus, two genetic changes have reduced ADSL activity in human tissues since modern and archaic humans separated, affecting purine biosynthesis, particularly in the brain.}, archive = {J_PNAS}, author = {Ju, Xiang-Chun and Lee, Shin-Yu and Ågren, Richard and Machado, Luiz Carlos and Xing, Jiawei and Azama, Chika and Roy, Michael C. and Endo, Toshihiro and Huttner, Wieland and Siepel, Adam and Fukunaga, Izumi and Zeberg, Hugo and Pääbo, Svante}, doi = {10.1073/pnas.2508540122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2508540122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The activity and expression of adenylosuccinate lyase were reduced during modern human evolution, affecting brain and behavior}, volume = {122}, year = {2025}, }
• (2025). Confined colloidal droplets dry to form circular mazes. PNAS, 122(32), e2508363122. (www)

  @article{ , abstract = {During drying, particle-laden sessile droplets will leave so-called coffee-stain rings behind. This phenomenon is well known and well understood (Deegan et al ., Nature 389 , 827–829 (1997). Here, we show that when particle-laden droplets confined in a slit are allowed to evaporate very slowly, they do not deposit coffee rings, but form surprisingly intricate, circular maze-like patterns. We present experiments that illustrate this pattern formation and discuss the factors that determine when such patterns can form. We are not aware of reports of natural examples of the formation of such beautiful patterns under confinement, although it seems likely that they exist.}, archive = {J_PNAS}, author = {Beechey-Newman, Ilaria and Kizilova, Natalya and Hennig, Andreas Andersen and Flekkøy, Eirik Grude and Eiser, Erika}, doi = {10.1073/pnas.2508363122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2508363122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Confined colloidal droplets dry to form circular mazes}, volume = {122}, year = {2025}, }
• (2025). A twisted chromophore powers a turn-on fluorescent protein chloride sensor. PNAS, 122(32), e2508094122. (www)

  @article{ , abstract = {Fluorescent proteins (FPs) are noninvasive genetically encodable probes that have revolutionized bioimaging and health fields with vivid images and an ever-growing repertoire from jellyfish to sea anemones and corals. Inside the protein matrix, chromophore nonplanarity and flexibility have long been argued to govern the fluorescence efficiency of FPs, yet their fundamental roles and relative importance have been elusive which hinder the rational design of versatile FPs and biosensors. Herein, we tackle this central question by investigating two recently engineered FP-based turn-on chloride (Cl – ) sensors, ChlorON1 and 3, using an ultrafast electronic and vibrational spectroscopic toolset together with advanced multireference simulations for both structure and spectrum. We elucidate that fluorescence enhancement of the chloride-bound ChlorON3 stems from a substantially more twisted chromophore than ChlorON1 via comprehensive simulations starting from the available crystal structure of parent protein (mNeonGreen), also featuring an enhanced radiative pathway due to an adjacent leucine residue in the emissive population. This finding indicates that the commonly stated chromophore planarity is not, but conformational rigidity is, the decisive factor for high fluorescence efficiency. Such mechanistic insights into FPs are generalizable to chromoproteins and other photosensitive biomolecules, which can facilitate the targeted design of brighter and/or tunable biosensors.}, archive = {J_PNAS}, author = {Chen, Cheng and Pathiranage, Vishaka and Ong, Whitney S. Y. and Dodani, Sheel C. and Walker, Alice R. and Fang, Chong}, doi = {10.1073/pnas.2508094122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2508094122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A twisted chromophore powers a turn-on fluorescent protein chloride sensor}, volume = {122}, year = {2025}, }
• (2025). Human eyelid behavior is driven by segmental neural control of the orbicularis oculi. PNAS, 122(32), e2508058122. (www)

  @article{ , abstract = {The eyelid performs critical functions to protect the eye and preserve functional vision. These functions are driven by contraction of the orbicularis oculi (OO), which is a unique skeletal muscle with a circular geometry and diffuse innervation. It is thought that this distributed innervation may allow for differential segmental activation and contraction, but it is not currently understood how sequenced activation patterns relate to differential muscle contraction, nor how segmental contraction creates the kinematics that drive the eyelid’s critical functions. In fact, motion of the eyelid has predominantly been modeled in only a single dimension (open–close). Here, we show that eyelid motion has important two-dimensional features that vary between eyelid behaviors. Using distributed intramuscular electromyography, we further show that activation differs segmentally across the OO, and that patterns of activation change to produce different behavior-specific eyelid kinematics. Our results demonstrate the role of segmental activation in eyelid motion, highlighting the importance of precise neural control in producing natural eyelid behavior. We anticipate that this research is a starting point for robust mechanistic models of eyelid function. This knowledge has critical implications for diagnosis and treatment of eyelid paralysis.}, archive = {J_PNAS}, author = {Kim, Jinyoung and Shirriff, Ashley and Cornwell, Jordan N. and Mutis, Maria Paula Quintero and Delis, Ereni and Wang, Sophia and Rootman, Daniel B. and Clites, Tyler R.}, doi = {10.1073/pnas.2508058122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2508058122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Human eyelid behavior is driven by segmental neural control of the orbicularis oculi}, volume = {122}, year = {2025}, }
• (2025). A genomic test of sex-biased dispersal in white sharks. PNAS, 122(32), e2507931122. (www)

  @article{ , abstract = {Mitonuclear discordance has been observed in several shark species. Female philopatry has often been invoked to explain such discordance but has never been explicitly tested. Here, we focus on the white shark, for which female philopatry has been previously proposed, and produced a chromosome-level genome, high-coverage whole-genome autosomal, and uniparental datasets to investigate mitonuclear discordance. We first reconstructed the historical population demography of the species based on autosomal data. We show that this species once comprised a single panmictic population, which experienced a steady decline until recent times when it fragmented into at least three main autosomal genetic groups. Mitochondrial data depict a strikingly different picture, inconsistent with the spatial distribution of autosomal diversity. Using the demographic scenario established from autosomal data, we performed coalescent and forward simulations to test for the occurrence of female philopatry. Coalescent simulations showed that the model can reproduce the autosomal variability, confirming its robustness. A forward simulation framework was further built to explicitly account for a sex-biased reproduction model and track both autosomal and uniparental markers (Y chromosome and mitochondrial DNA). While our model generates data that are consistent with the observed Y chromosome variation, the mitochondrial pattern is never reproduced even under extreme female philopatry (no female migration), strongly suggesting that demography alone cannot explain the mitonuclear discordance. Our framework could, and perhaps should, be extended to other shark species where philopatry has been suggested. It is possible that the proposed widespread occurrence of female philopatry in sharks should be revisited.}, archive = {J_PNAS}, author = {Laso-Jadart, Romuald and Corrigan, Shannon L. and Yang, Lei and Lee, Szu-Hsuan and Gay, Elise J. and Fedrigo, Olivier and Lowe, Christopher G. and Skomal, Gregory and Cliff, Geremy and Padilla, Mauricio Hoyos and Huveneers, Charlie and Lyons, Kady and Sato, Keiichi and Glancy, James and Lesturgie, Pierre and Mona, Stefano and Naylor, Gavin J. P}, doi = {10.1073/pnas.2507931122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2507931122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A genomic test of sex-biased dispersal in white sharks}, volume = {122}, year = {2025}, }
• (2025). Cryptic intronic transcriptional initiation generates efficient endogenous mRNA templates for c9orf72-associated RAN translation. PNAS, 122(32), e2507334122. (www)

  @article{ , abstract = {Intronic GGGGCC hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite its intronic location, this repeat avidly supports synthesis of pathogenic dipeptide repeat (DPR) proteins via repeat-associated non-AUG (RAN) translation. However, the template RNA species that undergoes RAN translation endogenously remains unclear. Using long-read based 5′ RNA ligase-mediated rapid amplification of cDNA ends (5′ Repeat-RLM-RACE), we identified C9orf72 transcripts initiating within intron 1 in a C9BAC mouse model, patient-derived iNeurons, and iNeuron-derived polysomes. These cryptic m 7 G-capped mRNAs are at least partially polyadenylated and are more abundant than transcripts derived from intron retention or circular intron lariats. In RAN translation reporter assays, intronic template transcripts–even those with short (32 nucleotide) leaders–exhibited robust expression compared to exon–intron and repeat-containing lariat reporters. To assess endogenous repeat-containing lariat RNA contributions to RAN translation, we enhanced endogenous lariat stability by knocking down the lariat debranching enzyme Dbr1. However, this modulation did not impact DPR production in patient-derived iNeurons. These findings identify cryptic, linear, m 7 G-capped intron-initiating C9orf72 mRNAs as an endogenous template for RAN translation and DPR production, with implications for disease pathogenesis and therapeutic development.}, archive = {J_PNAS}, author = {Miller, Shannon L. and Green, Katelyn M. and Crone, Bradley and Switzenberg, Jessica A. and Tank, Elizabeth M. H. and Krans, Amy and Jansen-West, Karen and Wieland, Clare M. and Ji, Eric W. and Petrucelli, Leonard and Barmada, Sami J. and Boyle, Alan P. and Todd, Peter K.}, doi = {10.1073/pnas.2507334122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2507334122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryptic intronic transcriptional initiation generates efficient endogenous mRNA templates for c9orf72-associated RAN translation}, volume = {122}, year = {2025}, }
• (2025). Reduction of TRAF3 by heterozygosity or aging impacts b cell function. PNAS, 122(32), e2507217122. (www)

  @article{ , abstract = {TNF receptor-associated factor 3 (TRAF3) is a signaling adaptor protein that is ubiquitously expressed but has highly distinct cell type–specific functions. TRAF3 plays critical roles in restraint of B lymphocyte activation, differentiation, and homeostatic survival. Consistent with such roles, loss-of-function mutations in TRAF3 have long been found in various human B cell malignancies. Mice lacking TRAF3 specifically in B cells have autoimmune manifestations, lymphadenopathy, and increased incidence of B cell lymphomas. More recently, human patients with germline TRAF3 mutations leading to haploinsufficiency have been reported; the phenotypes of these patients show striking similarities with those of mice with TRAF3-deficient B cells. This raises the important knowledge gap of how relative quantity of TRAF3 protein regulates B cells. To address this question, we investigated the effect of decreased B cell TRAF3 using mice whose B cells are heterozygous for loss of Traf3 . Traf3 +/− B cells displayed multiple functional abnormalities, to an extent intermediate between Traf3 +/+ and Traf3 −/− B cells, indicating a striking dose–response of B cells to relative quantities of TRAF3. Additionally, B cell TRAF3 protein—but not transcript—was reduced in B cells from normal aged mice and humans, consistent with increased occurrence of both B cell hyperactivity and B cell malignancies in older populations. Treatment of aged mice with a proteasome inhibitor restored the level of B cell TRAF3, suggesting age-related chronic signaling through receptors that lead to TRAF3 degradation. Thus, relative levels of B cell TRAF3 protein have important biological impacts on B cell function.}, archive = {J_PNAS}, author = {Hornick, Emma L. and Oxley, Kyp and Wieting, Nathaniel and Treco, Emma and Hostager, Bruce S. and Bishop, Gail A.}, doi = {10.1073/pnas.2507217122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2507217122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reduction of TRAF3 by heterozygosity or aging impacts b cell function}, volume = {122}, year = {2025}, }
• (2025). Transcription termination promotes splicing efficiency and fidelity in a compact genome. PNAS, 122(32), e2507187122. (www)

  @article{ , abstract = {Splicing of terminal introns is coupled to 3′-end processing by cleavage and polyadenylation (CPA) in mammalian genes. Whether this functional coupling is universally conserved across eukaryotes is unclear. Here, we show using long read RNA sequencing in Saccharomyces cerevisiae that splicing inactivation does not result in widespread CPA impairment, and that inactivation of CPA has limited impact on splicing efficiency. The negative impact of CPA inactivation on splicing is mainly due to transcription termination defects that promote readthrough transcription, leading to splicing inhibition for downstream intron-containing genes. The deleterious effect of 5′ extensions on splicing is length-dependent and can be detected independently from CPA inactivation for endogenous or synthetic genes. Deficient termination can also promote usage of cryptic splice sites and long-range intergenic splicing events. These results argue against a broad coupling between splicing and CPA in S. cerevisiae but show that efficient CPA-mediated transcription termination is critical for splicing fidelity and efficiency in a compact genome.}, archive = {J_PNAS}, author = {Barr, Keaton and He, Kevin L. and Krumbein, Andreas J. and Chanfreau, Guillaume F.}, doi = {10.1073/pnas.2507187122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2507187122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transcription termination promotes splicing efficiency and fidelity in a compact genome}, volume = {122}, year = {2025}, }
• (2025). RNA polymerase III transcription–associated polyadenylation promotes the accumulation of noncoding retrotransposons during infection. PNAS, 122(32), e2507186122. (www)

  @article{ , abstract = {The accumulation of RNA Polymerase III (Pol III) transcribed short interspersed nuclear element (SINE) retrotransposon RNA is a hallmark of various cellular stressors, including DNA virus infection. However, the molecular mechanisms driving the induction of these normally repressed loci are largely undefined. Here, we reveal that in addition to Pol III transcriptional induction, gammaherpesvirus infection stimulates mRNA-like 3′ end processing of SINE RNAs that leads to their stabilization. We developed a convolutional neural network (CNN)-based model that identified a polyadenylation-associated motif as the key hallmark of infection-induced SINEs. Indeed, mRNA polyadenylation machinery is recruited in a Pol III-dependent manner to virus-induced loci, including B2 SINE and tRNA genes. Infection causes enhanced polyadenylation of SINE ncRNA, which is required for its stable accumulation. This virus–host interaction therefore highlights an inducible, coupled relationship between Pol III transcription and mRNA-like polyadenylation. It also reveals that co-option of the polyadenylation machinery by Pol III is a mechanism to increase the abundance of noncoding RNA during pathogenic stress.}, archive = {J_PNAS}, author = {Lari, Azra and Shah, Sahil B. and Mao, Xiaowen and Sanghrajka, Priyanka and Karijolich, John and Lareau, Liana F. and Glaunsinger, Britt A.}, doi = {10.1073/pnas.2507186122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2507186122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RNA polymerase III transcription–associated polyadenylation promotes the accumulation of noncoding retrotransposons during infection}, volume = {122}, year = {2025}, }
• (2025). Infrared spectroscopy–based zero-shot learning for identifying reaction intermediates in unseen systems. PNAS, 122(32), e2506834122. (www)

  @article{ , abstract = {Identifying reaction intermediates is a critical component of elucidating the mechanisms of chemical reactions. Spectroscopic techniques are instrumental in this identification process. The capacity of AI to establish the correlations between spectra and chemical substances renders it a suitable tool for spectra analysis. However, the presence of limited data, or even the absence of data, is a common occurrence for intermediates with transient characteristics. This poses a significant challenge in meeting the data requirements of AI models. Herein, we propose a generalizable machine learning model that utilizes zero-shot learning to identify chemical reaction intermediates by their spectra in unseen catalytic systems. Using SHapley Additive exPlanations (SHAP) analysis and visual dimensionality reduction, it was determined that the model’s superior generalizability is attributable to its capacity of learning common patterns of spectra-intermediates, effectively mapping disparate catalytic systems to analogous digital spaces. Therefore, the model can be directly used without fine-tuning parameters for unseen systems even in the presence of noise or solvents. This work demonstrates the application of zero-shot learning in machine learned spectroscopy and illustrates the prediction mechanism, providing a perspective for interpretable and robust cross-system prediction. It lays a solid foundation for the application of spectral descriptors in real reaction systems and the comprehension of chemical reaction mechanisms.}, archive = {J_PNAS}, author = {He, Yucheng and Huang, Yan and Xiao, Hengyu and Jiang, Jun and Wang, Song}, doi = {10.1073/pnas.2506834122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2506834122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Infrared spectroscopy–based zero-shot learning for identifying reaction intermediates in unseen systems}, volume = {122}, year = {2025}, }
• (2025). Intranasal measles virus– and mumps virus–based SARS-CoV-2 vaccine candidates prevent SARS-CoV-2 infection and transmission. PNAS, 122(32), e2506821122. (www)

  @article{ , abstract = {The emergence of immune-evasive SARS-CoV-2 Omicron subvariants highlights the need to develop a mucosal SARS-CoV-2 vaccine that can provide broad protection against virus infection and transmission. Here, we developed an intranasal monovalent SARS-CoV-2 vaccine expressing the six-proline-stabilized prefusion spike proteins (preS-6P) of Omicron XBB.1.5 based on the attenuated mumps virus (MuV) Jeryl Lynn (JL1) vaccine strain. We also developed an intranasal trivalent vaccine expressing the preS-6P of ancestral SARS-CoV-2 WA1 and two Omicron subvariants, BA.1 and XBB.1.5, using the attenuated measles virus (MeV) and MuV-JL1 and JL2 vaccine strains, respectively. Intranasal immunization of hamsters with the monovalent rMuV-JL1-XBB.1.5 or the trivalent vaccine induced high levels of neutralizing antibodies (NAbs) that efficiently neutralized Omicron subvariants XBB.1.5, EG.5, and JN.1, providing complete protection against these Omicron subvariants. Similar levels of Omicron XBB.1.5 NAbs were detected in monovalent rMuV-JL1-XBB.1.5 and trivalent vaccine groups even when hamsters had been preimmunized with the rMuV-JL2-WA1 vaccine, suggesting that both intranasal vaccines are effective in the presence of immune imprinting induced by the spike of SARS-CoV-2 WA1. Intranasal, but not subcutaneous, immunization generated high levels of S-specific mucosal IgA antibodies as well as lung-resident memory T cells in IFNAR1 −/− mice. Finally, intranasal immunization with the trivalent vaccine efficiently blocked transmission of SARS-CoV-2 WA1 and Omicron XBB.1.5 among hamsters in a direct contact transmission setting. In summary, we have developed intranasal MeV and MuV-based trivalent vaccines that induce broad NAbs, robust mucosal immunity, and strong protection against both virus challenge and virus transmission.}, archive = {J_PNAS}, author = {Hsu, Cheng Chih and Chamblee, Michelle and Ye, Chengjin and Shamseldin, Mohamed M. and Yoo, Sung J. and Li, Pei and Zhang, Yuexiu and Liu, Yajie and Hall, Jesse M. and Xu, Jiayu and Miao, Hanson and Thongpan, Ilada and K. C., Mahesh and Liang, Xueya and Yount, Jacob S. and Peeples, Mark E. and Boyaka, Prosper N. and Dubey, Purnima and Martinez-Sobrido, Luis and Liu, Shan-Lu and Li, Jianrong}, doi = {10.1073/pnas.2506821122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2506821122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intranasal measles virus– and mumps virus–based SARS-CoV-2 vaccine candidates prevent SARS-CoV-2 infection and transmission}, volume = {122}, year = {2025}, }
• (2025). Lattice materials with topological states optimized on demand. PNAS, 122(32), e2506787122. (www)

  @article{ , abstract = {Topological states of matter, first discovered in quantum systems, have opened new avenues for wave manipulation beyond the quantum realm. In elastic media, realizing these topological effects requires identifying lattices that support the corresponding topological bands. However, among the vast number of theoretically predicted topological states, only a small fraction has been physically realized. To close this gap, we present a strategy capable of systematically and efficiently discovering metamaterials with desired topological state. Our approach builds on topological quantum chemistry, which systematically classifies topological states by analyzing symmetry properties at selected wavevectors. Because this method condenses the topological character into mathematical information at a small set of wavevectors, it encodes a clear and computationally efficient objective for topology optimization algorithms. We demonstrate that, for certain lattice symmetries, this classification can be further reduced to intuitive morphological features of the phonon band structure. By incorporating these band morphology constraints into topology optimization algorithms and further fabricating obtained designs, we enable the automated discovery and physical realization of metamaterials with targeted topological properties. This methodology establishes a paradigm for engineering topological elastic lattices on demand, addressing the bottleneck in material realization and paving the way for a comprehensive database of topological metamaterial configurations.}, archive = {J_PNAS}, author = {Azizi, Pegah and Kundu, Rahul Dev and Li, Weichen and Sun, Kai and Zhang, Xiaojia Shelly and Gonella, Stefano}, doi = {10.1073/pnas.2506787122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2506787122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lattice materials with topological states optimized on demand}, volume = {122}, year = {2025}, }
• (2025). Prevalence of monogamy at the level of flowers in plants. PNAS, 122(32), e2506724122. (www)

  @article{ , abstract = {Different types of genomic conflicts are possible in plants with multiovulate ovaries that produce multiseeded fruits: between the maternal plant and its offspring, among developing seeds, between paternal and maternal genomes over seed development, and among paternal parents if different parents sire seeds within an ovary. We tested the hypothesis that such conflicts in multiseeded fruits can be reduced if seeds are sired by a single pollen parent. We conducted a meta-analysis of paternity in 63 species across diverse plant families to assess paternity within fruits. Our results reveal that almost 50% of flowering plant species with multiseeded fruits have a single pollen parent. Our results question the prevailing notion that multiple paternity of seeds within fruits is widespread, especially when, in addition to single paternity in multiseeded fruits, a large number of species have single-seeded fruits. We provide insights into the role of sibling rivalry and kin selection in driving genetic relatedness of seeds within fruits. Equally important, the observation of monogamy at the level of flowers is in line with the mating patterns observed in animals.}, archive = {J_PNAS}, author = {Bawa, Kamaljit S. and Tiwari, Namratha and Shivaprakash, K. Nagaraju}, doi = {10.1073/pnas.2506724122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2506724122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prevalence of monogamy at the level of flowers in plants}, volume = {122}, year = {2025}, }
• (2025). CRISPR–Cas9 screening reveals microproteins regulating adipocyte proliferation and lipid metabolism. PNAS, 122(32), e2506534122. (www)

  @article{ , abstract = {Small open reading frames (smORFs) encode microproteins that play crucial roles in various biological processes, yet their functions in adipocyte biology remain largely unexplored. In a previous study, we identified thousands of smORFs in white and brown adipocytes derived from the stromal vascular fraction of mice using ribosome profiling. Here, we expand on this work by identifying additional smORFs related to adipocytes using the in vitro 3T3-L1 preadipocyte model. To systematically investigate the functional relevance of these smORFs, we designed a custom CRISPR/Cas9 single guide RNA (sgRNA) library and screened for smORFs influencing adipocyte proliferation and differentiation. Through a dropout screen and fluorescence-assisted cell sorting of lipid droplets, we identified dozens of smORFs that regulate either cell proliferation or lipid accumulation. The smORFs on the 5’- and 3’-untranslated regions (i.e., upstream smORFs (uORFs) and downstream smORFs (dORFs)) of functional genes can exert activity through cis-regulatory effects of the main ORF on these messenger RNAs (mRNAs), such as uORFs of MDM2 that impact proliferation. However, other smORFs, especially those from mRNAs with no other ORFs, point to a functional microprotein. Indeed, we tested a candidate smORF 1183 from a long noncoding RNA 923011K14Rik and demonstrated that the microprotein regulates adipocyte differentiation. These findings highlight the potential of CRISPR/Cas9-based screening to uncover functional smORFs and provide a framework for further exploration of microproteins in adipocyte biology and metabolic regulation.}, archive = {J_PNAS}, author = {Pai, Victor J. and Shan, Huanqi and Donaldson, Cynthia J. and Vaughan, Joan M. and De Souza, Eduardo V. and O’Connor, Carolyn and Liem, Michelle and Pinto, Antonio F. M. and Diedrich, Jolene and Saghatelian, Alan}, doi = {10.1073/pnas.2506534122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2506534122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CRISPR–Cas9 screening reveals microproteins regulating adipocyte proliferation and lipid metabolism}, volume = {122}, year = {2025}, }
• (2025). Neural and computational evidence for a predictive learning account of the testing effect. PNAS, 122(32), e2506530122. (www)

  @article{ , abstract = {Testing enhances memory more than studying. Although numerous studies have demonstrated the robustness of this classic effect, its neural and computational origin remains debated. Predictive learning is a potential mechanism behind this phenomenon: Because predictions and prediction errors (mismatch between predictions and feedback) are more likely to be generated in testing (relative to in studying), testing can benefit more from predictive learning. We shed light on the testing effect from a multilevel analysis perspective via a combination of cognitive neuroscience experiments (fMRI) and computational modeling. Behaviorally and computationally, only a model incorporating predictive learning can account for the full breadth of behavioral patterns and the robust testing effect. At the neural level, testing and prediction error both activate the canonical reward-related brain areas in the ventral striatum, insula, and midbrain. Crucially, back sorting analysis revealed that activation in the ventral striatum, insula, and midbrain can enhance declarative memory. These results provide strong and converging evidence for a predictive learning account of the testing effect.}, archive = {J_PNAS}, author = {Chen, Haopeng and Verbeke, Pieter and Mattioni, Stefania and Calderon, Cristian Buc and Verguts, Tom}, doi = {10.1073/pnas.2506530122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2506530122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neural and computational evidence for a predictive learning account of the testing effect}, volume = {122}, year = {2025}, }
• (2025). The bacterial ESCRT-III PspA rods thin lipid tubules and increase membrane curvature through helix α0 interactions. PNAS, 122(32), e2506286122. (www)

  @article{ , abstract = {The phage shock protein A (PspA), a bacterial member of the endosomal sorting complexes required for transport (ESCRT)-III superfamily, forms rod-shaped helical assemblies that internalize membrane tubules. The N-terminal helix α0 of PspA (and other ESCRT-III members) has been suggested to act as a membrane anchor; the detailed mechanism, however, of how it binds to membranes and eventually triggers membrane fusion and/or fission events remains unclear. By solving a total of 15 cryoelectron microscopy (cryo-EM) structures of PspA and a truncation lacking the N-terminal helix α0 in the presence of Escherichia coli polar lipid membranes, we show in molecular detail how PspA interacts with and remodels membranes: Binding of the N-terminal helix α0 in the outer tubular membrane leaflet induces membrane curvature, supporting membrane tubulation by PspA. Detailed molecular dynamics simulations and free energy computations of interactions between the helix α0 and negatively charged membranes suggest a compensating mechanism between helix-membrane interactions and the energy contributions required for membrane bending. The energetic considerations are in line with the membrane structures observed in the cryo-EM images of tubulated membrane vesicles, fragmented vesicles inside tapered PspA rods, and shedded vesicles emerging at the thinner PspA rod ends. Our results provide insights into the molecular determinants and a potential mechanism of vesicular membrane remodeling mediated by a member of the ESCRT-III superfamily.}, archive = {J_PNAS}, author = {Hudina, Esther and Schott-Verdugo, Stephan and Junglas, Benedikt and Kutzner, Mirka and Ritter, Ilona and Hellmann, Nadja and Schneider, Dirk and Gohlke, Holger and Sachse, Carsten}, doi = {10.1073/pnas.2506286122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2506286122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The bacterial ESCRT-III PspA rods thin lipid tubules and increase membrane curvature through helix α0 interactions}, volume = {122}, year = {2025}, }
• (2025). Pervasive horizontal transfer of adeno-associated virus capsid genes. PNAS, 122(32), e2505928122. (www)

  @article{ , abstract = {Adeno-associated viruses (AAVs) are nonpathogenic DNA viruses with potent gene delivery capabilities, making them essential tools in gene therapy and biomedical research. Despite their therapeutic importance, key aspects of AAV natural biology remain obscure, complicating efforts to explain rare AAV-associated diseases and optimize gene therapy vectors. By analyzing sequence data from virus isolates and endogenous viral elements (EVEs), I reveal a striking evolutionary pattern: While AAV sublineages, defined by the replication-associated ( rep ) gene, have broadly codiverged with host groups over millions of years, capsid ( cap ) diversity has been shaped by extensive recombination. In particular, one capsid lineage, Mammalian-wide ( M-wide ), has spread horizontally across diverse rep lineages and host taxa through multiple recombination events. Furthermore, several AAVs with M-wide capsids—including AAV-4, AAV-12, and bovine AAV (BAAV)—originate from historical adenovirus (Ad) stocks, raising the possibility that laboratory conditions contributed to capsid transfer. Distinguishing natural from laboratory-driven recombination is essential for understanding AAV ecology and its implications for gene therapy. A systematic sequencing effort in human and primate populations is needed to assess the extent of recombinant capsid acquisition, determine the impact of laboratory-driven recombination on circulating AAV diversity, and track ongoing recombination events that could affect vector safety and efficacy.}, archive = {J_PNAS}, author = {Gifford, Robert J.}, doi = {10.1073/pnas.2505928122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2505928122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pervasive horizontal transfer of adeno-associated virus capsid genes}, volume = {122}, year = {2025}, }
• (2025). Exploring glycoform-dependent dynamic modulations in human immunoglobulin g via computational and experimental approaches. PNAS, 122(32), e2505473122. (www)

  @article{ , abstract = {We investigate the impact of glycoform alterations on the dynamic structure of the human immunoglobulin G1 (IgG1) Fc region using integrated computational and experimental approaches. Four distinct IgG1-Fc glycoforms, varying in core fucosylation and nonreducing terminal galactosylation, were generated through a combination of cell engineering and in vitro enzymatic reactions. Stable-isotope-assisted NMR spectroscopy, incorporating both glycan and protein signals, revealed that galactosylation induces chemical shift perturbations extending from the glycan–protein interface to the C H 2–C H 3 domain boundary. Molecular dynamics simulations demonstrated that the absence of galactose enhances the mobility of both the glycan and the C H 2 domain, broadening the conformational landscape of the Fc quaternary structure. This increased flexibility likely contributes to a greater entropic penalty upon binding to effector molecules, which constrain the Fc in an asymmetric conformation. Conversely, the effects of fucosylation are more localized, primarily influencing the dynamics of residues involved in Fcγ receptor IIIa binding. These findings provide atomic-level insights into the distinct yet synergistic mechanisms by which galactosylation and fucosylation modulate IgG1-Fc dynamics and effector functions, offering crucial information for the optimization of therapeutic antibodies.}, archive = {J_PNAS}, author = {Yanaka, Saeko and Sakae, Yoshitake and Miyanoiri, Yohei and Yamaguchi, Takumi and Isono, Yukiko and Kondo, Sachiko and Iwasaki, Miyuki and Onitsuka, Masayoshi and Yagi, Hirokazu and Kato, Koichi}, doi = {10.1073/pnas.2505473122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2505473122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exploring glycoform-dependent dynamic modulations in human immunoglobulin g via computational and experimental approaches}, volume = {122}, year = {2025}, }
• (2025). Fluid flow generates bacterial conjugation hot spots by increasing the rate of shear-driven cell–cell encounters. PNAS, 122(32), e2505446122. (www)

  @article{ , abstract = {Conjugation accelerates bacterial evolution by enabling bacteria to acquire genes horizontally from their neighbors. Plasmid donors must physically encounter and connect with recipients to allow plasmid transfer, and different environments are characterized by vastly different encounter rates between cells, based on mechanisms ranging from simple diffusion to fluid flow. However, how the environment affects the conjugation rate by setting the encounter rate has been largely neglected, mostly because existing experimental setups do not allow for direct control over cell encounters. Here, we describe the results of conjugation experiments in Escherichia coli in which we systematically varied the magnitude of shear flow using a cone-and-plate rheometer to control the encounter rate. We found that the conjugation rate increases with shear until it peaks at an optimal shear rate ( γ ˙ = 1 × 10 2 s − 1 ), reaching a conjugation rate fivefold higher than the baseline set by diffusion-driven encounters. This optimum marks the transition from a regime in which shear promotes conjugation by increasing the rate of cell–cell encounters to a regime in which shear disrupts conjugation. Regions of high fluid shear are widespread in aquatic systems, in the gut of host organisms, and in soil, and our results indicate that these regions could be hot spots of bacterial conjugation in the environment.}, archive = {J_PNAS}, author = {Zbinden, Matti and Huisman, Jana S. and Blitvic, Natasha and Stocker, Roman and Słomka, Jonasz}, doi = {10.1073/pnas.2505446122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2505446122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fluid flow generates bacterial conjugation hot spots by increasing the rate of shear-driven cell–cell encounters}, volume = {122}, year = {2025}, }
• (2025). Pelota-mediated ribosome-associated quality control counteracts aging and age-associated pathologies across species. PNAS, 122(32), e2505217122. (www)

  @article{ , abstract = {Ribosome-associated quality control (RQC) is a pivotal biological process that governs the fidelity of messenger RNA (mRNA) homeostasis and protein synthesis. Defects in RQC are implicated in cellular dysfunction and proteotoxicity, but their impact on aging remains elusive. Here, we show that Pelota, the ribosome rescue factor, promotes longevity and protects against age-related pathological phenotypes in multiple metazoan species. By performing a targeted genetic screen, we find that Pelota is indispensable for longevity in the nematode Caenorhabditis elegans . We show that Pelota mitigates premature senescence in cultured human cells, muscle aging in mice, and neuropathology in cellular and organoid models of Alzheimer’s disease. Mechanistically, we demonstrate that Pelota maintains autophagy-mediated proteostasis, by preventing the hyperactivation of mechanistic target of rapamycin signaling. Overall, our work highlights the conserved functional significance of RQC, regulated by Pelota, in extending lifespan and protecting diverse species against age-associated disease phenotypes.}, archive = {J_PNAS}, author = {Lee, Jongsun and Lee, Bora and Lee, Hyein and Kim, Eun Ji E. and Kim, Sieun S. and Kwon, Hyunwoo C. and Lee, Hanseul and Lee, Gee-Yoon and Hong, Woojin and Ham, Seokjin and Yang, Jae Won and Park, Heeju and Moreno, Tatiana M. and Brown, Michelle E. and Park, Hae-Eun H. and Kim, Eunah and Jung, Yoonji and Kang, Eunseok and Park, Sangsoon and Shin, Yeo Jin and Ha, Seokjun G. and Kwon, Sujeong and Hwang, Seungjae and Min, Hyemin and Kumsta, Caroline and Lim, Chunghun and Kang, Chanhee and Seo, Jinsoo and Lee, Kwang-Pyo and Lee, Seung-Jae V.}, doi = {10.1073/pnas.2505217122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2505217122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pelota-mediated ribosome-associated quality control counteracts aging and age-associated pathologies across species}, volume = {122}, year = {2025}, }
• (2025). Reinstating memories’ temporal context at encoding causes sisyphus-like memory rejuvenation. PNAS, 122(32), e2505120122. (www)

  @article{ , abstract = {As memories age, their immediate retrievability decreases albeit, due to ongoing memory consolidation, their future rate of forgetting weakens. Here, we show in two experiments ( N = 1.216 participants) that mentally traveling back in time to older memories’ temporal context at encoding reverses the two effects and makes the memories similar again to how they were at an earlier point in time. Mental time travel increased both the memories’ immediate retrievability and their future rate of forgetting when individuals attempted to reinstate context deliberately and actively and when they retrieved other memories sharing a similar temporal context. Intriguingly, the forgetting after mental time travel even followed the same trajectory as the forgetting after encoding. Attempts to reinstate memories’ encoding context thus rejuvenated memories, although the degree of rejuvenation decreased as temporal lag between encoding and the reinstatement attempts increased, which was mediated by the fact that, with increasing lag, decreasing proportions of the encoded memories were reactivated and reconsolidated in response to participants’ reinstatement attempts. Mentally traveling back in time creates rejuvenation cycles with enhanced retrievability followed by a restart of forgetting and consolidation processes. Recurring rejuvenation cycles may thus be key to maintain memories’ retrievability over longer periods of time, painting the picture of Sisyphus-like memory resurrection.}, archive = {J_PNAS}, author = {Bäuml, Karl-Heinz T. and Meixensperger, Sarah R. and Hirsch, Marilena L.}, doi = {10.1073/pnas.2505120122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2505120122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reinstating memories’ temporal context at encoding causes sisyphus-like memory rejuvenation}, volume = {122}, year = {2025}, }
• (2025). Immiscible proteins compete for RNA binding to order condensate layers. PNAS, 122(32), e2504778122. (www)

  @article{ , abstract = {Biomolecular condensates mediate diverse and essential cellular functions by compartmentalizing biochemical pathways. Many condensates have internal subdomains with distinct compositional identities. A major challenge lies in dissecting the multicomponent logic that relates biomolecular features to emergent condensate organization. Nuclear paraspeckles are paradigmatic examples of multidomain condensates, comprising core and shell layers with distinct compositions that are scaffolded by the lncRNA NEAT1, which spans both layers. A prevailing model of paraspeckle assembly proposes that core proteins bind directly and specifically to core-associated NEAT1 domains. Combining informatics and biochemistry, we unexpectedly find that the essential core proteins FUS and NONO bind and condense preferentially with shell-associated NEAT1 domains. The shell protein TDP-43 exhibits similar NEAT1 domain preferences on its own but forms surfactant-like shell layers around core protein-driven condensates when both are present. Together, experiments and physics-based simulations suggest that competitive RNA binding and immiscibility between core and shell proteins order paraspeckle layers. More generally, we propose that subcondensate organization can spontaneously arise from a balance of collaborative and competitive protein binding to the same domains of a lncRNA.}, archive = {J_PNAS}, author = {Snead, Wilton T. and Skillicorn, Mary K. and Shrinivas, Krishna and Gladfelter, Amy S.}, doi = {10.1073/pnas.2504778122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2504778122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Immiscible proteins compete for RNA binding to order condensate layers}, volume = {122}, year = {2025}, }
• (2025). Cryosectioning-enhanced super-resolution microscopy for single-protein imaging across cells and tissues. PNAS, 122(32), e2504578122. (www)

  @article{ , abstract = {DNA-points accumulation for imaging in nanoscale topography (DNA-PAINT) enables nanoscale imaging with virtually unlimited multiplexing and molecular counting. Here, we address challenges, such as variable imaging performance and target accessibility, that can limit its broader applicability. Specifically, we enhance its capacity for robust single-protein imaging and molecular counting by optimizing the integration of total internal reflection fluorescence microscopy with physical sectioning, in particular, Tokuyasu cryosectioning. Our method, tomographic and kinetically enhanced DNA-PAINT (tkPAINT), achieves 3 nm localization precision across diverse samples, enhanced imager binding, and improved cellular integrity. tkPAINT can facilitate molecular counting with DNA-PAINT inside the nucleus, as demonstrated through its quantification of the in situ abundance of RNA Polymerase II in both HeLa cells as well as mouse tissues. Anticipating that tkPAINT could become a versatile tool for the exploration of biomolecular organization and interactions across cells and tissues, we also demonstrate its capacity to support multiplexing, multimodal targeting of proteins and nucleic acids, and three-dimensional (3D) imaging.}, archive = {J_PNAS}, author = {Stein, Johannes and Ericsson, Maria and Nofal, Michel and Magni, Lorenzo and Aufmkolk, Sarah and McMillan, Ryan B. and Breimann, Laura and Herlihy, Conor P. and Lee, S. Dean and Willemin, Andréa and Wohlmann, Jens and Arguedas-Jimenez, Laura and Yin, Peng and Pombo, Ana and Church, George M. and Wu, Chao-ting}, doi = {10.1073/pnas.2504578122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2504578122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryosectioning-enhanced super-resolution microscopy for single-protein imaging across cells and tissues}, volume = {122}, year = {2025}, }
• (2025). The evolution of zero-sum and positive-sum worldviews. PNAS, 122(32), e2504339122. (www)

  @article{ , abstract = {People and cultures differ in the extent to which they view the world as a zero-sum environment (where one person’s gain is another’s loss) or a positive-sum environment (where certain actions can benefit everyone). These beliefs shape individuals’ willingness to work, invest, collaborate, or show hostility toward out-groups, and accept or reject various social policies. We model dyadic interactions in a heterogeneous population where individuals biased toward a zero-sum worldview are more likely to invest in competition, while those biased toward a positive-sum worldview are more likely to invest in cooperation. The environment alternates stochastically between cooperative and competitive states. Without social influence, the more accurate worldview yields higher utilities and spreads throughout the population. However, assortative matching by bias can favor the positive-sum worldview even if a positive-sum environment is somewhat less likely. With peer conformity, inaccurate worldviews can persist after a structural change in the environment, leading to cultural evolutionary mismatch. In the presence of cultural authorities who can alter beliefs, either both worldviews can coexist or one excludes the other. Moreover, when assortative matching and conformity interact, authorities may profit by amplifying individuals’ biases, creating enclaves of similarly biased people who can pay the authorities enough to make investment in persuasive technology economically viable. Cultural evolutionary mismatch is more likely in cultures marked by strong peer conformity and high responsiveness to authority when the authority promotes a suboptimal worldview. This study demonstrates how real-world conditions, peer influence, and authority interventions can perpetuate or shift zero-sum and positive-sum worldviews-at times leading to inaccurate beliefs.}, archive = {J_PNAS}, author = {Gavrilets, Sergey and Seabright, Paul}, doi = {10.1073/pnas.2504339122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2504339122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The evolution of zero-sum and positive-sum worldviews}, volume = {122}, year = {2025}, }
• (2025). How a toxic pollutant avoids photodegradation: Relaxation pathways of UV-excited 2,4-dinitrophenol in aqueous solution. PNAS, 122(32), e2504123122. (www)

  @article{ , abstract = {Nitroaromatic compounds are pollutants emitted from biomass burning and fossil fuel combustion. They are a major component of brown carbon aerosols, affecting radiative forcing in the lower atmosphere. Among these species, 2,4-dinitrophenol (DNP) is toxic to both plants and animals and is resistant to photodegradation when dissolved in water, such as in aqueous atmospheric aerosols. To understand this environmental photostability of DNP, the photochemistry of near-UV excited DNP in aqueous solution is investigated using transient absorption spectroscopy and time-resolved infrared spectroscopy, seamlessly spanning fs – μs timescales to reveal the pathways following photoexcitation. Building upon our understanding of simpler nitroaromatic species, and using linear-response time-dependent density functional theory (LR-TDDFT) to provide a framework for the interpretation of the results, the complex photochemistry of this species is unraveled. The majority of DNP relaxes within the singlet manifold, via intersection seams between the S 1 potential energy surface and the S 0 state, on timescales shorter than the few-picosecond limits of vibrational cooling. A second ground-state recovery pathway involves intersystem crossing from a region of the S 1 surface with nπ* electronic character into the triplet manifold, deprotonation to form the nitrophenolate anion and reprotonation in solution. Branching ratios between these pathways are influenced by the excitation wavelength. In aqueous solution, DNP will also exist as dinitrophenolate anions which, when photoexcited in the near-UV, undergo direct electronic relaxation on sub-ps timescales. Combinations of these pathways result in complete S 0 recovery, allowing this toxic species to resist solar photodegradation when dissolved in aqueous atmospheric aerosols.}, archive = {J_PNAS}, author = {Greene, Hallam J. M. and Ghosh, Deborin and Sazanovich, Igor V. and Phelps, Ryan and Mackintosh, Bembe C. and Curchod, Basile F. E. and Orr-Ewing, Andrew J.}, doi = {10.1073/pnas.2504123122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2504123122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How a toxic pollutant avoids photodegradation: Relaxation pathways of UV-excited 2,4-dinitrophenol in aqueous solution}, volume = {122}, year = {2025}, }
• (2025). Striatal and cerebellar interactions during reward-based motor performance. PNAS, 122(32), e2503373122. (www)

  @article{ , abstract = {Goal-directed motor performance relies on the brain’s ability to distinguish between actions that lead to successful and unsuccessful outcomes. The basal ganglia (BG) and cerebellum (CBL) are integral for processing performance outcomes, yet their functional interactions remain underexplored. We scanned participants’ brains with functional magnetic imaging (fMRI) while they performed a skilled motor task for monetary rewards, where outcomes depended on their motor performance and probabilistic events that were not contingent on their performance. Successful motor outcomes increased activity in the ventral striatum (VS), a functional subregion of the BG, whereas unsuccessful motor outcomes engaged the CBL. In contrast, for probabilistic outcomes unrelated to motor performance, the BG and CBL exhibited no differences in activity between successful and unsuccessful outcomes. Dynamic causal modeling revealed that VS-to-CBL connectivity was inhibitory following successful motor outcomes, suggesting that the VS may suppress CBL error processing for correct actions. Conversely, CBL-to-VS connectivity was inhibitory after unsuccessful motor outcomes, potentially preventing reinforcement of erroneous actions. Additionally, interindividual differences in task preference, assessed by having participants choose between performing the motor task or flipping a coin for monetary rewards, were related to inhibitory VS-CBL connectivity. These findings highlight a performance-mediated functional network between the VS and CBL, modulated by motivation and subjective preferences, that supports goal-directed behavior.}, archive = {J_PNAS}, author = {Lee, Joonhee Leo and Casamento-Moran, Agostina and Bastian, Amy J. and Cullen, Kathleen E. and Chib, Vikram S.}, doi = {10.1073/pnas.2503373122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2503373122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Striatal and cerebellar interactions during reward-based motor performance}, volume = {122}, year = {2025}, }
• (2025). Cancer cells suppress NK cell activity by actin-driven polarization of inhibitory ligands to the immunological synapse. PNAS, 122(32), e2503259122. (www)

  @article{ , abstract = {Natural killer (NK) cells engage target cells via the immunological synapse (IS), where inhibitory and activating signals determine whether NK cell cytotoxicity is suppressed or activated. We previously reported that cancer cells can rapidly remodel their actin cytoskeleton upon NK cell engagement, leading to F-actin accumulation at the synapse. Here, we show that this process inhibits NK cell activation as indicated by impaired MTOC and lytic granule polarization. Exploring the underlying mechanism, we demonstrate that actin remodeling drives the recruitment of inhibitory ligands, such as HLA-A, -B, and -C, to the synapse. Disrupting HLA interaction with their cognate inhibitory receptors KIRs restores NK cell activation. Using NK cells expressing inhibitory KIR receptors, matched or unmatched to HLA molecules on cancer cells, we show that synaptic F-actin accumulation and matching KIR–HLA interactions jointly suppress NK cell cytotoxicity. Our findings reveal an immune evasion strategy in which cancer cells impair NK cell activation by altering synaptic signaling through actin cytoskeleton–driven recruitment of inhibitory signals to the IS.}, archive = {J_PNAS}, author = {Hoffmann, Céline and Filali, Liza and Wurzer, Hannah and Pereira Fernandes, Diogo and Mgrditchian, Takouhie and Huang, Wanxin and Moreau, Flora and Krecké, Max and Thomas, Clément}, doi = {10.1073/pnas.2503259122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2503259122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cancer cells suppress NK cell activity by actin-driven polarization of inhibitory ligands to the immunological synapse}, volume = {122}, year = {2025}, }
• (2025). Time-resolved photocatalytic proximity labeling uncovers ER proteome dynamics underlying UPR-to-apoptosis transition. PNAS, 122(32), e2503115122. (www)

  @article{ , abstract = {Apoptosis is a critical outcome of stress-induced processes, with the endoplasmic reticulum (ER) playing a central role in apoptotic protein processing and stress signal transduction. Profiling the ER proteome during stress to cell death offers valuable insights into these processes, but existing methods often suffer from a loss of in situ information or requirement of genetic manipulation. In this study, we introduce CAT-ER, a nongenetic ER proteomics system that provides in situ labeling, spatiotemporal resolution, and compatibility across diverse cell types. By combining an ER-targeted iridium photocatalyst with a thio-quinone methide (thioQM) probe, CAT-ER achieves high specificity in enriching ER proteins, comparable to traditional enzymatic methods. Importantly, CAT-ER is free of genetic manipulation, allowing its use in hard-to-transfect cell types like HeLa and immune cells (e.g., Raji, Jurkat, and RAW264.7). Given the high spatiotemporal resolution of CAT-ER, we revealed dynamic ER proteome changes during thapsigargin (Tg)-induced unfolded protein response (UPR) to apoptosis. Notably, NFIP2 mitigated ER stress by halting translation when UPR initiated, while compromised EMC2 delayed apoptosis during prolonged stress. These findings provide insights into the molecular dynamics linking the UPR and apoptosis. Collectively, CAT-ER serves as a versatile tool for spatiotemporal proteomic analysis without the need for genetic manipulation, offering a powerful approach to study ER dynamics in various biological contexts.}, archive = {J_PNAS}, author = {Zhou, Nan and Zhang, Yan and Chen, Peng R. and Fan, Xinyuan}, doi = {10.1073/pnas.2503115122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2503115122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Time-resolved photocatalytic proximity labeling uncovers ER proteome dynamics underlying UPR-to-apoptosis transition}, volume = {122}, year = {2025}, }
• (2025). Hierarchical network of thermal plumes and their dynamics in turbulent Rayleigh–Bénard convection. PNAS, 122(32), e2502972122. (www)

  @article{ , abstract = {The link between characteristic coherent structures and their statistical properties in turbulent flows remains largely unclear and is thus a central bottleneck for a better understanding of turbulent flows. Here, we demonstrate this link for the important problem of thermal convection. We show how the hierarchical plume network in the near-wall region of the flow, which becomes increasingly sparse with increasing distance away from the wall, is connected to the marginal stability of the thermal boundary layer and the resulting global heat transport. Our results, which are based on a series of direct numerical simulations for Rayleigh numbers up to R a = 10 11 in a relatively shallow layer, suggest a highly fluctuating thermal boundary layer that is composed of local building blocks in terms of plumes, which are the essential drivers of turbulent heat transport. These thermal plumes are found in a dynamically perpetual process of formation and aggregation that can be described, particularly well for Rayleigh numbers R a ≳ 10 9 , by a von Smoluchowski equation resulting in a gamma distribution of the local plume spacing, consistent with measurements. Similarity manifests with respect to the horizontal extension of the network, the vertical hierarchical plume clustering away from the wall and the number of plumes, over an order of magnitude of the thermal boundary layer thickness. Our findings suggest the dominance of dynamical local processes near the wall, rather than a global boundary layer instability.}, archive = {J_PNAS}, author = {Shevkar, Prafulla P. and Samuel, Roshan J. and Zinchenko, Georgy and Bode, Mathis and Schumacher, Jörg and Sreenivasan, Katepalli R.}, doi = {10.1073/pnas.2502972122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2502972122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hierarchical network of thermal plumes and their dynamics in turbulent Rayleigh–Bénard convection}, volume = {122}, year = {2025}, }
• (2025). O-GlcNAc modulation of nuclear pore complexes orchestrates mRNA export efficiency. PNAS, 122(32), e2502687122. (www)

  @article{ , abstract = {Efficient gene expression depends on the tightly regulated export of messenger RNA (mRNA) through nuclear pore complexes (NPCs), which are densely modified by O-linked N-acetylglucosamine (O-GlcNAc). Although dysregulated O-GlcNAcylation has been linked to a variety of human diseases, the precise distribution of O-GlcNAc within the NPC and its effects on mRNA export remain poorly understood. Here, we combined single-point edge-excitation subdiffraction (SPEED) microscopy with stochastic optical reconstruction microscopy (STORM) to map the nanometer-scale distribution of an O-GlcNAc analog (GlcNAz) within NPCs and to quantify the export kinetics of mRNA–protein complexes (mRNPs) under both normal and perturbed O-GlcNAcylation conditions. Under basal conditions, GlcNAz is predominantly localized around the central channel of the NPC. However, both hypo- and hyper-O-GlcNAcylation cause GlcNAz to redistribute toward the nuclear and cytoplasmic peripheries. This shift is paralleled by changes in mRNP localization and altered distributions of key, highly O-GlcNAcylated, phenylalanine-glycine nucleoporins. These architectural rearrangements are accompanied by functional consequences: Elevated O-GlcNAcylation nearly doubles mRNA export efficiency (~61%), while reduced O-GlcNAcylation lowers it to ~16%, along with reduced NPC engagement. The transport receptor TAP exhibits analogous efficiency changes, reinforcing the role of O-GlcNAcylation as a key regulator of nucleocytoplasmic transport. Together, these results suggest that O-GlcNAcylation modulates NPC architecture and transport dynamics to fine-tune mRNA export, and indicate that targeted modulation of NPC O-GlcNAc levels may offer a promising strategy for addressing diseases associated with nuclear transport dysfunction.}, archive = {J_PNAS}, author = {Junod, Samuel L. and Rush, Coby and Tingey, Mark and Yang, Weidong}, doi = {10.1073/pnas.2502687122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2502687122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {O-GlcNAc modulation of nuclear pore complexes orchestrates mRNA export efficiency}, volume = {122}, year = {2025}, }
• (2025). Some topological genera and jacobi forms. PNAS, 122(32), e2502678122. (www)

  @article{ , abstract = {We revisit and elucidate the A ^ -genus, Hirzebruch’s L -genus, and Witten’s W -genus, cobordism invariants of special classes of manifolds. After slight modification, involving Hecke’s trick, we find that the A ^ -genus and L -genus arise directly from Jacobi’s theta function. For every k ≥ 0 , we obtain exact formulas for the quasimodular expressions of A ^ k and L k as “traces” of partition Eisenstein series A ^ k ( τ ) = Tr k ( ϕ A ^ ; τ ) and L k ( τ ) = Tr k ( ϕ L ; τ ) , which are easily converted to the original topological expressions. Surprisingly, Ramanujan defined twists of the A ^ k ( τ ) in his “lost notebook” in his study of derivatives of theta functions, decades before Borel and Hirzebruch rediscovered them in the context of spin manifolds. In addition, we show that the nonholomorphic G 2 ⋆ -completion of the characteristic series of the Witten genus is the Jacobi theta function avatar of the A ^ -genus.}, archive = {J_PNAS}, author = {Amdeberhan, Tewodros and Griffin, Michael J. and Ono, Ken}, doi = {10.1073/pnas.2502678122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2502678122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Some topological genera and jacobi forms}, volume = {122}, year = {2025}, }
• (2025). Protracted circum-continent subduction: A mechanism for craton destruction and a rationale for craton longevity. PNAS, 122(32), e2502618122. (www)

  @article{ , abstract = {The evolution of continents is shaped by the growth and destruction of long-lived cratons, which serve as their stable cores. Processes for craton destruction are controversial because most invoked mechanisms occur frequently throughout Earth history, making the preservation of cratons for billions of years problematic. Here, we address this issue by presenting a crustal-scale analytical signal-amplitude model obtained from high-resolution airborne and shipborne magnetic data across cratons within East Asia. Magmatic, magnetic, and basin-history constraints show that the eastern North China craton experienced focused weakening, thickening, and catastrophic destruction of its mantle lithosphere due to a unique combination of circum-craton subduction and subsequent collision since the Paleozoic. By contrast, the adjacent South China craton was not impacted in this way, and thus, its mantle root was spared from destruction. The long-term survival of cratons may stem from the infrequent occurrence of sustained circum-cratonic subduction or collisional processes capable of destabilizing their lithospheric roots.}, archive = {J_PNAS}, author = {Xu, Xi and Zuza, Andrew V. and Liu, Lijun and Zhu, Weilin and Sun, Yanyun and Wang, Baodi and Kuang, Xingtao and Han, Song and Zhang, Xuanjie and Zhang, Wan and Fu, Xiaowei and Pearson, D. Graham and Liu, Jingao}, doi = {10.1073/pnas.2502618122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2502618122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Protracted circum-continent subduction: A mechanism for craton destruction and a rationale for craton longevity}, volume = {122}, year = {2025}, }
• (2025). Split-YFP-coupled interaction–dependent TurboID identifies new functions of basal cell polarity in arabidopsis. PNAS, 122(32), e2502445122. (www)

  @article{ , abstract = {The formation of a body axis is one of the fundamental steps in developmental patterning in multicellular organisms. Ectopic expression of the stomatal protein BASL (BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE) reveals a proximal–distal cell polarity field in the leaf and an apical–basal field in the hypocotyl and root of Arabidopsis . This provides a framework for uncovering molecular components of body-axis cell polarity in higher plants. In this study, we developed a proximity labeling-based complementation system, termed tSYID ( t andem fusion of S plit- Y FP and Turbo ID ), to enable simultaneous visualization and identification of the tissue-wide cell polarity module marked by interacting BASL and BREVIS RADIX-LIKE 2 (BRXL2) proteins in Arabidopsis . This contact-based tSYID system focuses on identifying the protein interactome proximal to the protein–protein interaction site. By combining proximity labeling and mass spectrometry, we identified protein candidates associated with the tSYID-BASL/BRXL2 module, many of which remain uncharacterized in plants. Among them, an AGC protein kinase displayed highly polarized localization at the basal membrane in the hypocotyl and root. Knocking out two close AGC homologs in Arabidopsis resulted in compromised hypocotyl growth in the dark, suggesting a functional connection between basal cell polarity and plant upward growth. Our study demonstrates the power of using the Split-TurboID strategy to uncover proximal proteomes near protein activity sites and highlights an underappreciated crosstalk between developmentally programmed body axes and environmentally influenced growth vectors.}, archive = {J_PNAS}, author = {Huang, Aobo and Zhang, Jinming and Liu, Zhendong and Schoen, Vanessa and Verma, Deepanjali and Zheng, Haiyan and Pedmale, Ullas V. and Dong, Juan}, doi = {10.1073/pnas.2502445122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2502445122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Split-YFP-coupled interaction–dependent TurboID identifies new functions of basal cell polarity in arabidopsis}, volume = {122}, year = {2025}, }
• (2025). Refugees from ukraine value job opportunities over welfare. PNAS, 122(32), e2502420122. (www)

  @article{ , abstract = {Understanding refugees’ destination choices is key to designing appropriate policies, but little is known about this beyond correlational patterns and the effects of isolated policy changes. To derive causal evidence on how destination country characteristics affect refugees’ destination choices, we conducted a forced-choice conjoint experiment among 3,348 Ukrainian refugees across Europe. In the survey experiment, refugees repeatedly chose between two hypothetical countries that varied on eight relevant attributes. Ukrainian refugees are uniquely suited to study the relative importance of different host country attributes as they have the right to choose in which member state of the European Union they apply for temporary protection. We find that job opportunities are a much stronger driver of destination choice than social assistance. A one SD increase in average wages makes it 16.4 percentage points more likely that the country is chosen in the survey experiment, while a corresponding increase in social assistance increases the probability of the country being chosen by only 4.5 percentage points. The ease of finding a job matching one’s qualifications is valued even more than having friends or family and knowing the language of the country. We also find strong sorting in that respondents who value knowing the language and job opportunities in our survey experiments are also more likely to have settled in countries where this is the case. Conjoint experiments can be used to assess refugees’ anticipated migratory responses to proposed policy changes.}, archive = {J_PNAS}, author = {Adema, Joop and Chargaziia, Lasha and Giesing, Yvonne and Poutvaara, Panu}, doi = {10.1073/pnas.2502420122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2502420122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Refugees from ukraine value job opportunities over welfare}, volume = {122}, year = {2025}, }
• (2025). Evaluating plant growth–defense trade-offs by modeling the interaction between primary and secondary metabolism. PNAS, 122(32), e2502160122. (www)

  @article{ , abstract = {Understanding the molecular mechanisms behind plant response to stress can enhance breeding strategies and help us design crop varieties with improved stress tolerance, yield, and quality. To investigate resource redistribution from growth- to defense-related processes in an essential tuber crop, potato, here we generate a large-scale compartmentalized genome-scale metabolic model (GEM), potato-GEM. Apart from a large-scale reconstruction of primary metabolism, the model includes the full known potato secondary metabolism, spanning over 566 reactions that facilitate the biosynthesis of 182 distinct potato secondary metabolites. Constraint-based modeling identifies that the activation of the largest amount of secondary (defense) pathways occurs at a decrease of the relative growth rate of potato leaf, due to the costs incurred by defense. We then obtain transcriptomics data from experiments exposing potato leaves to two biotic stress scenarios, a herbivore and a viral pathogen, and apply them as constraints to produce condition-specific models. We show that these models recapitulate experimentally observed decreases in relative growth rates under treatment as well as changes in metabolite levels between treatments, enabling us to pinpoint the metabolic rewiring underlying growth–defense trade-offs. Potato-GEM thus presents a useful resource to study and broaden our understanding of potato and general plant defense responses under stress conditions.}, archive = {J_PNAS}, author = {Zrimec, Jan and Correa, Sandra and Zagorščak, Maja and Petek, Marko and Bleker, Carissa and Stare, Katja and Schuy, Christian and Sonnewald, Sophia and Gruden, Kristina and Nikoloski, Zoran}, doi = {10.1073/pnas.2502160122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2502160122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evaluating plant growth–defense trade-offs by modeling the interaction between primary and secondary metabolism}, volume = {122}, year = {2025}, }
• (2025). Yeast adapts to diverse ecological niches driven by genomics and metabolic reprogramming. PNAS, 122(32), e2502044122. (www)

  @article{ , abstract = {The famous model organism Saccharomyces cerevisiae is widely present in a variety of natural and human-associated habitats. Despite extensive studies of this organism, the metabolic mechanisms driving its adaptation to varying niches remain elusive. We here gathered genomic resources from 1,807 S. cerevisiae strains and assembled them into a high-quality pangenome, facilitating the comprehensive characterization of genetic diversity across isolates. Utilizing the pangenome, 1,807 strain-specific genome-scale metabolic models (ssGEMs) were generated, which performed well in quantitative predictions of cellular phenotypes, thus helping to examine the metabolic disparities among all S. cerevisiae strains. Integrative analyses of fluxomics and transcriptomics with ssGEMs showcased ubiquitous transcriptional regulation of metabolic flux in specific pathways (i.e., amino acid synthesis) at a population level. Additionally, the gene/reaction inactivation analysis through the ssGEMs refined by transcriptomics showed that S. cerevisiae strains from various ecological niches had undergone reductive evolution at both the genomic and metabolic network levels when compared to wild isolates. Finally, the compiled analysis of the pangenome, transcriptome, and metabolic fluxome revealed remarkable metabolic differences among S. cerevisiae strains originating from distinct oxygen-limited niches, including human gut and cheese environments, and identified convergent metabolic evolution, such as downregulation of oxidative phosphorylation pathways. Together, these results illustrate how yeast adapts to distinct niches modulated by genomic and metabolic reprogramming, and provide computational resources for translating yeast genotype to fitness in future studies.}, archive = {J_PNAS}, author = {Wang, Haoyu and Nielsen, Jens and Zhou, Yongjin J. and Lu, Hongzhong}, doi = {10.1073/pnas.2502044122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2502044122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Yeast adapts to diverse ecological niches driven by genomics and metabolic reprogramming}, volume = {122}, year = {2025}, }
• (2025). Structural insights into a citrate transporter that mediates aluminum tolerance in barley. PNAS, 122(32), e2501933122. (www)

  @article{ , abstract = {HvAACT1 is a major aluminum (Al)-tolerance gene in barley, encoding a citrate transporter that belongs to the multidrug and toxic compound extrusion (MATE) family. This transporter facilitates citrate secretion from the roots, thereby detoxifying external Al ions—a major constraint of crop production on acidic soils. In this study, we present the outward-facing crystal structure of HvAACT1, providing insights into a citrate transport mechanism. The putative citrate binding site consists of three basic residues—K126 in transmembrane helix 2 (TM2), R358 in TM7, and R535 in TM12—creating substantial positive charges in the C-lobe cavity. Proton coupling for substrate transport may involve two pairs of aspartate residues in the N-lobe cavity, one of which corresponds to the essential Asp pair found in prokaryotic H + -coupled MATE transporters belonging to the DinF subfamily. Structural coupling between proton uptake in the N-lobe and citrate extrusion in the C-lobe can be enabled by an extensive, unique hydrogen-bonding network at the extracellular half of the N-lobe. Mutation-based functional analysis, structural comparisons, molecular dynamics simulation, and phylogenic analysis suggest an evolutionary link between citrate MATE transporters and the DinF MATE subfamily. Our findings provide a solid structural basis for citrate transport by HvAACT1 in barley and contribute to a broader understanding of citrate transporter structures in other plant species.}, archive = {J_PNAS}, author = {Nguyen Thao, Tran and Mitani-Ueno, Namiki and Urano, Ryo and Saitoh, Yasunori and Wang, Peitong and Yamaji, Naoki and Shen, Jian-Ren and Shinoda, Wataru and Ma, Jian Feng and Suga, Michihiro}, doi = {10.1073/pnas.2501933122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2501933122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural insights into a citrate transporter that mediates aluminum tolerance in barley}, volume = {122}, year = {2025}, }
• (2025). Tracing SARS-CoV-2 clusters across local scales using genomic data. PNAS, 122(32), e2501435122. (www)

  @article{ , abstract = {A quantitative understanding of local transmission dynamics is essential for designing effective prevention strategies. In this study, we developed a computational workflow to identify viral introductions and trace locally circulating clusters. We analyzed over 26,000 SARS-CoV-2 genomes and their associated metadata, collected between January and October 2021, to explore introduction and local dispersal patterns in Greater Houston, a major metropolitan area known for its demographic diversity. Our analysis identified more than 1,000 independent introduction events, resulting in clusters of varying sizes. The majority of introductions originated from domestic sources, while international introductions occurred earlier and were associated with larger cluster sizes. An analysis of locally circulating clusters revealed age-structured transmission dynamics. Geographic reconstruction of cluster spread identified Harris County as the primary viral source for surrounding areas. The outbreak in the source population was characterized by 1) a smaller proportion of new cases associated with external viral imports and 2) longer persistence times of circulating lineages. Overall, our high-resolution spatiotemporal reconstruction of the epidemic provides essential insights into the local-scale transmission landscape, supporting outbreak-specific, regional response strategies and public health planning.}, archive = {J_PNAS}, author = {Lyu, Leke and Gill, Mandev and Stott, Guppy and Subedi, Sachin and Dailey, Cody and Veytsel, Gabriella and Alabady, Magdy and Fujimoto, Kayo and Penn, Ryker and Brown, Pamela and Sealy, Roger and Bahl, Justin}, doi = {10.1073/pnas.2501435122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2501435122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tracing SARS-CoV-2 clusters across local scales using genomic data}, volume = {122}, year = {2025}, }
• (2025). Engineering a highly selective, hemoprotein-based scavenger as a carbon monoxide poisoning antidote with no hypertensive effect. PNAS, 122(32), e2501389122. (www)

  @article{ , abstract = {Carbon monoxide (CO) poisoning causes 50,000 to 100,000 emergency department visits and ~1,500 deaths in the United States annually. Current treatments are limited to supplemental and/or hyperbaric oxygen to accelerate CO elimination. Even with oxygen therapy, nearly half of CO poisoning survivors suffer long-term cardiac and neurocognitive deficits related to slow CO clearance, highlighting a need for point of care antidotal therapies. Given the natural interaction between CO and ferrous heme, we hypothesized that the hemoprotein RcoM, a transcriptional regulator of microbial CO metabolism, would make an ideal platform for CO-selective scavenging from endogenous hemoproteins. We engineered an RcoM truncate (RcoM-HBD-CCC) that exhibits high CO affinity ( K a,CO = 2.8 × 10 10 M −1 ), remarkable selectivity for CO over oxygen ( K a,O2 = 1.4 × 10 5 M −1 ; K a,CO / K a,O2 = 1.9 × 10 5 ), thermal stability (T m = 72 °C), and slow autoxidation rate ( k ox = 1.1 h −1 ). In a murine model of acute CO poisoning, infused RcoM-HBD-CCC accelerated CO clearance from hemoglobin in red blood cells (RBCs) and was rapidly excreted in urine. Moreover, infused RcoM-HBD-CCC elicited minimal hypertension in mice compared to infused globins (hemoglobin, myoglobin, and neuroglobin), attributed to a comparatively limited reactivity toward nitric oxide (NO) via dioxygenation [ k NOD (RcoM) = 6 to 8 × 10 6 M −1 s −1 vs k NOD (Hb) = 6 to 8 × 10 7 M −1 s −1 ]. These data suggest that RcoM-HBD-CCC is a safe, selective, and efficacious CO scavenger. By limiting hypertension through minimal NO scavenging, RcoM-HBD-CCC improves end-organ adverse effects compared with other hemoprotein-based therapeutics.}, archive = {J_PNAS}, author = {Dent, Matthew R. and DeMartino, Anthony W. and Xu, Qinzi and Chen, Xiukai and Gandhi, Alay and Hwang, Hyon S. and Bocian, Kaitlin A. and Correnti, Jacob E. and Abdelghany, Youmna and Alipour, Elmira and Ucer, K. Burak and Baker, Stephen R. and Srimath Kandada, Ajay Ram and Bulbul, Angka and Kim-Shapiro, Daniel B. and Rose, Jason J. and Tejero, Jesus and Gladwin, Mark T.}, doi = {10.1073/pnas.2501389122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2501389122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Engineering a highly selective, hemoprotein-based scavenger as a carbon monoxide poisoning antidote with no hypertensive effect}, volume = {122}, year = {2025}, }
• (2025). Engineered Un1Cas12f1 with boosted gene-editing activity and expanded genomic coverage. PNAS, 122(32), e2501292122. (www)

  @article{ , abstract = {Compact programmable nucleases provide versatile genome editing tools with therapeutic potential, particularly when delivered via adeno-associated virus (AAV) vectors. However, their limited editing efficacy and stringent protospaceradjacent motif (PAM) requirements impose significant limitations in practical application. Here, we engineered MiniCasUltra, an optimized Un1Cas12f1 variant, through rational mutagenesis. MiniCasUltra exhibits sixfold higher editing activity than Un1Cas12f1, minimal off-target effects (on/off-target ratio > 10), and an expanded PAM preference (5′-WBTR). Using a single AAV vector encoding MiniCasUltra and two single-guide RNAs, we achieved simultaneous editing of two disease-causing genes ( Pten and Fah ) in mouse liver, with indel rates of 15.82% and 29.39%, respectively- significantly surpassing CasMINI V3.1 (3.45% and 10.98%). Furthermore, AAV delivery of MiniCasUltra targeting a noncanonical 5′-TCTG PAM site in human vascularendothelial growth factor A reduced choroidal neovascularization (CNV) lesions in a laser-induced CNV mouse model of neovascular age-related macular degeneration, a leading global cause of blindness. The broad and effective targeting capabilities of MiniCasUltra, coupled with its compact size, highlight its potential for in vivo genome editing and therapeutic interventions.}, archive = {J_PNAS}, author = {Chen, Li and Zhou, Xujiao and Huang, Chengsi and Zhang, Yirou and Xin, Changchang and Hong, Jiaxu and Wang, Yu}, doi = {10.1073/pnas.2501292122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2501292122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Engineered Un1Cas12f1 with boosted gene-editing activity and expanded genomic coverage}, volume = {122}, year = {2025}, }
• (2025). What people learn from punishment: A cognitive model. PNAS, 122(32), e2500730122. (www)

  @article{ , abstract = {Authorities, from parents of toddlers to leaders of formal institutions, use punishment to communicate disapproval and enforce social norms. Ideally, from whether and how severely a transgression is punished, targets and observers infer shared social norms. Yet in light of every punitive choice, observers also evaluate the motives and legitimacy of the authority. Here, we show that the effects of punishment can only be understood by considering these inferences simultaneously. We measured human observers’ joint inferences empirically in three preregistered experiments ( N = 1 , 254 ) and developed a rational Bayesian model using an inverse planning framework that captures and explains these inferences and their interactions quantitatively and parsimoniously. When people have different priors about norms or authorities, the model predicted and we experimentally confirmed that observing punishment by the authority can sustain polarization. This work reveals the rational logic behind how people learn from punishment and a key constraint on the function of punishment in establishing shared social norms.}, archive = {J_PNAS}, author = {Radkani, Setayesh and Tenenbaum, Joshua B. and Saxe, Rebecca}, doi = {10.1073/pnas.2500730122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2500730122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {What people learn from punishment: A cognitive model}, volume = {122}, year = {2025}, }
• (2025). Hide-and-seek genome editing reveals that gephyrin is required for axo-axonic synapse assembly. PNAS, 122(32), e2500726122. (www)

  @article{ , abstract = {The visualization and manipulation of proteins in neurons is widely used to deduce their functions. While every experimental approach has limitations, the concurrent knock-in and knockout of two different proteins can be especially challenging. To this end, we developed Hide-and-Seek genome editing, which allows the simultaneous visualization and knockout of proteins in neurons using Adeno-associated viral vectors and the CRISPR/Cas9 system. We demonstrate the efficacy and flexibility of this method for rapid, efficient, and simultaneous knock-in and knockout of proteins in vitro and in vivo, at the synapse, axon initial segment (AIS), nucleus, and mitochondria. Using Hide-and-Seek, we show that the scaffolding protein Gephyrin is required for the proper assembly of axo-axonic synapses at the AIS.}, archive = {J_PNAS}, author = {Ogawa, Yuki and Nguyen, Duc V. M. and Ogawa, Ayano and Rasband, Matthew N.}, doi = {10.1073/pnas.2500726122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2500726122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hide-and-seek genome editing reveals that gephyrin is required for axo-axonic synapse assembly}, volume = {122}, year = {2025}, }
• (2025). Late adolescents entering college intending a career as police officers hold more right-leaning views than their peers. PNAS, 122(32), e2500220122. (www)

  @article{ , abstract = {One longstanding explanation for bias and excessive force in policing is selection—the assertion that those who select to work in law enforcement are more likely to hold far-right, intolerant, and antiegalitarian, views than the public. While intuitive and widely believed, the evidence in support of the selection hypothesis is surprisingly thin. We offer a vital contribution to the literature by exploring selection at one of its earliest phases: late adolescents entering college and the career-formulation stage of life. Utilizing surveys of over 13 million late adolescents collected across 44 y in the United States, we find that those intending a career as a law enforcement officer hold more right-leaning views on race relations, immigration and intercultural relations, women and gender roles, homosexuality and gay rights, drug-use, freedom of speech, and criminal justice, than their peers intending other careers or their modal peer who is undecided with respect to career intentions and serves as a “blank slate” comparison group. Critically, these findings largely hold among Whites and non-Whites but are somewhat attenuated among women. These sources of heterogeneity are noteworthy given evidence suggesting that hiring more non-White officers may ameliorate bias and excessive force in policing and accompanying pushes to diversify police forces. Our findings add caution to such pushes by suggesting that the non-Whites who select into law enforcement may hold views that reproduce, vs. attenuate, existing police bias. In contrast, our findings direct reform efforts toward expanding the ranks of female officers, bias testing, and training during police recruitment.}, archive = {J_PNAS}, author = {Reny, Tyler T. and Roman, Marcel F. and Newman, Benjamin J. and Sears, David O.}, doi = {10.1073/pnas.2500220122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2500220122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Late adolescents entering college intending a career as police officers hold more right-leaning views than their peers}, volume = {122}, year = {2025}, }
• (2025). Discovery and development of an oral analgesic targeting the α2B adrenoceptor. PNAS, 122(32), e2500006122. (www)

  @article{ , abstract = {Noradrenaline is a major monoaminergic neurotransmitter involved in pain modulation through an α2A-adrenergic receptor. Hence, α2-adrenergic agonists such as clonidine and dexmedetomidine exhibit analgesic and opioid-sparing effects. However, their use is restricted to hospital settings due to potential risks of acute hypertension/hypotension and bradycardia. Here, we report that ( Z )-1-(3-ethyl-5-fluorobenzo[ d ] thiazol-2(3 H )-ylidene)propan-2-one [adrenergic inducer of analgesia (ADRIANA)], a newly identified α2B subtype-specific antagonist, specifically promotes noradrenaline release in the murine spinal dorsal horn and produces analgesic effects by stimulating the α2A-dependent pain inhibitory pathway. Orally administered ADRIANA has potent analgesic effects in several nociceptive pain models of mice and nonhuman primates without cardiovascular effects. Mice with genetic loss of the α2B adrenoceptor showed normal responses to mechanical pain, but the analgesic effect of ADRIANA was not significantly detected. These findings reveal that the α2B adrenoceptor is a promising target for nonopioid analgesics through the activation of the α2A-dependent descending pathway.}, archive = {J_PNAS}, author = {Toyomoto, Masayasu and Kurihara, Takashi and Nakagawa, Takayuki and Inoue, Asuka and Kimura, Ryo and Kii, Isao and Sawada, Teruo and Ogihara, Takashi and Nagayasu, Kazuki and Kishi, Takayuki and Onogi, Hiroshi and Im, Dohyun and Asada, Hidetsugu and Iwata, So and Taguchi, Jumpei and Sumida, Yuto and Yoshida, Suguru and Aoki, Junken and Hosoya, Takamitsu and Hagiwara, Masatoshi}, doi = {10.1073/pnas.2500006122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2500006122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Discovery and development of an oral analgesic targeting the α2B adrenoceptor}, volume = {122}, year = {2025}, }
• (2025). Dipole-induced transition in 3 dimensions. PNAS, 122(32), e2427273122. (www)

  @article{ , abstract = {The Kosterlitz–Thouless and the Hexatic phase transitions are celebrated examples of dipole (vortex, dislocation) induced transitions in condensed matter physics. For very clear reasons, these important “topological” transitions are restricted to 2-dimensions. Here, we present a genuine dipole-induced transition in the 3-dimensional response of (athermal) amorphous solids to applied strain. Similarly to the existence of a hexatic phase between normal solid and fluid, we identify an intermediate phase between a phase of normal elastic response at high pressure, and fluid matter at zero pressure. The mechanical response in the intermediate phase is accompanied by plasticity that is generically associated with “nonaffine” quadrupolar events seen in the resulting displacement field. Gradients of the quadrupolar fields act as dipole charges that screen elasticity, breaking both translational and chiral symmetries. We highlight angular correlations that exhibit diverging correlation lengths at this transition and determine the critical scaling exponents.}, archive = {J_PNAS}, author = {Procaccia, Itamar and Samanta, Tuhin}, doi = {10.1073/pnas.2427273122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2427273122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dipole-induced transition in 3 dimensions}, volume = {122}, year = {2025}, }
• (2025). Logarithmic kinetics and bundling in random packings of elongated 3D physical links. PNAS, 122(32), e2427145122. (www)

  @article{ , abstract = {We explore the impact of excluded volume interactions on the local assembly of linear physical networks, where nodes are spheres and links are rigid cylinders with varying length. To focus on the effect of elongated links, we introduce a minimal 3D model that helps us zoom into confined regions of these networks whose distant parts are sequentially connected by the random deposition of physical links with a very large aspect ratio. We show that the nonequilibrium kinetics at which these elongated links, or spaghetti, adhere to the available volume without mutual crossings is logarithmic in time, as opposed to the algebraic growth in lower dimensions for needle-like packings. We attribute this qualitatively different behavior to a delay in the activation of depletion forces caused by the 3D nature of the problem. Equally important, we find that this slow kinetics is metastable, allowing us to analytically predict the kinetic scaling characterizing an algebraic growth due to the nucleation of local bundles. Our findings offer a theoretical benchmark to study the local assembly of physical networks, with implications for the modeling of nest-like packings far from equilibrium.}, archive = {J_PNAS}, author = {Bonamassa, Ivan and Ráth, Balázs and Pósfai, Márton and Abért, Miklós and Keliger, Dániel and Szegedy, Balázs and Kertész, János and Lovász, László and Barabási, Albert-László}, doi = {10.1073/pnas.2427145122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2427145122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Logarithmic kinetics and bundling in random packings of elongated 3D physical links}, volume = {122}, year = {2025}, }
• (2025). Phase transfer–driven formation of solid metal–organic materials with tunable optical and adsorption properties. PNAS, 122(32), e2427096122. (www)

  @article{ , abstract = {Precise control of the physicochemical properties of metal–organic materials has been a challenge in the fields of materials science and engineering and can be achieved through the construction of morphology/size-dependent supramolecular functional model systems. The development of diverse hierarchical micro/nanostructured systems based on similar molecules and the elucidation of their morphology-dependent characteristics provide the possibility for efficiently constructing this system and studying its structure–function relationships. Herein, three pyrene-based metal–organic cycles (MOCs) were synthesized and used as building blocks to create supramolecular model systems and investigate their morphology/size-dependent properties. Changes in the substituents or coordination sites at the molecular level can greatly influence the assembly behavior of metallacycles, further generate entities, including MOC-based secondary structures such as polyhedrons and nanorods, associated with MOC-based tertiary structures of nanorod/nanoribbon clusters. In turn, the optical properties and specific surface area of materials can be finely regulated.}, archive = {J_PNAS}, author = {Du, Jia-Xing and Liu, Lingran and Yu, Mei-Lin and Zhang, Fengmin and Stang, Peter J. and Sun, Yan}, doi = {10.1073/pnas.2427096122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2427096122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phase transfer–driven formation of solid metal–organic materials with tunable optical and adsorption properties}, volume = {122}, year = {2025}, }
• (2025). Immune-responsive gene 1: The mitochondrial key to th17 cell pathogenicity in CNS autoimmunity. PNAS, 122(32), e2427052122. (www)

  @article{ , abstract = {Pathogenic Th17 cells play crucial roles in CNS autoimmune diseases such as multiple sclerosis (MS), but their regulation by endogenous mechanisms remains unknown. Through RNA-seq analysis of primary brain glial cells, we identified immune-responsive gene 1 ( Irg1 ) as one of the highly upregulated genes under inflammatory conditions. Validation in the spinal cords of animals with experimental autoimmune encephalomyelitis (EAE), a preclinical MS model, confirmed elevated Irg1 levels in myeloid, CD4, and B cells in the EAE group, raising concerns as to whether Irg1 is detrimental or protective. Irg1 knockout (KO) mice exhibited severe EAE disease, increased mononuclear cell infiltration, and increased levels of triple-positive CD4+ T cells expressing IL17a, GM-CSF, and IFNγ. Adoptive transfer in Rag-1 KO and single-cell RNA sequencing highlighted the crucial role of Irg1 in shaping pathogenic Th17 cells. A lack of Irg1 in macrophages elevates Class II expression, promoting the polarization of myelin-primed CD4+ T cells into pathogenic Th17 cells via the NLRP3/IL-1β axis. Moreover, bone marrow chimeras revealed that immune cells lacking Irg1 maintained pathogenic and inflammatory phenotypes, suggesting its protective role in autoimmune diseases, including MS.}, archive = {J_PNAS}, author = {Nematullah, Mohammad and Fatma, Mena and Zhou, Guoli and Prajapati, Bharat and Rashid, Faraz and Ayasolla, Kameshwar and Ahmed, Mohammad Ejaz and She, Ruicong and Mir, Sajad and Zahoor, Insha and Hoda, Nasrul and Rattan, Ramandeep and Giri, Shailendra}, doi = {10.1073/pnas.2427052122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2427052122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Immune-responsive gene 1: The mitochondrial key to th17 cell pathogenicity in CNS autoimmunity}, volume = {122}, year = {2025}, }
• (2025). Protective antigen–mediated delivery of an anti-CRISPR protein for precision genome editing. PNAS, 122(32), e2426960122. (www)

  @article{ , abstract = {Precise control over the dosage of Cas9-based technologies is essential because off-target effects, mosaicism, chromosomal aberrations, immunogenicity, and genotoxicity can arise with prolonged Cas9 activity. Type II anti-CRISPR proteins (Acrs) inhibit and control Cas9 but are generally impermeable to the cell membrane due to their size and anionic charge. Moreover, existing Acr delivery methods are long-lived and operate within hours (e.g., viral and nonviral vectors) or require external devices (e.g., electroporation), limiting therapeutic applications. To address these problems, we developed a protein-based anti-CRISPR delivery platform, LF N -Acr/PA, which delivers Acrs into cells within minutes. LF N -Acr/PA is a nontoxic, two-component protein system derived from anthrax toxin, where protective antigen (PA) proteins bind receptors widespread in human cells, forming a pH-triggered endosomal pore that an engineered Acr (LF N -Acr) binds and uses to enter the cell. In the presence of PA, LF N -Acr enters human cells (e.g., immortalized cell lines, embryonic stem cells, and 3D cell cultures) at concentrations as low as 2.5 pM to inhibit up to 95% of Cas9-mediated knockout, knock-in, transcriptional activation, and base editing. Timing LF N -Acr delivery reduces off-target base editing and increases Cas9 specificity by 41%. LF N -Acr/PA is the most potent known cell-permeable CRISPR-Cas inhibition system, significantly improving the utility of CRISPR for genome editing.}, archive = {J_PNAS}, author = {Vera, Axel O. and Truex, Nicholas L. and Sreekanth, Vedagopuram and Pentelute, Bradley L. and Choudhary, Amit and Raines, Ronald T.}, doi = {10.1073/pnas.2426960122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2426960122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Protective antigen–mediated delivery of an anti-CRISPR protein for precision genome editing}, volume = {122}, year = {2025}, }
• (2025). Rapid, interpretable data-driven models of neural dynamics using recurrent mechanistic models. PNAS, 122(32), e2426916122. (www)

  @article{ , abstract = {Obtaining predictive models of a neural system is notoriously challenging. Detailed models suffer from excess model complexity and are difficult to fit efficiently. Simplified models must negotiate a tradeoff between tractability, predictive power, and ease of interpretation. We present a modeling paradigm for estimating predictive, mechanistic models of neurons and small circuits that navigates these issues using methods from systems theory. The key insight is that membrane currents can be modeled using two scalable system components optimized for learning: linear state space models, and nonlinear artificial neural networks. Combining these components, we construct two types of membrane currents: lumped currents, which are flexible, and data-driven conductance-based currents, which are interpretable. The resulting class of models—which we call recurrent mechanistic models (RMMs)—can be trained in a matter of seconds to minutes on intracellular recordings during an electrophysiology experiment, representing a step change in performance over previous approaches. As a proof-of-principle, we use RMMs to learn the dynamics of two groups of neurons, and their synaptic connections, in the Stomatogastric Ganglion, a well-known central pattern generator. Due to their reliability, efficiency, and interpretability, RMMs enable qualitatively new kinds of experiments using predictive models in closed-loop neurophysiology and online estimation of neural properties in living preparations.}, archive = {J_PNAS}, author = {Burghi, Thiago B. and Ivanova, Maria and Morozova, Ekaterina and Wang, Huaxinyu and Marder, Eve and O’Leary, Timothy}, doi = {10.1073/pnas.2426916122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2426916122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rapid, interpretable data-driven models of neural dynamics using recurrent mechanistic models}, volume = {122}, year = {2025}, }
• (2025). Quantitative and sensitive sequencing of somatic mutations induced by a maize transposon. PNAS, 122(32), e2426650122. (www)

  @article{ , abstract = {Cells accumulate mutations throughout development, contributing to cancer, aging, and evolution. Quantitative data on the abundance of de novo mutations within plants or animals are limited, as new mutations are often rare within a tissue and fall below the limits of current sequencing depths and error rates. Here, we show that mutations induced by the maize Mutator (Mu) transposon can be reliably quantified down to a detection limit of 1 part in 16,000. We measured the abundance of millions of de novo Mu insertions across four tissue types. Within a tissue, the distribution of de novo Mu allele frequencies was highly reproducible between plants, showing that, despite the stochastic nature of mutation, repeated statistical patterns of mutation abundance emerge. In contrast, there were significant differences in the allele frequency distribution between tissues. At the extremes, root was dominated by a small number of highly abundant de novo insertions, while endosperm was characterized by thousands of insertions at low allele frequencies. Finally, we used the measured pollen allele frequencies to reinterpret a classic genetic experiment, showing that evidence for late Mu activity in pollen is better explained by cell division statistics. These results provide insight into the complexity of mutation accumulation in multicellular organisms and a system to interrogate the factors that shape mutation abundance.}, archive = {J_PNAS}, author = {Scherer, Justin and Hinczewski, Michael and Nelms, Brad}, doi = {10.1073/pnas.2426650122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2426650122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantitative and sensitive sequencing of somatic mutations induced by a maize transposon}, volume = {122}, year = {2025}, }
• (2025). The e3 ligase HECTD4 regulates COX-2-dependent tumor progression and metastasis. PNAS, 122(32), e2425621122. (www)

  @article{ , abstract = {E3 ubiquitin ligases mediating turnover of proteins engaged in cancer progression point to key regulatory nodes. To uncover modifiers of metastatic competency, we conducted an in vivo genome-wide CRISPR-inactivation screen using cultured breast circulating tumor cells, following intravascular seeding and lung colonization. We identified HECTD4, a previously uncharacterized gene encoding a conserved potential homologous to E6AP C-terminus domain–containing ubiquitin transferase, as a potent tumor and metastasis suppressor. We show that purified HECTD4 mediates ubiquitin conjugation in vitro, and proteomic studies combined with ubiquitin remnant profiling identify a major degradation target as the prostaglandin synthetic enzyme cyclooxygenase-2 ( COX-2 ; PTGS2 ). In addition to COX-2 itself, HECTD4 targets its regulatory kinase MKK7. In breast cancer models, HECTD4 expression is induced as cells lose adherence to the matrix, and its depletion massively increases COX-2 expression, enhancing anchorage-independent proliferation and tumorigenesis. Genetic or pharmacologic suppression of COX-2 reverses the protumorigenic and prometastatic phenotype of HECTD4-depleted cells. Thus, HECTD4 encodes an E3 ubiquitin ligase that downregulates COX-2 suppressing anchorage independence in epithelial cancer cells.}, archive = {J_PNAS}, author = {Vuille, Joanna A. and Tanriover, Cem and Antmen, Ezgi and Micalizzi, Douglas S. and Ebright, Richard Y. and Animesh, Sambhavi and Morris, Robert and Hajizadeh, Soroush and Nicholson, Zachary J. and Russell, Hunter C. and Zaniewski, Eric F. and Wittner, Ben S. and Wesley, Ben K. and Kwak, Ji Eun and Grünewald, Julian and Szalay, Regan N. and Fox, Douglas B. and Yang, Min and Joung, J. Keith and Gulhan, Doga C. and Elia, Andrew E. H. and Haas, Wilhelm and Oh, Eugene and Maheswaran, Shyamala and Haber, Daniel A.}, doi = {10.1073/pnas.2425621122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2425621122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The e3 ligase HECTD4 regulates COX-2-dependent tumor progression and metastasis}, volume = {122}, year = {2025}, }
• (2025). Endocannabinoids inhibit contextual fear memory generalization via hippocampal GABAergic synaptic transmission. PNAS, 122(32), e2423974122. (www)

  @article{ , abstract = {Memory generalization allows an organism to adapt to new conditions, but overgeneralization of fear or traumatic experiences can be detrimental to survival and contributes to the development of various mental disorders. However, the cellular and molecular mechanisms underlying fear memory generalization, especially in the hippocampus, remain largely unknown. In this study, utilizing a well-established mouse model of fear memory generalization, we investigated the role of endocannabinoids (eCBs)-mediated GABAergic synaptic inputs to hippocampal pyramidal neurons in regulating contextual fear memory generalization. Our results revealed that pharmacological or genetic blockade of CB1R in hippocampal CA1 resulted in overgeneralization of contextual fear memory but not fear memory expression. Subsequent investigations in conditional knockout mice revealed the involvement of CB1R in GABAergic neurons, but not those in glutamatergic neurons or astrocytes, in this overgeneralization. In addition, activation of GABA A receptors on pyramidal neurons was required for inducing overgeneralization via AM281, a CB1R antagonist. Neural mechanistic studies showed that eCBs/CB1R signaling regulates both the activity and plasticity of inhibitory synapses during generalization, highlighting the prominence of the disinhibition of CB1R in interneurons during this process. Subsequently, we delved into the downstream effects and found that eCB-dependent long-term potentiation (LTP) in CA1 pyramidal neurons was regulated by the aforementioned mechanisms. Our findings illustrate that the eCBs/CB1R signaling pathway modulates the balance between fear memory discrimination and generalization by controlling inhibitory inputs to hippocampal pyramidal neurons, accompanied by alterations in excitatory plasticity within this region.}, archive = {J_PNAS}, author = {Ge, Qian and Zhang, Jinming and Huo, Qing and Yu, Jing and Zheng, Qiaohua and Qian, Zhaoqiang and Wei, Chunling and Jiang, Tongtong and Liu, Yihui and Liu, Zhiqiang and Ren, Wei and Sun, Zongpeng and Jia, Zhengping and Han, Jing}, doi = {10.1073/pnas.2423974122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2423974122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Endocannabinoids inhibit contextual fear memory generalization via hippocampal GABAergic synaptic transmission}, volume = {122}, year = {2025}, }
• (2025). The radiation and geographic expansion of primates through diverse climates. PNAS, 122(32), e2423833122. (www)

  @article{ , abstract = {One of the most influential hypotheses about primate evolution postulates that their origin, radiation, and major dispersals were associated with exceptionally warm conditions in tropical forests at northern latitudes (henceforth the warm tropical forest hypothesis ). However, this notion has proven difficult to test given the overall uncertainty about both geographic locations and paleoclimates of ancestral species. By the resolution of both challenges, we reveal that early primates dispersed and radiated in higher latitudes, through diverse climates, including cold, arid, and temperate conditions. Contrary to expectations of the warm tropical forest hypothesis, warmer global temperatures had no effect on dispersal distances or the speciation rate. Rather, the amount of change in local temperature and precipitation substantially predicted geographic and species diversity. Our results suggest that nontropical, changeable environments exerted strong selective pressures on primates with higher dispersal ability – promoting the primate radiation and their subsequent colonization of tropical climates millions of years after their origin.}, archive = {J_PNAS}, author = {Avaria-Llautureo, Jorge and Püschel, Thomas A. and Meade, Andrew and Baker, Joanna and Nicholson, Samuel L. and Venditti, Chris}, doi = {10.1073/pnas.2423833122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2423833122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The radiation and geographic expansion of primates through diverse climates}, volume = {122}, year = {2025}, }
• (2025). Gaming the cancer–immunity cycle by synchronizing the dose schedules. PNAS, 122(32), e2423775122. (www)

  @article{ , abstract = {We introduce a mathematical model of the cancer–immunity cycle and use it to test several hypotheses regarding the combination, timing, and optimization associated with chemotherapy and immunotherapy dosing schedules in the context of competition and time-dependent selection pressure. A key idea is the value of synchronizing the dosing schedules with the fundamental period of the cancer–immunity cycle. The competitors in the population dynamics evolutionary game are the cancer cells, healthy (normal) cells, and T cells, which conceptually form a nontransitive rock-paper-scissor chain. The chemotherapy and immunotherapy dosing schedules each act as control functions whose timing and magnitudes we synchronize with the fundamental period of the underlying nonlinear dynamical system. With the model, we show among other more detailed results, that chemotherapy and immunotherapy pulse-dosing schedules do not commute; the best duration of the chemotherapy is one-quarter of the cancer–immunity cycle, whereas for immunotherapy it is one-half cycle; immunotherapy dosing should precede chemotherapy dosing and last twice as long. A general conclusion is that optimized timing of the dosing schedules can make up for lower total dose, opening up new possibilities for designing less toxic and more efficacious dosing regimens with drugs currently in use. Obtaining and calibrating more accurate measurements of the cycle-period across patient populations would be an important step in making some of these ideas clinically actionable.}, archive = {J_PNAS}, author = {Mahmoodifar, Saeedeh and Stuckey, Kristina and Newton, Paul K.}, doi = {10.1073/pnas.2423775122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2423775122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Gaming the cancer–immunity cycle by synchronizing the dose schedules}, volume = {122}, year = {2025}, }
• (2025). Autophagy activator AA-20 improves proteostasis and extends caenorhabditis elegans lifespan. PNAS, 122(32), e2423455122. (www)

  @article{ , abstract = {The degradation of cellular components through autophagy is essential for longevity and healthy aging. However, autophagy function decreases with aging, contributing to age-related diseases. In this study, we characterized a small-molecule activator of autophagy called AA-20 that enhances autophagy and lipid droplet clearance in human cells and in the nematode Caenorhabditis elegans . AA-20 reduces polyglutamine aggregation in an autophagy-dependent manner in both human cells and C. elegans , where it also promotes fitness. Consistently, we found that AA-20 extends lifespan in WT C. elegans, but not in autophagy-deficient mutants. Interestingly, our findings suggest that AA-20 acts, at least in part, through a mechanism involving the transcription factor EB, but without inhibiting the protein kinase mammalian target of rapamycin complex 1. Collectively, our results identify an autophagy activator AA-20 , which may have potential therapeutic implications for aging-related proteinopathies and lipid storage disorders.}, archive = {J_PNAS}, author = {Tan, Ee Phie and Lyang, Nora and Doroodian, Saam and Sanz-Martinez, Pablo and Xu, Jin and Zaretski, Sviatlana and Nieto-Torres, José L. and Ebata, Hiroshi and Lim, Shaun H. Y. and Hou, William C. and Clay, Khalyd J. and Yoon, Leonard and Massey, Lynée A. and Rhoades, Derek and Garza, Danny and Johnson, Kristen A. and To, Alan and Ambaye, Lydia and Bentley, Emily P. and Petrascheck, Michael and Stolz, Alexandra and Kelly, Jeffery W. and Hansen, Malene}, doi = {10.1073/pnas.2423455122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2423455122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Autophagy activator AA-20 improves proteostasis and extends caenorhabditis elegans lifespan}, volume = {122}, year = {2025}, }
• (2025). Abundant fluids in southern kumano basin linked to fluid source and slow earthquakes at the plate boundary in the nankai trough. PNAS, 122(32), e2423440122. (www)

  @article{ , abstract = {The Nankai Trough is a major subduction zone in southern Japan capable of generating the next M7 or larger earthquake off Kii Peninsula. In addition to earthquakes characterized by sharp P and S arrivals, there are numerous slow earthquakes without clear P phases at the subducting plate boundary corresponding to transient slips that are related to fluids at the plate boundary and high pore pressure. In this study, we perform ambient noise differential adjoint tomography to derive the S-wave velocity model beneath a linear Ocean Bottom Seismometer (OBS) array, which was previously difficult based on airgun active source study. We find that S-wave velocities in the southern (seaward) Kumano Basin are significantly lower than in the northern (landward) Kumano Basin, suggesting weak upper plate and abundant fluids in the southern Kumano Basin. The fluid-rich southern Kumano Basin lies above a weak interplate coupling zone with shallow slow earthquakes and pressurized fluids due to plate interface dehydration. Conversely, the northern Kumano Basin overlies a strong interplate coupling zone with few slow earthquakes, suggesting fluid migration from the weak-coupling interface to the forearc basin above.}, archive = {J_PNAS}, author = {Liu, Xin and Nakanishi, Ayako and Fujie, Gou and Tonegawa, Takashi and Nakamura, Yasuyuki and Obana, Koichiro and Kodaira, Shuichi}, doi = {10.1073/pnas.2423440122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2423440122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Abundant fluids in southern kumano basin linked to fluid source and slow earthquakes at the plate boundary in the nankai trough}, volume = {122}, year = {2025}, }
• (2025). Anisotropic stretch biases the self-organization of actin fibers in multicellular hydra aggregates. PNAS, 122(32), e2423437122. (www)

  @article{ , abstract = {During development, groups of cells generate shape by coordinating their mechanical properties through an interplay of self-organization and prepatterning. Hydra displays a striking planar pattern of actin fibers at the organism scale, and mechanics influence the morphogenesis of biological structures during its prepatterned regeneration. However, how mechanics participate in the formation of an ordered pattern from a totally disordered state remains unknown. To study this, we used cellular aggregates formed from dissociated Hydra cells, which initially lose all actin polarity yet regenerate a long-range actin pattern. We showed quantitatively that the actin meshwork evolves from a disordered symmetric state to an ordered state in which rotational symmetry is broken, and translation symmetry is partially broken, with the nematic and smectic order parameters increasing over days. During the first hours, the actin meshwork displayed spatial heterogeneity in the nematic order parameter, and ordered domains separated by line defects progressively grew and fused. This suggests that local cell–cell interactions drive the transition from disorder to order. To understand the mechanism of ordering, we perturbed the tissue’s physical constraints. We showed that while topology and geometry do not have a direct effect, anisotropic stretch biases the emerging orientation of the actin meshwork within hours. Surprisingly, although a Wnt head organizer is expected to play a role in the actin ordering, the stretch-associated alignment happened without the prior formation of a head organizer. This demonstrates the role of tissue mechanics in the alignment of the actin fibers during the disorder-to-order transition.}, archive = {J_PNAS}, author = {Bailles, Anaïs and Serafini, Giulia and Andreas, Heino and Zechner, Christoph and Modes, Carl D. and Tomancak, Pavel}, doi = {10.1073/pnas.2423437122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2423437122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Anisotropic stretch biases the self-organization of actin fibers in multicellular hydra aggregates}, volume = {122}, year = {2025}, }
• (2025). Influenza a virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation. PNAS, 122(32), e2423066122. (www)

  @article{ , abstract = {The nonstructural protein 1 (NS1) of influenza A virus performs a broad variety of proviral activities in the infected cell, primarily mediating evasion from the host innate immune response by being the main viral interferon antagonist. However, there are several interactions whose biological relevance remains obscure, such as the ability of NS1 to bind and activate class IA phosphoinositide 3-kinases (PI3Ks). PI3Ks are highly regulated lipid kinases that act as critical nodes in multiple cell signaling networks and are also important proto-oncogenes. This activation is mediated by NS1 binding specifically to the p85β subunit. To better understand the consequences of this interaction, we developed a bimolecular fluorescence complementation (BiFC) assay to selectively track the different PI3K heterodimers and, using this system, we found that NS1 induces an isoform-specific relocation and activation of the different PI3K heterodimers. We found that clinically relevant oncogenic mutations in both catalytic and regulatory subunits of PI3K could mimic the effect caused by NS1, and partially rescue the loss of viral fitness in a recombinant virus encoding a p85β-binding deficient NS1.}, archive = {J_PNAS}, author = {Aslam, Sadaf and Sánchez-Aparicio, María T. and Siempelkamp, Braden D. and Dornan, Gillian L. and Tsolakos, Nikos and Burke, John E. and Hale, Benjamin G. and García-Sastre, Adolfo and Ayllon, Juan}, doi = {10.1073/pnas.2423066122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2423066122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Influenza a virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation}, volume = {122}, year = {2025}, }
• (2025). Role of wettability, adhesion, and instabilities in transitions during lubricated sliding friction. PNAS, 122(32), e2421122122. (www)

  @article{ , abstract = {Lubricated contacts in soft materials are important in various engineering systems and natural settings. Three major lubrication regimes are boundary (BL), mixed (ML), and elastohydrodynamic (EHL) lubrication, where the contact region is dry, partially wetted, or fully wetted, respectively. The transition between these regimes is insufficiently understood, especially for soft contacts, which impedes desired control of lubricated sliding friction. Here, we report on the role of solid wettability and adhesion on these transitions. Wettability of glycerol on polydimethylsiloxane (PDMS) surfaces and adhesion between a glass indenter and PDMS were varied by exposure of the PDMS to an ultraviolet light–ozone cleaner. By combining friction tests and visualization, we demonstrate that the transition from ML to BL regime is dominated by the wettability of the lubricant; increasing wettability of glycerol makes removal of liquid from the contact region more difficult. Transition from EHL to ML is related to a series of events with increasing normal load, which are thinning of the lubricant layer, sudden jump to contact between the glass indenter and solid substrate across a gap of tens of nanometers, and attendant mechanical instabilities such as wrinkling and stick–slip. These results provide a deeper understanding of transitions in lubricated frictional behavior of soft materials which govern the maximum and minimum friction achievable.}, archive = {J_PNAS}, author = {Dong, Hao and Siddiquie, Reshma Y. and Xiao, Xuemei and Andrews, Michael and Bergman, Brian and Hui, Chung-Yuen and Jagota, Anand}, doi = {10.1073/pnas.2421122122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2421122122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Role of wettability, adhesion, and instabilities in transitions during lubricated sliding friction}, volume = {122}, year = {2025}, }
• (2025). Phosphatidic acid production on the vacuole harboring legionella pneumophila is a signal for recognition of interferon-induced GTPases. PNAS, 122(32), e2420096122. (www)

  @article{ , abstract = {The interferon (IFN)-inducible GTPases play a crucial role in cell autonomous immunity against intracellular pathogens. Particularly, these GTPases directly recognize the host membrane-derived vacuole containing pathogens and subsequently destroy it. Although it has been revealed that these GTPases target the membrane of Legionella pneumophila ( L. pneumophila )-containing vacuole (LCV), molecular mechanism has been totally uncleared. Here, we show that mouse guanylate-binding protein 2 (mGBP2) is specifically recruited to the LCV and subsequently ruptures it. Furthermore, we also show that mGBP2 recognizes phosphatidic acid (PA) produced by the Legionella effector Lpg2552 and fails to target the vacuole harboring Lpg2552-depleted L. pneumophila . Consistently, this strain successfully grows in cells expressing mGBP2. We additionally identified lysine 585 (K585) of mGBP2 is required for the binding to PA and K585-mutated mGBP2 fails to recognize LCV. Interestingly, this lysine residue is only conserved in GBP1 among human GBPs and the conserved lysine residue is important for PA recognition and subsequent LCV distribution. Importantly, L. pneumophila lacking Lpg2552 exhibits high resistance against IFN stimulation in THP-1-derived human macrophage.}, archive = {J_PNAS}, author = {Oide, Hiromu and Kubori, Tomoko and Nagai, Hiroki and Nozawa, Takashi and Nakagawa, Ichiro and Sasai, Miwa and Yamamoto, Masahiro and Arasaki, Kohei}, doi = {10.1073/pnas.2420096122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2420096122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phosphatidic acid production on the vacuole harboring legionella pneumophila is a signal for recognition of interferon-induced GTPases}, volume = {122}, year = {2025}, }
• (2025). The entities enabling scientific fraud at scale are large, resilient, and growing rapidly. PNAS, 122(32), e2420092122. (www)

  @article{ , abstract = {Science is characterized by collaboration and cooperation, but also by uncertainty, competition, and inequality. While there has always been some concern that these pressures may compel some to defect from the scientific research ethos—i.e., fail to make genuine contributions to the production of knowledge or to the training of an expert workforce—the focus has largely been on the actions of lone individuals. Recently, however, reports of coordinated scientific fraud activities have increased. Some suggest that the ease of communication provided by the internet and open-access publishing have created the conditions for the emergence of entities—paper mills (i.e., sellers of mass-produced low quality and fabricated research), brokers (i.e., conduits between producers and publishers of fraudulent research), predatory journals, who do not conduct any quality controls on submissions—that facilitate systematic scientific fraud. Here, we demonstrate through case studies that i) individuals have cooperated to publish papers that were eventually retracted in a number of journals, ii) brokers have enabled publication in targeted journals at scale, and iii), within a field of science, not all subfields are equally targeted for scientific fraud. Our results reveal some of the strategies that enable the entities promoting scientific fraud to evade interventions. Our final analysis suggests that this ability to evade interventions is enabling the number of fraudulent publications to grow at a rate far outpacing that of legitimate science.}, archive = {J_PNAS}, author = {Richardson, Reese A. K. and Hong, Spencer S. and Byrne, Jennifer A. and Stoeger, Thomas and Amaral, Luís A. Nunes}, doi = {10.1073/pnas.2420092122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2420092122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The entities enabling scientific fraud at scale are large, resilient, and growing rapidly}, volume = {122}, year = {2025}, }
• (2025). Cognitive processes of ingroup favoritism across 20 countries: An eye-tracking investigation of culture, behavior, and cognition. PNAS, 122(32), e2417456122. (www)

  @article{ , abstract = {Whether and to what degree culture modifies cognition has been an area of research often limited by possibilities to gather relevant data across societies. In this project, we leverage webcam-based eye-tracking to study cultural variations of cognitive processes underlying in-group favoritism. Participants (n = 1850, k = 20) are assigned to an in-group based on a color perception task, complete a group reinforcement stage, and then make decisions to allocate points between themselves and random matched players in a repeated decomposed dictator game, facing either an in- or an out-group member. During this task, we recorded eye-gaze with participants’ webcams. Results show substantial variation in behavioral in-group favoritism across cultures, linking discrimination based on group membership to higher societal uncertainty. Individual preferences for prosociality conditioned differences in visual search effort, but the directionality of the effect differs between countries. Individual-level predictors explained participants remaining colorblind toward others’ group membership, where society-level predictors did not. Overall, we demonstrate the importance of taking culture into account when assessing cognitive processes underlying behavior. Implications for globally oriented policymaking to reduce discrimination are discussed.}, archive = {J_PNAS}, author = {Rahal, Rima-Maria and Schulze Spüntrup, Frederik}, doi = {10.1073/pnas.2417456122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2417456122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cognitive processes of ingroup favoritism across 20 countries: An eye-tracking investigation of culture, behavior, and cognition}, volume = {122}, year = {2025}, }
• (2025). A 75,000-y-old scandinavian arctic cave deposit reveals past faunal diversity and paleoenvironment. PNAS, 122(32), e2415008122. (www)

  @article{ , abstract = {During the last glacial period (~118 to 11.7 ka), the Arctic has been characterized by a major redistribution of flora and fauna as a consequence of extreme climatic fluctuations, with associated glacial advances and retreats, sea-level changes, and shifting sea ice extent. In the high-latitude regions of Northern Europe that are currently subject to rapid climate warming, we lack a comprehensive understanding of faunal biodiversity in the last glacial period due to the extreme rarity of preserved organic remains. Here, we present a stratified sediment deposit with a diverse faunal composition preserved in a bone-bearing layer in Arne Qvamgrotta, part of the Storsteinhola cave system (68.10° N 16.38° E) in Northern Norway. Chronological analyses of sediments and bones including radiocarbon, optically stimulated luminescence, uranium–thorium, and phylogenetic dating place the faunal assemblage in Marine Isotope Stage 5a (MIS 5a, Odderade interstadial, ~85 to 71 ka). Combining comparative osteology and bulk-bone metabarcoding, we identify 46 taxa, including mammals, birds, and fish, with several species not previously found in Fennoscandia. The fauna implies a nonanalogous cold-adapted coastal community, with close proximity to sea ice and nearby freshwater bodies. Mitogenome analyses of a subset of taxa identify extinct lineages which attest to a lack of habitat tracking and the absence of a local refugium during the subsequent fully glaciated periods. This faunal record demonstrates long-term faunal dynamics and coastal environmental conditions during MIS 5a in the European Arctic.}, archive = {J_PNAS}, author = {Walker, Samuel J. and Boilard, Aurélie and Henriksen, Mona and Lord, Edana and Robu, Marius and Buylaert, Jan-Pieter and Beijersbergen, Liselotte M. Takken and Halvorsen, Lene Synnøve and Cintrón-Santiago, Adriana M. and Onshuus, Emma Katrin and Cockerill, Christopher Alan and Ujvari, Gabor and Palcsu, László and Temovski, Marjan and Maccali, Jenny and Linge, Henriette and Olsen, Jesper and Aksnes, Sverre and Bertheussen, Anastasia and Lygre, Ola and Alsos, Inger G. and Dalén, Love and Star, Bastiaan and Hufthammer, Anne Karin and van Kolfschoten, Thijs and Lauritzen, Stein-Erik and Lødøen, Trond Klungseth and Boessenkool, Sanne}, doi = {10.1073/pnas.2415008122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2415008122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A 75,000-y-old scandinavian arctic cave deposit reveals past faunal diversity and paleoenvironment}, volume = {122}, year = {2025}, }
• (2025). Eliminating hunger in a world serious about climate mitigation. PNAS, 122(32), e2410202122. (www)

  @article{ , abstract = {What will it take to eliminate hunger in a world that is increasingly serious about climate change mitigation? For the past two decades, climate activism and mitigation efforts have largely focused on energy, industry, and transportation as the main contributors to anthropogenic warming. Although there is a long way to go to eliminate emissions from these sources, increasing international ambition means that attention is now turning to other hard-to-decarbonize sectors. Net zero food systems in particular pose unique challenges for humanity, given the moral dimensions of food security and the strong potential for vicious cycles: Globally hunger is back on the rise, the changing climate is already making food production for a growing population more difficult, and food shocks could lead to more land use change emissions that accelerate warming and feed back to negatively impact agricultural productivity and hunger. The dynamics of food production and consumption differ from other sectors and reveal several dimensions in which it will be critical to get policy right. Recent science suggests that two coordinated efforts will be needed to meet this challenge—a revamped focus on smallholder adaptation and productivity, and new “safety valve” institutions that sit at the intersection of food production and climate mitigation efforts and can operate at the relevant spatial and temporal scales to avoid negative tradeoffs in the quest to eliminate hunger and stabilize earth’s climate.}, archive = {J_PNAS}, author = {Burney, Jennifer A.}, doi = {10.1073/pnas.2410202122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2410202122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Eliminating hunger in a world serious about climate mitigation}, volume = {122}, year = {2025}, }
• (2025). Tuning fermi liquids with polaritonic cavities. PNAS, 122(32), e2407995122. (www)

  @article{ , abstract = {The question of whether or not passive subwavelength cavities can alter the properties of quantum materials is currently attracting a great deal of attention. In this article, we show that the Fermi liquid parameters of a two-dimensional metal are modified by cavity polariton modes, and that these changes can be monitored by measuring a paradigmatic magneto-transport phenomenon, Shubnikov–de Haas oscillations in a weak perpendicular magnetic field. This effect is intrinsic, and totally unrelated to disorder. As an illustrative example, we carry out explicit calculations of the quasiparticle velocity of graphene in a planar van der Waals cavity formed by natural hyperbolic crystals and metal gates. The largest effects of the cavity occur when the phonon polariton modes of the former match energetically the graphene plasmon. For typical graphene carrier densities this occurs in the Terahertz spectral range.}, archive = {J_PNAS}, author = {Riolo, Riccardo and Tomadin, Andrea and Mazza, Giacomo and Asgari, Reza and MacDonald, Allan H. and Polini, Marco}, doi = {10.1073/pnas.2407995122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2407995122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tuning fermi liquids with polaritonic cavities}, volume = {122}, year = {2025}, }
• (2025). Regulation of CD45 isoforms during human effector and memory CD8 t cell differentiation: Implications for t cell nomenclature. PNAS, 122(32), e2322982122. (www)

  @article{ , abstract = {This study examines the expression of CD45 isoforms on human yellow fever virus vaccine (YFV-17D) specific CD8 T cells longitudinally after vaccination. As expected, effector CD8 T cells at day 14 express CD45RO but within 4 to 6 wk these virus-specific CD8 T cells become CD45RA positive and remain CD45RA for >10 y. The journey for these YFV-specific CD8 T cells goes from naive (CD45RA+ CCR7+) to effector/effector memory (CD45RO+ CCR7−) to Temra (CD45RA+ CCR7−) to stem-cell memory (CD45RA+ CCR7+). These YFV-specific CD8 T cells rarely acquire the canonical Tcm phenotype (CD45RO+ CCR7+). This CD45RO to RA switch coincides with clearance of YFV, so we hypothesized that antigen may be playing a role in regulating CD45 expression. We addressed this issue by ex vivo analysis and provide evidence that this switch is indeed regulated by antigen. Sorted YFV-specific CD45RO effector CD8 T cells reexpress CD45RA when cultured ex vivo in the absence of antigen and retain CD45RO in the presence of cognate peptide. We also extended these ex vivo analysis to human cytomegalovirus (CMV)-specific CD8 T cells and show that CD45RO cells transition to CD45RA in the absence of antigen and CD45RA cells become CD45RO when stimulated with CMV peptide. We then show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific CD8 T cells can repeatedly undergo the same CD45RA to RO to RA transition in vivo after the SARS-CoV-2 mRNA vaccination. Again, the canonical Tcm phenotype spike-specific memory CD8 T cells were not readily detectable. These studies warrant a reevaluation of how human memory CD8 T cells are defined.}, archive = {J_PNAS}, author = {McGuire, Donald J. and Akondy, Rama S. and Yang, Shu and Edupuganti, Srilatha and Nagar, Shashi and Michael, Garett and De Rosa, Stephen C. and Newell, Evan W. and Farber, Donna L. and Kissick, Haydn T. and McElrath, M. Juliana and Ahmed, Rafi}, doi = {10.1073/pnas.2322982122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {32}, pages = {e2322982122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Regulation of CD45 isoforms during human effector and memory CD8 t cell differentiation: Implications for t cell nomenclature}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(31), eiti3125122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti3125122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {eiti3125122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). QnAs with blake c. meyers. PNAS, 122(31), e2518195122. (www)

  @article{ , archive = {J_PNAS}, author = {Ravindran, Sandeep}, doi = {10.1073/pnas.2518195122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2518195122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {QnAs with blake c. meyers}, volume = {122}, year = {2025}, }
• (2025). Correction for yang et al., how surface charges affect interdroplet freezing. PNAS, 122(31), e2517575122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2517575122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2517575122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for yang et al., how surface charges affect interdroplet freezing}, volume = {122}, year = {2025}, }
• (2025). Profile of sharon y. strauss. PNAS, 122(31), e2517479122. (www)

  @article{ , abstract = {Evolutionary ecologist Sharon Y. Strauss, an early proponent of unifying the fields of ecology and evolution, helped advance both disciplines. Now a distinguished emeritus professor at the University of California, Davis, Strauss remains active in research. One major focus of her work is using phylogenetic evolutionary history to understand current ecology, an approach applied to research reported in her Inaugural Article. Strauss et al. determined that certain plant species may be less adaptable than expected to climate change. The finding holds widespread implications for conservation and management.}, archive = {J_PNAS}, author = {Viegas, Jennifer}, doi = {10.1073/pnas.2517479122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2517479122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profile of sharon y. strauss}, volume = {122}, year = {2025}, }
• (2025). Correction for das et al., mycobacteriophage-mediated gene transfer enables in vitro drug screening and in vivo tracking of mycobacterium leprae. PNAS, 122(31), e2517475122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2517475122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2517475122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for das et al., mycobacteriophage-mediated gene transfer enables in vitro drug screening and in vivo tracking of mycobacterium leprae}, volume = {122}, year = {2025}, }
• (2025). Correction for ferraro et al., outdated reproductive norms, the naturalistic fallacy, and misunderstandings of welfare in recent call for zoo breed-and-feed programs. PNAS, 122(31), e2517345122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2517345122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2517345122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for ferraro et al., outdated reproductive norms, the naturalistic fallacy, and misunderstandings of welfare in recent call for zoo breed-and-feed programs}, volume = {122}, year = {2025}, }
• (2025). Correction for clegg and gross, cross-feeding creates tipping points in microbiome diversity. PNAS, 122(31), e2517344122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2517344122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2517344122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for clegg and gross, cross-feeding creates tipping points in microbiome diversity}, volume = {122}, year = {2025}, }
• (2025). Brian larkins, a plant science pioneer, leader, mentor, and friend. PNAS, 122(31), e2515273122. (www)

  @article{ , abstract = {Brian Larkins died in January 2025 at the age of 78 leaving a legacy of seminal scientific contributions that were fundamental to the establishment of the field of plant molecular biology. He elucidated the key processes in maize endosperm development and delivered technical breakthroughs in isolation of polysomes and translation of associated messenger RNAs. His models for protein body structure and his work to understand the molecular basis for restoring transparency to mutant maize seeds provided fundamental insights to improving nutritional quality of maize. Brian was an inspirational, beloved, and effective mentor to students, postdocs, and colleagues, leading by example and service. His visionary efforts during challenging financial times strengthened professional societies through exceptional fund-raising to support early career scientists thus providing a pathway for continued success.}, archive = {J_PNAS}, author = {Boston, Rebecca S. and Marks, M. David and Cohen, Jerry D.}, doi = {10.1073/pnas.2515273122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2515273122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Brian larkins, a plant science pioneer, leader, mentor, and friend}, volume = {122}, year = {2025}, }
• (2025). Tat-dependent bundling pilus of a halophilic archaeon assembles by a strand donation mechanism and facilitates biofilm formation. PNAS, 122(31), e2514980122. (www)

  @article{ , abstract = {Diverse extracellular filaments present on the surface of archaea mediate multiple key processes, such as motility, adhesion, and biofilm formation. Although several archaeal filament types have been characterized in considerable detail, many remain understudied, particularly those utilizing noncanonical secretion systems. Here, we describe the Tafi bundling pilus that facilitates biofilm formation in the haloarchaeon Natrinema sp. J7-2. Unlike previously characterized archaeal pili, Tafi is secreted via the twin-arginine translocation (Tat) pathway, which transports fully folded proteins across the cytoplasmic membrane. Structural analysis reveals that although Tafi pili assemble via a canonical strand-donation mechanism, the pilin subunit (TafE) adopts a distinct structural topology that sets it apart from the previously characterized Sec-dependent pilins that form bundling pili in archaea. Sequence analyses show that TafE homologs are also present in thermophilic archaea from different phyla, but Tat-signal sequences are exclusive to pilins of halophilic archaea. Nevertheless, we find that Tat signal peptides in haloarchaeal TafE-like pili were exchanged back to the Sec signal peptides on multiple independent occasions. These findings expand our understanding of the diversity and evolution of archaeal extracellular filaments and highlight the Tat pathway as a route for pilus assembly in halophilic archaea.}, archive = {J_PNAS}, author = {Sonani, Ravi R. and Liu, Ying and Xiang, Jialin and Cvirkaite-Krupovic, Virginija and Du, Shishen and Chen, Xiangdong and Krupovic, Mart and Egelman, Edward H.}, doi = {10.1073/pnas.2514980122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2514980122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tat-dependent bundling pilus of a halophilic archaeon assembles by a strand donation mechanism and facilitates biofilm formation}, volume = {122}, year = {2025}, }
• (2025). Essential new insights into human cerebellar purkinje cell biology from studies of essential tremor. PNAS, 122(31), e2514663122. (www)

  @article{ , archive = {J_PNAS}, author = {Millen, Kathleen J.}, doi = {10.1073/pnas.2514663122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2514663122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Essential new insights into human cerebellar purkinje cell biology from studies of essential tremor}, volume = {122}, year = {2025}, }
• (2025). Decide, act, reflect, and maybe a self in all this?. PNAS, 122(31), e2514623122. (www)

  @article{ , archive = {J_PNAS}, author = {Parvizi, Josef}, doi = {10.1073/pnas.2514623122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2514623122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Decide, act, reflect, and maybe a self in all this?}, volume = {122}, year = {2025}, }
• (2025). Surface delivery quantification reveals distinct trafficking efficiencies among clustered protocadherin isoforms. PNAS, 122(31), e2514178122. (www)

  @article{ , abstract = {Proteins that transmit molecules and signals across the plasma membrane are crucial in cell biology because they enable cells to sense and respond to their surroundings. A major challenge for studying cell surface proteins is that often they do not fold or traffic properly to the plasma membrane when produced in heterologous cells. We developed a strategy for quantifying surface localization from fluorescence microscopy images of surface-stained cells. Using clustered protocadherins, a protein family important for cell–cell recognition during neuronal development, we found that surface delivery levels vary among clustered protocadherin isoforms and between wild-type and engineered variants. Quantifying these differences provides evidence that cis dimerization is not tightly coupled to surface delivery for clustered protocadherins. This work establishes a generalizable framework for screening proteins and variants of interest for proper cell surface localization.}, archive = {J_PNAS}, author = {May, Elizabeth J. and Gaudet, Rachelle}, doi = {10.1073/pnas.2514178122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2514178122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Surface delivery quantification reveals distinct trafficking efficiencies among clustered protocadherin isoforms}, volume = {122}, year = {2025}, }
• (2025). Face (e)motion and the third visual pathway. PNAS, 122(31), e2513881122. (www)

  @article{ , archive = {J_PNAS}, author = {Puce, Aina}, doi = {10.1073/pnas.2513881122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2513881122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Face (e)motion and the third visual pathway}, volume = {122}, year = {2025}, }
• (2025). Structural basis of auxin binding and transport by arabidopsis thaliana AUX1. PNAS, 122(31), e2513424122. (www)

  @article{ , abstract = {Indole-3-acetic acid (IAA), the major form of auxin, is essential for plant growth. Auxin resistant 1 (AUX1), the first identified auxin importer, plays a crucial role in polar auxin transport (PAT). Here, we present cryo-EM structures of Arabidopsis thaliana AUX1 in the IAA-free and IAA-bound states. AUX1 exists as a monomer that contains 11 transmembrane helices (TMs). TMs 1 to 5 and 6 to 10 constitute the two halves of a classic LeuT-fold, and TM11 interacts with both halves at the interface. In the IAA-bound state, IAA is specifically recognized in a central pocket formed by TM1, TM3, TM6, and TM8. In the presence of IAA, TM1 and TM6 undergo marked conformational changes that are critical for IAA transport. His249 stands out to be a key residue for substrate uptake and release. Our structures reveal the molecular basis for AUX1-mediated IAA binding and transport.}, archive = {J_PNAS}, author = {Jing, Dan and Kong, Fang and Lu, Xiaoli and Huang, Gaoxingyu and Huang, Jing and Wang, Haolin and Shi, Yigong and Wang, Chengcheng}, doi = {10.1073/pnas.2513424122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2513424122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis of auxin binding and transport by arabidopsis thaliana AUX1}, volume = {122}, year = {2025}, }
• (2025). Larval diapause slows adult epigenetic aging in an insect model, nasonia vitripennis. PNAS, 122(31), e2513020122. (www)

  @article{ , abstract = {Epigenetic clocks based on DNA methylation provide robust biomarkers of biological age, yet the mechanistic basis and functional significance of slowing these clocks remain unclear. Progress has been limited by the lack of short-lived, genetically tractable model organisms with functional DNA methylation systems. The jewel wasp, Nasonia vitripennis , offers a unique solution. It combines a functional DNA methylation system with a short lifespan and established tools for experimental manipulation. We previously developed an epigenetic clock in Nasonia , but whether this clock reflects plastic, environmentally driven aging processes was unknown. Here, we test this directly by experimentally inducing larval diapause, a naturally occurring developmental arrest triggered by environmental cues. Diapause extended median adult lifespan by 36% and significantly slowed the rate of epigenetic aging. Using whole-genome bisulfite sequencing across multiple adult timepoints, we show that while adults that have passed through diapause as larvae initially emerge epigenetically older, their subsequent epigenetic aging proceeds 29% more slowly than adults that have not passed through diapause as larvae. Clock CpGs were enriched for gene ontology terms related to conserved nutrient-sensing and developmental pathways, including insulin/IGF signaling and mTOR, supporting the established mechanistic link between development and epigenetic aging. These findings demonstrate that epigenetic aging is plastic in Nasonia and can be experimentally modulated by early-life environment, establishing this animal model as a tractable system for dissecting the causal mechanisms of epigenetic aging.}, archive = {J_PNAS}, author = {Foley, Erin E. B. and Thomas, Christian L. and Kyriacou, Charalambos P. and Mallon, Eamonn B.}, doi = {10.1073/pnas.2513020122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2513020122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Larval diapause slows adult epigenetic aging in an insect model, nasonia vitripennis}, volume = {122}, year = {2025}, }
• (2025). Perchlorate in stratospheric aerosol particles. PNAS, 122(31), e2512783122. (www)

  @article{ , abstract = {Perchlorate is a toxic, regulated contaminant in drinking water. According to previous isotopic studies, much of the perchlorate deposited to the Earth’s surface is formed in the atmosphere, with 36 Cl suggesting a large contribution from the stratosphere. Here, we present measurements of perchlorate in stratospheric aerosol particles and confirm that the stratosphere is an important source of perchlorate, whereas we did not observe production in the troposphere. Mass mixing ratios of aerosol perchlorate in the stratosphere were 1 to 10 parts per trillion by mass (pptm), with the highest concentrations observed in summer and in the Southern Hemisphere. Almost all of the perchlorate is in biomass burning and nitrogen-rich particles, despite those types contributing only a few percent of the aerosol particles. Such particles are less acidic than the majority of sulfuric acid particles. If the formation of perchlorate is sensitive to acidity, then the injection of some materials for solar radiation modification might significantly increase the global production of perchlorate.}, archive = {J_PNAS}, author = {Murphy, Daniel M. and Abou-Ghanem, Maya and Ahern, Adam T. and Brock, Charles A. and Cziczo, Daniel J. and Hintsa, Eric J. and Jacquot, Justin L. and Lawler, Michael J. and Lyu, Ming and Moore, Fred L. and Robinson, Michael A. and Roberts, James M. and Schill, Gregory P. and Shen, Xiaoli and Thornberry, Troy D. and Veres, Patrick R.}, doi = {10.1073/pnas.2512783122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2512783122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Perchlorate in stratospheric aerosol particles}, volume = {122}, year = {2025}, }
• (2025). How RAG1/2 evolved from ancestral transposases to initiate V(D)J recombination without transposition. PNAS, 122(31), e2512362122. (www)

  @article{ , abstract = {The recombination activating genes 1 and 2 (RAG1/2) recombinase, which initiates V(D)J recombination in jawed vertebrates, evolved from RNaseH-like transposases such as Transib and ProtoRAG. However, its postcleavage transposase activity is strictly suppressed. Previous structural studies have focused only on the conserved core domains of RAG1/2, leaving the regulatory mechanisms of the noncore regions unclear. To investigate how RAG1/2 suppresses transposition and regulates DNA cleavage, we determined cryo-electron microscopy (cryo-EM) structures of nearly full-length RAG1/2 complexed with cleaved recombination signal sequences (RSS) in a signal-end complex (SEC) at resolutions up to 2.95 Å. Two key structures, SEC-0 and SEC-Plant Homeodomain (PHD), reveal distinct regulatory roles of RAG2, which is absent in Transib transposase. SEC-0 displays a closed conformation, revealing that the core RAG2 facilitates sequential DNA cleavage by stabilizing the RSS-cleaved states in a “spring-loaded” mechanism. SEC-PHD reveals how RAG2’s noncore PHD and Acidic Hinge (AH), which are absent in ProtoRAG, inhibit target DNA binding in transposition. Histone H3K4me3, which recruits RAG1/2 to RSS sites, does not influence RAG1/2 binding to V, D, or J gene segments bordered by RSS. In contrast, the suppressed transposition can be activated by H3K4me3 peptides that dislodge the inhibitory PHD. To achieve this derepression in vivo, however, would require an unlikely close placement of two nucleosomes flanking a target DNA bent by nearly 180°. Our structural and biochemical results elucidate how RAG1 has acquired RAG2 and utilizes its core and noncore domains to enhance V(D)J recombination and suppress transposition.}, archive = {J_PNAS}, author = {Chen, Xuemin and Yao, Liangrui and Li, Wenwen and Ma, Shanshan and Yuan, Xingyun and Yang, Yang and Yuan, Yuan and Liu, Yumei and Liu, Lan and Wang, Huaibin and Gellert, Martin and Yang, Wei}, doi = {10.1073/pnas.2512362122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2512362122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How RAG1/2 evolved from ancestral transposases to initiate V(D)J recombination without transposition}, volume = {122}, year = {2025}, }
• (2025). SCoTCH-seq reveals that 5-hydroxymethylcytosine encodes regulatory information across DNA strands. PNAS, 122(31), e2512204122. (www)

  @article{ , abstract = {In mammalian genomes, cytosine modifications form a layer of regulatory information alongside the genetic code. Decoding this information is crucial to our understanding of biology and disease. Established sequencing methods cannot simultaneously resolve cytosine’s three most common forms—cytosine (C), 5-methylcytosine (mC), and 5-hydroxymethylcytosine (hmC)—across both strands of the DNA double helix. Thus, how epigenetic information is distributed in DNA remains unclear. Here, we present S trand- Co upled T andem C ytosine H ydroxymethylation and methylation sequencing (SCoTCH-seq): an accurate and quantitative, base-resolution approach to sequence genomes, together with mC and hmC, in both strands of the same DNA fragment. We show that different forms of cytosine combine across the double helix at CpG sites to form discrete information states in the mouse epigenome. These CpG states have distinct genomic distributions—including at promoters, enhancers, and gene bodies—and have different relationships with transcription. We show that while all possible forms of hydroxymethylation occur, hmC is predominantly asymmetric and that different forms of asymmetric hmC are not equivalent. Our findings demonstrate that 5-hydroxymethylcytosine combines with different cytosine variants across the DNA double helix to form distinct states of regulatory information.}, archive = {J_PNAS}, author = {Hardwick, Jack S. and Dhir, Somdutta and Kirchner, Angie and Simeone, Angela and Flynn, Sean M. and Edgerton, James M. and de Cesaris Araujo Tavares, Rafael and Esain-Garcia, Isabel and Tannahill, David and Golder, Paula and Monahan, Jack M. and Gosal, Walraj S. and Balasubramanian, Shankar}, doi = {10.1073/pnas.2512204122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2512204122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SCoTCH-seq reveals that 5-hydroxymethylcytosine encodes regulatory information across DNA strands}, volume = {122}, year = {2025}, }
• (2025). Coupling of excitation energy to photochemistry in natural marine phytoplankton communities under iron stress. PNAS, 122(31), e2511916122. (www)

  @article{ , abstract = {Oxygenic photosynthesis requires excitation energy transfer from light-harvesting complexes (LHCs) to reaction centers (RCs) to drive photochemical redox chemistry. The effective absorption cross section of RCs dynamically responds to the light environment on time scales of seconds to days, allowing rapid acclimations to changes in spectral irradiance and photoprotection under high light, thereby optimizing light absorption for photochemistry. Although energy coupling between LHC–RCs has been studied for decades in laboratory cultures, it remains poorly understood in real-world conditions, where it is potentially influenced by nutrients. In the oceans, one of the most critical micronutrients for photosynthesis is iron (Fe). To investigate the effects of Fe stress on the energetic coupling between LHC–RCs in natural phytoplankton assemblages in the Southern Atlantic Ocean, we assessed photophysiological responses using a pair of custom-built fluorometers measuring chlorophyll-a variable fluorescence and picosecond fluorescence lifetimes. Detailed analysis based on the functional absorption cross section of the oxygen-evolving complex, quantum yield of photochemistry, energetic connectivity of RCs, and the average lifetime of in vivo chlorophyll fluorescence suggested that between 10 and 25% of LHCs remain uncoupled from RCs and do not effectively contribute to photochemical charge separation. Addition of Fe to samples under trace metal-clean on-board incubations indicates relatively rapid recoupling (< 24 h) of antennae to photochemistry, followed by biophysical stabilization of recoupled complexes. Our findings highlight the crucial role of micronutrients in controlling the excitation energy transfer from LHCs to RCs in marine phytoplankton and the overall primary productivity in the real-world oceans.}, archive = {J_PNAS}, author = {Pupulewatte, Heshani and Gorbunov, Maxim Y. and Moore, C. Mark and Selden, Corday R. and Ryan-Keogh, Thomas J. and Furby, Joe and Hawley, Ruth and Lohan, Maeve C. and Bibby, Thomas S. and Falkowski, Paul G.}, doi = {10.1073/pnas.2511916122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2511916122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Coupling of excitation energy to photochemistry in natural marine phytoplankton communities under iron stress}, volume = {122}, year = {2025}, }
• (2025). In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment. PNAS, 122(31), e2511890122. (www)

  @article{ , abstract = {Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson’s disease by mutations in PINK1 and PRKN . Parkin-expressing U2 osteosarcoma (U2OS) cells were treated with the depolarizing agents oligomycin and antimycin A (OA) and subjected to cryo-focused ion beam milling and in situ cryo-electron tomography. Mitochondria were fragmented and devoid of matrix calcium phosphate crystals. Phagophores were visualized, with bridge-like lipid transporter densities connected to mitophagic phagophores. A subpopulation of ATP synthases relocalized from cristae to the inner boundary membrane. The structure of the dome-shaped prohibitin complex, a dodecamer of PHB1-PHB2 dimers, was determined in situ by subtomogram averaging in untreated and treated cells and found to exist in open and closed conformations, with the closed conformation being enriched by OA treatment. These findings provide a set of native snapshots of the manifold nano-structural consequences of mitochondrial depolarization and provide a baseline for future in situ dissection of Parkin-dependent mitophagy.}, archive = {J_PNAS}, author = {Rose, Kevin and Herrmann, Eric and Kakudji, Eve and Lizarrondo, Javier and Celebi, A. Yasemin and Wilfling, Florian and Lewis, Samantha C. and Hurley, James H.}, doi = {10.1073/pnas.2511890122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2511890122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment}, volume = {122}, year = {2025}, }
• (2025). Methane-munching symbionts fuel sea spiders in the deep sea. PNAS, 122(31), e2511508122. (www)

  @article{ , archive = {J_PNAS}, author = {Dubilier, Nicole}, doi = {10.1073/pnas.2511508122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2511508122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Methane-munching symbionts fuel sea spiders in the deep sea}, volume = {122}, year = {2025}, }
• (2025). Revisiting the eoarchean akilia quartz-pyroxene rock with potassium isotopes: Implications for early-ocean sedimentation. PNAS, 122(31), e2510228122. (www)

  @article{ , abstract = {The Eoarchean quartz-pyroxene rock from Akilia Island in Greenland has been proposed as one of Earth’s oldest banded iron formations (BIF) and a potential host for the earliest biosignatures. However, the origin of its protolith, whether it metamorphosed from an igneous or sedimentary precursor, remains debated. Here, we revisit this longstanding Akilia controversy using potassium isotope analyses, comparing Akilia samples with BIFs and black shales spanning the Eoarchean to Mesoproterozoic. Our results demonstrate that BIFs and black shales show systematic potassium isotope variations correlated with their potassium contents. Potassium-poor BIF layers display heavier isotopic compositions close to seawater values, whereas clay-rich layers exhibit elevated potassium contents and lighter isotopic signatures. The Akilia quartz-pyroxene rock was initially characterized by low potassium concentrations and heavy potassium isotopic compositions consistent with chemical sediments deposited from ancient seawater. It was subsequently modified by metasomatic fluids derived from nearby metamorphosed igneous rocks. These findings support a sedimentary origin for the Akilia quartz-pyroxene rock. Furthermore, our study provides an isotopic framework for interpreting ancient oceanic environments and offers insights into the potassium cycling and habitability of early Earth.}, archive = {J_PNAS}, author = {Long, Zheng-Yu and Moynier, Frédéric and Dai, Wei and van Zuilen, Mark and Deng, Jun and Qiu, Kun-Feng}, doi = {10.1073/pnas.2510228122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2510228122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Revisiting the eoarchean akilia quartz-pyroxene rock with potassium isotopes: Implications for early-ocean sedimentation}, volume = {122}, year = {2025}, }
• (2025). Ultradian rhythms of CRHPVN neuron activity, behavior, and stress hormone secretion. PNAS, 122(31), e2510083122. (www)

  @article{ , abstract = {The stress axis is always active, even in the absence of any threat. This manifests as hourly pulses of corticosteroid stress hormone secretion over the day. Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (CRH PVN ) control both the neuroendocrine stress axis as well as stress-associated behaviors. However, it is currently unclear how the resting activity of these neurons is coordinated with both spontaneous behavior and ultradian pulses of corticosteroid secretion. To investigate this, we performed fiber photometry recordings of CRH PVN neuron activity in Crh-Ires-Cre mice and a newly generated line of Crh-Ires-Cre rats. In both mice and rats, CRH PVN neurons displayed an ultradian rhythm of activity with reoccurring upstates of activity approximately once per hour over the 24-h day. Upstates in activity were coordinated with increases in animal activity/arousal. Chemogenetic activation of CRH PVN neurons was also sufficient to induce behavioral arousal. In rats, increases in CRH neural activity preceded some pulses of corticosteroid secretion but not others. Thus, while CRH PVN neurons display an ultradian rhythm of activity over the 24-h day that is coordinated with behavioral arousal, the relationship between CRH PVN activity and pulses of corticosteroid secretion is not one-to-one.}, archive = {J_PNAS}, author = {Zheng, Shaojie and Focke, Caroline M. B. and Young, Calvin K. and Tripp, Isaac and Ganeshan, Dharshini and Power, Emmet M. and Schwenke, Daryl O. and Herbison, Allan E. and Kim, Joon S. and Iremonger, Karl J.}, doi = {10.1073/pnas.2510083122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2510083122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ultradian rhythms of CRHPVN neuron activity, behavior, and stress hormone secretion}, volume = {122}, year = {2025}, }
• (2025). Generation of actionable, cancer-specific neoantigens from KRAS(G12C) with adagrasib. PNAS, 122(31), e2509012122. (www)

  @article{ , abstract = {Effective immune therapy against cancer ideally should target a cancer-specific antigen, an antigen that is present exclusively in cancer cells. However, there is a paucity of cancer-specific antigens that are endogenously produced. HapImmune™ technology utilizes covalent inhibitors directed to an intracellular cancer driver to create cancer-specific neoantigens in the form of drug–peptide conjugates presented by class I MHC molecules. Our previous study with sotorasib, an FDA-approved covalent inhibitor of KRAS(G12C), demonstrated that drug-treated cells produce such neoantigens and can be killed by T cell engagers directed against the drug–peptide/MHC complex. Thus, this technology can unite targeted and immune therapies. In the present study, we examined whether this approach could generalize to another FDA-approved KRAS(G12C) inhibitor, adagrasib, whose chemical structure and cysteine reactivity differ substantially from sotorasib. We developed antibodies selective to adagrasib-KRAS(G12C) peptides presented by HLA-A*03 and A*11 that also show cross-reactivity to other KRAS(G12C) inhibitors presented in the same manner. Cryoelectron microscopy structures revealed a mode of adagrasib-peptide/HLA recognition distinctly different from that of sotorasib-directed HapImmune antibodies. The antibodies in a bispecific T cell engager format killed adagrasib-resistant lung cancer cells upon adagrasib treatment. These results support the broad applicability of the HapImmune approach for creating actionable cancer-specific neoantigens and offer candidates for therapeutic development.}, archive = {J_PNAS}, author = {Maso, Lorenzo and Rajak, Epsa and Hattori, Takamitsu and Hu, Zhengshan and Koide, Akiko and Neel, Benjamin G. and Koide, Shohei}, doi = {10.1073/pnas.2509012122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2509012122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Generation of actionable, cancer-specific neoantigens from KRAS(G12C) with adagrasib}, volume = {122}, year = {2025}, }
• (2025). Synthesis of large single-transcript pathways from oligonucleotide pools: Design of STARBURST, an autobioluminescent reporter. PNAS, 122(31), e2508109122. (www)

  @article{ , abstract = {Methods for fast and inexpensive gene synthesis from oligonucleotide pools enable rapid iteration of genetic designs. Here, we describe iggypop (indexed Golden Gate gene assembly from PCR-amplified oligonucleotide pools), a simple computational–experimental pipeline that allows for low-cost design and synthesis of hundreds of genes from oligonucleotide pools using Golden Gate assembly methods. We used iggypop to synthesize a series of single-transcript autonomously bioluminescent reporters (STARBURSTs) that link the five genes of a fungal bioluminescence pathway via ribosomal skipping LP4/2A sequences into a 9.5 kb transcript that function in planta. We also synthesized RUBY reporters (a reporter gene system producing red betalain pigment) recoded to match dicot codon usage, as RUBY was codon optimized for rice codon usage and has a high GC content. Surprisingly, the recoded RUBYs substantially reduced betalain production in transient Nicotiana benthamiana assays. Based on this observation, we synthesized six GC-boosted STARBURSTs, which produced robust luminescence in both transient assays and transgenic Arabidopsis plants. Thus, iggypop enabled the rapid synthesis of multiple genetic designs to deliver a bright single transcript autobioluminescent reporter. Iggypop should enable the facile synthesis and optimization of new genetic parts and complex polycistronic pathways.}, archive = {J_PNAS}, author = {Dvir, Gony and Xing, Zenan and Beldman, Irina and Rivera, Andrés and Wheeldon, Ian and Cutler, Sean R.}, doi = {10.1073/pnas.2508109122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2508109122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synthesis of large single-transcript pathways from oligonucleotide pools: Design of STARBURST, an autobioluminescent reporter}, volume = {122}, year = {2025}, }
• (2025). Absence of phonon softening across a charge density wave transition due to quantum fluctuations. PNAS, 122(31), e2507135122. (www)

  @article{ , abstract = {Kagome metals have emerged as a frontier in condensed matter physics due to their potential to host exotic quantum states. Among these, CsV 3 Sb 5 has attracted significant attention for the unusual coexistence of charge density wave (CDW) order and unconventional superconductivity, presenting an ideal system for exploring the emergent phenomena from the interplay of phonons, electronic fluctuations, and topological effects. The nature of CDW formation in CsV 3 Sb 5 is unconventional and has sparked considerable debate. In this study, we examine the origin of the CDW state via ab initio finite-temperature simulations of the lattice dynamics. Through a comparative study of CsV 3 Sb 5 and 2H-NbSe 2 , we demonstrate that the experimental absence of phonon softening—a hallmark of conventional CDW transition—in CsV 3 Sb 5 along with the presence of a weakly first-order transition, can be attributed to quantum zero-point atomic motion. This zero-point motion smears the free energy landscape of CDW, effectively stabilizing the pristine structure even below the CDW transition temperature. We argue that this surprising behavior could cause coexistence of pristine and CDW structures across the transition and lead to a weak first-order transition. Our predicted lattice dynamical behavior is supported by coherent phonon spectroscopy in single-crystalline CsV 3 Sb 5 . Our results provide crucial insights into the formation mechanism of CDW materials that exhibit little to no phonon softening, including cuprates, and highlight the surprising role of quantum effects in emergent properties of relatively heavy-element materials like CsV 3 Sb 5 .}, archive = {J_PNAS}, author = {Chen, Yubi and Kongruengkit, Terawit and Salinas, Andrea Capa and Yang, Runqing and Quan, Yujie and Zhang, Fanghao and Pokharel, Ganesh and Kautzsch, Linus and Wilson, Stephen D. and Mu, Sai and Harter, John W. and Liao, Bolin}, doi = {10.1073/pnas.2507135122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2507135122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Absence of phonon softening across a charge density wave transition due to quantum fluctuations}, volume = {122}, year = {2025}, }
• (2025). Foraging ants as liquid brains: Movement heterogeneity shapes collective efficiency. PNAS, 122(31), e2506930122. (www)

  @article{ , abstract = {Liquid brains conceptualize living systems that operate without central control, where collective outcomes emerge from local and dynamic interactions. This concept extends beyond ants and other social insects to include immune systems, slime molds, and microbiomes. In such systems, connectivity scales with population density, facilitating more efficient information transfer as group size increases. However, in sparse conditions, where fewer individuals interact, movement likely plays a crucial role in shaping connectivity, ensuring optimal collective efficiency. We tested this hypothesis during the foraging process of Aphaenogaster senilis , an ant species that does not primarily rely on chemical communication. We empirically measured ant movement behavior and characterized their foraging dynamics across large spatiotemporal scales, closely reflecting the species’ natural ecology. Integrating observed movement heterogeneity into a neuronal-like model, we quantitatively replicated ants foraging efficiency and spatiotemporal dynamics. Our results reveal that a simple feedback mechanism, mediated by local interactions, governs the foraging patterns of A. senilis . Such feedback is modulated by adjusting the proportion of two coexisting movement behaviors: recruits, which facilitated information transfer and food exploitation by aggregating closely to the nest and the food patches, and scouts, which could bypass this feedback and discover alternative food sources. Therefore, distinct movement patterns contributed differently to optimizing each phase of the foraging process, proving an adaptive mechanism to balance exploration and exploitation. Our findings underscore how incorporating specific biologically grounded insights into complex systems frameworks, enhances our understanding of the mechanisms underlying collective intelligence in biological systems.}, archive = {J_PNAS}, author = {Fernández-López, Pol and Oro, Daniel and Lloret-Cabot, Roger and Genovart, Meritxell and Garriga, Joan and Bartumeus, Frederic}, doi = {10.1073/pnas.2506930122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2506930122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Foraging ants as liquid brains: Movement heterogeneity shapes collective efficiency}, volume = {122}, year = {2025}, }
• (2025). C11orf54 catalyzes L-xylulose formation in human metabolism. PNAS, 122(31), e2506597122. (www)

  @article{ , abstract = {Excretion of L-xylulose is the hallmark of pentosuria, the fourth of Garrod’s inborn errors of metabolism, yet the molecular basis for L-xylulose formation remains unknown. Here, by projecting coevolutionary data for 511,114 orthogroups across 1,929 eukaryotic genomes onto metabolic maps, we screen for unmapped genes in human metabolism. Among these, we show that the DUF1907 domain of C11orf54 catalyzes formation of L-xylulose by establishing a zinc-coordinated Michaelis complex with β-keto-L-gulonate (BKG). The identification of BKG decarboxylase completes the pentose pathway, in which pentose sugars are produced by decarboxylation of nonphosphorylated hexose precursors. The pathway was present in the unicellular ancestor of animals and is conserved in all deuterostomes, in contrast to the alternative L-ascorbate (vitamin C) biosynthesis pathway. An increased flux toward pentoses may have represented an evolutionary tradeoff, favoring energy metabolism and redox cofactor balance at the expense of ascorbate biosynthesis in organisms, such as humans and other Haplorhini primates, where dietary vitamin C intake prevents scurvy.}, archive = {J_PNAS}, author = {Malatesta, Marco and De Rito, Carlo and Gasparini, Francesca and Merici, Giovanni and Dell’Accantera, Davide and Quilici, Giacomo and Sansone, Francesco and Percudani, Riccardo}, doi = {10.1073/pnas.2506597122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2506597122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {C11orf54 catalyzes L-xylulose formation in human metabolism}, volume = {122}, year = {2025}, }
• (2025). Serum metabolic patterns reveal the diagnostic and prognostic role of alanine abnormality in ocular adnexal lymphoma. PNAS, 122(31), e2506345122. (www)

  @article{ , abstract = {Ocular adnexal lymphoma (OAL) is the most common orbital malignancy in adults. Advanced tools for precise diagnosis and prognosis of OAL are in demand. Here, the nanoparticle-enhanced laser desorption/ionization mass spectrometry was applied for the construction of OAL-associated serum metabolic patterns (SMPs) from 239 participants (104 OAL and 135 non-OAL). Through machine learning, the diagnostic performance with an area-under-the-curve (AUC) of 0.901 was achieved for OAL based on SMPs. Furthermore, a diagnostic metabolic panel was constructed with an AUC of 0.875. Moreover, a prognosis scoring system was built and its desirable prediction efficacy for progression-free survival of OAL was confirmed ( P < 0.05). Specifically, the decreased serum alanine level was found to play both vital roles in the diagnosis and prognosis of OAL, and we demonstrated that uptake of alanine promotes glycolysis and cell growth in lymphoma cells. Our study highlights the value of the serum metabolite biomarkers in the clinical management of OAL.}, archive = {J_PNAS}, author = {Huang, Yida and Lin, Huimin and Shi, Jiahao and Chen, Yifan and Sang, Qi and Wang, Ruimin and Liu, Wanshan and Wu, Jiao and Li, Yanyan and Xu, Xiaoyu and Ding, Chunmeng and Yang, Shouzhi and Zhang, Juxiang and Jia, Renbing and Fan, Xianqun and Qian, Kun and Zhou, Yixiong}, doi = {10.1073/pnas.2506345122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2506345122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Serum metabolic patterns reveal the diagnostic and prognostic role of alanine abnormality in ocular adnexal lymphoma}, volume = {122}, year = {2025}, }
• (2025). Trauma-predictive brain network connectivity adaptively responds to mild acute stress. PNAS, 122(31), e2505965122. (www)

  @article{ , abstract = {Past traumatic experiences shape neural responses to future stress, but the mechanisms underlying this dynamic interaction remain unclear. Here, we assessed how trauma-related brain networks respond to current acute stress in real time. Using a machine learning approach, we trained and tested brain functional connectivity networks to predict past trauma exposure in a community sample of adults ( N = 170). We then evaluated the response of these trauma-predictive brain networks to an acute emotional and physiological stressor in a subsample of participants ( N = 92) and to a pharmacological manipulation (hydrocortisone) in an independent crossover study ( N = 27). We found that connectome-based predictive modeling successfully predicted past trauma exposure. The network associated with greater trauma exposure showed high involvement of salience network connections, with model prediction driven by connectivity in the medial frontal cortex, salience network, motor regions, default mode network, and cerebellum. Notably, connectivity in this trauma-predictive network was significantly attenuated following an acute stressor relative to control. A similar pattern was observed in the pharmacology sample, with decreased connectivity under hydrocortisone compared to placebo within this trauma-predictive network. Finally, attenuated trauma-predictive network connectivity after acute stress was associated with lower depressive symptoms in the stress-exposed group, but not control group. These findings suggest that stress may induce blunted connectivity of brain networks related to past traumatic experiences and that the reduced engagement of these trauma-predictive brain networks may facilitate adaptive regulatory response to later stress.}, archive = {J_PNAS}, author = {Hardi, Felicia A. and Ye, Jean and Zhou, Irene and Bai, Zihan and Nguyen, D. T. and Loetscher, Krystian B. and Pratt, Julia G. and Harris, Bailey B. and Gee, Dylan G. and Goldfarb, Elizabeth V.}, doi = {10.1073/pnas.2505965122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2505965122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Trauma-predictive brain network connectivity adaptively responds to mild acute stress}, volume = {122}, year = {2025}, }
• (2025). PyReconstruct: A fully open-source, collaborative successor to reconstruct. PNAS, 122(31), e2505822122. (www)

  @article{ , abstract = {As the serial section community transitions to volume electron microscopy, tools are needed to balance rapid segmentation efforts with documenting the fine detail of structures that support cell function. New annotation applications should be accessible to users and meet the needs of the neuroscience and connectomics communities while also being useful across other disciplines. Issues not currently addressed by a single, modern annotation application include 1) built-in curation systems with utilities for expert intervention to provide quality assurance, 2) integrated alignment features that allow for image registration on-the-fly as image flaws are found during annotation, 3) simplicity for nonspecialists within and beyond the neuroscience community, 4) a system to store experimental metadata with annotation data in a way that researchers remain masked regarding condition to avoid potential biases, 5) local management of large datasets appropriate for circuit-level analyses, and 6) fully open-source codebase allowing development of new tools, and more. Here, we present PyReconstruct, a modern successor to the Reconstruct annotation tool. PyReconstruct operates in a field-agnostic manner, runs on all major operating systems, breaks through legacy RAM limitations, features an intuitive and collaborative curation system, and employs a flexible and dynamic approach to image registration. It can be used to analyze, display, and publish experimental or connectomics data. PyReconstruct is suited for generating ground truth to implement in automated segmentation, outcomes of which can be returned to PyReconstruct for proofreading and quality control.}, archive = {J_PNAS}, author = {Chirillo, Michael A. and Falco, Julian N. and Musslewhite, Michael D. and Lindsey, Larry F. and Harris, Kristen M.}, doi = {10.1073/pnas.2505822122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2505822122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PyReconstruct: A fully open-source, collaborative successor to reconstruct}, volume = {122}, year = {2025}, }
• (2025). Integrating spatial omics and single-cell mass spectrometry imaging reveals tumor–host metabolic interplay in hepatocellular carcinoma. PNAS, 122(31), e2505789122. (www)

  @article{ , abstract = {Metabolic crosstalk among diverse cellular populations contributes to shaping a competitive and symbiotic tumor microenvironment (TME) to influence cancer progression and immune responses, highlighting vulnerabilities that can be exploited for cancer therapy. Using a spatial multiomics platform to study the cell-specific metabolic spectrum in hepatocellular carcinoma (HCC), we map the metabolic interactions between different cells in the HCC TME and identify a unique tumor-immune-cancer-associated fibroblast (CAF) “interface” zone, where cell–cell interactions are enhanced and accompanied by significant upregulation of lactic acid and long-chain polyunsaturated fatty acids. Further combining single-cell mass spectrometry imaging of patient-derived tumor organoids, cocultured CAFs, and macrophages, we demonstrate that CAFs increase glycolysis and secrete lactic acid to the surrounding microenvironment to drive immunosuppressive macrophage M2 polarization. These findings facilitate the understanding of cancer-associated metabolic interactions in complex TME and provide clues for targeted clinical therapies.}, archive = {J_PNAS}, author = {Chen, Panpan and Geng, Haoyuan and Ma, Bangzhen and Zhang, Yaqi and Zhu, Zihan and Li, Min and Chen, Shiping and Wang, Xiao and Sun, Chenglong}, doi = {10.1073/pnas.2505789122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2505789122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Integrating spatial omics and single-cell mass spectrometry imaging reveals tumor–host metabolic interplay in hepatocellular carcinoma}, volume = {122}, year = {2025}, }
• (2025). Physics-tailored machine learning reveals unexpected physics in dusty plasmas. PNAS, 122(31), e2505725122. (www)

  @article{ , abstract = {Dusty plasma is a mixture of ions, electrons, and macroscopic charged particles that is commonly found in space and planetary environments. The particles interact through Coulomb forces mediated by the surrounding plasma, and as a result, the effective forces between particles can be nonconservative and nonreciprocal. Machine learning (ML) models are a promising route to learn these complex forces, yet their structure should match the underlying physical constraints to provide useful insight. Here, we demonstrate and experimentally validate an ML approach that incorporates physical intuition to infer force laws in a laboratory dusty plasma. Trained on 3D particle trajectories, the model accounts for inherent symmetries, nonidentical particles, and learns the effective nonreciprocal forces between particles with exquisite accuracy ( R 2 > 0.99). We validate the model by inferring particle masses in two independent yet consistent ways. The model’s accuracy enables precise measurements of particle charge and screening length, identifying large deviations from common theoretical assumptions. Our ability to identify unknown physics from experimental data demonstrates how ML-powered approaches can guide new routes of scientific discovery in many-body systems. Furthermore, we anticipate our ML approach to be a starting point for inferring laws from dynamics in a wide range of many-body systems, from colloids to living organisms.}, archive = {J_PNAS}, author = {Yu, Wentao and Abdelaleem, Eslam and Nemenman, Ilya and Burton, Justin C.}, doi = {10.1073/pnas.2505725122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2505725122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Physics-tailored machine learning reveals unexpected physics in dusty plasmas}, volume = {122}, year = {2025}, }
• (2025). Six million years of vole dental evolution shaped by tooth development. PNAS, 122(31), e2505624122. (www)

  @article{ , abstract = {Morphological change occurs over macroevolutionary timescales under the action of natural selection and genetic drift combined with developmental processes shaping organogenesis. Although determining their relative weight is made difficult by discrepancies between paleontological and neontological data, mammalian tooth morphology may bridge the gap between fossil record and laboratory observations. Fossils indicate that mammals have frequently diversified after evolving molars bearing more cusps, while developmental biology shows these emerge through the iterative signaling of enamel knots. However, this theoretical evo-devo model of mammalian tooth evolution has not been tested with empirical data from both fossils and laboratory experiments. In doing so, we identify a shared developmental basis for the convergent, ratcheted evolution of increasingly complex molars in arvicoline rodents (voles, lemmings, muskrats). Longer, narrower molars lead to more cusps throughout development and deep time, suggesting that tooth development directed morphological evolution. Both the arvicoline fossil record and vole tooth development show slower transitions toward the highest cusp counts. This pattern suggests that the developmental processes fueling the evolution of increasingly complex molars may also limit the potential for further complexity increases. Integrating paleontological and developmental data shows that long-term evolutionary trends can be accurately and mostly explained by the simple tinkering of developmental pathways.}, archive = {J_PNAS}, author = {Lafuma, Fabien and Renvoisé, Élodie and Clavel, Julien and Corfe, Ian J. and Escarguel, Gilles}, doi = {10.1073/pnas.2505624122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2505624122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Six million years of vole dental evolution shaped by tooth development}, volume = {122}, year = {2025}, }
• (2025). How cancer arises: Genetics releases, plasticity creates, genetics stabilizes. PNAS, 122(31), e2505377122. (www)

  @article{ , abstract = {Cancer is the origin of a novel tissue that attracts resources, spreads beyond boundaries, avoids normal controls, and escapes immunity. How does a novel tissue arise? The puzzle is that two seemingly different processes appear to be the primary driving force. On the one hand, overwhelming evidence links (epi)genetic driver mutations to the origin and progression of tumors. Common oncogenic mutations such as KRAS accelerate cell division, and common knockouts of tumor suppressors such as TP53 abrogate cell death or checks on cell division. On the other hand, cancerous tissues create complex traits that require intricate changes in cells and multiple interactions between different cell types. Such novelty often arises by hijacking the developmental plasticity that normally creates the diverse cells and tissues of our bodies from a single original zygotic cell. How can we reconcile the simple genetic changes in carcinogenesis with the complex developmental plasticity that creates novel tissues? This perspective advocates a new model. (Epi)genetic mutations release developmental plasticity. That developmental plasticity creates novel cellular interactions and complex tissues. Initially, novel traits created by developmental plasticity may not be stably heritable, thus subsequent (epi)genetic changes must stabilize the phenotypic novelty. Recent studies show how classic oncogenic and tumor suppressor driver mutations, such as KRAS and TP53 , may primarily act in early carcinogenesis as broad releasers of developmental plasticity rather than as stimulators of cell division or knockout of limitations on cellular clonal expansion. In the new model, genetics releases, plasticity creates, and genetics stabilizes.}, archive = {J_PNAS}, author = {Frank, Steven A.}, doi = {10.1073/pnas.2505377122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2505377122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How cancer arises: Genetics releases, plasticity creates, genetics stabilizes}, volume = {122}, year = {2025}, }
• (2025). Hybridization of molecules via a common photonic mode. PNAS, 122(31), e2505161122. (www)

  @article{ , abstract = {Atoms and molecules usually hybridize and form bonds when they come in very close proximity of each other. In this work, we show that molecules can hybridize even through far-field electromagnetic interactions mediated by the shared mode of an optical microcavity. We discuss a collective enhancement of the vacuum Rabi splitting and study super- and subradiant states that arise from the cavity-mediated coupling both in the resonant and dispersive regimes. Moreover, we demonstrate a two-photon transition that emerges between the ground and excited states of the new optical compound. Our experimental data are in excellent agreement with the predictions of the Tavis–Cummings Hamiltonian and open the door to the realization of hybrid light–matter materials.}, archive = {J_PNAS}, author = {Nobakht, Jahangir and Pscherer, André and Renger, Jan and Götzinger, Stephan and Sandoghdar, Vahid}, doi = {10.1073/pnas.2505161122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2505161122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hybridization of molecules via a common photonic mode}, volume = {122}, year = {2025}, }
• (2025). Casimir self-assembly: A platform for measuring nanoscale surface interactions in liquids. PNAS, 122(31), e2505144122. (www)

  @article{ , abstract = {Self-assembly (SA) plays a pivotal role in nanotechnology, offering cost-effective methods for bottom–up fabrication and providing versatile model systems for investigating fundamental interactions in various bioinspired systems. However, current methods for investigating and quantifying the dynamics of SA systems are limited in their applicability to planar interfaces, particularly in liquid environments. These methods typically rely on analyzing the collective behavior of particle suspensions rather than directly probing the specific interactions between individual particles. Here, we introduce Casimir self-assembly (CaSA) as a platform, integrating colloidal science, nanophotonics, and fluctuational electrodynamics to study long-range interactions and stability in planar SA systems. Using thermal fluctuations as a probe and visible-range Fabry–Pérot resonances as an optical readout, we demonstrate that CaSA enables a direct in situ study of the Casimir–Lifshitz electrostatic interaction. This approach allows us to map stability regimes of colloidal materials by varying ionic strength and identifying conditions for stable assembly and aggregation limits, and moreover is used to measure the surface charge density of an individual colloidal object down to fractions of an electron charge per square nanometer. Our platform overcomes the limitations of current methods, providing an experimental tool for exploring SA dynamics in situ and expanding the understanding of suspension stability in liquids at the single-particle level. With potential for future applications, CaSA is scalable for studying interfacial forces and is adaptable to multivalent electrolytes and biosensing.}, archive = {J_PNAS}, author = {Hošková, Michaela and Kotov, Oleg V. and Küçüköz, Betül and Murphy, Catherine J. and Shegai, Timur O.}, doi = {10.1073/pnas.2505144122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2505144122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Casimir self-assembly: A platform for measuring nanoscale surface interactions in liquids}, volume = {122}, year = {2025}, }
• (2025). Lysosomal glucocerebrosidase is needed for ciliary hedgehog signaling: A convergent pathway contributing to parkinson’s disease. PNAS, 122(31), e2504774122. (www)

  @article{ , abstract = {Parkinson’s disease is characterized by loss of dopamine neurons that project to the dorsal striatum, and mutations in LRRK2 and GBA1 are the most common genetic causes of familial Parkinson’s disease. Previously, we showed that pathogenic LRRK2 mutations inhibit primary cilia formation in rare interneurons and astrocytes of the mouse and human dorsal striatum. This blocks Hedgehog signaling and reduces synthesis of neuroprotective GDNF and NRTN, which normally support dopamine neurons vulnerable in PD. Here, we show that GBA1 mutations also impair Hedgehog signaling and Hedgehog-dependent neuroprotective factor production by a distinct mechanism. Loss of GBA1 activity increases lysosomal accessible cholesterol and thus decreases accessible cholesterol in primary cilia of cultured cells; this change in lipid composition blocks ciliary Hedgehog signaling that depends on accessible cholesterol. Consistent with defects in Hedgehog signaling in the mouse dorsal striatum, GBA1 mutant mice show reduced Hedgehog-induced Gdnf RNA expression in striatal cholinergic interneurons, with no detectable impact on cilia formation. Also, both LRRK2 and GBA1 mutations suppress Hedgehog-induced Bdnf expression in striatal astrocytes. These findings underscore the role of Hedgehog signaling in the nigrostriatal circuit and reveal a convergent mechanism by which distinct LRRK2 and GBA1 mutations may contribute to PD pathogenesis.}, archive = {J_PNAS}, author = {Nair, Sreeja V. and Jaimon, Ebsy and Adhikari, Ayan and Nikoloff, Jonas and Pfeffer, Suzanne R.}, doi = {10.1073/pnas.2504774122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2504774122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lysosomal glucocerebrosidase is needed for ciliary hedgehog signaling: A convergent pathway contributing to parkinson’s disease}, volume = {122}, year = {2025}, }
• (2025). DICER-LIKE 5 loss causes thermosensitive male sterility in durum wheat and reveals an AU-rich motif guiding 24-nt phasiRNA biogenesis. PNAS, 122(31), e2504349122. (www)

  @article{ , abstract = {Reproductive, male-enriched small RNAs are present in flowering plants and animals, yet their role in plants remains underexplored. We generated dicer-like 5 ( dcl5 ) mutants in durum wheat ( Triticum turgidum ssp. durum 2n = 4× = 28; AABB), revealing temperature-sensitive genic male sterility. Loss of DCL5 depleted premeiotic and meiotic 24-nt phasiRNA production, correlating with sterility under standard growth conditions and partial fertility recovery at higher temperatures. A single functional DCL5 allele restored complete fertility, presenting a promising alternative to current methods for hybrid production. We demonstrate that premeiotic 24-nt phasiRNA biogenesis is independent of miRNA-mediated cleavage and driven by a conserved motif initiating DCL5 activity. In the dcl5 mutant developing under sterility-inducing conditions, developmental defects are observed during pollen maturation, rather than at peak 24-nt phasiRNA accumulation in premeiotic and meiotic anthers. Although no visible morphological abnormalities were apparent during early development, single-cell RNA sequencing revealed that dcl5 mutant cells exhibit transcriptional profiles distinct from those of wild-type cells, when premeiotic 24-nt phasiRNAs are accumulating at the early developmental stage. Finally, the coexpression of Argonaute ( AGO1b , AGO4a, and AGO6 ) homeologs in 24-nt phasiRNA-producing cells identifies candidate effectors and suggests a role for 24-nt phasiRNAs in transcriptional gene silencing.}, archive = {J_PNAS}, author = {Bélanger, Sébastien and Martín, Azahara C. and Marchant, D. Blaine and Zhan, Junpeng and McGregor, Madison and Smedley, Mark and Hayta, Sadiye and Moore, Graham and Meyers, Blake C.}, doi = {10.1073/pnas.2504349122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2504349122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {DICER-LIKE 5 loss causes thermosensitive male sterility in durum wheat and reveals an AU-rich motif guiding 24-nt phasiRNA biogenesis}, volume = {122}, year = {2025}, }
• (2025). Structural basis for the evolution of a domesticated group II intron–like reverse transcriptase to function in host cell DNA repair. PNAS, 122(31), e2504208122. (www)

  @article{ , abstract = {A previous study found that a bacterial group II intron–like reverse transcriptase (G2L4 RT) evolved to function in double-strand break repair (DSBR) via microhomology-mediated end-joining (MMEJ) and that a mobile group II intron-encoded RT has a basal DSBR activity that uses conserved structural features of non-long terminal repeat (non-LTR)-retroelement RTs. Here, we determined G2L4 RT apoenzyme and snap-back DNA synthesis structures revealing unique structural adaptations that optimized its cellular function in DSBR. These included an RT3a structure that stabilizes the apoenzyme in an inactive conformation until encountering a DNA substrate; a longer N-terminal extension/RT0-loop with conserved residues that together with a modified active site favors strand annealing; and a conserved dimer interface that localizes G2L4 RT homodimers to DSBR sites with both monomers positioned for MMEJ. Our findings reveal how an RT can function in DNA repair and suggest ways of optimizing related RTs for genome engineering applications.}, archive = {J_PNAS}, author = {Park, Seung Kuk and Guo, Mo and Stamos, Jennifer L. and Kim, Wantae and Lee, Sidae and Zhang, Y. Jessie and Lambowitz, Alan M.}, doi = {10.1073/pnas.2504208122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2504208122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis for the evolution of a domesticated group II intron–like reverse transcriptase to function in host cell DNA repair}, volume = {122}, year = {2025}, }
• (2025). General anesthesia in early infancy accelerates visual cortical development. PNAS, 122(31), e2504172122. (www)

  @article{ , abstract = {How human brain function is established through protracted trajectories of development is not yet fully understood. Maturation of γ-aminobutyric acid (GABA) circuits drives critical periods of cortical development in animal models. Whether early functional inhibition similarly impacts the pace of human brain development remains unknown. Here, in a longitudinal study of 93 infants across a range of repeated exposures to general anesthesia shortly after birth, we observed a dramatically accelerated development of visual evoked potential (VEP) waveforms (but not their latency) consistent with a conserved biological mechanism across species. Such sequelae of prolonged GABA-active anesthesia in the first half year after birth may particularly impact those at-risk of altered excitatory–inhibitory circuit balance.}, archive = {J_PNAS}, author = {Gabard-Durnam, Laurel J. and McCormick, Sarah A. and Underwood, Ellen and Tao, Alice and Kim, Isabelle and Coffman, Siobhan and Benster, Lindsay and Graziano, Maria and Nelson, Charles A. and Berde, Charles B. and Cornelissen, Laura and Hensch, Takao K.}, doi = {10.1073/pnas.2504172122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2504172122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {General anesthesia in early infancy accelerates visual cortical development}, volume = {122}, year = {2025}, }
• (2025). Combining MicroED and native mass spectrometry for structural discovery of enzyme–small molecule complexes. PNAS, 122(31), e2503780122. (www)

  @article{ , abstract = {With the goal of accelerating the discovery of small molecule–protein complexes, we leverage fast, low-dose, event-based electron counting microcrystal electron diffraction (MicroED) data collection and native mass spectrometry. This approach, which we term electron diffraction with native mass spectrometry (ED-MS), allows assignment of protein target structures bound to ligands with data obtained from crystal slurries soaked with mixtures of known inhibitors and crude biosynthetic reactions. This extends to libraries of printed ligands dispensed directly onto TEM grids for later soaking with microcrystal slurries, and complexes with noncovalent ligands. ED-MS resolves structures of the natural product, epoxide-based cysteine protease inhibitor E-64, and its biosynthetic analogs bound to the model cysteine protease, papain. It further identifies papain binding to its preferred natural products, by showing that two analogs of E-64 outcompete others in binding to papain crystals, and by detecting papain bound to E-64 and an analog from crude biosynthetic reactions, without purification. ED-MS also resolves binding of the CTX-M-14 β-lactamase, a target of active drug development, to the non-β-lactam inhibitor, avibactam, alone or in a cocktail of unrelated compounds. These results illustrate the utility of ED-MS for natural product ligand discovery and for structure-based screening of small molecule binders to macromolecular targets, promising utility for drug discovery.}, archive = {J_PNAS}, author = {Vlahakis, Niko W. and Flowers, Cameron W. and Liu, Mengting and Agdanowski, Matthew P. and Johnson, Samuel and Summers, Jacob A. and Jacobs, Lian M. C. and Keyser, Catherine and Russell, Phoebe and Rose, Samuel L. and Orlans, Julien and Adhami, Nima and Chen, Yu and Sawaya, Michael R. and Basu, Shibom and de Sanctis, Daniele and Wakatsuki, Soichi and Nelson, Hosea M. and Loo, Joseph A. and Tang, Yi and Rodriguez, Jose A.}, doi = {10.1073/pnas.2503780122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2503780122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Combining MicroED and native mass spectrometry for structural discovery of enzyme–small molecule complexes}, volume = {122}, year = {2025}, }
• (2025). Genomic origins and evolution of neo-sex chromosomes in pacific island birds. PNAS, 122(31), e2503746122. (www)

  @article{ , abstract = {The standard model of sex chromosome evolution is based on ancient XY or ZW systems. Young neo-sex chromosomes that form via the translocation of autosomal material to preexisting sex chromosomes provide materials to study early events in sex chromosome evolution. Neo-sex chromosomes are taxonomically widespread but, until recently, appeared to be rare in female-heterogametic taxa, including birds. Here, we report on the comparative evolutionary genomics of newly discovered neo-Z and neo-W sex chromosomes in two Pacific Island birds, the honeyeater species, Myzomela tristrami and M. cardinalis . Our results show that 19 to 21 Mya, ~85% of chr5 , an autosome, translocated to the pseudoautosomal region (PAR) of an ancestral sex chromosome (Z or W) and rapidly recombined onto its heterolog, leaving the remainder of chr5 to segregate as a remnant autosome. A large inversion then established a nonrecombining (NR) neo-W region and a neo-PAR. The accumulation of at least seven additional inversions created interspersed blocks of ancestral and neo-W sequence, without expanding the NR region. The neo-W experienced mass invasion by endogenous retrovirus repeats, a reduced efficacy of selection, and functional degeneration. Many of our observations are consistent with predictions of the standard model, whereas others highlight idiosyncrasies of neo-sex chromosomes that arise via translocation of autosomal sequence to ancestral sex chromosomes. We speculate, in particular, that the repository of retrotransposons on the ancestral W may have been an accelerant in the evolution of neo-W structure, content, and functional degeneration.}, archive = {J_PNAS}, author = {Muirhead, Christina A. and Martí, Emiliano and Shogren, Elsie H. and Uy, J. Albert C. and Presgraves, Daven C.}, doi = {10.1073/pnas.2503746122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2503746122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genomic origins and evolution of neo-sex chromosomes in pacific island birds}, volume = {122}, year = {2025}, }
• (2025). Three things we can do now to reduce the risk of avian influenza spillovers. PNAS, 122(31), e2503565122. (www)

  @article{ , archive = {J_PNAS}, author = {Yeh, Kenneth B. and Bahnfleth, William P. and Bradforda, Elaine and Cardona, Carol and Coleman, Kristen K. and Hudson, Peter J. and Dadonaite, Bernadeta and Hutchins, Rebecca J. and Maresso, Anthony and MacIntyre, C. Raina and Scotch, Matthew}, doi = {10.1073/pnas.2503565122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2503565122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Three things we can do now to reduce the risk of avian influenza spillovers}, volume = {122}, year = {2025}, }
• (2025). SARS-CoV-2 uptake and inflammatory response in senescent endothelial cells are regulated by the BSG/VEGFR2 pathway. PNAS, 122(31), e2502724122. (www)

  @article{ , abstract = {Aging is a risk factor for severe COVID-19, characterized by vascular endothelial dysfunction. Although possible susceptibility of vascular endothelial cells (ECs) to SARS-CoV-2 infection has been suggested, the details of entry into cells have not been clarified. Previously, we reported that in an aged mouse model of severe COVID-19, ECs show a massive viral uptake and inflammatory response. Here, we focused on the endocytic capacity of senescent ECs. We found that the senescent ECs showed high endocytic capacity and SARS-CoV-2 virus uptake. This triggers an nuclear factor-kappa B (NF-κB) pathway–mediated inflammatory response. Further, Basigin enhanced endocytosis in the senescent ECs by activating the intracellular vascular endothelial growth factor signaling. Thus, EC senescence is associated with enhanced SARS-CoV-2 endocytosis and subsequent vascular endothelial dysfunction. This could prove a potential target for treating severe COVID-19 in older adults.}, archive = {J_PNAS}, author = {Sakurai, Yuya and Fujioka, Yoichiro and Maishi, Nako and Takeda, Ryo and Ohba, Yusuke and Sasaki, Michihito and Teshirogi, Takahito and Ito, Wataru and Hida, Yasuhiro and Matsuda, Aya and Kido, Kanta and Orba, Yasuko and Sawa, Hirofumi and Hida, Kyoko}, doi = {10.1073/pnas.2502724122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2502724122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SARS-CoV-2 uptake and inflammatory response in senescent endothelial cells are regulated by the BSG/VEGFR2 pathway}, volume = {122}, year = {2025}, }
• (2025). Neuronal processes contain the essential components for the late steps of ribosome biogenesis. PNAS, 122(31), e2502424122. (www)

  @article{ , abstract = {Neurons rely on spatial and temporal control of protein synthesis to respond rapidly and locally to external stimuli, a process facilitated by the dynamic localization and modification of ribosomes. While previous research has shown that neuronal activity can regulate ribosome localization and modify translation rates, little is known about ribosomal assembly within neuronal processes. Here, we investigated the potential for local ribosome maturation in rat neurons using proteomics, RNA sequencing, and imaging methods. We detected an abundance of ribosome biogenesis factors in distal neuronal compartments, particularly those associated with the late stages of ribosome assembly. Moreover, we detected cytosolic pre-ribosomal RNA species in dendrites, as well as the enzymes necessary for their processing, suggesting that local ribosome maturation can occur far from the nucleus. These findings challenge conventional models that confine ribosome biogenesis to nuclear and perinuclear regions and suggest that neurons may fine-tune local protein synthesis by regulating ribosome assembly near synaptic sites. This mechanism may enable rapid modulation of the translational capacity in response to physiological changes, regulating synaptic plasticity and local protein synthesis in neurons.}, archive = {J_PNAS}, author = {Fusco, Claudia M. and Staab, Anja and Bourke, Ashley M. and Tushev, Georgi and Desch, Kristina and Lins, Erico Moreto and Ciirdaeva, Elena and tom Dieck, Susanne and Kaltenschnee, Nina and Heckel, Alexander and Langer, Julian D. and Schuman, Erin M.}, doi = {10.1073/pnas.2502424122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2502424122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neuronal processes contain the essential components for the late steps of ribosome biogenesis}, volume = {122}, year = {2025}, }
• (2025). A bacteria-based search for drugs against avian and swine flu yields a potent and resistance-resilient channel blocker. PNAS, 122(31), e2502240122. (www)

  @article{ , abstract = {Influenza represents a significant threat with seasonal epidemics that can transition to global pandemics, and cross-species infection presenting a continuous challenge. While vaccines and several antiviral drugs are available, constant genetic changes vitiate these prevention and treatment options. Consequently, we decided to search for inhibitors against one of the virus’s validated drug targets, its M2 channel that is blocked by aminoadamantanes. Regrettably, widespread mutations in M2 abolish the antiflu activity of said blockers. Therefore, we devised bacteria-based genetic assays that can screen for drugs against aminoadamantane-sensitive and resistant M2 channels and map the resistance potential of any identifiable blocker. Subsequent in cellulo testing and structure–activity relationship studies yielded a synergistic combination of two compounds, Theobromine and Arainosine, that exhibited remarkable antiviral activity by directly inhibiting the virus’s channel. The drug duo was potent against H1N1 pandemic swine flu, H5N1 pandemic avian flu, and aminoadamantane-resistant and sensitive strains alike, exhibiting activity that surpassed oseltamivir, the leading antiflu drug on the market. When this drug duo was tested in an animal model, it once more outperformed oseltamivir, considerably reducing disease symptoms and viral RNA progeny. Importantly, harnessing the bacterial genetic selection, we could demonstrate that the drug duo’s potential for eliciting drug resistance is significantly smaller and molecularly distinct from that of aminoadamantanes. In conclusion, the outcome of this study represents a new potential treatment option for influenza alongside an approach that is sufficiently general and readily applicable to other viral targets.}, archive = {J_PNAS}, author = {Lahiri, Hiya and Israeli, Eitan and Krugliak, Miriam and Basu, Kingshuk and Britan-Rosich, Yelena and Ravins Yaish, Tamar and Arkin, Isaiah T.}, doi = {10.1073/pnas.2502240122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2502240122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A bacteria-based search for drugs against avian and swine flu yields a potent and resistance-resilient channel blocker}, volume = {122}, year = {2025}, }
• (2025). Whole-genome duplication increases genetic diversity and load in outcrossing arabidopsis arenosa. PNAS, 122(31), e2501739122. (www)

  @article{ , abstract = {Genetic variation underpins evolutionary change, but mutation accumulation increases genetic load. Various factors affect the extent of load, such as population size and breeding system, but other important determinants remain unexplored. In particular, whole-genome duplication (WGD)—a pervasive macromutation occurring broadly across Eukaryotes—remains poorly understood in terms of its impact on neutral and selective processes within populations. Using iterative forward simulations and empirical analysis of 632 short- and 16 long-read sequenced individuals of Arabidopsis arenosa (in 23 diploid and 42 natural autotetraploid populations), we measure the effects of WGD on genome-wide diversity and mutation load. Our simulations show how genetic variation gradually rises in autotetraploids due to increased mutational target size. Moreover, mutation load increases due to relaxed purifying selection as ploidies rise, when deleterious mutations are masked by additional chromosome copies. Empirical data confirm these patterns, showing significant increases in nucleotide diversity, ratios of nonsynonymous to synonymous SNPs, and numbers of indels and large structural variants in A. arenosa autotetraploids. However, a rather modest increase in load proxies together with a broad distribution and niche of autotetraploids suggests load accumulation has not yet limited their successful expansion. Overall, we demonstrate a complex interplay between neutral processes and purifying selection in shaping genetic variation following WGD and highlight ploidy as an important determinant of mutation load, genetic diversity, and therefore adaptive potential in natural populations.}, archive = {J_PNAS}, author = {Vlček, Jakub and Hämälä, Tuomas and Vives Cobo, Cristina and Curran, Emma and Šrámková, Gabriela and Slotte, Tanja and Schmickl, Roswitha and Yant, Levi and Kolář, Filip}, doi = {10.1073/pnas.2501739122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2501739122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Whole-genome duplication increases genetic diversity and load in outcrossing arabidopsis arenosa}, volume = {122}, year = {2025}, }
• (2025). Orexin effect on physiological pulsations of the human brain. PNAS, 122(31), e2501578122. (www)

  @article{ , abstract = {Sleep promotes cerebrospinal fluid (CSF) to interstitial fluid (ISF) exchange in the brain facilitated by brain pulsations. Especially brain vasomotion and arterial pulsations modulated by noradrenaline drive the intracranial fluid dynamics. Narcolepsy type 1 (NT1) entails lessened orexinergic output to wake-promoting systems including the noradrenergic locus coeruleus. As arousal state and noradrenergic signaling affect CSF-ISF clearance, we chose patients with NT1 as a human orexin-targeted model of sleep-related pathology bridging the gap between healthy awake and sleep with respect to CSF flow pulsations. We also investigated the sensitivity of magnetic resonance encephalography to detect flow with a phantom model and sought to replicate earlier pulsation findings in sleep. In this case–control study, we used fast functional MRI to map brain pulsations in groups of healthy sleeping controls (n = 13), healthy awake controls (n = 79), and awake NT1 (n = 21) patients. We measured the very low frequency (0.008 to 0.1) and cardiorespiratory frequencies and calculated in each frequency band the coefficient of variation, spectral power, and full band spectral entropy to obtain brain pulsation maps. We uncovered a brain pulsation profile from healthy waking to sleep to a sleep-related pathology NT1 prominently affected in the vascular-related vasomotor and brain arterial pulsations. Our results established how drivers of brain hydrodynamics are affected by a specific loss of key neurotransmitter governing arousal compared to healthy sleep. We also showed with a phantom model that MREG is sensitive to flow-related signal changes and solidified evidence of brain pulsations in the healthy states of sleep and wakefulness.}, archive = {J_PNAS}, author = {Järvelä, Matti and Kananen, Janne and Helakari, Heta and Korhonen, Vesa and Huotari, Niko and Väyrynen, Tommi and Hautamäki, Katariina and Raitamaa, Lauri and Tuunanen, Johanna and Kallio, Mika and Piispala, Johanna and Ansakorpi, Hanna and Kiviniemi, Vesa}, doi = {10.1073/pnas.2501578122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2501578122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Orexin effect on physiological pulsations of the human brain}, volume = {122}, year = {2025}, }
• (2025). ELAPOR1 is a copper-dependent tethering factor driving proacrosomal vesicle fusion during acrosome biogenesis. PNAS, 122(31), e2501302122. (www)

  @article{ , abstract = {The acrosome is a crucial organelle essential for sperm function and male fertility. During acrosome biogenesis, numerous proacrosomal vesicles (PAVs) are transported to the concave region of the nuclear membrane and fuse to form the acrosome. However, the mechanisms governing the fusion of PAVs to form the acrosome remain poorly understood. Here, we identify endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1), a conserved protein, as a key factor in PAVs fusion during acrosome biogenesis. Male mice lacking Elapor1 ( Elapor1 −/− ) are infertile, exhibiting defective acrosome biogenesis and a globozoospermia-like phenotype. Using cryo-electron microscopy revealed that ELAPOR1 forms a square planar homodimer in cis, which assembles into a trans-tetramer via head-to-head homophilic interactions dependent on copper chelation. Notably, ELAPOR1 exhibits dual membrane orientation, with a predicted N in − C out topology and a noncanonical N out − C in topology in vesicles. The noncanonical N out − C in topology enables ELAPOR1 to function as a tethering factor bridging vesicles through head-to-head homophilic interactions. A mutant ELAPOR1 (ELAPOR1 4HA ) incapable of copper chelation forms cis homodimers but fails to mediate homophilic interactions in vitro, leading to defective PAVs fusion in mice, phenocopying the Elapor1 -deficient mice. Additionally, ELAPOR1 was shown to interact with soluble N-ethylmaleimide sensitive factor attachment protein receptors protein STX12. Conditional knockout of Stx12 in germ cells resulted in similar defects in acrosome biogenesis. Collectively, our findings suggest that ELAPOR1 functions as a tethering factor that regulates PAV fusion through a copper-dependent mechanism.}, archive = {J_PNAS}, author = {Shao, Tianyu and Ma, Jiahao and Tan, Xinshui and Shan, Hongcheng and Xu, Dan and Zhang, Kexin and Zheng, Sanduo and Wang, Fengchao}, doi = {10.1073/pnas.2501302122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2501302122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ELAPOR1 is a copper-dependent tethering factor driving proacrosomal vesicle fusion during acrosome biogenesis}, volume = {122}, year = {2025}, }
• (2025). Synergies between speciation and conservation science yield novel insights for mitigating the biodiversity crisis of the anthropocene. PNAS, 122(31), e2500713122. (www)

  @article{ , archive = {J_PNAS}, author = {Wang, Silu and Yoder, Anne D.}, doi = {10.1073/pnas.2500713122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2500713122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synergies between speciation and conservation science yield novel insights for mitigating the biodiversity crisis of the anthropocene}, volume = {122}, year = {2025}, }
• (2025). Nonsubstrate PI(4,5)P2 interacts with the interdomain linker to control electrochemical coupling in voltage-sensing phosphatase (VSP). PNAS, 122(31), e2500651122. (www)

  @article{ , abstract = {Voltage-sensing phosphatase (VSP) comprises a voltage sensor domain (VSD) and a cytoplasmic catalytic region (CCR), achieving a unique electrochemical signal conversion. Previous studies suggest that phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ), a membrane phospholipid known to be critical for activities of diverse voltage-gated ion channels, associates with a linker connecting the VSD with the CCR of VSP and regulates VSD-CCR coupling. However, the details of PI(4,5)P 2 interaction with the linker of VSP remain elusive. Here, we exploit advantage of sensitivity of a fluorescent unnatural amino acid, 3-(6-acetylnaphthalen-2-ylamino)-2-aminopropanoic acid (Anap), to changes in local environment to study interaction between PI(4,5)P 2 and the linker of Ciona intestinalis VSP (Ci-VSP). We found that a conserved tyrosine residue (Y255) as well as neighboring basic residues interacts with PI(4,5)P 2 and this interaction was maintained in G365A Ci-VSP mutant which lacks the substrate PI(4,5)P 2 at the active site and Ci-VSP/human phosphatase and tensin homolog (PTEN) chimera which does not dephosphorylate PI(4,5)P 2 , indicating that the linker interacts with nonsubstrate, regulatory PI(4,5)P 2 outside the active site. Molecular dynamics simulations demonstrated that the linker formed stable interaction with PI(4,5)P 2 in the activated state. These findings indicate that regulation of coupling to an effector region downstream of the VSD through PI(4,5)P 2 binding to the linker is shared among voltage-dependent membrane proteins.}, archive = {J_PNAS}, author = {Mizutani, Natsuki and Yonezawa, Yasushige and Nakagawa, Atsushi and Okamura, Yasushi}, doi = {10.1073/pnas.2500651122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2500651122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nonsubstrate PI(4,5)P2 interacts with the interdomain linker to control electrochemical coupling in voltage-sensing phosphatase (VSP)}, volume = {122}, year = {2025}, }
• (2025). Actions of the antiseizure drug carbamazepine in the thalamic reticular nucleus: Potential mechanism of aggravating absence seizures. PNAS, 122(31), e2500644122. (www)

  @article{ , abstract = {Carbamazepine (CBZ) is a widely used antiepileptic drug effective in managing partial and generalized tonic-clonic seizures. Despite its established therapeutic efficacy, CBZ has been reported to worsen seizures in another form of epilepsy, generalized absence seizures, in both clinical and experimental settings. In this study, we focused on thalamic reticular (RT) neurons, which regulate thalamocortical network activity in absence seizures, to investigate whether CBZ alters their excitability, thereby contributing to the exacerbation of seizures. Using ex vivo whole-cell patch-clamp electrophysiology, we found that CBZ selectively inhibits the tonic firing of RT neurons in a dose-dependent manner without affecting burst firing. At the RT-thalamocortical synapse, CBZ significantly increases the failure rate of GABAergic synaptic transmission, with greater effects on somatostatin–than parvalbumin-expressing RT neurons. In vivo EEG recordings and open-field behavior in Scn8a med± mouse model confirmed that CBZ treatment exacerbates absence seizures, increasing both seizure frequency and duration while reducing locomotor activity. In addition, CBZ further amplifies the preexisting reduction in tonic firing of RT neurons in Scn8a med± mice. These findings uncover a mechanism by which CBZ exacerbates absence seizures through selective inhibition of RT neuron excitability and disruption of GABAergic synaptic transmission. This work provides mechanistic insights into the paradoxical effects of CBZ and suggests potential avenues for optimizing epilepsy treatment strategies.}, archive = {J_PNAS}, author = {Jang, Sung-Soo and Agranonik, Nicole and Huguenard, John R.}, doi = {10.1073/pnas.2500644122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2500644122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Actions of the antiseizure drug carbamazepine in the thalamic reticular nucleus: Potential mechanism of aggravating absence seizures}, volume = {122}, year = {2025}, }
• (2025). Rare variants in BMAL1 are associated with a neurodevelopmental syndrome. PNAS, 122(31), e2427085122. (www)

  @article{ , abstract = {Through international gene-matching efforts, we identified 10 individuals with ultrarare heterozygous variants, including 5 de novo variants, in BMAL1 , a core component of the molecular clock. Instead of an isolated circadian phenotype seen with disease-causing variants in other molecular clock genes, all individuals carrying BMAL1 variants surprisingly share a clinical syndrome manifest as developmental delay and autism spectrum disorder, with variably penetrant sleep disturbances, seizures, and marfanoid habitus. Variants were functionally tested in cultured cells using a Per2 -promoter driven luciferase reporter and revealed both loss-of-function and gain-of-function changes in circadian rhythms. The tested BMAL1 variants disrupted PER2 mRNA cycling, but did not cause significant shifts in cellular localization or binding with CLOCK. Conserved variants were further tested in Drosophila , which confirmed variant-dependent effects on behavioral rhythms. Remarkably, flies expressing variant cycle , the ortholog of BMAL1 , also demonstrated deficits in short- and long-term memory, reminiscent of the highly prevalent developmental delay observed in our cohort. We suggest that ultrarare variants in the BMAL1 core clock gene contribute to a neurodevelopmental disorder.}, archive = {J_PNAS}, author = {Cuddapah, Vishnu Anand and Chen, Dechun and Cho, Bumsik and Moore, Rebecca and Suri, Mohnish and Safraou, Hana and Tran-Mau-Them, Frederic and Wilson, Ashley and Odgis, Jacqueline and Rehman, Atteeq U. and Saunders, Carol and Ganesan, Shiva and Jobanputra, Vaidehi and Scherer, Stephen W. and Helbig, Ingo and Sehgal, Amita}, doi = {10.1073/pnas.2427085122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2427085122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rare variants in BMAL1 are associated with a neurodevelopmental syndrome}, volume = {122}, year = {2025}, }
• (2025). Cryo-EM structure and polar assembly of the PS2 S-layer of corynebacterium glutamicum. PNAS, 122(31), e2426928122. (www)

  @article{ , abstract = {The polar-growing Corynebacteriales have a complex cell envelope architecture characterized by the presence of a specialized outer membrane composed of mycolic acids. In some Corynebacteriales , this mycomembrane is further supported by a proteinaceous surface layer or “S-layer,” whose function, structure, and mode of assembly remain largely enigmatic. Here, we isolated ex vivo PS2 S-layers from the industrially important Corynebacterium glutamicum and determined its atomic structure by 3D cryo-EM reconstruction. PS2 monomers consist of a six-helix bundle “core,” a three-helix bundle “arm,” and a C-terminal transmembrane (TM) helix. The PS2 core oligomerizes into hexameric units anchored in the mycomembrane by a channel-like coiled-coil of the TM helices. The PS2 arms mediate trimeric lattice contacts, crystallizing the hexameric units into an intricate semipermeable lattice. Using pulse-chase live cell imaging, we show that the PS2 lattice is incorporated at the poles, coincident with the actinobacterial elongasome. Finally, phylogenetic analysis shows a paraphyletic distribution and dispersed chromosomal location of PS2 in Corynebacteriales as a result of multiple recombination events and losses. These findings expand our understanding of S-layer biology and enable applications of membrane-supported self-assembling bioengineered materials.}, archive = {J_PNAS}, author = {Sogues, Adrià and Sleutel, Mike and Petit, Julienne and Megrian, Daniela and Bayan, Nicolas and Wehenkel, Anne Marie and Remaut, Han}, doi = {10.1073/pnas.2426928122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2426928122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryo-EM structure and polar assembly of the PS2 S-layer of corynebacterium glutamicum}, volume = {122}, year = {2025}, }
• (2025). Semantic change in adults is not primarily a generational phenomenon. PNAS, 122(31), e2426815122. (www)

  @article{ , abstract = {A central question in the study of language change is whether or not such change is generational. If a language changes over time generation-by-generation, the process looks as follows: New generations of speakers introduce innovations, while older speakers conserve their usage patterns, and the language changes as new generations replace older ones. At the opposite extreme, language change could be a zeitgeist phenomenon, in which changes are universally adopted by speakers simultaneously, regardless of age or generational cohort. This paper asks this question in the context of word meaning change. We analyze meaning change in over 100 words across more than 7.9 million U.S. congressional speeches, to observe whether, when a word sense rises or falls in prominence, adult speakers from different generations uniformly adopt it, or those from older generations conserve their prior usage. Using language model-based word sense induction methods, we identify different senses of each word, and then model the prevalence of each of these word senses as a function of time and speaker age. We find that most words show a small but statistically significant effect of speaker age; across almost 140 y of Congress, older speakers typically take longer than younger speakers to follow changes in word usage, but nevertheless do so within a few years. Our findings indicate that despite minor age-based differences, word meaning change among mature speakers is likely not a generational process, but rather a zeitgeist process, in which older adult speakers can readily adopt new word usage patterns.}, archive = {J_PNAS}, author = {Kamath, Gaurav and Yang, Michelle and Reddy, Siva and Sonderegger, Morgan and Card, Dallas}, doi = {10.1073/pnas.2426815122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2426815122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Semantic change in adults is not primarily a generational phenomenon}, volume = {122}, year = {2025}, }
• (2025). Exact linear theory of perturbation response in a space- and feature-dependent cortical circuit model. PNAS, 122(31), e2426758122. (www)

  @article{ , abstract = {What are the principles that govern the responses of cortical networks to their inputs and the emergence of these responses from recurrent connectivity? Recent experiments have probed these questions by measuring cortical responses to two-photon optogenetic perturbations of single cells in the mouse primary visual cortex. A robust theoretical framework is needed to determine the implications of these responses for cortical recurrence. Here, we propose a formulation of the dependence of cell-type-specific connectivity on spatial distance that yields an exact analytic solution for the linear perturbation response of a model with multiple cell types and space- and feature-dependent connectivity. Importantly and unlike previous approaches, the solution is valid in regimes of strong as well as weak intracortical coupling. Analysis reveals the structure of connectivity implied by various features of single-cell perturbation responses, such as the surprisingly narrow spatial radius of nearby excitation beyond which inhibition dominates, the number of transitions between mean excitation and inhibition thereafter, and the dependence of these responses on feature preferences. Comparison of these results to existing optogenetic perturbation data yields constraints on cell-type-specific connection strengths and their tuning dependence. Finally, we provide experimental predictions regarding the response of inhibitory neurons to single-cell perturbations and the modulation of perturbation response by neuronal gain.}, archive = {J_PNAS}, author = {Chau, Ho Yin and Miller, Kenneth D. and Palmigiano, Agostina}, doi = {10.1073/pnas.2426758122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2426758122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exact linear theory of perturbation response in a space- and feature-dependent cortical circuit model}, volume = {122}, year = {2025}, }
• (2025). Active bacterial baths in droplets. PNAS, 122(31), e2426096122. (www)

  @article{ , abstract = {Suspensions of self-propelled objects represent a novel paradigm in colloidal science. In such “active baths,” traditional concepts such as Brownian motion, fluctuation–dissipation relations, and work extraction from heat reservoirs, must be extended beyond the conventional framework of thermal baths. Unlike thermal baths, which are characterized by a single parameter, the temperature, the fundamental descriptors of an active bath remain elusive. Particularly relevant are confined environments, which are common conditions for bacteria in Nature and in microbioreactor devices. In this study, buoyant passive tracers are employed as generalized probes to extract the properties of an active bath comprising motile bacteria confined within a droplet. By describing the bacterial suspension as a colored noise acting on the tracer, we extract the temporal memory τ b and characteristic intensity u b of such noise, finding that τ b varies little across the explored experimental conditions and u b is positively correlated with bacterial concentration. Notably, we put forward the generalizing concept of “bath diffusivity,” D b = u b 2 τ b , as a central predictor for the momentum transfer properties of this out-of-equilibrium situation. We show that D b scales linearly with bacterial concentration, modulated by a factor representing the role of confinement, expressed as the ratio of the confining radius to the probe radius. This finding, while still awaiting a complete theoretical explanation, offers insights into the transport or mixing properties of confined active baths and paves the way for a deeper understanding of active emulsions driven by confined active matter.}, archive = {J_PNAS}, author = {Villalobos-Concha, Cristian and Liu, Zhengyang and Ramos, Gabriel and Goral, Martyna and Lindner, Anke and López-León, Teresa and Clément, Eric and Soto, Rodrigo and Cordero, María Luisa}, doi = {10.1073/pnas.2426096122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2426096122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Active bacterial baths in droplets}, volume = {122}, year = {2025}, }
• (2025). Identification of an on-pathway intermediate illuminates the kinetic competition between protein folding and misfolding. PNAS, 122(31), e2425999122. (www)

  @article{ , abstract = {Our current understanding of protein folding is based predominantly on studies of small (<150 aa) proteins that refold reversibly from a chemically denatured state. However, as protein length increases so does the competition between off-pathway misfolding and on-pathway folding, creating a more complex energy landscape ("folding funnel"). Little is known about how intermediates populated during the folding of larger proteins affect navigation of this more complex landscape. Previously, we reported extremely slow folding rates for the 539 aa β-helical passenger domain of pertactin (P.69T), including conditions that favor the formation of a kinetically trapped, off-pathway partially folded state (PFS). Existence of an on-pathway intermediate for P.69T folding was speculated but its characterization remained elusive. In this work, we exploited the extremely slow kinetics of PFS unfolding to develop a double-jump “denaturant challenge” assay. With this assay, we identified a transient unfolding intermediate, PFS*, that adopts a similar structure to PFS, including C-terminal folded structure and a disordered N terminus, yet unfolds much more quickly than PFS. Additional experiments revealed that PFS* also functions as an on-pathway intermediate for P.69T folding. Collectively, these results support a C-to-N-terminal model for P.69T folding, with folding initiated in the C-terminus with the rate-limiting formation of the transient on-pathway PFS* intermediate, which sits at the junction of the kinetic competition between folding and misfolding. Notably, processive folding from C-to-N terminus also occurs during C-to-N-terminal translocation of P.69T across the bacterial outer membrane. These results illuminate the crucial role of kinetics when navigating a complex energy landscape for protein folding.}, archive = {J_PNAS}, author = {Luan, Qing and Clark, Patricia L.}, doi = {10.1073/pnas.2425999122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2425999122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identification of an on-pathway intermediate illuminates the kinetic competition between protein folding and misfolding}, volume = {122}, year = {2025}, }
• (2025). Evolutionary features in a minimal physical system: Diversity, selection, growth, inheritance, and adaptation. PNAS, 122(31), e2425753122. (www)

  @article{ , abstract = {We present a simple physical model that recapitulates several features of biological evolution, while being based only on thermally driven attachment and detachment of elementary building blocks. Through its dynamics, this model samples a large and diverse array of nonequilibrium steady states, both within and between independent trajectories. These dynamics exhibit directionality with a quantity that increases in time, selection, and preferential spatial expansion of particular states, as well as inheritance in the form of correlated compositions between successive states, and environment-dependent adaptation. The model challenges common conceptions regarding the requirements for life-like properties: It does not involve separate mechanisms for metabolism, replication, and compartmentalization; stores and transmits digital information without template replication or assembly of large molecules; exhibits selection both without and with reproduction; and undergoes growth without autocatalysis. As the model is based on generic physical principles, it is amenable to various experimental implementations.}, archive = {J_PNAS}, author = {Bunin, Guy and Rivoire, Olivier}, doi = {10.1073/pnas.2425753122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2425753122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolutionary features in a minimal physical system: Diversity, selection, growth, inheritance, and adaptation}, volume = {122}, year = {2025}, }
• (2025). Micro magnetic resonance spectroscopy for noninvasive metabolic screening of mammalian embryos and oocytes. PNAS, 122(31), e2424459122. (www)

  @article{ , abstract = {Analyzing cellular health and metabolism without compromising cell integrity is a major challenge. We present a noninvasive technique using micro magnetic resonance spectroscopy (micro MRS) for nondestructive metabolic fingerprinting at the single-cell scale. This is an application of micro MRS to bovine preimplantation embryos (~8 cells) and oocytes (single cell), with measurements performed on a total of over 150 samples. Among various applications, this method holds significant potential for assisted reproductive technologies (ART), where metabolic assessments of preimplantation embryos could improve treatment outcomes. Early results indicate that classification models using micro MRS data effectively distinguish embryos with high developmental potential and show correlation with oocytes maturity. Furthermore, a multigenerational safety study in a mouse model revealed no adverse effects from embryo exposure to static magnetic field. These findings indicate that micro MRS is a promising, safe tool for assessing embryo metabolism, potentially improving the efficiency and outcomes of ART.}, archive = {J_PNAS}, author = {Sivelli, Giulia and Barakat, Arthur and Marable, Kathryn B. and Gruet, Guillaume and Bitetti, Serena L. and Behr, Barry and Lodde, Valentina and Luciano, Alberto Maria and Herrera, Carolina and Blom, Michelle and Grisi, Marco}, doi = {10.1073/pnas.2424459122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2424459122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Micro magnetic resonance spectroscopy for noninvasive metabolic screening of mammalian embryos and oocytes}, volume = {122}, year = {2025}, }
• (2025). Evolution and evolvability of rifampicin resistance across the bacterial tree of life. PNAS, 122(31), e2424307122. (www)

  @article{ , abstract = {Predicting the ability of bacteria to develop antibiotic resistance is challenging, especially for the vast majority of species for which no experimental data are available. Here, we investigated the evolvability and intrinsic presence of rifampicin resistance across the bacterial tree of life. We compiled a comprehensive panel of known rifampicin resistance mutations, comprising 57 amino acid substitutions within the gene rpoB . We then screened more than 18,000 genomes from all major bacterial groups for the presence of those mutations and determined which mutations can evolve through point mutations. Our results demonstrate that although the evolvability of individual mutations varies considerably across species, overall predicted evolvability is high and relatively homogeneous across bacterial taxa. Rifampicin resistance mutations are present intrinsically in 8% of species that tend to be phylogenetically clustered. Our analysis provides a global picture of the mutational landscape of rifampicin resistance, affording insight into existing observations and informing future discoveries such as the identification of probiotics.}, archive = {J_PNAS}, author = {Bolourchi, Negin and Brown, Christopher R. P. and Letten, Andrew D. and Engelstädter, Jan}, doi = {10.1073/pnas.2424307122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2424307122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolution and evolvability of rifampicin resistance across the bacterial tree of life}, volume = {122}, year = {2025}, }
• (2025). SMARCA5 restricts chromatin accessibility to promote male meiosis and fertility in mammals. PNAS, 122(31), e2422356122. (www)

  @article{ , abstract = {Establishment of correct chromatin configuration in male meiosis is essential for sperm formation and male fertility. However, how chromatin remodeling contributes to meiotic progression in male germ cells is not well understood. Here, we find that the ISWI family ATP-dependent chromatin remodeling factor SMARCA5 (SNF2H) plays a critical role in regulating meiotic prophase progression during spermatogenesis in mice. Male mice with germ cell-specific depletion of SMARCA5 are infertile and unable to form sperm. Conditional knockout of Smarca5 results in meiotic progression failure, with abnormal spermatocytes appearing at the pachytene stage of meiosis I and subsequent accumulation of defects in chromosome synapsis, DNA repair, and transposon control, along with elevated rates of apoptosis. SMARCA5 interacts with known cofactors BAZ1A/ACF and BAZ2A/TIP5, as well as numerous DNA repair and recombination factors, in the testis. Single cell RNA sequencing confirmed failure to achieve a normal transcriptional state in premeiotic spermatogonia and during meiotic prophase, with reduced levels of meiotic gene transcripts and increasingly aberrant transcriptional states at later stages of spermatogenic development. Transcriptional misregulation in meiotic prophase was preceded by a widespread increase in chromatin accessibility in spermatogonia at promoters and repeat elements. Our findings suggest that SMARCA5 restricts chromatin accessibility in male germ cells to guide appropriate chromatin remodeling during meiotic recombination, contrasting with its role promoting chromatin accessibility during female meiosis.}, archive = {J_PNAS}, author = {Kataruka, Shubhangini and Malla, Aushaq B. and Rainsford, Shannon R. and Walters, Benjamin William and Heuer, Rachel A. and Marshall, Kira L. and Lesch, Bluma J.}, doi = {10.1073/pnas.2422356122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2422356122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SMARCA5 restricts chromatin accessibility to promote male meiosis and fertility in mammals}, volume = {122}, year = {2025}, }
• (2025). Early-life human CD8+ t cells exhibit rapid, short-lived effector responses and a unique transcription factor landscape. PNAS, 122(31), e2421106122. (www)

  @article{ , abstract = {Neonates and infants are distinct in their clinical and cellular responses to viral infections, with neonatal CD8 + T cells displaying innate-like characteristics and a low threshold for T cell receptor activation. However, specific molecular programs that drive these unique responses are incompletely understood, particularly in humans, and targetable pathways to modulate viral illness in this vulnerable population remain to be elucidated. Early-life immune responses may be developmentally programmed to prioritize avoidance of tissue immunopathology, especially while maternal immunoglobulin provides passive immunity. We set out to define the unique response characteristics and transcription factor landscape of neonatal human CD8 + T cells. Here, we report evidence that naïve neonatal human CD8 + T cells are poised for an accelerated effector switch, with elevations of killer cell lectin-like receptor G1 (KLRG1), killer cell lectin-like receptor B1 (KLRB1/CD161), Fc epsilon receptor I-gamma ( FCER1G ), DNAX accessory molecule-1 (DNAM1/CD226), granzymes, tumor necrosis factor alpha (TNFα), interleukin 2 (IL-2), and glycolysis compared to naïve adult CD8 + T cells. Further, rapid proliferation and cell death occur upon activation of neonatal CD8 + T cells, with cell viability largely rescued by IL-2 or IL-7. These features are coupled with a unique transcription factor landscape, including high expression of thymocyte selection associated high mobility group box (TOX) and HELIOS ( IKZF2 ), and these signatures continue in postnatal life until at least 2 mo of age. We conclude that early-life human CD8 + T cells maintain a unique transcriptional state associated with an accelerated effector switch and short-lived effector program, revealing key nodes of regulation relevant for the unique immunobiology of neonatal humans.}, archive = {J_PNAS}, author = {Brodsky, Nina N. and Chakder, Monisha and Kumar, Dinesh Babu Uthaya and Barmada, Anis and Wang, Julia and Gu, Weihong and Olaloye, Oluwabunmi and Ramaswamy, Anjali and Wats, Aanchal and Konnikova, Liza and Lucas, Carrie L.}, doi = {10.1073/pnas.2421106122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2421106122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Early-life human CD8+ t cells exhibit rapid, short-lived effector responses and a unique transcription factor landscape}, volume = {122}, year = {2025}, }
• (2025). Indigenous territories and protected areas are crucial for ecosystem connectivity in the amazon basin. PNAS, 122(31), e2418189122. (www)

  @article{ , abstract = {Ecosystem connectivity—the uninterrupted flow of natural processes within and among ecosystems—is critical for maintaining healthy ecosystem functions. However, in the Amazon drainage basin, multiple anthropogenic activities are rapidly disrupting connectivity. To assess the severity of this problem, we analyzed the spatial distributions of six major anthropogenic activities: dam construction, deforestation, fire, mining, oil and gas exploitation, and roads. We examined their impacts across four key landscapes: Amazonian Andes, lowland nonflooded forests, wetlands, and rivers. Using a resistance-based connectivity model, we quantified connectivity across terrestrial, wetland, and river ecosystems and found a marked decline in connectivity across the basin. A central focus of our study was the role of Indigenous Territories and Protected Areas (ITPAs), which collectively cover over 50% of the basin. Our findings show that ITPAs sustain significantly high levels of ecosystem connectivity. Only 14 to 16% of ITPA land is impacted by anthropogenic activities, compared to 38% in unprotected areas. Terrestrial ecosystems in the southern and eastern Amazon are heavily impacted by deforestation, mining, and fires, with significantly higher connectivity inside ITPAs than in unprotected areas ( P < 0.01). Wetlands and riverine ecosystems also face severe fragmentation, particularly from dams and illegal mining—but maintain stronger connectivity within ITPAs (wetlands: P < 0.01; rivers: P < 0.001), with the few remaining free-flowing Andean rivers increasingly isolated from the lowland Amazon. Strengthening governance and sustainable initiatives in ITPAs, in partnership with local inhabitants, represents an expedient, efficient, and cost-effective strategy for conserving ecosystem connectivity in the Amazon basin.}, archive = {J_PNAS}, author = {Duarte Ritter, Camila and Muñoz, Jesús and Fabrício Machado, Arielli and Albert, James S. and Ribas, Camila C. and Carnaval, Ana C. and Ulloa Ulloa, Carmen and Carrillo, Juan D. and Tuomisto, Hanna and Armenteras, Dolors and Guayasamin, Juan M.}, doi = {10.1073/pnas.2418189122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2418189122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Indigenous territories and protected areas are crucial for ecosystem connectivity in the amazon basin}, volume = {122}, year = {2025}, }
• (2025). Prg4+ fibroadipogenic progenitors in muscle are crucial for bone fracture repair. PNAS, 122(31), e2417806122. (www)

  @article{ , abstract = {Clinically, compromised fracture healing often occurs at sites with less muscle coverage and muscle flaps can provide the necessary healing environment for appropriate healing in severe bone loss. However, the underlying mechanisms are largely unknown. Here, we established a mouse reporter model for studying muscle cell contribution to bone fracture repair. Analyzing skeletal muscle scRNA-seq datasets revealed that Prg4 marks a fibroadipogenic progenitor (FAP) subpopulation. In mice, Prg4 + cells were specifically located in the skeletal muscle, but not at the periosteum or inside cortical bone. These cells expressed FAP markers, responded to muscle injury, and became periosteal cells under normal and muscle injury conditions. Fracture fragmented muscle fibers, rapidly expanded Prg4 + FAPs at the injury site and promoted their migration into the fracture gap. Later, they gave rise to many chondrocytes, osteoblasts, and osteocytes in the outer periphery of callus next to muscle. In repaired bones, the descendants of Prg4 + FAPs were detected as mesenchymal progenitors in the periosteum and osteocytes at the prior fracture site. A second fracture activated those cells and stimulated them to become osteoblasts in the inner part of callus. Importantly, ablation of Prg4 + FAPs impaired fracture healing and functional repair. In an intramembranous bone injury model (drill-hole), Prg4 + FAPs became periosteal cells, but their contribution to bone defect repair was significantly less than in fractures. Taken together, we demonstrate the critical role of FAPs in endochondral bone repair and uncover a mechanism by which mesenchymal progenitors transform from muscle to cortical bone.}, archive = {J_PNAS}, author = {He, Qi and Lu, Jiawei and Liang, Qiushi and Yao, Lutian and Sun, Tingfang and Wang, Huan and Duffy, Michael and Jiang, Xi and Lin, Yuewei and Lee, Ji-Hyung and Ahn, Jaimo and Dyment, Nathaniel A. and Mourkioti, Foteini and Boerckel, Joel D. and Qin, Ling}, doi = {10.1073/pnas.2417806122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2417806122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prg4+ fibroadipogenic progenitors in muscle are crucial for bone fracture repair}, volume = {122}, year = {2025}, }
• (2025). A minimal model of panimmunity maintenance by horizontal gene transfer in the ecological dynamics of bacteria and phages. PNAS, 122(31), e2417628122. (www)

  @article{ , abstract = {Bacteria and phages have been in an ongoing arms race for billions of years. To resist phages bacteria have evolved numerous defense systems, which nevertheless are still overcome by counterdefense mechanisms of specific phages. These defense/counterdefense systems are a major element of microbial genetic diversity and have been demonstrated to propagate between strains by horizontal gene transfer (HGT). It has been proposed that the totality of defense systems found in microbial communities collectively form a distributed “pan-immune” system with individual elements moving between strains via ubiquitous HGT. Here, we formulate a Lotka–Volterra type model of a bacteria/phage community interacting via a combinatorial variety of defense/counterdefense systems and show that HGT enables stable maintenance of diverse defense/counterdefense genes in the microbial pan-genome even when individual microbial strains inevitably undergo extinction. This stability requires the HGT rate to be sufficiently high to ensure that some descendant of a “dying” strain survives, thanks to the immunity acquired through HGT from the community at large, thus establishing a new strain. This mechanism of persistence for the pan-immune gene pool is fundamentally similar to the “island migration” model of ecological diversity, with genes moving between genomes instead of species migrating between islands.}, archive = {J_PNAS}, author = {Cui, Wenping and Fendley, Jemma M. and Srikant, Sriram and Shraiman, Boris I.}, doi = {10.1073/pnas.2417628122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2417628122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A minimal model of panimmunity maintenance by horizontal gene transfer in the ecological dynamics of bacteria and phages}, volume = {122}, year = {2025}, }
• (2025). AI–AI bias: Large language models favor communications generated by large language models. PNAS, 122(31), e2415697122. (www)

  @article{ , abstract = {Are large language models (LLMs) biased in favor of communications produced by LLMs, leading to possible antihuman discrimination? Using a classical experimental design inspired by employment discrimination studies, we tested widely used LLMs, including GPT-3.5, GPT-4 and a selection of recent open-weight models in binary choice scenarios. These involved LLM-based assistants selecting between goods (the goods we study include consumer products, academic papers, and film-viewings) described either by humans or LLMs. Our results show a consistent tendency for LLM-based AIs to prefer LLM-presented options. This suggests the possibility of future AI systems implicitly discriminating against humans as a class, giving AI agents and AI-assisted humans an unfair advantage.}, archive = {J_PNAS}, author = {Laurito, Walter and Davis, Benjamin and Grietzer, Peli and Gavenčiak, Tomáš and Böhm, Ada and Kulveit, Jan}, doi = {10.1073/pnas.2415697122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2415697122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {AI–AI bias: Large language models favor communications generated by large language models}, volume = {122}, year = {2025}, }
• (2025). A granulin-positive macrophage subtype in mycobacterial granulomas alleviates tissue damage by limiting excessive inflammation. PNAS, 122(31), e2413946122. (www)

  @article{ , abstract = {Granulomas play a crucial role in the pathology of tuberculosis, but the immune environment governing their formation remains largely unknown. To explore the dynamic changes in the immune microenvironment during the formation of tuberculous granulomas, we infected adult zebrafish with Mycobacterium marinum and then examined uninfected and infected kidneys, as well as large and small granulomas in the kidneys. Using single-cell RNA sequencing technology, we identified two major macrophage subpopulations in the hematopoietic tissue (kidney) of zebrafish under uninfected physiological conditions: monocyte derived and tissue-resident macrophages. Interestingly, the infection induced the emergence of epithelioid cells and a previously undescribed grna.2 + macrophage subpopulation. Depletion of grna.2 + macrophages with the nitroreductase-metronidazole ablation system resulted in shortened zebrafish survival after infection, increased bacterial load, and more granulomas, especially necrotic granulomas. Depletion of grna.2 + macrophages also produced a denser granuloma structure with fewer T cells. RNA-seq and flow cytometry analysis revealed that depletion of grna.2 + macrophages led to upregulated inflammatory signaling pathways, including tnfα and il1β , and increased macrophage lytic cell death. Similarly, in samples from tuberculosis patients, we also identified GRN-positive macrophages, which exhibit similar anti-inflammatory functions. This subset of grna.2 + macrophages present in developing granulomas can suppress excessive inflammatory responses to alleviate macrophage lytic death, reduce tissue damage, promote T cell infiltration and ultimately help control mycobacterial growth in vivo.}, archive = {J_PNAS}, author = {Luo, Geyang and Wen, Yanling and Wang, Min and Wang, Hao and Li, Duoduo and Liao, Mingfeng and Zeng, Dong and Luo, Sizhu and Niu, Liangfei and Sun, Tao and Sun, Peng and Qin, Liyi and Li, Weimin and Song, Shu and Takiff, Howard E. and Zhang, Shuye and Gao, Qian and Zhang, Zheng and Yan, Bo}, doi = {10.1073/pnas.2413946122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2413946122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A granulin-positive macrophage subtype in mycobacterial granulomas alleviates tissue damage by limiting excessive inflammation}, volume = {122}, year = {2025}, }
• (2025). Data-driven equation discovery reveals nonlinear reinforcement learning in humans. PNAS, 122(31), e2413441122. (www)

  @article{ , abstract = {Computational models of reinforcement learning (RL) have significantly contributed to our understanding of human behavior and decision-making. Traditional RL models, however, often adopt a linear approach to updating reward expectations, potentially oversimplifying the nuanced relationship between human behavior and rewards. To address these challenges and explore models of RL, we utilized a method of model discovery using equation discovery algorithms. This method, currently used mainly in physics and biology, attempts to capture data by proposing a differential equation from an array of suggested linear and nonlinear functions. Using this method, we were able to identify a model of RL which we termed the Quadratic Q-Weighted model. The model suggests that reward prediction errors obey nonlinear dynamics and exhibit negativity biases, resulting in an underweighting of reward when expectations are low, and an overweighting of the absence of reward when expectations are high. We tested the generalizability of our model by comparing it to classical models used in nine published studies. Our model surpassed traditional models in predictive accuracy across eight out of these nine published datasets, demonstrating not only its generalizability but also its potential to offer insights into the complexities of human learning. This work showcases the integration of a behavioral task with advanced computational methodologies as a potent strategy for uncovering the intricate patterns of human cognition, marking a significant step forward in the development of computational models that are both interpretable and broadly applicable.}, archive = {J_PNAS}, author = {LaFollette, Kyle J. and Yuval, Janni and Schurr, Roey and Melnikoff, David and Goldenberg, Amit}, doi = {10.1073/pnas.2413441122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2413441122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Data-driven equation discovery reveals nonlinear reinforcement learning in humans}, volume = {122}, year = {2025}, }
• (2025). Mobile gene clusters and coexpressed plant–rhizobium pathways drive partner quality variation in symbiosis. PNAS, 122(31), e2411831122. (www)

  @article{ , abstract = {Plant–microbe symbioses such as the legume–rhizobium mutualism are vital in the web of ecological relationships within both natural and managed ecosystems, influencing primary productivity, crop yield, and ecosystem services. The outcome of these interactions for plant hosts varies quantitatively and can range from highly beneficial to even detrimental depending on natural genetic variation in microbial symbionts. Here, we take a systems genetics approach, harnessing the genetic diversity present in wild rhizobial populations to predict genes and molecular pathways crucial in determining partner quality, i.e., the benefits of symbiosis for legume hosts. We combine traits, dual-RNAseq of both partners from active nodules, pangenomics/pantranscriptomics, and Weighted Gene Co-expression Network Analysis (WGCNA) for a panel of 20 Sinorhizobium meliloti strains that vary in symbiotic partner quality. We find that genetic variation in the nodule transcriptome predicts host plant biomass, and WGCNA reveals networks of genes in plants and rhizobia that are coexpressed and associated with high-quality symbiosis. Presence–absence variation of gene clusters on the symbiosis plasmid (pSymA), validated in planta, is associated with high or low-quality symbiosis and is found within important coexpression modules. Functionally our results point to management of oxidative stress, amino acid and carbohydrate transport, and NCR peptide signaling mechanisms in driving symbiotic outcomes. Our integrative approach highlights the complex genetic architecture of microbial partner quality and raises hypotheses about the genetic mechanisms and evolutionary dynamics of symbiosis.}, archive = {J_PNAS}, author = {Riaz, Muhammad Rizwan and Sosa Marquez, Ivan and Lindgren, Hanna and Levin, Garrett and Doyle, Rebecca and Romero, Mario Cerón and Paoli, Julia C. and Drnevich, Jenny and Fields, Christopher J. and Geddes, Barney A. and Marshall-Colón, Amy and Heath, Katy D.}, doi = {10.1073/pnas.2411831122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2411831122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mobile gene clusters and coexpressed plant–rhizobium pathways drive partner quality variation in symbiosis}, volume = {122}, year = {2025}, }
• (2025). The effect of habitat loss and fragmentation on isolation by distance and divergence. PNAS, 122(31), e2410951122. (www)

  @article{ , abstract = {Natural habitats have undergone drastic changes in quality, continuity, and extent during the Pleistocene, influencing the distribution of many species. More recently, human activities have converted continuous habitats into fragmented and isolated patches. Recent meta-analyses suggest that habitat loss and fragmentation (HL&F) have negatively impacted the genetic diversity of species but very few studies have analyzed the consequences of HL&F on the spatial distribution of genetic diversity and on isolation by distance (IBD) patterns (i.e., correlations between genetic and geographical distances) observed in many species. In this work, we use spatial simulations to investigate the speed at which IBD patterns generated in continuous habitats are lost in a context of HL&F. We characterized the behavior of IBD in the case of i) instantaneous HL&F, ii) gradual (two-steps) HL&F, and iii) range expansion followed by instantaneous HL&F. In addition, we show that a spatially explicit theoretical framework based on previous IBD theoretical results can be modified and applied to a toroidal stepping-stone model undergoing HL&F. Our results suggest that IBD patterns can be maintained for long periods of time after HL&F, thus pointing to the long-term persistence of signatures associated to past habitat connectivity in the genetic diversity of many species, even if they went through major and sometimes ancient fragmentation events. This suggests that some present-day fragmented species, who still exhibit significant IBD patterns, may have been partly disconnected for very long periods, on the order of tens of thousands of years for species with long generation time.}, archive = {J_PNAS}, author = {Sgarlata, Gabriele Maria and Maié, Tiago and de Zoeten, Tiago and Salmona, Jordi and Rasteiro, Rita and Chikhi, Lounès}, doi = {10.1073/pnas.2410951122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2410951122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The effect of habitat loss and fragmentation on isolation by distance and divergence}, volume = {122}, year = {2025}, }
• (2025). The power of coalescent methods for inferring recent and ancient gene flow in endangered bactrian camels. PNAS, 122(31), e2410949122. (www)

  @article{ , abstract = {Genomic sequence data harbor valuable information concerning the history of species divergence and interspecific gene flow and may offer important insights into conservation of endangered species. However, extracting such information from genomic data requires powerful statistical inference methods. A recent analysis of genomic sequence data found little evidence for gene flow from domestic Bactrian camels into the endangered wild Bactrian species. Nevertheless, the methods used to infer gene flow are based on data summaries and lack the power and precision to represent the complex phylogenetic history of the species with gene flow. Here, we apply Bayesian methods to genomic sequence data to test for both recent and ancient gene flow among the three species in the genus Camelus and to estimate the strength and timing of gene flow. We detect a strong signal of gene flow from domestic into wild Bactrian camels, confirming early evidence based on mitochondrial DNA and the Y chromosome. Overall gene flow appears to affect the autosomal genome uniformly, with similar effective rates of gene flow for exonic and noncoding regions. Estimation of species divergence times is seriously affected if gene flow is not accommodated in the analysis. Our results highlight the power of the coalescent model in analysis of genomic data and the utility of the coding as well as noncoding parts of the genome in elucidating the evolutionary history of modern species.}, archive = {J_PNAS}, author = {Zhu, Tianqi and Wang, Zhen and Yang, Ziheng}, doi = {10.1073/pnas.2410949122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2410949122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The power of coalescent methods for inferring recent and ancient gene flow in endangered bactrian camels}, volume = {122}, year = {2025}, }
• (2025). From biologging to conservation: Tracking individual performance in changing environments. PNAS, 122(31), e2410947122. (www)

  @article{ , abstract = {Under an accelerating biodiversity crisis, increased urbanization, habitat fragmentation, and climate change require new approaches to assess conservation impact. We argue that animal biologging is a cost-effective method for monitoring biodiversity at its source, including tracked animals and the habitats they occupy. Biologging, or animal-mounted sensors to record data, can act as a reporting, measurement, and verification system, and deliver direct insights into environments of selection. Using a case study of migrating white storks ( Ciconia ciconia ), we show that biologging yields real-time measurements of individual performance, mechanistic insights into environments of selection, and the potential for gene flow across anthropogenically influenced habitats. These insights can inform the success of biodiversity targets and conservation initiatives and improve real-time species management. At the global scale, we further illustrate that biologging studies display substantial bias in the types of environments and human conditions sampled. Studies appear biased toward sparsely populated areas and remain particularly rare in highly urbanized areas, areas experiencing high rates of recent forest fragmentation, and key areas for global biodiversity conservation efforts. We highlight the need for equitable access to technology to leverage the biodiversity potential of biologging in the Global South. Advances in software-defined tracking technology will soon give real-time information on energy budgets, survival, reproduction, and ultimately demographic processes and population-level parameters. When deployed into areas most needed, biologging can operationalize access to key measures of biodiversity maintenance such as gene flow, especially in difficult-to-access areas that are key to the future persistence of a species.}, archive = {J_PNAS}, author = {Ellis-Soto, Diego and Flack, Andrea and Strandburg-Peshkin, Ariana and Wild, Timm A. and Williams, Hannah J. and O’Mara, M. Teague}, doi = {10.1073/pnas.2410947122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2410947122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {From biologging to conservation: Tracking individual performance in changing environments}, volume = {122}, year = {2025}, }
• (2025). Translocations contribute to population rescue in an imperiled woodpecker. PNAS, 122(31), e2410946122. (www)

  @article{ , abstract = {Anthropogenic destruction and fragmentation of habitat restrict many species to small, isolated populations, which often experience high extirpation risk. Restoring connectivity through translocations is one approach for mitigating the demographic and genetic perils faced by small populations. However, translocation interventions often lack substantial postrelease monitoring, and thus important information including the performance of translocated individuals, the long-term impacts on the recipient population, and the extent to which management objectives are fulfilled over time are often poorly known. Here, we examined the establishment dynamics and long-term outcomes of translocations from multiple donor populations into an intensively monitored population of the federally threatened red-cockaded woodpecker. We found evidence that translocations contributed to population growth and led to genetic admixture within the population. The translocated birds provided direct demographic benefits through high rates of establishment, breeding, and survival. We found that the survival and lifetime reproductive success of individuals were positively related to their amount of translocation ancestry, indicating that demographic benefits extended beyond the direct performances of the translocated birds. The translocations diversified the population’s genetic composition with the ancestry of most individuals in the latter years of the study deriving from multiple translocation donor populations. We found marked heterogeneity in the genetic contributions of translocated individuals and cohorts, leading to disproportionate representation of certain lineages. Encouragingly, despite some accumulation of inbreeding during the study, the translocations thus far have not substantially contributed to inbreeding. Our findings illustrate in precise detail how translocations can be an effective approach for managing imperiled taxa.}, archive = {J_PNAS}, author = {Lewanski, Alexander L. and Linderoth, Tyler and Thompson, Greg and Tringali, Angela and Angell, Emily and Bowman, Reed and Fitzpatrick, Sarah W.}, doi = {10.1073/pnas.2410946122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2410946122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Translocations contribute to population rescue in an imperiled woodpecker}, volume = {122}, year = {2025}, }
• (2025). Genetic rescue of florida panthers reduced homozygosity but did not swamp ancestral genotypes. PNAS, 122(31), e2410945122. (www)

  @article{ , abstract = {Pumas ( Puma concolor ) occupy a vast geographical range spanning from Canada to Argentina. Due to urbanization and unregulated hunting, pumas in Florida, known as panthers, are the only breeding population east of the Mississippi River. In the 1990s, Florida panthers numbered <30 individuals suffering from inbreeding depression. In 1995, eight pumas from Texas were translocated into southern Florida to mitigate the effects of isolation. This translocation reduced inbreeding depression and increased population size. While genetic rescue is often suggested as a means of ameliorating the effects of small population size, the underlying genetic mechanism and its long-term efficacy remain understudied. We sequenced the genomes of posttranslocation Florida panthers (PTFPs) to elucidate the genomic consequences of genetic rescue. We inferred local ancestry across the genomes of PTFPs and found that no regions have been entirely replaced by Texas ancestry, discarding the possibility of genetic swamping. Furthermore, the beneficial effects of the translocation were likely caused by a reduction in homozygosity, alleviating recessive deleterious load, rather than by a reduction in the number of deleterious variants. We did not find evidence that selection has favored replacement of original Florida DNA with Texas DNA in any systematic fashion. Using simulations, we found that heterozygosity increased in the long-term compared to a no translocation scenario; however, the effects on fitness are more transient. Our findings hold significant implications not only for the management of Florida's panther population, but also for informing strategies for genetic rescue in other wild, inbred populations encompassing broader conservation efforts.}, archive = {J_PNAS}, author = {Aguilar-Gómez, Diana and Yuan, Lin and Zhang, Yulin and Ochoa, Alexander and Culver, Melanie and Fitak, Robert R. and Onorato, Dave and Lohmueller, Kirk E. and Nielsen, Rasmus}, doi = {10.1073/pnas.2410945122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2410945122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genetic rescue of florida panthers reduced homozygosity but did not swamp ancestral genotypes}, volume = {122}, year = {2025}, }
• (2025). A trans-species cytoplasmic polymorphism is associated with seed shape and aridity across multiple species of sunflowers. PNAS, 122(31), e2410943122. (www)

  @article{ , abstract = {The cytoplasmic genomes of plants and animals often fail to track species boundaries. However, the mechanisms responsible for such patterns are poorly understood, in part because few studies have linked cytoplasmic variation to phenotypic traits or environmental differences. Here, we use 1,554 previously published and 185 new whole genome sequences representing 14 taxa from the sunflower genus Helianthus , 91 phenotypic traits measured in common gardens, and 39 environmental variables to test for environmental and phenotypic effects of cytoplasmic genome variation. In agreement with previous work, two distinct chloroplast clades were found across multiple species and the sharing of chloroplast clades between species was mainly due to repeated introgression rather than incomplete lineage sorting. Two mitochondrial clades were also found that matched the chloroplast clades for 98% of individuals, implying predominantly maternal inheritance of both genomes. Cytoplasmic clade was associated with differences in seed shape across several species, and likely with aridity, suggestive of a role in local adaptation. Conversely, we failed to find any credible cytonuclear interactions based on associations between chloroplast and nuclear variation. Taken together, this work suggests that cytoplasmic genomes in annual sunflowers represent a trans-species balanced polymorphism that is likely maintained by adaptation to different environments. More broadly, our results corroborate the syngameon concept, showing how introgression across even very strong reproductive barriers can facilitate environmental adaptation across a species complex.}, archive = {J_PNAS}, author = {Owens, Gregory L. and Cai, Zhe and Bercovich, Natalia and Todesco, Marco and Lee-Yaw, Julie A. and Rieseberg, Loren H.}, doi = {10.1073/pnas.2410943122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2410943122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A trans-species cytoplasmic polymorphism is associated with seed shape and aridity across multiple species of sunflowers}, volume = {122}, year = {2025}, }
• (2025). Suturing fragmented landscapes: Mosaic hybrid zones in plants may facilitate ecosystem resiliency. PNAS, 122(31), e2410941122. (www)

  @article{ , abstract = {Many widespread plant taxa of western North America have diversified into phenotypically and genetically divergent lineages due to complex biogeographic histories across heterogeneous landscapes. Mosaic hybrid zones can form when geographically co-occurring, yet environmentally distinct, lineages cross-pollinate and form hybrids that occupy unique environmental niches absent of a geographic cline. This expands the total environmental space across which parental and hybrid individuals grow, resulting in larger, less fragmented geographic distributions. Here, we highlight hybridization mosaics across three study systems containing taxa critical to widespread plant communities in western North America: Ericameria nauseosa , Artemisia tridentata , and Sphaeralcea fendleri . The systems contain diverged taxa that co-occur across the landscape and hybridize readily. Hybridization among taxa has facilitated niche expansion into intermediate environments consistent with unique combinations of adaptive genetic variation, creating more continuity within each study system—study systems occupy ~820 to 270,000 km 2 more geographic area by virtue of hybridization. Furthermore, hybrids are predicted to play important roles in future climates, as they may occupy 8 to 475% larger distributions compared to present. Convergent patterns signal mosaic hybridization as an underappreciated mechanism with broad ecological and evolutionary ramifications. Leveraging mosaic hybridization may assist the creation of restoration management plans that aim to mitigate the deleterious effects of habitat fragmentation on ecosystems in the context of climate change.}, archive = {J_PNAS}, author = {Massatti, Rob and Faske, Trevor M. and Barnes, Ivana M. and Leger, Elizabeth A. and Parchman, Thomas L. and Richardson, Bryce A. and Knowles, L. Lacey}, doi = {10.1073/pnas.2410941122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2410941122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Suturing fragmented landscapes: Mosaic hybrid zones in plants may facilitate ecosystem resiliency}, volume = {122}, year = {2025}, }
• (2025). Genomics of neotropical biodiversity indicators: Two butterfly radiations with rampant chromosomal rearrangements and hybridization. PNAS, 122(31), e2410939122. (www)

  @article{ , abstract = {A central question in evolutionary biology is what drives the diversification of lineages. Rapid, recent radiations are ideal systems for this question because they still show key morphological and ecological adaptations associated with speciation. While most research on recent radiations focuses on those occurring in insular environments, less attention has been given to continental radiations with complex species interactions. Here, we study the drivers of continental radiations of Melinaea and Mechanitis butterflies (Nymphalidae: Ithomiini), which have rapidly radiated in the continental Neotropics. They are classical models for Amazonian biogeography and color pattern mimicry and have been proposed as biodiversity indicators. We generated reference genomes for five species of each genus and whole-genome resequencing data of most species and subspecies covering a wide geographic range to assess phylogeographic relationships, hybridization patterns, and chromosomal rearrangements. Our data help resolve the classification of these taxonomically challenging butterflies and reveal very high diversification rates. We find rampant evidence of historical hybridization and putative hybrid species in both radiations, which may have facilitated their rapid diversification by enriching the genetic diversity. Moreover, we identified dozens of chromosomal fusions and fissions between congeneric species that have likely expedited reproductive isolation. We conclude that interactions between geography, hybridization and chromosomal rearrangements have contributed to these rapid radiations in the highly diverse Neotropical region. We hypothesize that rapid radiations may be spurred if repeated periods of geographic isolation are combined with lineage-specific rapid accumulation of incompatibilities, followed by secondary contact with some gene exchange.}, archive = {J_PNAS}, author = {van der Heijden, Eva S. M. and Näsvall, Karin and Seixas, Fernando A. and Beserra Nobre, Carlos Eduardo and Maia, Artur Campos D. and Salazar-Carrión, Patricio and Walker, Jonah M. and Szczerbowski, Daiane and Schulz, Stefan and Warren, Ian A. and Gavilanes Córdova, Kimberly Gabriela and Sánchez-Carvajal, María José and Chandi, Franz and Arias-Cruz, Alex P. and Rueda-M, Nicol and Salazar, Camilo and Dasmahapatra, Kanchon K. and Montgomery, Stephen H. and McClure, Melanie and Absolon, Dominic E. and Mathers, Thomas C. and Santos, Camilla A. and McCarthy, Shane and Wood, Jonathan M. D. and Lamas, Gerardo and Bacquet, Caroline and Freitas, André Victor Lucci and Willmott, Keith R. and Jiggins, Chris D. and Elias, Marianne and Meier, Joana I.}, doi = {10.1073/pnas.2410939122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2410939122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genomics of neotropical biodiversity indicators: Two butterfly radiations with rampant chromosomal rearrangements and hybridization}, volume = {122}, year = {2025}, }
• (2025). From science to impact: Conserving ecological connectivity in large conservation landscapes. PNAS, 122(31), e2410937122. (www)

  @article{ , abstract = {Implementing ecological connectivity conservation in large landscapes requires cutting-edge science combined with consideration of ecological, socioeconomic, and cultural factors that collectively shape the outcomes of conservation efforts. We outline a theory of change (ToC) for connectivity conservation to improve the ecological condition of landscapes and biodiversity and the ecosystem services upon which humans depend. We review connectivity conservation efforts on four continents in large landscapes that span gradients of latitude, fragmentation, biodiversity value, socioeconomic characteristics, and the richness of data used to assess connectivity and target action. We share the substantial but variable progress made in each landscape and outline specific challenges to achieving conservation goals. Opportunities and challenges in public and private sectors can further leverage the potential of large-scale connectivity conservation to reduce isolation and improve gene flow in functional landscapes worldwide.}, archive = {J_PNAS}, author = {Naidoo, Robin and Aylward, Cody and Elliott, Wendy and Keeley, Annika and Kinnaird, Margaret and Knight, Michael and Papp, Cristian-Remus and Thapa, Kanchan and Antelo, Rafael}, doi = {10.1073/pnas.2410937122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2410937122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {From science to impact: Conserving ecological connectivity in large conservation landscapes}, volume = {122}, year = {2025}, }
• (2025). Biodiversity conservation requires integration of species-centric and process-based strategies. PNAS, 122(31), e2410936122. (www)

  @article{ , abstract = {Conservation science and policy are geared primarily toward the preservation of species and habitats, with priority often given to the rarest, most vulnerable or most charismatic forms. This pattern-based approach has broad appeal and offers a pragmatic short-cut for targeting conservation action. However, the long-term efficacy of species and landscape conservation programs remains highly uncertain, amid growing evidence that sustainable conservation action requires an increased emphasis on preserving ecological and evolutionary processes. This reframing of conservation goals was first proposed 50 y ago, but the concept has struggled to gain traction, particularly in terms of translation into policy. Nonetheless, recent events have shifted the narrative, with multiple interlinked global challenges—including biological invasions, food security, disease, and climate change—putting ecological processes firmly back on the agenda. Concurrently, conservation finance is changing rapidly, driven in part by the 2022 Kunming-Montreal Global Biodiversity Framework, which prioritized actions to enhance and restore ecosystem stability, connectivity, and resilience. These ecosystem properties are fundamentally process-driven and appear to create an operational gulf between current conservation practice and the targets of international agreements. We describe how new approaches can be used to close this gap by redirecting conservation attention toward processes at the heart of ecosystem function, including adaptation, gene flow, dispersal, and trophic interactions. Wider adoption of these approaches is urgently needed to forge a deeper connection between conservation practice and policy targets, thereby ensuring that ongoing investment in biodiversity conservation goes beyond damage limitation and instead leaves a lasting legacy of resilient ecosystems.}, archive = {J_PNAS}, author = {Tobias, Joseph A. and Bullock, James M. and Dicks, Lynn V. and Forester, Brenna R. and Razgour, Orly}, doi = {10.1073/pnas.2410936122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2410936122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biodiversity conservation requires integration of species-centric and process-based strategies}, volume = {122}, year = {2025}, }
• (2025). Phylogenetic networks empower biodiversity research. PNAS, 122(31), e2410934122. (www)

  @article{ , abstract = {Reticulate evolution has long been recognized as a key mechanism that contributes to genetic and trait diversity. With the widespread availability of genomic data, investigating historical reticulate evolution across taxa has gained significant attention, driven by the rapid development of statistical methods for detecting nontreelike patterns. Phylogenetic networks provide a biologically intuitive approach to depicting evolutionary processes such as hybrid speciation and introgressive hybridization, which result in signatures of historical gene flow. Interpreting phylogenetic networks is especially critical for groups of conservation concern that lack reference genome resources and explicit hypotheses from prior investigation, such as those based on molecular data, morphology, or species distributions. Here, we highlight recent advances in computational methods for inferring networks from genome-scale data and offer guidelines for deriving biological insights from phylogenetic networks. Particular emphasis is placed on modeling hybridization and whole-genome duplication in the context of allopolyploidization. Practical recommendations for empirical studies and the limitations of commonly used methods are discussed throughout. We anticipate that phylogenetic networks will influence conservation biology and biodiversity research, emphasizing the need for careful consideration of reticulate evolution inferred from these networks in the near future. Networks will accelerate other pressing avenues of biodiversity research, especially investigations of orphan crops and climate change resilience in natural systems. The promise of phylogenetic networks connects with broader themes in the special feature Monitoring and restoring gene flow in the increasingly fragmented ecosystems of the Anthropocene by providing an emerging probabilistic framework for inferring historical connectivity between species and populations.}, archive = {J_PNAS}, author = {Kong, Sungsik and Solís-Lemus, Claudia and Tiley, George P.}, doi = {10.1073/pnas.2410934122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2410934122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phylogenetic networks empower biodiversity research}, volume = {122}, year = {2025}, }
• (2025). Fossil samples archive functional diversity in marine ecosystems: An empirical test from a present-day coastal environment. PNAS, 122(31), e2405727122. (www)

  @article{ , abstract = {The fossil record of functional diversity is increasingly used to study ecosystem evolution, extinction recovery, and factors affecting long-term trends in biodiversity. In addition, the youngest fossil record (late Quaternary) can provide insights into the natural range of functional variability of present-day ecosystems, providing a historical framework for conservation and restoration. However, the reliability of common functional diversity measures derived from fossils is uncertain. If fossils yield reasonable estimates of functional diversity, paleontological data could provide information on ecological attributes and trophic structure in past ecosystems allowing for temporally scalable assessments of ecological and evolutionary processes. To assess how well fossils preserve functional diversity across multiple types of marine invertebrates with varying preservation potential, we compared the live benthos (135 species from 6 phyla) with sympatric skeletal accumulations (150 species) and the predicted fossil record (112 species) for 51 coastal sites in North Carolina (USA). High functional fidelity between the live, dead, and fossil assemblages was supported by congruence in quantitative functional diversity indices (e.g., functional richness, redundancy, overredundancy, and vulnerability), overlap in multidimensional functional space, and species distributions among functional groups ( ρ > 0.85, P ≪ 0.001). Calculating vulnerability using a threshold of ≤2 species also reasonably approximated the vulnerability in the live assemblages. The results suggest that, despite differential preservation and time-averaging, functional estimates based on fossils may allow for historical assessments of ecological and evolutionary processes, including short-term community responses to human impacts as well as long-term macroevolutionary dynamics of marine ecosystems.}, archive = {J_PNAS}, author = {Tyler, Carrie L. and Kowalewski, Michał}, doi = {10.1073/pnas.2405727122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2405727122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fossil samples archive functional diversity in marine ecosystems: An empirical test from a present-day coastal environment}, volume = {122}, year = {2025}, }
• (2025). Deficiency in transmitter release triggers homeostatic transcriptional changes that increase presynaptic excitability. PNAS, 122(31), e2322714122. (www)

  @article{ , abstract = {Weakening of synaptic transmission at the Drosophila larval neuromuscular junction triggers two forms of homeostatic compensation, one that increases the probability of glutamate release per action potential ( P r ) and another that increases motoneuron (MN) activity. We investigated the molecular changes in MNs that underlie the increase in MN activity. RNA sequencing (RNA-seq) analysis on MNs whose glutamate release is weakened by knockdown of components of the MN transmitter release machinery reveals a reduction in expression of a group of genes that encode potassium channels and their positive modulators. These results identify a mechanism of compensation for weakened synaptic transmission by MNs, which engages a transcriptional program in those cells to increase firing and, thereby, ensure sufficient locomotory drive.}, archive = {J_PNAS}, author = {Cypranowska, Caroline A. and Feldthouse, Maya and Choi, Yoon Gi and Bakshinska, Dariya and Li, Rachel and Newman, Zachary L. and Isacoff, Ehud Y.}, doi = {10.1073/pnas.2322714122}, journal = {Proceedings of the National Academy of Sciences}, month = {8}, number = {31}, pages = {e2322714122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deficiency in transmitter release triggers homeostatic transcriptional changes that increase presynaptic excitability}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(30), eiti3025122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti3025122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {eiti3025122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Implementation science aims to improve healthcare by validating effective interventions. PNAS, 122(30), e2517704122. (www)

  @article{ , archive = {J_PNAS}, author = {Carey, John}, doi = {10.1073/pnas.2517704122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2517704122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Implementation science aims to improve healthcare by validating effective interventions}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for gozashti et al., horizontal transmission of functionally diverse transposons is a major source of new introns. PNAS, 122(30), e2517331122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2517331122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2517331122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for gozashti et al., horizontal transmission of functionally diverse transposons is a major source of new introns}, volume = {122}, year = {2025}, }
• (2025). Correction for lin et al., BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1–Chk1 pathway, implicating checkpoint dysfunction in microcephaly. PNAS, 122(30), e2517068122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2517068122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2517068122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for lin et al., BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1–Chk1 pathway, implicating checkpoint dysfunction in microcephaly}, volume = {122}, year = {2025}, }
• (2025). Retraction for goswami et al., a bifunctional tRNA import receptor from leishmania mitochondria. PNAS, 122(30), e2517057122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2517057122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2517057122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Retraction for goswami et al., a bifunctional tRNA import receptor from leishmania mitochondria}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for seigneur et al., cbln2 and cbln4 are expressed in distinct medial habenula-interpeduncular projections and contribute to different behavioral outputs. PNAS, 122(30), e2516923122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2516923122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2516923122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for seigneur et al., cbln2 and cbln4 are expressed in distinct medial habenula-interpeduncular projections and contribute to different behavioral outputs}, volume = {122}, year = {2025}, }
• (2025). Correction for richardson et al., a unifying principle for multispecies coexistence under resource fluctuations. PNAS, 122(30), e2516803122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2516803122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2516803122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for richardson et al., a unifying principle for multispecies coexistence under resource fluctuations}, volume = {122}, year = {2025}, }
• (2025). Correction for gao et al., subunit specialization in AAA+ proteins and substrate unfolding during transcription complex remodeling. PNAS, 122(30), e2516674122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2516674122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2516674122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for gao et al., subunit specialization in AAA+ proteins and substrate unfolding during transcription complex remodeling}, volume = {122}, year = {2025}, }
• (2025). Correction for wang et al., the proofreading mechanism of the human leading-strand DNA polymerase ε holoenzyme. PNAS, 122(30), e2516665122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2516665122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2516665122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for wang et al., the proofreading mechanism of the human leading-strand DNA polymerase ε holoenzyme}, volume = {122}, year = {2025}, }
• (2025). Retraction for kundu et al., selective neutralization of IL-12 p40 monomer induces death in prostate cancer cells via IL-12–IFN-γ. PNAS, 122(30), e2516531122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2516531122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2516531122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Retraction for kundu et al., selective neutralization of IL-12 p40 monomer induces death in prostate cancer cells via IL-12–IFN-γ}, volume = {122}, year = {2025}, }
• (2025). Profile of thomas y. hou. PNAS, 122(30), e2516518122. (www)

  @article{ , abstract = {Working at the interface between numerics and applied analysis, Caltech mathematician Thomas Hou has solved challenging problems concerning fluid dynamics and other multiscale systems. His research has applications in materials science, biomedical engineering, multiphase fluid dynamics, among other fields. Hou is currently addressing a longstanding open question in mathematical fluid dynamics: whether smooth initial data for the 3D incompressible Euler equations can form a finite-time singularity. Dating back to polymath Leonhard Euler (1707–1783), these equations lie at the core of theoretical fluid mechanics. Hou’s work in this area, reported in his Inaugural Article, provides key insights.}, archive = {J_PNAS}, author = {Viegas, Jennifer}, doi = {10.1073/pnas.2516518122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2516518122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profile of thomas y. hou}, volume = {122}, year = {2025}, }
• (2025). Joanne chory (1955–2024): Plant geneticist extraordinaire. PNAS, 122(30), e2515437122. (www)

  @article{ , abstract = {Joanne Chory (1955–2024) was a pioneering biologist whose research transformed our understanding of plant growth and development. Her groundbreaking work, based on many clever genetic screens, established a complete signaling pathway for brassinosteroids, from the biosynthesis of this important class of plant hormones and their transmembrane receptor to cytoplasmic and nuclear effectors. A beloved mentor and visionary leader, Chory championed science as both a rigorous discipline and a force for good. In her final years, she mobilized plant biologists across the world to address climate change, inspiring an entire generation to see plants as allies in securing a sustainable future. Her legacy lives on in her discoveries, her students, and the global scientific community she helped shape.}, archive = {J_PNAS}, author = {Nemhauser, Jennifer L. and Weigel, Detlef}, doi = {10.1073/pnas.2515437122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2515437122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Joanne chory (1955–2024): Plant geneticist extraordinaire}, volume = {122}, year = {2025}, }
• (2025). Previous epidemiological studies support the idea of ileal microbiota triggering multiple sclerosis. PNAS, 122(30), e2514491122. (www)

  @article{ , archive = {J_PNAS}, author = {Simka, Marian}, doi = {10.1073/pnas.2514491122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2514491122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Previous epidemiological studies support the idea of ileal microbiota triggering multiple sclerosis}, volume = {122}, year = {2025}, }
• (2025). Spatiotemporal decoupling of floristic endemism in response to Qinghai–Tibet plateau uplift. PNAS, 122(30), e2513876122. (www)

  @article{ , archive = {J_PNAS}, author = {Yang, Bao and Wang, Xuelian}, doi = {10.1073/pnas.2513876122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2513876122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatiotemporal decoupling of floristic endemism in response to Qinghai–Tibet plateau uplift}, volume = {122}, year = {2025}, }
• (2025). The kinesin KIF3AC recycles endocytosed integrin to polarize new adhesion formation toward the leading edge. PNAS, 122(30), e2513776122. (www)

  @article{ , abstract = {The recycling of integrin endocytosed during focal adhesion (FA) disassembly is critical for cell migration and contributes to the polarized formation of new FAs toward the leading edge. How this occurs is unclear. Here, we sought to identify the kinesin motor protein(s) that is involved in recycling endocytosed integrin back to the plasma membrane. We show that the kinesin-2 heterodimer, KIF3AC, and the Rab11 adaptor protein Rab coupling protein (RCP) are required for FA reformation after the disassembly of FAs in mouse and human fibroblasts. In the absence of KIF3AC, integrin does not return to the cell surface after FA disassembly and is found in the Rab11 endocytic recycling compartment. Biochemical pulldowns revealed that KIF3C associated with β1 integrin in an RCP-dependent fashion, but only after FA disassembly. KIF3AC knockdown inhibited cell migration, trafficking of RCP toward the leading edge, and polarized formation of FAs at the leading edge. These results show that KIF3AC promotes cell migration by recycling integrin so that it generates new FAs in a polarized fashion.}, archive = {J_PNAS}, author = {Rockenbach, Johnny A. Z. and Nader, Guilherme P. F. and Antoku, Susumu and Gundersen, Gregg G.}, doi = {10.1073/pnas.2513776122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2513776122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The kinesin KIF3AC recycles endocytosed integrin to polarize new adhesion formation toward the leading edge}, volume = {122}, year = {2025}, }
• (2025). Sharks and rays have the oldest vertebrate sex chromosome with unique sex determination mechanisms. PNAS, 122(30), e2513676122. (www)

  @article{ , abstract = {Sex determination has been investigated across vertebrate lineages to reveal the stepwise evolution of sex chromosomes and the diversity of responsible molecular mechanisms. However, these studies rarely include cartilaginous fishes, which diverged from the other vertebrates 450 Mya, hindering the comprehensive view of vertebrate sex determination. Here, we produced chromosome-scale genome assemblies of egg-laying shark species and comparatively investigated genome sequences and transcriptome profiles across diverse cartilaginous fishes. Sex chromosome identification, supported by cytogenetic experiments, elucidated the homology of X chromosomes between sharks and rays as well as an extensively degenerated Y chromosome harboring no detectable male-specific genes. Orthologs of documented sex-determining genes were identified, but not on these sex chromosomes. Transcriptomic analyses combined with histology of embryonic gonads revealed female-biased expression of X-linked genes—including those implicated in the TGF-β and IGF signaling pathways—attributed to incomplete dosage compensation. Our findings indicate that sharks and rays share the oldest sex chromosomes among vertebrates that originated around 300 Mya and the dosage-dependent sex determination mechanism composed of distinct molecules from other vertebrates. This study highlights the antiquity of sex chromosomes and the uniqueness of sex determination mechanisms in sharks and rays, which advances our understanding of evolutionary plasticity in vertebrate sex determination.}, archive = {J_PNAS}, author = {Niwa, Taiki and Uno, Yoshinobu and Ohishi, Yuta and Kadota, Mitsutaka and Aburatani, Naotaka and Kiyatake, Itsuki and Katooka, Daiki and Yorozu, Michikazu and Tsuzuki, Nobutaka and Toyoda, Atsushi and Takagi, Wataru and Nakamura, Masaru and Kuraku, Shigehiro}, doi = {10.1073/pnas.2513676122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2513676122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sharks and rays have the oldest vertebrate sex chromosome with unique sex determination mechanisms}, volume = {122}, year = {2025}, }
• (2025). Mechanistic modeling or machine learning for detecting variants of concern: Why not both?. PNAS, 122(30), e2513608122. (www)

  @article{ , archive = {J_PNAS}, author = {Wilke, Claus O. and Vieira, Luiz C.}, doi = {10.1073/pnas.2513608122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2513608122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mechanistic modeling or machine learning for detecting variants of concern: Why not both?}, volume = {122}, year = {2025}, }
• (2025). Mapping the development of neural structures supporting literacy. PNAS, 122(30), e2513604122. (www)

  @article{ , archive = {J_PNAS}, author = {Roy, Ethan}, doi = {10.1073/pnas.2513604122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2513604122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mapping the development of neural structures supporting literacy}, volume = {122}, year = {2025}, }
• (2025). An ancient immune pathway enables animal metamorphosis. PNAS, 122(30), e2512734122. (www)

  @article{ , archive = {J_PNAS}, author = {Heath-Heckman, Elizabeth}, doi = {10.1073/pnas.2512734122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2512734122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An ancient immune pathway enables animal metamorphosis}, volume = {122}, year = {2025}, }
• (2025). Impact of women’s political empowerment through gender quotas on improved drinking water access in africa. PNAS, 122(30), e2511977122. (www)

  @article{ , abstract = {Access to safely managed drinking water is a fundamental human right, essential for human health and well-being. However, 2.2 billion people around the world still lack this access, with significant geographical disparities. In this study, we leveraged the implementation of gender quota laws—specifically reserved parliamentary seats for women across African countries—to examine its impact on improved water availability. Our findings reveal that the implementation of gender quotas is associated with a 4.71 percentage point increase, on average, in the likelihood of people accessing safely managed water infrastructure. This effect becomes even more pronounced, rising to a 12.25 percentage point increase, when the quotas mandate reserving more than 20% of seats for women. Households with lower wealth, female-headed households, those living in rural areas, and households with lower levels of women’s empowerment and education benefit most from this policy. Further investigation into the underlying mechanisms, and anecdotal evidence, reveals that gender-reserved seat quotas lead to an increase in the proportion of women in parliaments and an expansion of women’s political and social rights, although these effects do not extend to economic status.}, archive = {J_PNAS}, author = {An, Jiafu and Wang, Tenghui and Chen, Bin and Gong, Peng and Lin, Chen and Stenseth, Nils Chr.}, doi = {10.1073/pnas.2511977122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2511977122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Impact of women’s political empowerment through gender quotas on improved drinking water access in africa}, volume = {122}, year = {2025}, }
• (2025). Threonine phosphorylation of STAT1 safeguards gut epithelial integrity and restricts interferon-mediated cytotoxicity. PNAS, 122(30), e2511957122. (www)

  @article{ , abstract = {Barrier tissues such as the intestine are constantly challenged by environmental stressors and must adapt to maintain integrity and prevent excessive inflammation. Although traditionally viewed as a proinflammatory effector of interferon (IFN) signaling, STAT1 is shown here to play a protective role in intestinal epithelial cells (IEC) by promoting resilience to damage and restraining IFN-induced cytotoxicity. We identify phosphorylation of threonine 748 (Thr748) on STAT1 as an evolutionarily selected adaptation—highly conserved between humans and mice—that reciprocally regulates IEC integrity and IFN responsiveness. Mice expressing a phospho-deficient T748A Stat1 mutant exhibit severe colitis-induced tissue damage comparable to Stat1-deficient littermates, underscoring the critical role of Thr748 phosphorylation in mediating Stat1-driven protection during intestinal inflammation. Bone marrow transfer experiments further demonstrate that this protective effect is nonhematopoietic. Integrated genomic and transcriptomic analyses reveal that Thr748 phosphorylation modulates STAT1 DNA binding, directly activates the Itgb4 promoter, and enhances integrin β4 expression in IEC following inflammation. In intestinal organoid models, gain- and loss-of-function experiments demonstrate that Thr748 phosphorylation drives integrin β4 expression and epithelial resilience independently of IFN-induced Tyrosine 701 (Tyr701) phosphorylation. In contrast, IFN stimulation via Tyr701 induces Zbp1—a cytotoxic nucleic acid sensor—while repressing integrin β4, resulting in epithelial injury that is mitigated by Thr748 phosphorylation. Together, these findings reveal a modular architecture of STAT1 signaling in which Thr748 phosphorylation functions as a molecular rheostat that safeguards epithelial integrity while tempering IFN-driven cytotoxic responses.}, archive = {J_PNAS}, author = {Metwally, Hozaifa and Elbrashy, Maha M. and Kayama, Hisako and Okuyama, Kazuki and Taniuchi, Ichiro and Takeda, Kiyoshi and Kishimoto, Tadamitsu}, doi = {10.1073/pnas.2511957122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2511957122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Threonine phosphorylation of STAT1 safeguards gut epithelial integrity and restricts interferon-mediated cytotoxicity}, volume = {122}, year = {2025}, }
• (2025). Modulation of histone tail electrostatic potentials in nucleosome core particles by acetylation and PARylation. PNAS, 122(30), e2511507122. (www)

  @article{ , abstract = {Cellular DNA is wrapped about an octamer composed of four histone proteins forming the fundamental unit of chromatin structure, the nucleosome core particle (NCP). The intrinsically disordered tails of the histones serve as scaffolds for binding an array of proteins that regulate the fidelity of the genome and gene expression. A variety of posttranslational modifications (PTMs) on the tails have been characterized, including some that alter their overall charge; however, per-residue changes in tail electrostatic potentials for different PTMs have not been reported. Here, using a solution NMR approach in which enhancements of transverse relaxation rates of tail amide and methyl group protons are quantified through the addition of paramagnetic cosolutes, we examine how acetylation and PARylation modulate histone tail electrostatic potentials. Notably, even though both PTMs decrease the net positive charge carried by each tail, their electrostatic potentials either increase or decrease in a tail-specific manner relative to an unmodified NCP. A simple model of tail–DNA interactions is presented to explain these results.}, archive = {J_PNAS}, author = {Bolik-Coulon, Nicolas and Rößler, Philip and Nosella, Michael L. and Kim, Tae Hun and Kay, Lewis E.}, doi = {10.1073/pnas.2511507122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2511507122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Modulation of histone tail electrostatic potentials in nucleosome core particles by acetylation and PARylation}, volume = {122}, year = {2025}, }
• (2025). Optimistic people are all alike: Shared neural representations supporting episodic future thinking among optimistic individuals. PNAS, 122(30), e2511101122. (www)

  @article{ , abstract = {Optimism is a critical personality trait that influences future-oriented cognition by emphasizing positive future outcomes and deemphasizing negative outcomes. How does the brain represent idiosyncratic differences in episodic future thinking that are modulated by optimism? In two functional MRI (fMRI) studies, participants were scanned during an episodic future thinking task in which they were presented with a series of episodic scenarios with different emotional valence and prompted to imagine themself (or their partner) in the situation. Intersubject representational similarity analysis revealed that more optimistic individuals had similar neural representations in the medial prefrontal cortex (MPFC), while less optimistic individuals exhibited more idiosyncratic neural representations in the MPFC. Additionally, individual difference multidimensional scaling of MPFC activity revealed that the referential target and emotional valence of imagined events were clearly mapped onto different dimensions. Notably, the weights along the emotional dimension were closely linked to the optimism scores of participants, suggesting that optimistic individuals imagine positive events as more distinct from negative events. These results suggest that shared neural processing of the MPFC among optimistic individuals supports episodic future thinking that facilitates psychological differentiation between positive and negative future events.}, archive = {J_PNAS}, author = {Yanagisawa, Kuniaki and Nakai, Ryusuke and Asano, Kohei and Kashima, Emiko S. and Sugiura, Hitomi and Abe, Nobuhito}, doi = {10.1073/pnas.2511101122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2511101122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Optimistic people are all alike: Shared neural representations supporting episodic future thinking among optimistic individuals}, volume = {122}, year = {2025}, }
• (2025). Mechanistic insights into the iron–sulfur cluster-dependent interaction of the autophagy receptor NCOA4 with the e3 ligase HERC2. PNAS, 122(30), e2510269122. (www)

  @article{ , abstract = {NCOA4, a dedicated autophagy receptor for mediating selective autophagy of ferritin (ferritinophagy), plays a vital role in maintaining cellular iron homeostasis. The cellular abundance of NCOA4 is regulated by the E3 ligase HERC2 that can specifically target NCOA4 for proteasomal degradation under iron-replete conditions. However, the detailed molecular mechanism governing the iron-dependent recognition of NCOA4 by HERC2 remains elusive. Here, using multidisciplinary approaches, we systematically characterize the HERC2-binding domain (HBD) of NCOA4 and its interaction with HERC2. We uncover that NCOA4 HBD harbors a [2Fe-2S] cluster and can exist in two different states, the apo -form state and the [2Fe-2S] cluster–bound state. Moreover, we unravel that HERC2 can effectively recognize the [2Fe-2S] cluster–bound NCOA4 HBD through its Cullin-7-PARC-HERC2 (CPH) domain and iron–sulfur cluster–dependent NCOA4-binding domain (INBD) with a synergistic binding mode. The determined crystal structures of HERC2(2540-2700) and its complex with the [2Fe-2S] cluster–bound NCOA4 HBD together with relevant biochemical and cellular results not only elucidate how NCOA4 HBD specifically senses cellular iron level by binding a [2Fe-2S] cluster but also reveal the molecular basis underlying the specific interaction of HERC2 with the [2Fe-2S] cluster–bound NCOA4 HBD. In summary, our findings provide mechanistic insights into the iron-dependent turnover of NCOA4 by HERC2 and expand our understanding of the regulatory mechanism of NCOA4-mediated ferritinophagy.}, archive = {J_PNAS}, author = {Liu, Haobo and Shen, Liqiang and Gong, Xinyu and Zhou, Xindi and Huang, Yichao and Zhou, Yuqian and Guo, Zhenpeng and Guo, Hanbo and Wang, Shichao and Pan, Lifeng}, doi = {10.1073/pnas.2510269122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2510269122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mechanistic insights into the iron–sulfur cluster-dependent interaction of the autophagy receptor NCOA4 with the e3 ligase HERC2}, volume = {122}, year = {2025}, }
• (2025). Ancient seabed checkerboard: How setae shaped spatial distributions of silurian brachiopods. PNAS, 122(30), e2509354122. (www)

  @article{ , abstract = {Understanding the drivers of spatial patterns in fossil communities is fundamental to paleoecology, yet direct evidence for biological mechanisms regulating interindividual spacing remains elusive. Brachiopod setae, hypothesized to function in feeding or defense, are exceedingly rare in the fossil record, especially among post-Cambrian taxa. Here, we present the report of exquisitely preserved setae from an exceptional in situ fossil assemblage of the early Silurian rhynchonelliform brachiopod Nucleospira calypta . Multiproxy analyses (scanning electron microscopy, X-ray fluorescence, and microcomputed tomography) revealed intricate ultrastructural details and diverse taphonomic pathways, leading to a reinterpretation of apparent calcitic preservation as primarily iron oxides with subsequent coating. Critically, the undisturbed nature of this aggregation allowed rigorous spatial point pattern analysis (Nearest-Neighbor Analysis, Thiessen polygons). This revealed a statistically significant, nonrandom, checkerboard-like distribution among individuals within the studied fossil deposit, indicative of active spacing regulation. Strikingly, the measured average interindividual spacing quantitatively relates to the length of the preserved setae. This provides the direct paleontological evidence demonstrating that these subtle morphological structures could have actively mediated spatial organization within a dense benthic community. Our findings illustrate a biological mechanism capable of shaping community structure, operating beyond passive environmental constraints or initial larval settlement preferences, and highlight the potential for subtle anatomical features to exert significant ecological influence in deep time.}, archive = {J_PNAS}, author = {Huang, Bing and Rong, Jiayu}, doi = {10.1073/pnas.2509354122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2509354122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ancient seabed checkerboard: How setae shaped spatial distributions of silurian brachiopods}, volume = {122}, year = {2025}, }
• (2025). Hydrogen cyanide and hydrocarbons mix on titan. PNAS, 122(30), e2507522122. (www)

  @article{ , abstract = {This work reveals a striking exception to the well-established rule in chemistry that polar and nonpolar compounds do not spontaneously mix: insertion of methane, ethane, and other small hydrocarbons into the crystal lattice of hydrogen cyanide (HCN), a highly polar molecule. By mixing these components at cryogenic temperatures, we can observe distinct shifts in vibrational modes using Raman spectroscopy. Our computational predictions confirm that cocrystal structures of HCN and ethane, which match our experimental vibrational shifts closely, are thermodynamically and kinetically stable. Given that methane, ethane, and HCN are major components of the atmosphere and surface of Saturn’s moon Titan—where they play key roles in shaping chemistry, weather, and landscape—our findings may prove instrumental for explaining Titan’s chemical and geological evolution.}, archive = {J_PNAS}, author = {Izquierdo-Ruiz, Fernando and Cable, Morgan L. and Hodyss, Robert and Vu, Tuan H. and Sandström, Hilda and Lobato, Alvaro and Rahm, Martin}, doi = {10.1073/pnas.2507522122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2507522122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hydrogen cyanide and hydrocarbons mix on titan}, volume = {122}, year = {2025}, }
• (2025). Kinetic pathways of solid–solid phase transitions dictated by short-range interactions. PNAS, 122(30), e2507403122. (www)

  @article{ , abstract = {Structural phase transformations allow us to design materials from the ground up. Predicting the structural transformation of crystals during solid–solid phase transitions, however, is challenging, as the transition can proceed through multiple pathways that are difficult to probe experimentally. Using minimal computational models, we show that distinct kinetic pathways between body-centered cubic (bcc) and face-centered cubic (fcc) crystal structures can be encoded into a system by specific particle interactions. By investigating the dynamics of these transitions, we resolve three different pathways at a particle-by-particle level: a direct bcc-to-fcc transition, a transition involving an intermediate, long-lived body-centered tetragonal (bct) phase, and a microstructure-dependent transition pathway with a competing hexagonal close-packed (hcp) phase. These kinetic pathways are intrinsically linked to the shape of the underlying particle–particle interactions, suggesting routes for controlling the transformation pathways of soft matter systems. Furthermore, our investigations provide fundamental insights into solid–solid phase transition mechanisms generalizable across length scales.}, archive = {J_PNAS}, author = {Pan, Hillary and Dshemuchadse, Julia}, doi = {10.1073/pnas.2507403122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2507403122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Kinetic pathways of solid–solid phase transitions dictated by short-range interactions}, volume = {122}, year = {2025}, }
• (2025). TMEM63A, associated with hypomyelinating leukodystrophies, is an evolutionarily conserved regulator of myelination. PNAS, 122(30), e2507354122. (www)

  @article{ , abstract = {Infantile hypomyelinating leukodystrophy 19 (HLD19) is a rare genetic disorder where patients exhibit reduced myelin in central nervous system (CNS) white matter tracts and present with varied neurological symptoms. The causative gene TMEM63A encodes a mechanosensitive ion channel whose role in myelination is largely unexplored. Our study shows that TMEM63A is a major regulator of oligodendrocyte (OL)-dependent myelination in the CNS. In mouse and zebrafish, Tmem63a inactivation led to early deficits in myelination, recapitulating the HLD19 phenotype. OL-specific conditional mouse knockouts of Tmem63a exhibited transient reductions in myelin, indicating that TMEM63A regulates myelination cell-autonomously. We show that TMEM63A is present at the plasma membrane and on lysosomes and modulates myelin production in the presence of mechanical cues. Intriguingly, HLD19-associated TMEM63A variants from patients blocked trafficking to cell membrane. Together, our results reveal an ancient role for TMEM63A in fundamental aspects of myelination in vivo and highlight two exciting models for the development of treatments for devastating hypomyelinating leukodystrophies.}, archive = {J_PNAS}, author = {Halford, Julia and Senatore, Amanda J. and Berryman, Sage and Muñoz, Antonio and Semidey, Destinee and Doan, Ryan A. and Coombs, Adam M. and Noimany, Brandon and Emberley, Katie and Emery, Ben and Monk, Kelly R. and Murthy, Swetha E.}, doi = {10.1073/pnas.2507354122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2507354122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TMEM63A, associated with hypomyelinating leukodystrophies, is an evolutionarily conserved regulator of myelination}, volume = {122}, year = {2025}, }
• (2025). Epigenetic instability and hypofunctionality of fetal tregs allow a permissive regulatory environment for t effector memory maturation. PNAS, 122(30), e2506673122. (www)

  @article{ , abstract = {The human gestational environment is commonly perceived to be predominantly suppressive and incompatible for T effector maturation. However, evidence of a competent effector fetal environment is mounting in the field. Here, we employed a high parametric, mass cytometry–based approach to study the fetal circulatory and microenvironmental immunomes, with the aim to understand the inception and extent of fetal effector T cell priming and its relation with regulatory mechanisms. We found evidence of fetal thymic immune imprinting, coupled with both circulatory and tissue effector memory development. Correspondingly, in the regulatory compartment, we detected the presence of Tbet + Treg in fetal tissues at elevated levels compared to adult tissues. Fetal Tregs, though capable of suppression, were hyposuppressive as compared with adult counterparts. We found that a proportion of fetal Tregs lost FoxP3 commitment during proliferation and exhibited higher TCR clonotype sharing with effector T cells, indicating higher plasticity in fetal Tregs than adult. Epigenetic profiling of the FoxP3 promoter locus reveals that fetal Tregs were only partially demethylated, possibly explaining the observed instability. In summary, our data provide evidence of a regulatory environment in the 2nd trimester permissive for T effector maturation, in part contributed by the relative instability and hypofunctionality in fetal Tregs.}, archive = {J_PNAS}, author = {Leong, Jing Yao and McGovern, Naomi and Mishra, Archita and Wasser, Martin and Kumar, Pavanish and Tay, Shi Huan and Nur Hazirah, Sharifah and Yeo, Joo Guan and Tan, Xiu Qi and Sutamam, Nursyuhadah and Azman, Farah Nadiah and Chua, Camillus Jian Hui and Chen, Phyllis ZiXuan and Ally, Fauziah and Dutertre, Charles-Antoine and Ramakrishna, Lakshmi and Poh, Su Li and Xie, Liang and Fan, Yiping and Donner, Catherine and Papadopoulou, Maria and Vermijlen, David and Arkachaisri, Thaschawee and Chan, Jerry Kok Yen and Ginhoux, Florent and Albani, Salvatore}, doi = {10.1073/pnas.2506673122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2506673122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Epigenetic instability and hypofunctionality of fetal tregs allow a permissive regulatory environment for t effector memory maturation}, volume = {122}, year = {2025}, }
• (2025). Differential representations of spatial location by aperiodic and alpha oscillatory activity in working memory. PNAS, 122(30), e2506418122. (www)

  @article{ , abstract = {Decades of research have shown working memory (WM) relies on sustained prefrontal cortical activity and visual extrastriate activity, particularly in the alpha (8 to 12 Hz) frequency range. This alpha activity tracks the spatial location of WM items, even when spatial position is task-irrelevant and no stimulus is currently being presented. Traditional analyses of putative oscillations using bandpass filters, however, conflate oscillations with nonoscillatory aperiodic activity. Here, we reanalyzed seven human electroencephalography visual WM datasets to test the hypothesis that aperiodic activity, which is thought to reflect the relative contributions of excitatory and inhibitory drive-plays a distinct role in visual WM from true alpha oscillations. To do this, we developed a time-resolved spectral parameterization approach to disentangle oscillations from aperiodic activity during WM encoding and maintenance. Across all seven tasks, totaling 112 participants, we captured the representation of spatial location from total alpha power using inverted encoding models (IEMs), replicating traditional analyses. We then trained separate IEMs to estimate the strength of spatial location representation from aperiodic-adjusted alpha (reflecting just the oscillatory component) and aperiodic activity and find that IEM performance improves for aperiodic-adjusted alpha compared to total alpha power that blends the two signals. We also identify a distinct role for aperiodic activity, where IEM performance trained on aperiodic activity is highest during stimulus presentation, but not during the WM maintenance period. Our results emphasize the importance of controlling for aperiodic activity when studying neural oscillations while uncovering a functional role for aperiodic activity in encoding visual WM information.}, archive = {J_PNAS}, author = {Bender, Andrew and Zhao, Chong and Vogel, Edward and Awh, Edward and Voytek, Bradley}, doi = {10.1073/pnas.2506418122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2506418122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Differential representations of spatial location by aperiodic and alpha oscillatory activity in working memory}, volume = {122}, year = {2025}, }
• (2025). ATP synthesis driven by atmospheric hydrogen concentrations. PNAS, 122(30), e2506353122. (www)

  @article{ , abstract = {All cells require a continuous supply of the universal energy currency, adenosine triphosphate (ATP), to drive countless cellular reactions. The universally conserved F 1 F o -ATP synthase regenerates ATP from ADP and P i by harnessing a transmembrane electrochemical proton gradient ( pmf ). Bacteria have evolved diverse pmf -forming strategies using light, organic, and inorganic energy sources. Recently, we proposed that many bacteria survive using atmospheric trace gases to produce ATP when limited for other energy sources. However, direct evidence that atmospheric energy sources are sufficient to generate pmf or drive ATP synthesis is still lacking. Here, we show that the membrane-associated hydrogen:quinone oxidoreductase Huc from Mycobacterium smegmatis can enable ATP synthesis from air. Purified Huc couples H 2 oxidation to the reduction of various ubiquinone and menaquinone analogues. We designed a minimal respiratory chain in which Huc interacts with liposomes containing the nonpumping, but pmf -generating, bd -I oxidase and F 1 F o -ATP synthase from Escherichia coli . Our experiments show that passive hydrogen exchange from air to solution is sufficient for the electron transfer and pmf generation required to accumulate ATP. By combining continuous culture bioenergetics measurements with theoretical calculations, we show this process is sufficient for mycobacteria to sustain pmf and ATP synthesis (two ATP molecules per H 2 oxidized) for maintenance energy requirements during nutrient starvation. These findings confirm that atmospheric energy sources can be dependable ‘lifeline’ substrates that enable continuous energy conservation during nutrient starvation. In addition, this work provides a unique tool for ATP production in synthetic applications, which unlike other approaches is traceless without by-product accumulation.}, archive = {J_PNAS}, author = {Soom, Sarah and Moning, Stefan Urs and Cook, Gregory M. and Lingford, James P. and Kropp, Ashleigh and Tran, Sieu and Grinter, Rhys and Greening, Chris and von Ballmoos, Christoph}, doi = {10.1073/pnas.2506353122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2506353122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ATP synthesis driven by atmospheric hydrogen concentrations}, volume = {122}, year = {2025}, }
• (2025). Cell type–specific purifying selection of synonymous mitochondrial DNA variation. PNAS, 122(30), e2505704122. (www)

  @article{ , abstract = {While somatic variants are well-characterized drivers of tumor evolution, their influence on cellular fitness in nonmalignant contexts remains understudied. We identified a mosaic synonymous variant (m.7076A > G) in the mitochondrial DNA (mtDNA)-encoded cytochrome c-oxidase subunit 1 (MT-CO1, p.Gly391=), present at homoplasmy in 47% of immune cells from a healthy donor. Single-cell multiomics revealed strong, lineage-specific selection against the m.7076G allele in CD8 + effector memory T cells, but not other T cell subsets, mirroring patterns of purifying selection of pathogenic mtDNA alleles. The limited anticodon diversity of mitochondrial tRNAs forces m.7076G translation to rely on wobble pairing, unlike the Watson–Crick–Franklin pairing used for m.7076A. Mitochondrial ribosome profiling confirmed stalled translation of the m.7076G allele. Functional analyses demonstrated that the elevated translational and metabolic demands of short-lived effector T cells (SLECs) amplify dependence on MT-CO1, driving this selective pressure. These findings suggest that synonymous variants can alter codon syntax, impacting mitochondrial physiology in a cell type–specific manner.}, archive = {J_PNAS}, author = {Lareau, Caleb A. and Maschmeyer, Patrick and Yin, Yajie and Gutierrez, Jacob C. and Dhindsa, Ryan S. and Gribling-Burrer, Anne-Sophie and Zielinski, Sebastian and Hsieh, Yu-Hsin and Nitsch, Lena and Dimitrova, Veronika and Nalbant, Benan and Buquicchio, Frank A. and Abay, Tsion and Stickels, Robert R. and Ulirsch, Jacob C. and Yan, Patrick and Wang, Fangyi and Miao, Zhuang and Sandor, Katalin and Daniel, Bence and Liu, Vincent and Mendez, Paul L. and Knaus, Petra and Meyer, Manpreet and Greenleaf, William J. and Kundaje, Anshul and Smyth, Redmond P. and Munschauer, Mathias and Ludwig, Leif S. and Satpathy, Ansuman T.}, doi = {10.1073/pnas.2505704122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2505704122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cell type–specific purifying selection of synonymous mitochondrial DNA variation}, volume = {122}, year = {2025}, }
• (2025). Unprecedentedly high global forest disturbance due to fire in 2023 and 2024. PNAS, 122(30), e2505418122. (www)

  @article{ , abstract = {Global forests provide key ecosystem services, from climate regulation to biodiversity habitat, but are under increasing pressure from the combined impacts of climate and land use change. Here, we show that forest disturbance due to fire is growing globally, with the most dramatic increases in intact forest landscapes, highlighting an existential threat to remaining high biomass, high biodiversity forests. The global annual area of forest disturbance due to fire for 2023 and 2024 was highest since the beginning of monitoring in 2001. Compared to 2002–2022 average annual forest disturbance due to fire, the 2023–2024 average was 2.2 times higher globally and 3 times higher in the Tropics. More than ¼ of all 2024 forest disturbance from fire occurred in tropical forests. We found a statistically significant increasing trend of forest disturbance due to fire from 2002 to 2024 in all climate domains except Subtropical. High forest, low deforestation tropical countries were not exempt, with Guyana and the Republic of the Congo experiencing record forest disturbance due to fire. Our results agree with recently estimated increases in global forest fire emissions and active fire detections. The unprecedented scale of fires in the world’s most remote forests is a potential harbinger of ecosystem tipping points. Protecting these remaining unfragmented high conservation value forests from this threat poses a daunting and as yet undeveloped policy and capacity challenge.}, archive = {J_PNAS}, author = {Potapov, Peter and Tyukavina, Alexandra and Turubanova, Svetlana and Hansen, Matthew C. and Giglio, Louis and Hernandez-Serna, Andres and Lima, André and Harris, Nancy and Stolle, Fred}, doi = {10.1073/pnas.2505418122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2505418122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unprecedentedly high global forest disturbance due to fire in 2023 and 2024}, volume = {122}, year = {2025}, }
• (2025). Cdc42 defect reveals insights into microvilli organization and function in t cell immunity. PNAS, 122(30), e2505291122. (www)

  @article{ , abstract = {Microvilli on T cells differ from those on epithelial cells, exhibiting filopodia-like characteristics that facilitate the clustering of molecules essential for sensing and cell migration. Recently, they have also been recognized as the structures from which T cell immunological synaptosomes (TIS) are released. In this study, we examined a key determinant of microvilli organization during T cell development and explored the functional roles of these structures, particularly in relation to T cell behaviors. During thymocyte maturation, single-positive thymocytes were found to develop more and longer microvilli than double-positive thymocytes. However, the deletion or inhibition of Cdc42, a small Rho family protein, significantly reduced both the number and length of microvilli in single-positive thymocytes, leading to decreased cell mass. This reduction in microvilli correlates with a decrease in antigen recognition, leading to diminished T cell activation and adhesion, as well as reduced TIS production, while intrinsic migratory properties remain unaffected. These findings highlight the filopodia-like characteristics of T cell microvilli. In this context, Cdc42 contributes significantly to microvilli formation, thereby shaping T cell function.}, archive = {J_PNAS}, author = {Soh, Won-Chang and Park, Sang-Moo and Park, Jeong-Su and Karabulut, Hatice and Kang, Hee-Tae and Kang, Sun-Kyoung and Kim, Min-Sang and Park, Jihwan and Lee, Sunjae and Kim, Hye-Ran and Jun, Chang-Duk}, doi = {10.1073/pnas.2505291122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2505291122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cdc42 defect reveals insights into microvilli organization and function in t cell immunity}, volume = {122}, year = {2025}, }
• (2025). Electroreception in treehoppers: How extreme morphologies can increase electrical sensitivity. PNAS, 122(30), e2505253122. (www)

  @article{ , abstract = {The link between form and function of an organism’s morphology is usually apparent or intuitive. However, some clades of organisms show remarkable diversity in their form, often exhibiting extreme morphologies, but with no obvious functional explanation. Treehoppers (Membracidae) are a family of insects that exemplify this, displaying an astounding morphological diversity, resulting in a plethora of extreme forms. The function of these morphological extremities and the reasons for their evolution have thus far remained largely enigmatic. However, this mystery can be considered in light of the capacity of many animals to detect electric fields in air via electrostatic actuation of mechanosensory structures on their body. Importantly, the strength of the electric field experienced by these mechanosensory structures is expected by physics to depend on the animal’s geometry, with sharp and elongated features producing the highest electric fields. Therefore, we hypothesize that the extreme morphologies of treehoppers increase their electrical sensitivity. Here, we show that treehoppers, along with their predators and mutualists, produce electric fields and that the treehopper Poppea capricornis can detect electric fields, responding behaviorally. We also demonstrate that predatory wasps and mutualist bees differ significantly in their electrostatic profiles, pointing to the sophistication of electrical information potentially available to treehoppers. Biophysical, computational, and mathematical techniques are then utilized to provide evidence that the pronotum of treehoppers is the site of electroreception and that its extreme shapes may enhance its sensitivity to electricity.}, archive = {J_PNAS}, author = {England, Sam J. and Palmer, Ryan A. and O’Reilly, Liam J. and Chenchiah, Isaac V. and Robert, Daniel}, doi = {10.1073/pnas.2505253122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2505253122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electroreception in treehoppers: How extreme morphologies can increase electrical sensitivity}, volume = {122}, year = {2025}, }
• (2025). Sound-evoked tonic motility of cochlear outer hair cells in mice with stereociliary defects. PNAS, 122(30), e2505176122. (www)

  @article{ , abstract = {Mammalian hearing sensitivity depends on the amplification of sound-induced cochlear vibrations by outer hair cells (OHCs). OHCs transduce deflections of their stereociliary bundles into receptor potentials that drive changes in cell length. While fast, phasic OHC length changes are thought to generate the forces that underlie cochlear amplification, OHCs also exhibit large tonic length changes in response to sound. These tonic length changes could theoretically arise from asymmetries in the mechanotransduction process that lead to tonic changes in membrane potential, though their exact origins and functional significance are uncertain. Here, in vivo cochlear vibration measurements reveal that sound can elicit tonic OHC motility in mice with stereociliary defects that eliminate cochlear amplification and presumably impair mechanotransduction. Tonic OHC motility in impaired mice was physiologically vulnerable but only weakly correlated with any residual phasic motility, suggesting a possible dissociation between the underlying mechanisms. Nevertheless, a simple model demonstrates how realistic changes to the OHC mechanotransducer function in impaired mice can lead to small but strongly asymmetric receptor potentials, producing sizable tonic length changes in the absence of any detectable phasic motility. Tonic OHC motility is therefore not a unique feature of sensitive ears and is the dominant active mechanical response in ears with certain types of deafness. Whether such tonic responses play a functional role in the normal or impaired cochlea remains to be determined.}, archive = {J_PNAS}, author = {Dewey, James B.}, doi = {10.1073/pnas.2505176122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2505176122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sound-evoked tonic motility of cochlear outer hair cells in mice with stereociliary defects}, volume = {122}, year = {2025}, }
• (2025). A preclinical pig model of angelman syndrome mirrors the early developmental trajectory of the human condition. PNAS, 122(30), e2505152122. (www)

  @article{ , abstract = {Angelman syndrome is a neurodevelopmental disorder characterized by severe motor and cognitive deficits. It is caused by the loss of the maternally inherited allele of the imprinted ubiquitin-protein ligase E3A ( UBE3A ) gene. Rodent models of Angelman syndrome do not fully recapitulate all the symptoms associated with the condition and are limited as a preclinical model for therapeutic development. Here, we show that pigs ( Sus scrofa ) with a maternally inherited deletion of UBE3A ( UBE3A -/+ ) have altered postnatal behaviors, impaired vocalizations, reduced brain growth, motor incoordination, and ataxia. Neonatal UBE3A -/+ pigs exhibited several symptoms observed in infants with Angelman syndrome, including hypotonia, suckling deficits, and failure to thrive. Collectively, these findings are consistent with the pathophysiology and developmental trajectory observed in individuals with Angelman syndrome. We anticipate that this pig model will advance our understanding of the pathophysiology of Angelman syndrome and be used as a preclinical large animal model for therapeutic development.}, archive = {J_PNAS}, author = {Myers, Luke S. and Christian, Sarah G. and Simpson, Sean and Sper, Renan and Taylor, Clint and Montes, Laura and Jepp, Thomas B. C. and Ramos, Daniela and Schuller, Livia and Konganti, Kranti and Friedeck, Wade and Habib, Ozair and Hodge, McKaela and Taylor, Alasdair J. and Coffell, Ashley and Schlafer, Annalise and Matt, Morgan and Revell, Bradley and Knight, Carol and Barreña, Cristina C. and Murphy, William J. and Weeber, Edwin J. and Segal, David J. and Anderson, Anne and Nash, Kevin R. and Silverman, Jill L. and Piedrahita, Jorge A. and Dindot, Scott V.}, doi = {10.1073/pnas.2505152122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2505152122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A preclinical pig model of angelman syndrome mirrors the early developmental trajectory of the human condition}, volume = {122}, year = {2025}, }
• (2025). Phage-based delivery of CRISPR-associated transposases for targeted bacterial editing. PNAS, 122(30), e2504853122. (www)

  @article{ , abstract = {Phage λ, a well-characterized temperate phage, has been recently leveraged for bacterial genome editing by selectively delivering base editors into targeted bacterial species. We extend this concept by engineering phage λ to deliver CRISPR-guided transposases, accomplishing large insertions and targeted gene disruptions. To achieve this, we engineered phage λ using homologous recombination paired with Cas13a-based counterselection for precise phage modifications. Initially, we established the utility of Cas13a in phage λ by conducting minimal recoding edits, deletions, and insertions. Subsequently, we scaled up the engineering to embed the comprehensive DNA-editing CRISPR-Cas transposase (DART) system within the phage genome, creating λ-DART phages. These modified λ-DART phages were then employed to infect Escherichia coli , generating CRISPR RNA-guided transposition events in the host genome. Applying our engineered λ-DART phages to monocultures and a mixed bacterial community comprising three genera led to efficient, precise, and specific gene knockouts and insertions in the targeted E. coli cells, achieving editing efficiencies surpassing 50% of the population. This research enhances phage-mediated genome editing by enabling efficient in situ gene integrations in bacteria, offering an avenue for further application in microbial community contexts. This scalable method enables flexible microbial genome editing in situ to manipulate the function and composition of diverse ecosystems.}, archive = {J_PNAS}, author = {Roberts, Avery and Adler, Benjamin A. and Cress, Brady F. and Doudna, Jennifer A. and Barrangou, Rodolphe}, doi = {10.1073/pnas.2504853122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2504853122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phage-based delivery of CRISPR-associated transposases for targeted bacterial editing}, volume = {122}, year = {2025}, }
• (2025). Lipid residue analysis reveals divergent culinary practices in japan and korea at the dawn of intensive agriculture. PNAS, 122(30), e2504414122. (www)

  @article{ , abstract = {The dispersal of millet and rice agriculture from Korea to Japan from around 3,000 y ago has been well documented through radiocarbon analysis of botanical remains and surveying seed impressions on pottery. Much less is known about the extent to which these novel crops were consumed and incorporated into everyday culinary practices. In Japan, agriculturalists moving from Korea would have encountered large, sedentary Final Jomon populations who had well-established hunting, foraging, and cultivation strategies for exploiting indigenous fauna and flora. The degree to which these encounters hindered or enhanced the emergence of agriculture is a key question. To investigate potential changes in food exploitation, we analyzed the contents of pottery through lipid residue analysis of 260 vessels from Bronze Age (Mumun) Korea and contemporary Jomon and Yayoi pottery from Northern Kyushu. A lipid biomarker for broomcorn millet was only found in samples from Korea, suggesting that this crop was not routinely prepared in early agricultural pottery from Japan, despite some botanical evidence for its cultivation. Instead, aquatic products continued to be used in early agricultural pottery, pointing to continuity from the Jomon period despite the arrival of new “continental” ceramic forms. Rice remains difficult to identify conclusively, but by modeling carbon isotope values, we were able to determine the maximum extent that rice may have contributed. Overall, we show that there was a change in culinary practices as agriculture dispersed from Korea to Japan, most likely influenced by different long-standing traditions of preparing and cooking foods in each locality.}, archive = {J_PNAS}, author = {Craig, Oliver E. and Lundy, Jasmine and Bondetti, Manon and Nicholson-Lailey, Sesha and Murakami, Natsuki and Suzuki, Miho and Stevens, Chris and Lucquin, Alexandre and Talbot, Helen M. and Son, Joon-ho and Fujio, Shinichiro and Sakamoto, Minoru and Yamashita, Yusuke and Kobayashi, Kenichi and Crema, Enrico R. and Shoda, Shinya}, doi = {10.1073/pnas.2504414122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2504414122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lipid residue analysis reveals divergent culinary practices in japan and korea at the dawn of intensive agriculture}, volume = {122}, year = {2025}, }
• (2025). Ras-mediated dynamic and biphasic regulation of cell migration. PNAS, 122(30), e2503847122. (www)

  @article{ , abstract = {Ras has traditionally been regarded as a positive regulator and therapeutic target due to its role in cell proliferation, but recent findings indicate a more nuanced role in cell migration, where suppressed Ras activity can unexpectedly promote migration. To clarify this complexity, we systematically modulate Ras activity using various RasGEF and RasGAP proteins and assess their effects on migration dynamics. Leveraging optogenetics, we assess the immediate, nontranscriptional effects of Ras signaling on migration. Local RasGEF recruitment to the plasma membrane induces protrusions and new fronts to effectively guide migration, even in the absence of GPCR/G-protein signaling, whereas global recruitment causes immediate cell spreading halting cell migration. Local RasGAP recruitment suppresses protrusions, generates new backs, and repels cells, whereas global relocation either eliminates all protrusions to inhibit migration or preserves a single protrusion to maintain polarity. Consistent local and global increases or decreases in signal transduction and cytoskeletal activities accompany these morphological changes. Additionally, we performed cortical tension measurements and found that Ras activity is regulated by guanine nucleotide exchange factors generally increase cortical tension while Ras activity is regulated by GTPase-activating proteins decrease it. Our results reveal a biphasic relationship between Ras activity and cellular dynamics, reinforcing our previous findings that optimal Ras activity and cortical tension are critical for efficient migration.}, archive = {J_PNAS}, author = {Lin, Yiyan and Parajón, Eleana and Yuan, Qinling and Ye, Siyu and Qin, Guanghui and Deng, Yu and Borleis, Jane and Koyfman, Ariel and Iglesias, Pablo A. and Konstantopoulos, Konstantinos and Robinson, Douglas N. and Devreotes, Peter N.}, doi = {10.1073/pnas.2503847122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2503847122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ras-mediated dynamic and biphasic regulation of cell migration}, volume = {122}, year = {2025}, }
• (2025). The gln-rich protein twip1 promotes high-density {110} twins formation in the shell of the limpet cellana rota. PNAS, 122(30), e2503336122. (www)

  @article{ , abstract = {Aragonite, a polymorph of calcium carbonate (CaCO 3 ), exhibits enhanced mechanical properties due to crystal defects such as twins, which are particularly prevalent in biogenic aragonite and can inhibit crack propagation. Despite the importance, the molecular mechanisms responsible for the formation of aragonite {110} twins in marine organisms have remained poorly understood. Identifying a key inducer for {110} twins could help us understand how crystal defects are controlled in biomineralization. In this study, we explore the role of a protein, twip1, in inducing a high density of {110} twins within the aragonite layers of the limpet Cellana rota shell. Through a combination of layer-specific protein profiling and in vitro aragonite binding assays, twip1 is identified as a potential protein preferentially binding to the aragonite (110) plane. Gene expression analysis via quantitative PCR (qPCR) confirmed that twip1 is specifically expressed in the mantle tissue. To further investigate its function, recombinant twip1 (rtwip1) is produced using an Escherichia coli expression system. X-ray diffraction (XRD) and electron microscopy observations reveal that rtwip1 significantly increases {110} twin density during in vitro aragonite synthesis. Moreover, in vivo knockdown shows that reducing twip1 expression results in abnormal shell growth and {110} twin boundary reduction. Enhancing the formation of {110} twins in aragonite can improve its toughness and elasticity. This research highlights the crucial role of specific proteins in regulating crystal defect formation, offering a promising direction for future biomineralization studies and advanced material design.}, archive = {J_PNAS}, author = {Li, Sicheng and Liu, Xinlu and Zheng, Zehua and Oshima, Keisuke and Zhu, Lingxiao and Kato, Yugo and Negishi, Lumi and Kurumizaka, Hitoshi and Okumura, Taiga and Nagata, Koji and Pokroy, Boaz and Suzuki, Michio}, doi = {10.1073/pnas.2503336122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2503336122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The gln-rich protein twip1 promotes high-density {110} twins formation in the shell of the limpet cellana rota}, volume = {122}, year = {2025}, }
• (2025). Characterizing a highly excited and sustained brain response activity during gaming: P300-CE. PNAS, 122(30), e2502135122. (www)

  @article{ , abstract = {Inspired by the high engagement and sustained behavioral excitement observed in video game players, we hypothesized that distinct brain activity patterns occur during gaming compared to a generic nongame setting. Using electroencephalography (EEG), we characterized the brain’s response to critical in-game events, focusing on the response magnitude and adaptation. Data from a large participant cohort (n = 140 for game tasks, n = 200 for nongame tasks) revealed a clear, definite, and consistent temporospatial structure of brain response patterns triggered by critical in-game events. Most notably, this response displayed unusually large magnitudes and a lack of adaptation over repeated exposures—markedly different from the observed neural responses to typical events in lab-based tasks (e.g., regarding novelty, unexpected events or errors). The identification of this distinctive response component in gaming contexts may inspire further research into fundamental cognitive systems, such as motivation, reward, emotional engagement, and their dynamic interplay in gaming environments.}, archive = {J_PNAS}, author = {Pei, Leisi and Green, C. Shawn and Ouyang, Guang}, doi = {10.1073/pnas.2502135122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2502135122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Characterizing a highly excited and sustained brain response activity during gaming: P300-CE}, volume = {122}, year = {2025}, }
• (2025). An electron-bifurcating “plug” to a protein nanowire in tungsten-dependent aldehyde detoxification. PNAS, 122(30), e2501900122. (www)

  @article{ , abstract = {Members of the tungsten-containing oxidoreductase (WOR) family, which contain a tungstopyranopterin (Tuco) cofactor, are typically either monomeric (WorL) or heterodimeric (WorLS). These enzymes oxidize aldehydes to the corresponding acids while reducing the redox protein ferredoxin. They have been structurally characterized mainly using WORs from hyperthermophilic archaea. The WORs of some bacteria contain three additional subunits of the BfuABC family and these chimeric WorABCSL enzymes catalyze an electron-bifurcating reaction in which aldehyde oxidation is coupled to the simultaneous reduction of ferredoxin and nicotinamide adenine dinucleotide. In human gut microbes, electron bifurcation by WorABSL is proposed to enable the detoxification of aldehydes generated from cooked foods and in the tungstocentric production of beneficial short chain fatty acids from lactate, potentially impacting health. Herein we present the high-resolution cryogenic electron microscopy (cryo-EM) structure of the WorABCSL purified from the bacterium Acetomicrobium mobile. The structure reveals a surprising 1:3 stoichiometry between WorABC and WorSL, with the WorSL units forming a nanowire-like architecture leading from three Tuco-containing catalytic sites in WorL via strings of multiple iron-sulfur clusters in WorS to a single bifurcating WorABC core. Our structure uncovers a distinct domain arrangement that links three Tuco-dependent aldehyde oxidation sites with the bifurcation process and potentially facilitates environmental aldehyde oxidation.}, archive = {J_PNAS}, author = {Feng, Xiang and Schut, Gerrit J. and Putumbaka, Saisuki and Li, Huilin and Adams, Michael W. W.}, doi = {10.1073/pnas.2501900122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2501900122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An electron-bifurcating “plug” to a protein nanowire in tungsten-dependent aldehyde detoxification}, volume = {122}, year = {2025}, }
• (2025). Static allometries of caste-associated traits vary with genotype but not environment in the clonal raider ant. PNAS, 122(30), e2501716122. (www)

  @article{ , abstract = {Polyphenic traits in animals often exhibit nonlinear scaling with body size. Static allometries (i.e., scaling relationships) themselves can exhibit plasticity, such that individuals of the same size and genotype differ in body proportions across different environments. In ants, both larval environment and genotype regulate the expression of caste-associated traits, including body size and ovariole number. However, it remains untested whether caste-associated traits are independently regulated by environmental variables or whether they covary due to coupled developmental mechanisms. If caste traits are regulated independently, developmental plasticity should affect both trait expression and the scaling relationships between traits. Using the clonal raider ant, Ooceraea biroi , we tested this by manipulating the rearing environment of genetically identical larvae. We found that caregiver genotype, temperature, and food quantity influenced caste morphology strictly in tandem with body size, producing similar static allometries across rearing conditions (i.e., no allometric plasticity was detected). In contrast, clonal genotypes differed in average body size and their static allometries. Thus, size-matched individuals of the same genotype from different rearing environments exhibited no differences in mean caste trait expression, while those of different genotypes did. This absence of plasticity in the static allometries of different caste traits suggests that they are developmentally coupled due to systemic regulatory factors. Our findings contrast with reports of allometric plasticity in other insects, suggesting that ant caste traits are exceptionally integrated and therefore constrained in their independent responses to environmental variation. We discuss how these results inform contemporary hypotheses for ant caste development and evolution.}, archive = {J_PNAS}, author = {Piekarski, Patrick K. and Valdés-Rodríguez, Stephany and Trible, Waring and Kronauer, Daniel J. C.}, doi = {10.1073/pnas.2501716122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2501716122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Static allometries of caste-associated traits vary with genotype but not environment in the clonal raider ant}, volume = {122}, year = {2025}, }
• (2025). Bivalent interaction through an intrinsically disordered linker promotes transcription activation complex assembly in notch signaling. PNAS, 122(30), e2501607122. (www)

  @article{ , abstract = {The Notch signaling pathway regulates cellular differentiation by activating transcription through an unusual heterotrimeric complex comprising the Notch receptor’s intracellular domain (NICD), the DNA-binding protein CSL, and the coactivator MAML. NICD has two binding sites for CSL, a short motif in the RAM region and an ankyrin domain (ANK), connected by an intrinsically disordered linker and which form a bivalent ternary complex with CSL and MAML. Although bivalency is required for maximal transcription activation, the energetic contributions of bivalency and heterotrimer formation within this essential complex are unknown. To elucidate the energetics of bivalency, we first determine the free energy of the CSL-ANK-MAML heterotrimer, using isothermal titration calorimetry and developing an obligate heterotrimer model to analyze the data. By comparing this heterotrimerization reaction with binding reactions involving different regions of RAMANK, we determine the energetic contribution of bivalency to heterotrimer assembly. We show that bivalency through the disordered linker increases the effective concentration of ANK, and that the bivalent interaction enhances occupancy of RAM and ANK at their binding sites on CSL by about three orders of magnitude. By redefining the standard state to a lower, more physiological protein concentration, we reveal the importance of the RAMANK intrinsically disordered linker for assembly of the Notch transcription activation complex. This work provides a framework whereby the energetic contributions of intrinsically disordered linkers to higher-order multivalent assembly may be analyzed.}, archive = {J_PNAS}, author = {Cook, Cyril and Ramsey, Kristen M. and Barrick, Doug}, doi = {10.1073/pnas.2501607122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2501607122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bivalent interaction through an intrinsically disordered linker promotes transcription activation complex assembly in notch signaling}, volume = {122}, year = {2025}, }
• (2025). Central memory t cells with key TCR repertoires and gene expression profiles dominate influenza CD8+ t cell pools across the human lifespan. PNAS, 122(30), e2501167122. (www)

  @article{ , abstract = {Central memory CD8 + T cells (T cm ) represent the prominent memory T cell subset in human blood, yet the persistence of T cell receptor (TCR) clonotypic and transcriptional features of epitope-specific T cm pools across the human lifespan remains unknown. We analyzed T cm CD8 + T cells specific for HLA-A*02:01-M1 58–66 (A2/M1 58 ; a prominent influenza epitope) in newborns, children, adults, and older adults directly ex vivo. Our data provide evidence that epitope-specific T cm CD8 + pools dominate influenza-specific memory A2/M1 58 + CD8 + T cell responses from the early childhood until old age. T cm gene signatures were largely maintained across the age groups, although self-renewal genes defined T cm pools in children, while older adult T cm A2/M1 58 + CD8 + T cells displayed detoxication and stress profiles. TCRαβ diversity within T cm A2/M1 58 + CD8 + T cell pools was greater in children and older adults, when compared to adults. The key public-associated TCRαβ clonotypes largely persisted across the human lifespan, although their highest frequency was detected in adults, reflecting lower TCRαβ diversity in this group. Older adults displayed increased TCRαβ heterogeneity, underpinned by large TCRαβ clonotype expansions of private TCRαβ clonotypes. Our study highlights the importance of largely preserved virus-specific T cm pools across the human lifespan and advocates for boosting persistent TCRαβ clonotypes within this key peripheral blood subset.}, archive = {J_PNAS}, author = {Menon, Tejas and McQuilten, Hayley A. and Samir, Jerome and Nguyen, Thi H. O. and Lim, Ratana and Kaur, Jasveen and Rizzetto, Simone and Eltahla, Auda and Thomas, Paul G. and Lappas, Martha and Rossjohn, Jamie and Gras, Stephanie and Crowe, Jane and Flanagan, Katie L. and Luciani, Fabio and Doherty, Peter C. and van de Sandt, Carolien E. and Kedzierska, Katherine}, doi = {10.1073/pnas.2501167122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2501167122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Central memory t cells with key TCR repertoires and gene expression profiles dominate influenza CD8+ t cell pools across the human lifespan}, volume = {122}, year = {2025}, }
• (2025). Interfacial effects determine nonequilibrium phase behaviors in chemically driven fluids. PNAS, 122(30), e2501145122. (www)

  @article{ , abstract = {Coupling between chemical fuel consumption and phase separation can lead to condensation at a nonequilibrium steady state, resulting in phase behaviors that are not described by equilibrium thermodynamics. Theoretical models of such “chemically driven fluids” typically invoke near-equilibrium approximations at small length scales. However, because dissipation occurs due to both molecular-scale chemical reactions and mesoscale diffusive transport, it has remained unclear which properties of phase-separated reaction–diffusion systems can be assumed to be at an effective equilibrium. Here, we use microscopic simulations to show that mesoscopic fluxes are dependent on nonequilibrium fluctuations at phase-separated interfaces. We further develop a first-principles theory to predict nonequilibrium coexistence curves, localization of mesoscopic fluxes near phase-separated interfaces, and droplet size-scaling relations in good agreement with simulations. Our findings highlight the central role of interfacial properties in governing nonequilibrium condensation and have broad implications for droplet nucleation, coarsening, and size control in chemically driven fluids.}, archive = {J_PNAS}, author = {Cho, Yongick and Jacobs, William M.}, doi = {10.1073/pnas.2501145122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2501145122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Interfacial effects determine nonequilibrium phase behaviors in chemically driven fluids}, volume = {122}, year = {2025}, }
• (2025). Seed dispersal disruption limits tropical forest regrowth. PNAS, 122(30), e2500951122. (www)

  @article{ , abstract = {Identifying linkages between biodiversity loss and climate change is required for understanding the scope of these interconnected challenges and developing approaches to address them. One crucial yet underexplored aspect is the influence of seed-dispersing animals on forest carbon storage. Here, we show that 81% of tropical trees rely on animals for seed dispersal and that disruption of this process, due to declines in animal diversity and movement, significantly hampers the carbon accumulation potential of regrowing tropical forests. Using a synthesis of animal biodiversity, movement, and seed dispersal data covering thousands of animal species, we developed an index of seed dispersal disruption and modeled its relationship to carbon accumulation observed across 3,026 tropical regrowth plots. Naturally regrowing areas with lowest seed dispersal disruption had aboveground carbon accumulation rates four times higher than those with most severe disruption. Across areas identified as locations suitable for reforestation, current levels of seed dispersal disruption yield a 57% average reduction in local carbon accumulation potential. Tropical regrowth forests currently represent the largest land-based carbon sink; ongoing animal biodiversity losses diminish their ability to recover naturally from disturbances and therefore threaten their climate mitigation potential. These results advance understanding of animal biodiversity’s impact on carbon dynamics and emphasize the need to address biodiversity loss and climate change together.}, archive = {J_PNAS}, author = {Fricke, Evan C. and Cook-Patton, Susan C. and Harvey, Charles F. and Terrer, César}, doi = {10.1073/pnas.2500951122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2500951122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Seed dispersal disruption limits tropical forest regrowth}, volume = {122}, year = {2025}, }
• (2025). Optimal kinetics for catalytic cycles from a single path-sampling simulation. PNAS, 122(30), e2500934122. (www)

  @article{ , abstract = {A catalyst’s efficiency for accelerating a reaction rate is determined by its molecular structure and interactions with the substrate. While one can predict kinetics for a particular molecular model, tuning the (potentially many) model parameters to reach a desired or optimal kinetics for a catalytic cycle is usually considered computationally prohibitively expensive, especially in solvated systems. Here, we show for a simple model representing a minimal catalytic cycle that such optimization is possible using only one single (path-sampling) simulation, by applying a maximum caliber based path reweighting method. We compute the path ensemble for a single parameter setting of the molecular interactions and then expand the kinetic landscape around these parameters. We find that optimal catalytic turnover or efficiency is orders of magnitude improved and is achieved by relevant parameters that induce strain in the system. Thus, path-reweighting based optimization is not only capable of finding important ingredients that lead to desired kinetic rates but can also identify the mechanistic origins of the rate optimization at a fraction of the costs of a direct evaluation. We demonstrate the versatility of the methodology on a minimal model for kinase signaling. The approach promises efficient computational design of (complex) catalysts using realistic models.}, archive = {J_PNAS}, author = {Bolhuis, Peter G.}, doi = {10.1073/pnas.2500934122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2500934122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Optimal kinetics for catalytic cycles from a single path-sampling simulation}, volume = {122}, year = {2025}, }
• (2025). Mutualism between degraders and nondegraders stabilizes the function of a natural biopolymer-degrading community. PNAS, 122(30), e2500664122. (www)

  @article{ , abstract = {Natural biopolymer-degrading microbial communities drive carbon biogeochemical cycling. Within these communities, polymer degraders facilitate the growth of nondegraders by breaking down polymers through extracellular enzymes. However, the contributions of nondegraders to community dynamics, as well as the mechanisms that limit their access to degradation products, remain poorly understood. Here, we investigate EMSD5, a lignocellulose-degrading microbial community that efficiently converts corncob into isopropanol. We demonstrate that nondegraders, such as Escherichia coli , enable the growth of degraders (e.g., Lachnoclostridium sp. and Clostridium beijerinckii ) by creating anaerobic conditions and supplying biotin. Within such expanded niches, lignocellulose degradation proceeds sequentially, and the availability of breakdown products to E . coli is constrained by two interlinked processes. Specifically, Lachnoclostridium sp. produces oligosaccharides that are largely inaccessible to E . coli . A subset of these oligosaccharides is utilized by C . beijerinckii to produce monosaccharides that support E . coli growth, while glycosidase secretion by C . beijerinckii is reduced under coculture conditions. Building on these findings, we designed a synthetic consortium by coculturing C. beijerinckii with an engineered E . coli strain that expresses xylanase genes from an unculturable Lachnoclostridium . This consortium achieved isopropanol production from hemicellulose without requiring anaerobic conditions. Our findings reveal the niche-expanding role of nondegraders and the processes that constrain their access to degradation products, offering insights into maintaining stable cooperation in biopolymer-degrading communities and designing efficient consortia for biopolymer conversion.}, archive = {J_PNAS}, author = {Liu, Liang and Tian, Changfu and Wang, Miaoxiao and Luo, Ying and Huang, Yaru and Jiang, Tingting and Zhao, Hongwen and Yu, Qijun and Wang, Entao and Yang, Jinshui and Yuan, Hongli}, doi = {10.1073/pnas.2500664122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2500664122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mutualism between degraders and nondegraders stabilizes the function of a natural biopolymer-degrading community}, volume = {122}, year = {2025}, }
• (2025). Tenure and research trajectories. PNAS, 122(30), e2500322122. (www)

  @article{ , abstract = {Tenure is a cornerstone of the US academic system, yet its relationship to faculty research trajectories remains poorly understood. Conceptually, tenure systems may act as a selection mechanism, screening in high-output researchers; a dynamic incentive mechanism, encouraging high output prior to tenure but low output after tenure; and a creative search mechanism, encouraging tenured individuals to undertake high-risk work. Here, we integrate data from seven different sources to trace US tenure-line faculty and their research outputs at a remarkable scale and scope, covering over 12,000 researchers across 15 disciplines. Our analysis reveals that faculty publication rates typically increase sharply during the tenure track and peak just before obtaining tenure. Post-tenure trends, however, vary across disciplines: In lab-based fields, such as biology and chemistry, research output typically remains high post-tenure, whereas in non-lab-based fields, such as mathematics and sociology, research output typically declines substantially post-tenure. Turning to creative search, faculty increasingly produce novel, high-risk research after securing tenure. However, this shift toward novelty and risk-taking comes with a decline in impact, with post-tenure research yielding fewer highly cited papers. Comparing outcomes across common career ages but different tenure years or comparing research trajectories in tenure-based and non-tenure-based research settings underscores that breaks in the research trajectories are sharply tied to the individual’s tenure year. Overall, these findings provide an empirical basis for understanding the tenure system, individual research trajectories, and the shape of scientific output.}, archive = {J_PNAS}, author = {Tripodi, Giorgio and Zheng, Xiang and Qian, Yifan and Murray, Dakota and Jones, Benjamin F. and Ni, Chaoqun and Wang, Dashun}, doi = {10.1073/pnas.2500322122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2500322122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tenure and research trajectories}, volume = {122}, year = {2025}, }
• (2025). Structure reveals a regulation mechanism of plant outward-rectifying k+ channel GORK by structural rearrangements in the CNBD–Ankyrin bridge. PNAS, 122(30), e2500070122. (www)

  @article{ , abstract = {Guard cells, which regulate stomatal apertures in plants, possess a sophisticated mechanism for regulating turgor pressure. The outward-rectifying “K + out ” channel GORK, expressed in guard cells of the plant Arabidopsis thaliana , is a central component that promotes stomatal closure by releasing K + to the extracellular space, thereby lowering turgor pressure. To date, the structural basis underlying the regulation of the K + transport activity of GORK is unclear. Using cryo-EM, we determined the structures of the GORK outward-rectifying K + channel with a resolution of 3.16 to 3.27 Å in five distinct conformations that differ significantly in their C-terminal cyclic nucleotide binding domain (CNBD) and ankyrin repeat (ANK) domain. The C-linker connects the transmembrane domains to the C-terminal domains, i.e., CNBD, CNBD–Ankyrin bridge, and ANK. The structural changes and interactions in the C-linker determine whether the closed state of GORK is closer to the preopen state or in a more removed state from the open state of the channel. In particular, interconversion in the short sequence within the CNBD–Ankyrin bridge plays a decisive role in this determination. This region forms an α-helix in the preopened state, while it adopts a nonhelical structure in further distant closed states. The dynamics of the cytosolic region strongly suggest that the K + channel activity of GORK is regulated by cytosolic signaling factors during stomatal closure.}, archive = {J_PNAS}, author = {Yamanashi, Taro and Muraoka, Yuki and Furuta, Tadaomi and Kume, Tsukasa and Sekido, Natsuko and Saito, Shunya and Terashima, Shota and Yokoyama, Takeshi and Tanaka, Yoshikazu and Miyamoto, Atsushi and Sato, Kanane and Ito, Tomoyuki and Nakazawa, Hikaru and Umetsu, Mitsuo and Tanudjaja, Ellen and Tsujii, Masaru and Dreyer, Ingo and Schroeder, Julian I. and Ishimaru, Yasuhiro and Uozumi, Nobuyuki}, doi = {10.1073/pnas.2500070122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2500070122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure reveals a regulation mechanism of plant outward-rectifying k+ channel GORK by structural rearrangements in the CNBD–Ankyrin bridge}, volume = {122}, year = {2025}, }
• (2025). Polyploidy promotes transformation of epithelial cells into nonprofessional phagocytes. PNAS, 122(30), e2427293122. (www)

  @article{ , abstract = {Removal of dead and damaged cells is critical for organismal health. Under stress conditions such as nutritional deprivation, infection, or temperature shift, the clearance of nonessential cells becomes a universal strategy to conserve energy and maintain tissue homeostasis. Typically, this task is performed by professional phagocytes such as macrophages. However, nonprofessional phagocytes (NPPs) can also adopt a phagocytic fate under specific circumstances. Similar to professional phagocytes, NPPs undergo transitions from immature to mature states and activation, but the precise cellular and molecular mechanisms governing their maturation, induction, and phagocytic execution remain largely unknown. A notable example of stress-induced phagocytosis is the removal of germline cells by follicle cell–derived NPPs during oogenesis in Drosophila . In this study, we report that the transformation of follicle cells (FCs) into NPPs is dependent on Notch signaling activation during mid-oogenesis. Moreover, Notch overactivation is sufficient to trigger germline cell death and clearance (GDAC). We further show that polyploidy, driven by Notch signaling-induced endoreplication, is essential for the transformation of FCs into NPPs. Polyploidy facilitates the activation of JNK signaling, which is crucial for the phagocytic behavior of these cells. Additionally, we show that polyploidy in epidermal cells, another type of NPPs, is important for their engulfment of dendrites during induced degeneration. Together, these findings suggest that polyploidy is a critical factor in the transformation of epithelial cells into NPPs, enabling their phagocytic functions, which are essential for maintaining cellular and organismal homeostasis during stress conditions.}, archive = {J_PNAS}, author = {Huang, Yi-Chun and Almeida Machado Costa, Caique and Vergara Ruiz, Nicolas and Wang, Xianfeng and Jevitt, Allison and Breneman, Christina Marie and Han, Chun and Deng, Wu-Min}, doi = {10.1073/pnas.2427293122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2427293122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Polyploidy promotes transformation of epithelial cells into nonprofessional phagocytes}, volume = {122}, year = {2025}, }
• (2025). Tautomerism induces bending and twisting of biogenic crystals. PNAS, 122(30), e2426814122. (www)

  @article{ , abstract = {Understanding and exploiting material flexibility through phenomena such as the bending and twisting of molecular crystals has been a subject of increased interest owing to the number of applications that benefit from these properties, such as optoelectronics, mechanophotonics, soft robotics, and smart sensors. Here, we report the growth of spontaneously bent and twisted ammonium urate crystals induced by the keto–enol tautomerism of the urate molecule. The major tautomer is native to biogenic crystals, whereas the minor tautomer functions as an effective crystal growth modifier to induce naturally bent and twisted ammonium urate crystals. We show that the degree of curvature can be tailored based on the judicious selection of growth conditions. A combination of state-of-the-art microscopy and spectroscopy techniques are used to characterize the origin of bending. Spatially resolved nano-electron diffraction and high-resolution electron microscopy of naturally bent crystals show nearly single crystallinity with local lattice deformations generated by a combination of screw and edge dislocations. These observations are consistent with photoinduced force microscopy and contact resonance atomic force microscopy, which confirmed spatially resolved changes in the intermolecular interactions and the mechanical properties throughout the cross-sectional and axial regions of bent crystals. A mechanism of bending involving the generation of regionally specific dislocations is proposed as an alternative to more commonly reported models. These findings highlight a unique characteristic of tautomeric crystals that may have broader implications for other biogenic materials.}, archive = {J_PNAS}, author = {Tang, Weiwei and Yang, Taimin and Tu, Qing and Calderon, Hector A. and Robles Hernandez, Francisco C. and O’Reilly, Padraic and Jing, Yun and Park, Sung and Rimer, Jeffrey D.}, doi = {10.1073/pnas.2426814122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2426814122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tautomerism induces bending and twisting of biogenic crystals}, volume = {122}, year = {2025}, }
• (2025). Thioether editing generally increases the photostability of rhodamine dyes on self-labeling tags. PNAS, 122(30), e2426354122. (www)

  @article{ , abstract = {Self-labeling protein tags are widely used in advanced bioimaging where dyes with high-photon budgets outperform their fluorescent protein counterparts. Further increasing the emitted photon numbers of dye-tag systems is actively pursued by both new fluorophore chemistry and protein engineering. By scrutinizing the protein microenvironment of fluorophores, here we propose that proximal thioether groups negatively affect the photostability of the dye-tag system. We attribute the disparity in photostability of rhodamine dyes on HaloTag, SNAP-tag, and TMP-tag3 to the influence of the inherent thioether linkage within the SNAP-tag and TMP-tag3. This photochemical pathway leads us to further devise tags with higher photostability. We first show that rhodamine dyes on TMP-tag3.1, which employs a proximity-induced SuFEx reaction instead of a thiol-acrylamide addition to replace the thioether adduct, achieve photon budgets comparable to those ligands on HaloTag. We further showcase that by mutating the methionine near the fluorophore pocket, HaloTag: M175L generally gives up to four times enhancement on photostability when labeled with red and far-red rhodamines. The enhancement of HaloTag modification is demonstrated with single-molecule fluorescence imaging, live-cell fluorescence imaging, and voltage imaging. During time-lapse imaging, gradual photooxidation of Met leads to a reduced photobleaching rate, mechanistically supporting the thioether pathway hypothesis. Our findings suggest that thioether editing on self-labeling tags is a general strategy to enhance the photostability of fluorophores for advanced time-lapse imaging techniques.}, archive = {J_PNAS}, author = {Ling, Jing and Zhang, Yuan and Hei, Yongzhen and Kompa, Julian and Yang, Chen and Wang, Bo and Zhang, Junwei and Du, Jiasheng and Rudi, Tatjana and Zhang, Kecheng and Sun, Jingfu and Wang, Wenjuan and Fabritz, Sebastian and Li, Yulong and Deng, Wulan and Zou, Peng and Chen, Chunlai and Chen, Zhixing}, doi = {10.1073/pnas.2426354122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2426354122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Thioether editing generally increases the photostability of rhodamine dyes on self-labeling tags}, volume = {122}, year = {2025}, }
• (2025). Effects of the gut microbiota on placental angiogenesis and intrauterine growth in gnotobiotic mice. PNAS, 122(30), e2426341122. (www)

  @article{ , abstract = {Environmental causes of intrauterine growth restriction (IUGR) remain poorly characterized. Here, we compare germ-free (GF) and conventionally raised (CONV-R) mice to assess the effects of the gut microbiota on placental/fetal development at embryonic day (E)11.5 (end of placentation) and E17.5 (near term). Pregnancy- and microbiota-associated changes in gene expression occur along the gut, including those related to angiogenesis, while bacterial composition and fermentation activity remain stable. Placental weights at E11.5 and fetal weights at E17.5 are significantly reduced in GF animals. Compared to CONV-R dams, the GF maternal decidua exhibits similar vascular histomorphometric features at E11.5 and E17.5, and numbers of uterine NK-cells (effectors of vascular remodeling) at E11.5. In contrast, angiogenesis is disturbed in the GF fetal-derived placental compartment (junctional and/or labyrinth zones) at E11.5, as judged by i) increased levels of proangiogenic proteins (angiopoietin-2, FGF-2, follistatin, SDF-1, VEGF-A, VEGF-C); ii) increased levels of phos-VEGFR2 and phos-p38-MAPK yet reduction in phos-ERK1/2; and iii) reduced expression of junctional zone glycoprotein genes associated with angiogenesis and fetal growth, resulting in reduced endothelial cell density at the labyrinth zone at E17.5. Colonization of GF mice before pregnancy with cecal microbiota from CONV-R animals rescues fetal growth and altered transcriptomic, proteomic, and immunohistochemical features in the fetal GF placental compartment. Single-nucleus RNA-sequencing demonstrated increased expression of mitochondrial and ribosomal-associated oxidative stress genes in endothelial cell clusters in the GF fetal placental compartment (E11.5, E17.5), mimicking oxidative stress signatures in human IUGR. These results provide a rationale for seeking microbial targets for treating/preventing IUGR.}, archive = {J_PNAS}, author = {Coskun, Reyan and Chang, ZeNan L. and Marcial Rodríguez, Athziri and Liu, Haoxin and Cheng, Jiye and Alippe, Yael and Diamond, Michael S. and Gordon, Jeffrey I.}, doi = {10.1073/pnas.2426341122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2426341122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Effects of the gut microbiota on placental angiogenesis and intrauterine growth in gnotobiotic mice}, volume = {122}, year = {2025}, }
• (2025). A multifunctional anti-O-antigen human monoclonal antibody protects against shigella sonnei infection in vivo. PNAS, 122(30), e2426211122. (www)

  @article{ , abstract = {Shigellosis is a global public health challenge that mostly affects low- and middle-income countries and causes considerable morbidity and mortality among children under 5 y of age. Multi- and extensively drug-resistant Shigella sonnei strains associated with recent outbreaks in high-income countries exacerbate the problem and have prompted the World Health Organization to include Shigella spp. among the high-risk pathogens for which novel prophylactic and therapeutic tools are urgently needed. Among the most promising and cutting-edge solutions, monoclonal antibodies are gaining considerable attention in the infectious diseases field. Here, we report the discovery of human monoclonal antibodies against S. sonnei , a species whose prevalence is constantly increasing worldwide and is associated with frequent drug-resistant infections. We isolated antibodies generated in response to an experimental S. sonnei vaccine followed by a controlled human infection and screened them by using a panel of high-throughput assays. We identified a molecule which exhibited potent bactericidal activity in vitro, inhibition of invasion of epithelial cells and conferred full protection from S. sonnei infection in vivo. Overall, our study provides a candidate antibody that can rapidly progress to industrial development for application as a prophylactic, therapeutic, and diagnostic tool against shigellosis.}, archive = {J_PNAS}, author = {Ridelfi, Matteo and Vezzani, Giacomo and Roscioli, Emanuele and Batani, Giampiero and Boero, Elena and Nannini, Francesco and Marini, Eleonora and Bhaumik, Ushasi and Desalegn, Girmay and Serpino, Ornella and Molinaro, Antonio and Paciello, Ida and Mugnaini, Chiara and De Santi, Concetta and Maccari, Giuseppe and De Rosa, Antonella and Valensin, Silvia and Duatti, Assia and Di Benedetto, Roberta and Raso, Maria Michelina and Alfini, Renzo and Sammicheli, Chiara and Tavarini, Simona and Quigley, Christina and Podda, Audino and Kabanova, Anna and Andreano, Emanuele and Cardamone, Dario and Gasperini, Gianmarco and Necchi, Francesca and Pizza, Mariagrazia and Martin, Laura B. and Frenck, Robert W. and Grassart, Alexandre and Silipo, Alba and Pasetti, Marcela F. and Berlanda Scorza, Francesco and Giannelli, Carlo and Rossi, Omar and Micoli, Francesca and Sala, Claudia and Rappuoli, Rino}, doi = {10.1073/pnas.2426211122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2426211122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A multifunctional anti-O-antigen human monoclonal antibody protects against shigella sonnei infection in vivo}, volume = {122}, year = {2025}, }
• (2025). Gibberellin-deactivating GA2OX enzymes act as a hub for auxin–gibberellin cross talk in arabidopsis thaliana root growth regulation. PNAS, 122(30), e2425574122. (www)

  @article{ , abstract = {Plant bodies are built from immobile cells, making the regulation of cell expansion essential for growth, development, and adaptation. In roots, cell elongation executes the movement of the root tips through the soil. This process is tightly controlled by numerous signaling pathways. Among these, gibberellin and auxin signaling stand out for their contrasting effects on root growth, interacting through complex cross talk at multiple regulatory levels. Here, we reveal the molecular basis of the auxin–gibberellin cross talk in the model plant Arabidopsis thaliana . We show that the auxin signaling pathway steers the expression of GIBBERELLIN 2-OXIDASES (GA2OXs) , key gibberellin-deactivating enzymes in the root elongation zone (EZ). GA2OXs are negative regulators of root cell elongation; GA2OX8 overexpression decreases gibberellin levels and inhibits root cell elongation; in contrast, the ga2ox heptuple mutant roots show elevated gibberellin levels in the EZ and grow longer roots. Intriguingly, shoot-derived auxin can regulate GA2OX6 and GA2OX8 expression in roots, linking systemic auxin signaling to local gibberellin level modulation. Together, our findings identify GA2OX6 and GA2OX8 enzymes as key mediators of auxin–gibberellin cross talk, providing insights into their roles in root elongation. These results expand our understanding of how auxin integrates with gibberellin signaling to coordinate root development and growth dynamics.}, archive = {J_PNAS}, author = {Kubalová, Monika and Griffiths, Jayne and Müller, Karel and Levenets, Lev and Tylová, Edita and Tarkowská, Danuše and Jones, Alexander M. and Fendrych, Matyáš}, doi = {10.1073/pnas.2425574122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2425574122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Gibberellin-deactivating GA2OX enzymes act as a hub for auxin–gibberellin cross talk in arabidopsis thaliana root growth regulation}, volume = {122}, year = {2025}, }
• (2025). A quantitative figure of merit for battery SEI films and their use as functional solid-state electrolytes. PNAS, 122(30), e2425556122. (www)

  @article{ , abstract = {As a key passivation film that governs battery operation, the solid electrolyte interphase (SEI) has long been credited for enabling high-performance batteries or blamed for their eventual death. However, qualitative descriptions of the SEI often found in the literature (e.g., “conductive,” “passivating”) highlight our incomplete understanding of this layer, where even the most basic properties foundational to SEI function remain difficult to measure. Here, we quantify SEI conductivities and SEI transference numbers using a separator-free Cu|SEI|Li architecture that treats the SEI as a functional solid-state electrolyte (SSE). We find that while any SEI property alone (e.g., electronic conductivity) is weakly correlated (R 2 < 0.67) with battery performance (e.g., Coulombic efficiency), a strong correlation (R 2 > 0.99) can be achieved by defining the “SEI cT number” as a product between the SEI transference number ( T ) and the ratio of SEI conductivities ( c ). Analogous to the thermoelectric figure of merit (i.e., zT ), SEI cT quantitatively benchmarks the holistic impact of SEI properties on battery performance and underscores the pitfalls of citing such properties in isolation. Perhaps most strikingly, we demonstrate that Li metal deposition and stripping at room temperature is possible in our separator-free Cu|SEI|Li cell, confirming that the SEI can function precisely as an SSE. Together, these results enrich our understanding of the SEI, not just as a passivation layer but as a functional structure that can potentially have important implications for solid-state batteries.}, archive = {J_PNAS}, author = {Liu, Bo and Zhao, Dingyi and Lyle, Katelyn and Yuan, Xintong and Chen, Po-Hung and Zhang, Xinyue and Kim, Jin Koo and Wang, Tian-Yu and Wu, Haoyang and Wang, Chongzhen and Yu, Jiayi and Liang, Keyue and Kim, Jung Tae and Liang, Kaiyan and Li, Yuzhang}, doi = {10.1073/pnas.2425556122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2425556122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A quantitative figure of merit for battery SEI films and their use as functional solid-state electrolytes}, volume = {122}, year = {2025}, }
• (2025). Amino acid transfer free energies reveal thermodynamic driving forces in biomolecular condensate formation. PNAS, 122(30), e2425422122. (www)

  @article{ , abstract = {The self-assembly of intrinsically disordered proteins into biomolecular condensates depends on their primary sequence, leading to sequence-dependent phase separation. Computational methods to study this behavior often rely on residue-level interaction potentials that estimate the propensity of amino acids to partition between the dilute and dense phases. While distribution coefficients would provide the most direct measure of these potentials, their unavailability has led to the use of proxies, most notably, hydropathy. However, recent studies have highlighted limitations in hydropathy-based models. Here, we address this fundamental gap by calculating the transfer free energies for amino acid side chain analogs moving from the dilute phase to the dense phase of biomolecular condensates. We find that, net transfer free energies arise from a balance between favorable protein-mediated and unfavorable water-mediated interactions, with a striking asymmetry between the contributions of positive and negatively charged residues. This asymmetry originates from the stronger solvation of negatively charged species, and extends to modified amino acids. We further demonstrate that the sequence features of the condensate-forming protein modulate these transfer free energies in a context-dependent, but qualitatively similar manner. These findings help explain nontrivial experimental trends and provide a foundation for interpreting the sequence-dependent driving forces underlying condensate formation.}, archive = {J_PNAS}, author = {Rekhi, Shiv and Mittal, Jeetain}, doi = {10.1073/pnas.2425422122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2425422122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Amino acid transfer free energies reveal thermodynamic driving forces in biomolecular condensate formation}, volume = {122}, year = {2025}, }
• (2025). Leveraging chromatin packing domains to target chemoevasion in vivo. PNAS, 122(30), e2425319122. (www)

  @article{ , abstract = {Cancer cells exhibit a remarkable resilience to cytotoxic stress, often adapting through transcriptional changes linked to alterations in chromatin structure. In several types of cancer, these adaptations involve epigenetic modifications and restructuring of topologically associating domains. However, the underlying principles by which chromatin architecture facilitates such adaptability across different cancers remain poorly understood. To investigate the role of chromatin in this process, we developed a physics-based model that connects chromatin organization to cell fate decisions, such as survival following chemotherapy. Our model builds on the observation that chromatin forms packing domains, which influence transcriptional activity through macromolecular crowding. The model accurately predicts chemoevasion in vitro, suggesting that changes in packing domains affect the likelihood of survival. Consistent results across diverse cancer types indicate that the model captures fundamental principles of chromatin-mediated adaptation, independent of the specific cancer or chemotherapy mechanisms involved. Based on these insights, we hypothesized that compounds capable of modulating packing domains, termed Transcriptional Plasticity Regulators (TPRs), could prevent cellular adaptation to chemotherapy. We conducted a proof-of-concept compound screen using live-cell chromatin imaging to identify several TPRs that synergistically enhanced chemotherapy-induced cell death. The most effective TPR significantly improved therapeutic outcomes in a patient-derived xenograft model of ovarian cancer. These findings underscore the central role of chromatin in cellular adaptation to cytotoxic stress and present a framework for enhancing cancer therapies, with broad potential across multiple cancer types.}, archive = {J_PNAS}, author = {Frederick, Jane and Virk, Ranya K. A. and Ye, I Chae and Almassalha, Luay M. and Wodarcyk, Greta M. and VanDerway, David and Gong, Ruyi and Dunton, Cody L. and Kuo, Tiffany and Medina, Karla I. and Loxas, Margarita and Ahrendsen, Jared T. and Gursel, Demirkan B. and Gonzalez, Paola Carrillo and Nap, Rikkert J. and John, Saira and Agrawal, Vasundhara and Anthony, Nicholas M. and Carinato, John and Li, Wing Shun and Kakkaramadam, Rivaan and Jain, Surbhi and Shahabi, Shohreh and Ameer, Guillermo A. and Szleifer, Igal G. and Backman, Vadim}, doi = {10.1073/pnas.2425319122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2425319122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Leveraging chromatin packing domains to target chemoevasion in vivo}, volume = {122}, year = {2025}, }
• (2025). Tensor-based quantum phase difference estimation for large-scale demonstration. PNAS, 122(30), e2425026122. (www)

  @article{ , abstract = {We develop an energy calculation algorithm leveraging quantum phase difference estimation (QPDE) scheme and a tensor-network-based unitary compression method in the preparation of superposition states and time-evolution gates. Alongside its efficient implementation, this algorithm reduces depolarization noise affections exponentially. We demonstrated energy gap calculations for one-dimensional Hubbard models on IBM superconducting devices using circuits up to 32-system (plus one-ancilla) qubits, a five-fold increase over previous Quantum phase estimation (QPE) demonstrations, at the 7242 controlled-Z gate level of standard transpilation, utilizing a Q-CTRL error suppression module. Additionally, we propose a technique toward molecular executions using spatial orbital localization and index sorting, verified linear polyene simulations up to 21 qubits. Since QPDE can handle the same objectives as QPE, our algorithm represents a leap forward in quantum computing on real devices.}, archive = {J_PNAS}, author = {Kanno, Shu and Sugisaki, Kenji and Nakamura, Hajime and Yamauchi, Hiroshi and Sakuma, Rei and Kobayashi, Takao and Gao, Qi and Yamamoto, Naoki}, doi = {10.1073/pnas.2425026122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2425026122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tensor-based quantum phase difference estimation for large-scale demonstration}, volume = {122}, year = {2025}, }
• (2025). Spatial and temporal scale–dependent feedbacks govern dynamics of biocrusts in drylands. PNAS, 122(30), e2424836122. (www)

  @article{ , abstract = {Biota could be ecosystem engineers in generating an intrinsic heterogeneous landscape through scale-dependent feedbacks. Thereby, they can form resource-enriched patchiness or islands of fertility, comprising self-organizing spatial patterns. Research so far has largely focused on the self-organized spatial patterns of plant communities in drylands. It, however, remains unclear whether and how biocrusts having distinct morphology and life history from plant communities could self-organize themselves and form unique spatial patterns. Here, we conducted field observations of biocrusts across successional stages and employed a probabilistic cellular automaton model to investigate the distinct self-organized spatial patterns exhibited by mosaic patches of mosses and lichens with different patch size distributions (PSDs). Our study demonstrates that short-range positive feedbacks initially promote the development of patches, featured with a heavy-tailed PSD, while long-range negative feedbacks subsequently curtail further expansion of big patches, thereby establishing a characteristic patch scale with regular PSDs. Strikingly, only lichens reverted back to the heavy-tailed PSD in the late succession stage, presumably implying self-organized critical fragmentation of lichen patches. Field measurements of biocrust performance at the center and edge of patches of varying sizes along succession stages further support the classic scale-dependent feedback mechanism for Turing pattern formation. Collectively, our results clearly demonstrate the capability of the biocrust communities to self-organize themselves to form distinct spatial patterns governed by the spatial and temporal scale–dependent feedbacks, potentially impacting dryland ecosystem functions and resilience.}, archive = {J_PNAS}, author = {Sun, Jingyao and Yu, Kailiang and Rietkerk, Max and Chen, Ning and Zhang, Hongxia and Song, Guang and Li, Xinrong}, doi = {10.1073/pnas.2424836122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2424836122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatial and temporal scale–dependent feedbacks govern dynamics of biocrusts in drylands}, volume = {122}, year = {2025}, }
• (2025). OGG1 augments the transcriptional activation of foxp3 to promote iTreg differentiation for IBD alleviation. PNAS, 122(30), e2424733122. (www)

  @article{ , abstract = {8-oxo-7,8-dihydroguanine (8-oxoG), the most frequent form of oxidative-DNA-base lesion caused by ROS, is recognized and repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) through base excision repair (BER) pathway. Beyond its role in DNA repair, OGG1 has been shown to promote transcriptional activation of proinflammatory mediators and contribute to both acute and chronic lung inflammation. However, pioneering studies have shown an anti-inflammation role for OGG1 in inflammatory bowel disease (IBD), but its underlying molecular mechanism remains unclear. In the present study, we unveiled that OGG1 plays an important role in the differentiation of inducible regulatory T cells (iTregs). Binding of OGG1 to 8-oxoG facilitated the recruitment of Smad3 to the Foxp3 promoter, leading to the transcriptional activation. Moreover, OGG1 binding promoted demethylation of CpG sites in the conserved noncoding sequence 2 (CNS2) region of Foxp3 by decreasing Dnmt1 occupancy and enhancing recruitment of Tet1/2. Notably, the S326C variant—a naturally occurring polymorphism in humans—was more effective than the wild-type protein in promoting iTreg differentiation and showed a negative correlation with IBD incidence. Furthermore, treatment with O8, a selective OGG1 inhibitor that blocks base excision activity without affecting substrate binding, significantly alleviated IBD in a mouse model, suggesting a promising therapeutic strategy. Together, these findings extend the understanding of OGG1’s epigenetic role in transcriptional regulation and highlight its protective function in inflammatory diseases, potentially shaped by aerobic evolution.}, archive = {J_PNAS}, author = {Tian, Miaomiao and Hao, Fengqi and Wang, Xinyu and Zheng, Xu and Wang, Huiyue and Li, Jing and Li, Zilin and Xia, Mingjie and Li, Changfeng and Zhao, Zhexuan and Han, Jinling and Li, Dan and Nakabeppu, Yusaku and Boldogh, Istvan and Wei, Min and Ba, Xueqing}, doi = {10.1073/pnas.2424733122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2424733122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {OGG1 augments the transcriptional activation of foxp3 to promote iTreg differentiation for IBD alleviation}, volume = {122}, year = {2025}, }
• (2025). Exploring the social life of urban spaces through AI. PNAS, 122(30), e2424662122. (www)

  @article{ , abstract = {We analyze changes in pedestrian behavior over a 30-y period in four urban public spaces located in New York, Boston, and Philadelphia. Building on William Whyte’s observational work, which involved manual video analysis of pedestrian behaviors, we employ computer vision and deep learning techniques to examine video footage from 1979–80 and 2008–10. Our analysis measures changes in walking speed, lingering behavior, group sizes, and group formation. We find that the average walking speed has increased by 15%, while the time spent lingering in these spaces has halved across all locations. Although the percentage of pedestrians walking alone remained relatively stable (from 67% to 68%), the frequency of group encounters declined, indicating fewer interactions in public spaces. This shift suggests that urban residents are using streets as thoroughfares rather than as social spaces, which has important implications for the role of public spaces in fostering social engagement.}, archive = {J_PNAS}, author = {Salazar-Miranda, Arianna and Fan, Zhuangyuan and Baick, Michael and Hampton, Keith N. and Duarte, Fabio and Loo, Becky P. Y. and Glaeser, Edward and Ratti, Carlo}, doi = {10.1073/pnas.2424662122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2424662122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exploring the social life of urban spaces through AI}, volume = {122}, year = {2025}, }
• (2025). SETDB1 ensures the continuity of embryonic to adult neural stem cells through metabolic alterations in the dentate gyrus. PNAS, 122(30), e2424315122. (www)

  @article{ , abstract = {Embryonic neural progenitors give rise to adult neural stem cells (aNSCs), which share transcriptomic similarities with astrocytes while sustaining neurogenesis in the adult brain. How embryonic neural progenitors transit into aNSCs while preventing astrocyte fate to maintain the aNSC pool remains unclear. Here, we found that the Setdb1 -mediated metabolic state is essential for the transition from embryonic neural progenitors to aNSCs. Loss of the histone methyltransferase SETDB1 during dentate gyrus development leads to increased astrocyte production at the expense of aNSCs and ultimately constraining neurogenesis. Single-cell RNA sequencing reveals a specific metabolic alteration following Setdb1 loss, notably implicating the cytochrome c oxidase, subunit 6b2 ( Cox6b2 )—a component of the mitochondrial complex—as a key target of SETDB1. COX6B2 modulates oxidative phosphorylation (OXPHOS) to control aNSC fate over astrocyte differentiation. Elevated Cox6b2 levels promote astrocyte fate during dentate gyrus development. Thus, our findings reveal a mechanism underlying the continuity of neural progenitors to generate aNSC enabling the production of new neurons in the adult brain, highlighting the potential therapeutic strategies for transforming astrocytes into neurons via aNSCs.}, archive = {J_PNAS}, author = {Huang, Yunyun and Zhu, Yue and Zhu, Yueyan and Jiang, Yan and Xie, Yunli}, doi = {10.1073/pnas.2424315122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2424315122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SETDB1 ensures the continuity of embryonic to adult neural stem cells through metabolic alterations in the dentate gyrus}, volume = {122}, year = {2025}, }
• (2025). EIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer. PNAS, 122(30), e2424286122. (www)

  @article{ , abstract = {Most breast cancers depend on hormone-stimulated estrogen receptor alpha (ER) activity and are sensitive to ER inhibition. Resistance can arise from activating mutations in the gene encoding ER ( ESR1 ) or from reactivation of downstream targets. Newer ER antagonists occasionally show efficacy but are largely ineffective as single agents in the long term. Here, we show that ER translation is eIF4E/cap-independent yet sensitive to inhibitors of the translation initiation factor eIF4A. EIF4A inhibition reduces the expression of ER and cell cycle regulators such as cyclin D1. This leads to growth suppression in ligand-independent breast cancer models, including those driven by ER mutants and fusion proteins. Efficacy is enhanced by adding the ER degrader, fulvestrant. The combination further lowers ER expression and blocks tumor growth in vitro and in vivo. In an early clinical trial (NCT04092673), the eIF4A inhibitor zotatifin was combined with either fulvestrant or fulvestrant plus CDK4 inhibitor, abemaciclib, in patients with acquired resistance to these agents. Multiple clinical responses including a handful of durable regressions were observed, with little toxicity. Thus, eIF4A inhibition could be useful for treating ER+ breast cancer resistant to other modalities.}, archive = {J_PNAS}, author = {Boyer, Jacob A. and Rosen, Ezra Y. and Sharma, Malvika and Dorso, Madeline A. and Mai, Nicholas and Amor, Corina and Reiter, Jason M. and Kannan, Ram and Gadal, Sunyana and Xu, Jianing and Miele, Matthew and Li, Zhuoning and Chen, Xiaoping and Chang, Qing and Pareja, Fresia and Worland, Stephan and Warner, Douglas and Sperry, Sam and Chiang, Gary G. and Thompson, Peggy A. and Yang, Guangli and Ouerfelli, Ouathek and Drilon, Alexander and de Stanchina, Elisa and Wendel, Hans-Guido and Chandarlapaty, Sarat and Rosen, Neal}, doi = {10.1073/pnas.2424286122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2424286122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {EIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer}, volume = {122}, year = {2025}, }
• (2025). Thermal mismatch models derived from occurrence data predict pathogen prevalence in frogs. PNAS, 122(30), e2423706122. (www)

  @article{ , abstract = {Emerging infectious diseases increasingly threaten many wildlife populations, yet the impacts of pathogens vary considerably both within and among host species. The environmental tolerance mismatch hypothesis (ETMH) suggests that this variability stems in part from differences in the relative performance of hosts and pathogens under varying environmental conditions. According to the ETMH, pathogen impacts should be more severe in environments where pathogen performance is high and host performance is low, and vice versa. However, testing the ETMH with field data is challenging due to the difficulty of measuring host and pathogen performance among locations and quantifying performance mismatches. Here, we demonstrate that a measure of thermal mismatch, based on species realized thermal niches derived from species occurrence data, can reliably predict variation in the prevalence of the amphibian fungal pathogen Batrachochytrium dendrobatidis (Bd—chytrid fungus) within and among 42 frog host species in Australia. Specifically, we show that 1) within species, more warm-adapted host species show a steeper decline in Bd prevalence with increasing mean annual temperature, potentially reflecting greater host advantage at warmer temperatures; and 2) among host species, mean pathogen prevalence declines as the thermal affinity of hosts diverges from that of the pathogen. Our findings strongly support the ETMH and, importantly, offer a promising approach to predicting pathogen outcomes both spatially and temporally using species occurrence data. This approach enhances our understanding of variability in pathogen impacts and could inform management actions to mitigate these effects.}, archive = {J_PNAS}, author = {Duncan, Richard P. and Scheele, Ben C. and Clulow, Simon}, doi = {10.1073/pnas.2423706122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2423706122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Thermal mismatch models derived from occurrence data predict pathogen prevalence in frogs}, volume = {122}, year = {2025}, }
• (2025). Trigger factor accelerates nascent chain compaction and folding. PNAS, 122(30), e2422678122. (www)

  @article{ , abstract = {Conformational control of nascent chains is poorly understood. Chaperones are known to stabilize, unfold, and disaggregate polypeptides away from the ribosome. In comparison, much less is known about the elementary conformational control mechanisms at the ribosome. Yet, proteins encounter major folding and aggregation challenges during translation. Here, using selective ribosome profiling and optical tweezers with correlated single-molecule fluorescence, with dihydrofolate reductase (DHFR) as a model system, we show that the Escherichia coli chaperone trigger factor (TF) accelerates nascent chain folding. TF scans nascent chains by transient binding events, and then locks into a stable binding mode as the chain collapses and folds. This interplay is reciprocal: TF binding collapses nascent chains and stabilizes partial folds, while nascent chain compaction prolongs TF binding. Ongoing translation controls these cooperative effects, with TF-accelerated folding depending on the emergence of a peptide segment that is central to the core DHFR beta-sheet. The folding acceleration we report here impacts processes that depend on folding occurring cotranslationally, including cotranslational protein assembly, protein aggregation, and translational pausing, and may be relevant to other domains of life.}, archive = {J_PNAS}, author = {Till, Katharina and Seinen, Anne-Bart and Wruck, Florian and Sunderlikova, Vanda and Galmozzi, Carla V. and Katranidis, Alexandros and Bukau, Bernd and Kramer, Günter and Tans, Sander J.}, doi = {10.1073/pnas.2422678122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2422678122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Trigger factor accelerates nascent chain compaction and folding}, volume = {122}, year = {2025}, }
• (2025). Soil nitrogen drives inverse acclimation of xylem growth cessation to rising temperature in northern hemisphere conifers. PNAS, 122(30), e2421834122. (www)

  @article{ , abstract = {Controlled experiments suggest that the seasonal build-up of nitrogen (N) limitation constrains the responses of forest autumn phenology to elevated temperatures. Therefore, rising soil N is expected to increase the delaying effects of elevated temperature on the end of the season, i.e., leaf senescence. However, the interactive effects of temperature, soil N, and aridity on xylem autumn phenology remain unknown. We conducted a wide spatial analysis from 75 conifer sites in the Northern Hemisphere and found that rising soil N increases the delaying effects of elevated temperature on the end of xylem cell wall thickening but reduced the delaying effects on the cessation of cell enlargement, especially in humid regions. The contrasting effects of elevated soil N on cell enlargement versus cell wall thickening could affect xylem cell anatomy, thereby induce changes in wood density, and induce a decoupling of stem size growth from photosynthate production. These analyses extend previous findings on forest autumn phenology by systematically investigating the spatial variation in the interactive effects of temperature and soil N on xylem autumn phenology at the cellular scale.}, archive = {J_PNAS}, author = {Zhang, Yaling and Huang, Jian-Guo and Wang, Minhuang and Wang, Wenjin and Yang, Feiyu and Deslauriers, Annie and Fonti, Patrick and Liang, Eryuan and Mäkinen, Harri and Oberhuber, Walter and Rathgeber, Cyrille B. K. and Tognetti, Roberto and Treml, Václav and Yang, Bao and Zhai, Lihong and Antonucci, Serena and Buttò, Valentina and Camarero, J. Julio and Campelo, Filipe and Čufar, Katarina and Luis, Martin De and Fajstavr, Marek and Giovannelli, Alessio and Gričar, Jožica and Gruber, Andreas and Gryc, Vladimír and Güney, Aylin and Jyske, Tuula and Kašpar, Jakub and King, Gregory and Krause, Cornelia and Lemay, Audrey and Lombardi, Fabio and Castillo, Edurne Martinez del and Morin, Hubert and Nabais, Cristina and Nöjd, Pekka and Peters, Richard L. and Prislan, Peter and Saracino, Antonio and Shishov, Vladimir V. and Vavrčík, Hanuš and Vieira, Joana and Zeng, Qiao and Rossi, Sergio}, doi = {10.1073/pnas.2421834122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2421834122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Soil nitrogen drives inverse acclimation of xylem growth cessation to rising temperature in northern hemisphere conifers}, volume = {122}, year = {2025}, }
• (2025). Nucleation at solid–liquid interfaces is accompanied by the reconfiguration of electrical double layers. PNAS, 122(30), e2421635122. (www)

  @article{ , abstract = {In electrochemical systems, the structure of electrical double layers (EDLs) near electrode surfaces is crucial for energy conversion and storage functions. While the electrodes in real-world systems are usually heterogeneous, to date the investigation of EDLs is mainly limited to planar, homogeneous substrates. To bridge this gap, here we image the EDL structure of an ionic liquid/graphite battery anode system in the initial stage of interfacial nucleation and growth using our recently developed electrochemical 3D atomic force microscopy. Upon surface nucleation of lithium-containing compounds, the local EDL layers exhibit pronounced restructuring, featuring bending, breaking, and/or reconnecting patterns that switch when the size of the local interphase cluster changes. These EDL reconfiguration patterns are likely universal during nucleation and growth, calling into attention the hitherto hidden contribution of EDL heterogeneity on electrochemical processes.}, archive = {J_PNAS}, author = {Ai, Qian and Bonagiri, Lalith Krishna Samanth and Panse, Kaustubh S. and Kim, Jaehyeon and Zhou, Shan and Zhang, Yingjie}, doi = {10.1073/pnas.2421635122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2421635122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nucleation at solid–liquid interfaces is accompanied by the reconfiguration of electrical double layers}, volume = {122}, year = {2025}, }
• (2025). Can we still use the Michaelis–Menten model for enzymatic microneedle sensors?. PNAS, 122(30), e2418168122. (www)

  @article{ , abstract = {Since the 1960s, enzymatic sensors have been vital in healthcare and environmental monitoring due to their high selectivity. Traditionally, their performance is interpreted using the Michaelis–Menten (MM) equation, which assumes idealized, homogeneous, well-mixed laboratory conditions. However, integrating these sensors with microneedle (MN) patches for wearable applications introduces challenges such as spatial and temporal variations and limited reactant availability. Applying the MM model in such scenarios can lead to dramatic errors in enzyme kinetics and biomarker estimates, risking inaccurate substrate measurements and potentially life-threatening decisions. Here, we generalize the reaction–diffusion framework for enzymatic sensors and integrate it with analytical models for MN sensors. Our approach captures time-dependent MM variables, quantifies the rate of product formation, accounts for mass transport limitations, and provides expressions for response time and active substrate levels. This physics-based framework enables a) quantification of otherwise inaccessible parameters such as active substrate levels, b) accurate response-time predictions to reach steady-state conditions, c) improved data interpretation, and d) projection of enzymatic responses across various conditions. The study highlights the need for careful application of MM model in wearable microneedle sensors, where key assumptions may not hold. Our model can also extend to sensor degradation, inactivation, and hypoxia, making it broadly applicable to enzymatic sensors in diverse environments.}, archive = {J_PNAS}, author = {Fratus, Marco and Alam, Muhammad A.}, doi = {10.1073/pnas.2418168122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2418168122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Can we still use the Michaelis–Menten model for enzymatic microneedle sensors?}, volume = {122}, year = {2025}, }
• (2025). Traveling waves link human visual and frontal cortex during working memory–guided behavior. PNAS, 122(30), e2415573122. (www)

  @article{ , abstract = {Traveling waves guide the spatial propagation of neural activity and computational processes across the brain. Traveling waves could contribute to the control of memory-guided behaviors by flexibly organizing the timing and direction of interactions between brain regions responsible for storing memory content with those responsible for producing task-relevant behaviors. Using short-term memory as a test case, we report evidence supporting this possibility. Analyses of human EEG data revealed forward- and backward-propagating traveling waves linking visual and motor brain areas around the time of a memory-guided behavior. These waves predicted intra- and interindividual differences in task performance, could not be explained by eye movements or passive volume conduction, and were absent when participants planned but could not execute a memory-guided behavior. These findings implicate traveling waves as a mechanism in the initiation and control of memory-guided behaviors.}, archive = {J_PNAS}, author = {Luo, Canhuang and Ester, Edward F.}, doi = {10.1073/pnas.2415573122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2415573122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Traveling waves link human visual and frontal cortex during working memory–guided behavior}, volume = {122}, year = {2025}, }
• (2025). How publics in small-island states view climate change and international responses to it. PNAS, 122(30), e2415324122. (www)

  @article{ , abstract = {Climate change caused by carbon pollution from the world’s largest economies poses an existential threat to small-island states and territories this century. These places bear virtually no responsibility for climate change but will face sea-level rise, fresh water resource degradation, and intensified storms that will kill or dislocate exposed publics, and damage local economies. To alleviate this crisis, the global community has begun discussing who is responsible for climate mitigation and adaptation costs for those affected by climate change, in addition to continued debates around the distribution of responsibility for climate change. Missing from this analysis, however, are systematic efforts to elicit the preferences and perceptions of publics in these threatened small-island states and territories. Here, we report results from a large-sample (n = 14,710) cross-national survey of publics living in climate-vulnerable states and territories, conducted in June–July 2022. By quota sampling through Facebook’s ad platform, we generate survey samples at the national or territorial level for publics in 55 small-island states, territories, and subnational regions in the South Pacific, Indian Ocean, and Caribbean. We find widespread awareness and concern about the threat posed by climate change and sea-level rise, in contrast to what existing research finds in the Global North. We also find that climate-vulnerable publics believe their home governments, large polluters, and former colonial powers are all responsible for helping to manage the climate crisis, irrespective of these actors’ relative carbon emissions. These findings fill an important gap by depicting climate beliefs among the communities at the frontlines of climate change.}, archive = {J_PNAS}, author = {Mildenberger, Matto and Constantino, Sara M. and Mahdavi, Paasha and Bergquist, Parrish and De Roche, Gabriel and Franzblau, Emma and Martinez-Alvarez, Cesar and Sturm, Ingmar}, doi = {10.1073/pnas.2415324122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2415324122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How publics in small-island states view climate change and international responses to it}, volume = {122}, year = {2025}, }
• (2025). Human land use promotes range expansion of soil protists from temperate to subtropical regions in china. PNAS, 122(30), e2413220122. (www)

  @article{ , abstract = {Land-use changes are reshaping the distribution of aboveground species worldwide. However, the impact of land-use changes on the distribution of soil organisms remains poorly understood. In particular, we lack a mechanistic understanding of the environmental factors reshaping the distribution of soil microbiota in response to global biological homogenization. Here, we used metabarcoding to investigate the biogeography of protists and their relationships with prey and hosts in three human-dominated ecosystem types, i.e., farmlands, residential areas, and parks, along with natural forests, in subtropical and temperate climatic regions across China. We found that human land-use systems extended the distribution range of habitat-generalist protists compared to forests. This human-facilitated spread of protists was highly directional and mainly driven by temperate to subtropical range expansion of soil taxa. Put simply, increases in soil pH associated with human land uses mitigate the natural acidity barrier typically found in subtropical ecosystems, facilitating the temperate to subtropical range expansion of protist species. However, in temperate regions, the northward expansion of subtropical species is likely restricted by a more arid climate with even higher soil pH. The cross-region spread of soil protists was more pronounced in phagotrophs than phototrophs and parasites, reflecting codispersal of phagotroph protists and microbial prey (especially bacteria) related to tight predator–prey specialization and/or similar responses to environmental changes. Our findings indicate that land-use changes create hotspots of potential microbial invasions, particularly in subtropical and tropical regions, highlighting that understudied regions are likely to be strongly affected by biological homogenization related to introduction of exotic species.}, archive = {J_PNAS}, author = {Li, Zhi-Peng and Sun, Xin and Yao, Haifeng and Shangguan, Hua-Yuan and Hu, Hang-Wei and Tang, Zhiyao and Li, Gang and Zhang, Weixin and Delgado-Baquerizo, Manuel and Scheu, Stefan and Zhu, Yong-Guan}, doi = {10.1073/pnas.2413220122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2413220122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Human land use promotes range expansion of soil protists from temperate to subtropical regions in china}, volume = {122}, year = {2025}, }
• (2025). Stress-induced translocation of the endoplasmic reticulum chaperone GRP78/BiP and its impact on human disease and therapy. PNAS, 122(30), e2412246122. (www)

  @article{ , abstract = {Since their discoveries in the 1960s as a family of proteins produced by cells in response to stress, molecular chaperones are increasingly recognized as major regulators of cellular homeostasis in health and disease. Among the heat shock protein 70 family, the 78-kDa glucose-regulated protein (GRP78), also referred to as BiP and encoded by the HSPA5 gene, contains a signal peptide targeting it into the endoplasmic reticulum (ER). Through its interaction with the transmembrane ER stress sensors, GRP78 acts as a master regulator of the Unfolded Protein Response (UPR) which allows cells to adapt to stress observed in many human diseases. The discovery that ER stress not only upregulates GRP78 to cope with ER protein quality control but also actively promotes its relocation to other cellular compartments where they vastly expand its functional repertoire beyond the ER represents a paradigm shift. This Perspective describes the origin and linkage of GRP78 to the UPR and the mechanisms whereby ER stress actively promotes export of GRP78 from the ER, as exemplified by its translocation to the cell surface where it acts as a multifaceted receptor and a conduit for drug and viral entry, as well as its translocation into the nucleus, where it assumes the surprising role of a transcriptional regulator whereby reprogramming the cell’s transcriptome. Furthermore, this Perspective addresses how these and other atypical localizations of GRP78 impact human disease, with emphasis on cancer and COVID-19, and the exciting prospect that drugs targeting GRP78 could dually suppress tumorigenesis and viral infections.}, archive = {J_PNAS}, author = {Lee, Amy S.}, doi = {10.1073/pnas.2412246122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2412246122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stress-induced translocation of the endoplasmic reticulum chaperone GRP78/BiP and its impact on human disease and therapy}, volume = {122}, year = {2025}, }
• (2025). RACK1A positively regulates opening of the apical hook in arabidopsis thaliana via suppression of its auxin response gradient. PNAS, 122(30), e2407224122. (www)

  @article{ , abstract = {Apical hook development is an ideal model for studying differential growth in plants and is controlled by complex phytohormonal crosstalk, with auxin being the major player. Here, we identified a bioactive small molecule that decelerates apical hook opening in Arabidopsis thaliana . Our genetic studies suggest that this molecule enhances or maintains the auxin maximum found in the inner hook side and requires certain auxin signaling components to modulate apical hook opening. Using biochemical approaches, we then revealed the WD40 repeat scaffold protein RECEPTOR FOR ACTIVATED C KINASE 1A (RACK1A) as a direct target of this compound. We present data in support of RACK1A playing a positive role in apical hook opening by activating specific auxin signaling mechanisms and negatively regulating the differential auxin response gradient across the hook, thereby adjusting differential cell growth, an essential process for organ structure and function in plants.}, archive = {J_PNAS}, author = {Ma, Qian and Liu, Sijia and Doyle, Siamsa M. and Raggi, Sara and Pařízková, Barbora and Barange, Deepak Kumar and Ratnakaram, Hemamshu and Wilkinson, Edward G. and Crespo Garcia, Isidro and Bygdell, Joakim and Wingsle, Gunnar and Boer, Dirk Roeland and Strader, Lucia C. and Almqvist, Fredrik and Novák, Ondřej and Robert, Stéphanie}, doi = {10.1073/pnas.2407224122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {30}, pages = {e2407224122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RACK1A positively regulates opening of the apical hook in arabidopsis thaliana via suppression of its auxin response gradient}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(29), eiti2925122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti2925122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {eiti2925122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for yi et al., transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation. PNAS, 122(29), e2516641122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2516641122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2516641122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for yi et al., transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation}, volume = {122}, year = {2025}, }
• (2025). Correction for beal et al., nutrient-dense foods and diverse diets are important for ensuring adequate nutrition across the life course. PNAS, 122(29), e2516301122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2516301122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2516301122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for beal et al., nutrient-dense foods and diverse diets are important for ensuring adequate nutrition across the life course}, volume = {122}, year = {2025}, }
• (2025). Correction for spirandelli et al., exotic self-assembly of hard spheres in a morphometric solvent. PNAS, 122(29), e2516290122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2516290122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2516290122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for spirandelli et al., exotic self-assembly of hard spheres in a morphometric solvent}, volume = {122}, year = {2025}, }
• (2025). QnAs with hans f. coetzee. PNAS, 122(29), e2515788122. (www)

  @article{ , archive = {J_PNAS}, author = {Hardcastle, Matthew}, doi = {10.1073/pnas.2515788122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2515788122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {QnAs with hans f. coetzee}, volume = {122}, year = {2025}, }
• (2025). Growing recognition of post-acute infection syndromes. PNAS, 122(29), e2513877122. (www)

  @article{ , archive = {J_PNAS}, author = {Komaroff, Anthony L.}, doi = {10.1073/pnas.2513877122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2513877122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Growing recognition of post-acute infection syndromes}, volume = {122}, year = {2025}, }
• (2025). Predicting regime shifts and beyond. PNAS, 122(29), e2513605122. (www)

  @article{ , archive = {J_PNAS}, author = {Thygesen, Uffe Høgsbro}, doi = {10.1073/pnas.2513605122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2513605122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Predicting regime shifts and beyond}, volume = {122}, year = {2025}, }
• (2025). Decoding nature’s grammar with DNA language models. PNAS, 122(29), e2512889122. (www)

  @article{ , archive = {J_PNAS}, author = {Morrell, Peter L. and Pakhomov, Serguei V.}, doi = {10.1073/pnas.2512889122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2512889122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Decoding nature’s grammar with DNA language models}, volume = {122}, year = {2025}, }
• (2025). Impact forecasting for humanitarianism: Opportunities and challenges. PNAS, 122(29), e2512728122. (www)

  @article{ , archive = {J_PNAS}, author = {Baylis, Kathy and Lentz, Erin C.}, doi = {10.1073/pnas.2512728122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2512728122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Impact forecasting for humanitarianism: Opportunities and challenges}, volume = {122}, year = {2025}, }
• (2025). Accelerating countermeasure candidate discovery for A-series chemical warfare agent exposure. PNAS, 122(29), e2512471122. (www)

  @article{ , abstract = {The recent alleged use of A-series chemical warfare agents (CWAs) highlights the urgent need to better understand their inhibition of cholinesterase enzymes and the reported shortcomings of traditional oxime countermeasures. Here, using high-throughput (HT) mass spectrometry (MS) technologies, we characterized the largely unknown inhibition kinetics of A-series CWAs on human acetylcholinesterase ( h AChE) and its reactivation by oximes, achieving label-free quantitation at rates of up to 7,000 reactions per hour. Our findings indicate i) A-series agents exhibit inhibitory potencies similar to traditional CWAs like sarin and VX, and ii) bipyridinium-based oximes can reactivate A-series-adducted h AChE in vitro, challenging prior reports on oxime efficacy. These results underscore the need for continued exploration of countermeasure candidates against A-series CWAs and demonstrate the potential of HT-MS for rapidly and safely characterizing emerging toxic chemicals.}, archive = {J_PNAS}, author = {Morato, Nicolás M. and Mason, Katelyn E. and Corzett, Todd H. and Valdez, Carlos A. and Alfaro, Teneile M. and Hok, Saphon and Cooks, R. Graham and Mayer, Brian P.}, doi = {10.1073/pnas.2512471122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2512471122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Accelerating countermeasure candidate discovery for A-series chemical warfare agent exposure}, volume = {122}, year = {2025}, }
• (2025). Correction carozza et al., whole-brain white matter variation across childhood environments. PNAS, 122(29), e2512453122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2512453122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2512453122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction carozza et al., whole-brain white matter variation across childhood environments}, volume = {122}, year = {2025}, }
• (2025). Photoselective isotope fractionation dynamics of n2 with cosmo and atmospheric chemistry perspectives. PNAS, 122(29), e2511172122. (www)

  @article{ , abstract = {Stable isotope ratio measurements provide valuable insights into a broad range of natural processes, from planetary atmospheres and climate to interstellar chemistry. Nitrogen, which has two stable isotopes, exhibits varying isotope ratios across the solar system. To model these observations, the isotope fraction as a function of energy is essential. At the Advanced Light Source (ALS), we measured the photodissociation of molecular nitrogen (N 2 ) with vacuum UV photons where a single photon is sufficiently energetic to dissociate the strong bond. The nitrogen atoms produced are scavenged with H 2 to form ammonia, whose isotopic makeup is determined. Blending the experiments with dynamical computations that include the shielding of light, we examine the isotopic composition and electronic atomic states produced. The measured photodissociation of N 2 at a natural isotopic composition with a frequency broad light beam exceptionally strongly favors the formation of the heavier nitrogen isotope, 15 N. Computations concur and suggest that the maximum in the quantum yield reflects significant variations in the specific electronic quantum states of the product N atoms that have quite different reactivities. Our quantum computations show that at similar energies, photodissociation of 14 N 14 N and 15 N 14 N can lead to different product channels. The computed dynamics include extensive state-selective spin–orbit and nonadiabatic couplings affecting the light absorption and dissociation pathways that proceed via the triplet manifold of states. Our results are relevant for future exploration missions, both in situ and sample-return and for other molecules such as O 2 and CO.}, archive = {J_PNAS}, author = {Komarova, Ksenia and Gelfand, Natalia A. and Remacle, Francoise and Levine, Raphael D. and Chakraborty, Subrata and Jackson, Teresa L. and Kostko, Oleg and Thiemens, Mark H.}, doi = {10.1073/pnas.2511172122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2511172122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Photoselective isotope fractionation dynamics of n2 with cosmo and atmospheric chemistry perspectives}, volume = {122}, year = {2025}, }
• (2025). Amino acid coating enables micromotor operation in physiological conditions. PNAS, 122(29), e2510091122. (www)

  @article{ , abstract = {Physiological environment with high ionic strength will quench the propulsion of micro/nanomotors (MNMs) by suppressing electric double layers, especially for those motors based on electrolyte diffusiophoresis and electrophoresis. Herein, we demonstrate an efficient, general, and simple strategy to improve the ion tolerance of light-driven titanium dioxide (TiO 2 ) micromotors with amino acid surface modification. Compared to the bare TiO 2 counterpart, L-arginine (Arg)-treated TiO 2 micromotors display over 200 times higher ion tolerance, which is mainly attributed to the increased surface conductivity. This simple ion tolerance improvement strategy can also be applicable to other motors driven by self-electrophoresis. As TiO 2 is an efficient sonosensitizer, we combined the light-guiding ability with ultrasound to generate reactive oxygen species to effectively induce in situ tumor apoptosis. We envision that this simple amino acid surface modification can not only provide a solution for MNMs to tolerate the ionic environment but also open up opportunities for further biomedical and translational research of MNMs.}, archive = {J_PNAS}, author = {Sun, Jia and Ding, Yusen and Ye, Yicheng and Wang, Fei and Tian, Hao and Jiang, Jiamiao and Li, Huaan and Gao, Junbin and Tan, Haixin and Peng, Fei and Tang, Jinyao and Tu, Yingfeng}, doi = {10.1073/pnas.2510091122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2510091122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Amino acid coating enables micromotor operation in physiological conditions}, volume = {122}, year = {2025}, }
• (2025). Neutron and time-resolved X-ray crystallography reveal the substrate recognition and catalytic mechanism of human nudix hydrolase MTH1. PNAS, 122(29), e2510085122. (www)

  @article{ , abstract = {Human MTH1, a Nudix enzyme, hydrolyzes several oxidized nucleotides such as 8-oxo-dGTP and 2-oxo-dATP, owing to its broad substrate specificity. MTH1 has also attracted attention as an anticancer target, and its substrate recognition is of biological and medical interest. Previous studies have suggested that MTH1 exhibits broad substrate specificity by changing the protonation states of Asp119 and Asp120 with high p K a . However, the recognition mechanism remains unclear, owing to the difficulty in directly observing hydrogen atoms. Furthermore, a recent time-resolved X-ray study has proposed that Nudix hydrolases catalyze reactions through a new three-metal-ion mechanism. To understand the substrate recognition and catalytic mechanisms of human MTH1, we performed neutron and time-resolved X-ray crystallography. The neutron structures of MTH1 complexed with 8-oxo-dGTP and 2-oxo-dATP revealed the protonation states of the active-site residues, substrates, and water molecules, crucial for substrate binding and catalysis, providing direct experimental evidence that changes in the protonation states of Asp119 and Asp120 enable broad substrate recognition of MTH1. Time-resolved X-ray crystallography was used to visualize the entire reaction process through Mn 2+ ion. The combination of neutron and time-resolved X-ray crystallography led to the proposal of a reaction mechanism for MTH1 via three metal-binding sites, including the conformational dynamics of a loop region, nucleophilic substitution, and a potential deprotonation pathway. Overall, the mechanism involving three metal-binding sites may be a general feature in the catalysis of Nudix hydrolases.}, archive = {J_PNAS}, author = {Hirata, Keisuke and Fujimiya, Kana and Ostermann, Andreas and Schrader, Tobias E. and Hiromoto, Takeshi and Goto, Masataka and Arimori, Takao and Hirano, Yu and Kusaka, Katsuhiro and Tamada, Taro and Nakamura, Teruya}, doi = {10.1073/pnas.2510085122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2510085122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neutron and time-resolved X-ray crystallography reveal the substrate recognition and catalytic mechanism of human nudix hydrolase MTH1}, volume = {122}, year = {2025}, }
• (2025). The intensification of the strongest nor’easters. PNAS, 122(29), e2510029122. (www)

  @article{ , abstract = {Nor’easters are coastal extratropical cyclones that feed upon both thermal contrasts (meridional and land-ocean) and oceanic latent heat release, causing them to intensify along the U.S. East Coast. With central pressures that sometimes rival those of tropical cyclones, they represent a significant coastal hazard and are often associated with strong winds, heavy snowfall, disruption, and damage. While interest in studying the impacts of climate change on storm behavior is growing, nor’easters have historically received far less attention than tropical cyclones, largely due to challenges in documenting and categorizing these storms combined with the relatively short observational record. Here, we address these challenges by employing a cyclone tracking approach in concurrence with long-term reanalysis data to create a reliable historical database of these storms. We find a significant increasing trend in the maximum wind speeds of the most intense (>66th percentile) nor’easters. We also observe an increasing trend in hourly precipitation rates associated with these storms. Such changes have profound implications for coastal cities and shorelines, increasing the risk of coastal flooding and erosion.}, archive = {J_PNAS}, author = {Chen, Kevin and Li, Xueke and Weaver, Mackenzie M. and Christiansen, Shannon A. and Horton, Annabelle L. and Mann, Michael E.}, doi = {10.1073/pnas.2510029122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2510029122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The intensification of the strongest nor’easters}, volume = {122}, year = {2025}, }
• (2025). Optimizing the application order under precedent-based decision-making. PNAS, 122(29), e2509985122. (www)

  @article{ , abstract = {We study the decision problem of a Proposer who has a set of applications to submit for approval to an Authority and can choose an order of submission. The Proposer’s utility depends on the Authority’s rulings. The Authority has to be consistent with its past decisions, which we model using the nearest-neighbor criterion. If the Proposer’s utility increases with the set of approved applications, then any greedy strategy is optimal for her: She should submit any application that, given the current history, would be approved. However, if her utility increases with some approvals but decreases with others, the Proposer’s problem becomes significantly more complex. In the single-dimensional case, an optimal strategy can be computed in polynomial time. In the general case, however, finding an optimal strategy is NP-hard. Thus, even in the absence of uncertainty or strategic behavior on the part of the Authority, evaluating the impact of current submissions on future outcomes can be computationally intractable.}, archive = {J_PNAS}, author = {Argenziano, Rossella and Gilboa, Itzhak}, doi = {10.1073/pnas.2509985122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2509985122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Optimizing the application order under precedent-based decision-making}, volume = {122}, year = {2025}, }
• (2025). Cell-type-informed genotyping of mosaic focal epilepsies reveals cell-autonomous and non-cell-autonomous disease-associated transcriptional programs. PNAS, 122(29), e2509622122. (www)

  @article{ , abstract = {While it is widely accepted that somatic variants that activate the PI3K-mTOR pathway are a major cause of drug-resistant focal epilepsy, typically associated with focal cortical dysplasia (FCD) type 2, understanding the mechanism of epileptogenesis requires identifying genotype-associated changes at the single-cell level, which is technically challenging with existing methods. Here, we performed single-nucleus RNA-sequencing (snRNA-seq) of 18 FCD type 2 samples removed surgically for treatment of drug-resistant epilepsy, and 17 non-FCD control samples, and analyzed additional published data comprising >400,000 single nuclei. We also performed simultaneous single-nucleus genotyping and gene expression analysis using two independent approaches: 1) a method that we called genotyping of transcriptomes enhanced with nanopore sequencing (GO-TEN) that combines targeted cDNA long-read sequencing with snRNA-seq, 2) ResolveOME snRNA-seq and DNA genotyping. snRNA-seq showed similar cell identities and proportions between cases and controls, suggesting that mosaic pathogenic variants in PI3K-mTOR pathway genes in FCD exert their effect by disrupting transcription in conserved cell types. GO-TEN and ResolveOME analyses confirmed that pathogenic variant-carrying cells have well-differentiated neuronal or glial identities, with enrichment of variants in cells of the neuroectodermal lineage, pointing to cortical neural progenitors as possible loci of somatic mutation. Within FCD type 2 lesions, we identified upregulation of PI3K-mTOR signaling and related pathways in variant-carrying neurons, downregulation of these pathways in non-variant-carrying neurons, as well as associated changes in microglial activation, cellular metabolism, synaptic homeostasis, and neuronal connectivity, all potentially contributing to epileptogenesis. These genotype-specific changes in mosaic lesions highlight potential disease mechanisms and therapeutic targets.}, archive = {J_PNAS}, author = {Bizzotto, Sara and Talukdar, Maya and Stronge, Edward A. and Ramirez, Rosita B. and Yang, Yingxi and Huang, August Yue and Hu, Qiwen and Hou, Yingping and Hylton, Norma K. and Finander, Benjamin and Tillett, Ashton and Zhou, Zinan and Chhouk, Brian H. and D’Gama, Alissa M. and Yang, Edward and Green, Timothy E. and Reutens, David C. and Mullen, Saul A. and Scheffer, Ingrid E. and Hildebrand, Michael S. and Buono, Russell J. and Blümcke, Ingmar and Poduri, Annapurna H. and Khoshkhoo, Sattar and Walsh, Christopher A.}, doi = {10.1073/pnas.2509622122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2509622122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cell-type-informed genotyping of mosaic focal epilepsies reveals cell-autonomous and non-cell-autonomous disease-associated transcriptional programs}, volume = {122}, year = {2025}, }
• (2025). Block copolymer molecular design to address practical limitations to recycling polyolefin blends. PNAS, 122(29), e2508921122. (www)

  @article{ , abstract = {Plastics offer innumerable societal benefits but simultaneously contribute to persistent environmental pollution, dominated by polyethylene (PE) and isotactic polypropylene ( i PP). Melt blending and reformulating postconsumer PE and i PP into useful materials presents a promising recycling approach. However, such repurposed plastics are generally mechanically inferior due to an inability to efficiently separate polyolefins in mixed waste streams; phase separation of PE and i PP results in brittleness as a consequence of poor interfacial strength. Recently, we demonstrated that a small amount (1 wt%) of a poly(ethylene)- block -poly(ethyl ethylene- ran -ethylene)- block -poly(ethylene) (EXE) triblock copolymer, synthesized by low-cost anionic polymerization of 1,3-butadiene followed by solution hydrogenation, restores tensile toughness to levels equivalent to virgin polyolefins. Unfortunately, low-temperature solvent insolubility of EXE, driven by crystallization of the E blocks containing 1.5 ethyl branches per 100 backbone repeat units (EB), presents a challenge for industrial hydrogenation. Comparable toughness (ca. > 400% strain at break) was achieved in the present work with 1.5 ≤ EB ≤ 6.5, accompanied by reduced EXE crystallinity and dissolution in cyclohexane down to room temperature at the highest EB content. This remarkable toughening behavior is attributed to a synergy between chain entanglements between the E end blocks and semicrystalline PE homopolymer and formation of E block “crystal nodules” that prevent chain pullout, along with topological constraints between the X loops and semicrystalline i PP. Our findings overcome barriers to commercial production of EXE with existing industrial facilities, providing a cost-effective strategy for recycling PE and i PP.}, archive = {J_PNAS}, author = {Cui, Shuquan and Jeong, Daun and Shi, Yukai and Jahan, Nusrat and Lodge, Timothy P. and Bates, Frank S. and Ellison, Christopher J.}, doi = {10.1073/pnas.2508921122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2508921122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Block copolymer molecular design to address practical limitations to recycling polyolefin blends}, volume = {122}, year = {2025}, }
• (2025). Visual adaptation stronger at the horizontal than the vertical meridian: Linking performance with v1 cortical surface area. PNAS, 122(29), e2507810122. (www)

  @article{ , abstract = {Visual adaptation reduces bioenergetic expenditure by decreasing sensitivity to repetitive and similar stimuli. In human adults, visual performance varies systematically around the polar angle for many visual dimensions and tasks: Performance is superior along the horizontal than the vertical meridian (horizontal–vertical anisotropy, HVA) and the lower than upper vertical meridian (vertical meridian asymmetry, VMA). These asymmetries are resistant to spatial and temporal attention. However, it remains unknown whether visual adaptation differs around the polar angle. Here, we investigated how adaptation influences contrast sensitivity at the fovea and perifovea across the four cardinal meridian locations for both horizontal and vertical stimuli in an orientation discrimination task. In the nonadapted conditions, the HVA was more pronounced for horizontal than vertical stimuli. For both orientations, adaptation was stronger along the horizontal than the vertical meridian, exceeding foveal adaptation. Additionally, perifoveal adaptation effects positively correlated with individual V1 cortical surface area. These findings reveal that visual adaptation mitigates the HVA in contrast sensitivity, fostering perceptual uniformity around the visual field while conserving bioenergetic resources.}, archive = {J_PNAS}, author = {Lee, Hsing-Hao and Carrasco, Marisa}, doi = {10.1073/pnas.2507810122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2507810122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Visual adaptation stronger at the horizontal than the vertical meridian: Linking performance with v1 cortical surface area}, volume = {122}, year = {2025}, }
• (2025). Structures of chaetomium thermophilum TOM complexes with bound preproteins. PNAS, 122(29), e2507279122. (www)

  @article{ , abstract = {Mitochondria import most of their proteins from the cytoplasm through the TOM complex. Preproteins containing targeting signals are recognized by the TOM receptor subunits and translocated by Tom40 across the outer mitochondrial membrane. We present four structures of the preprotein-bound and preprotein-free TOM core and holo complexes from the thermophilic fungus Chaetomium thermophilum , obtained by single-particle electron cryomicroscopy. Our structures reveal the symmetric arrangement of two copies of the Tom20 receptor subunit in the TOM holo complex. Several different conformations of Tom20 within the TOM holo complex highlight the dynamic nature of the receptor. The structure of preprotein-bound Tom20 provides insight into the early stages of protein translocation.}, archive = {J_PNAS}, author = {Agip, Ahmed-Noor A. and Ornelas, Pamela and Yang, Tzu-Jing and Uboldi, Ermanno and Häder, Sabine and McDowell, Melanie A. and Kühlbrandt, Werner}, doi = {10.1073/pnas.2507279122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2507279122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structures of chaetomium thermophilum TOM complexes with bound preproteins}, volume = {122}, year = {2025}, }
• (2025). Structural basis of the inhibition of TRPV1 by analgesic sesquiterpenes. PNAS, 122(29), e2506560122. (www)

  @article{ , abstract = {The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in primary nociceptive afferents, which participate in processes such as pain and inflammation. Considerable efforts have been directed toward finding inhibitors of TRPV1 and understanding the molecular details of their interactions with this channel. α-humulene (AH) is a sesquiterpene derived from plants such as hops and other members of Cannabaceae family, with a long history of popular use as an analgesic and anti-inflammatory. Using a combination of behavioral assays, electrophysiology, site-directed mutagenesis, cryo-EM, and molecular dynamics simulations, we show that AH inhibits TRPV1-related pain responses and currents by interacting with a region composed of the S2, S2-S3 linker, and S3 transmembrane segments and stabilizing the closed conformation of the channel. The interaction of ligands in this region of the TRPV1 channel has not been previously described and the results of the present study highlight that it may constitute part of a negative regulatory region. These findings allow us to understand the molecular basis by which substances such as some sesquiterpenes, abundantly found in medicinal plants used by humans for hundreds of years, reduce pain. Pain management can include the use of opioids, which results in hepatic and renal damage and possible addiction. Our study offers insight into a poorly understood group of compounds that could be used as scaffold to produce novel nonopioid analgesic therapies and clarifies the molecular mechanisms that underlie the effects of these analgesic molecules.}, archive = {J_PNAS}, author = {Sánchez-Hernández, Raúl and Benítez-Angeles, Miguel and Talyzina, Irina A. and Llorente, Itzel and González-Avendaño, Mariela and Sierra, Félix and Méndez-Reséndiz, Angélica and Mercado, Francisco and Vergara-Jaque, Ariela and Sobolevsky, Alexander I. and Islas, León D. and Rosenbaum, Tamara}, doi = {10.1073/pnas.2506560122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2506560122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis of the inhibition of TRPV1 by analgesic sesquiterpenes}, volume = {122}, year = {2025}, }
• (2025). Emergence of isochorismate-based salicylic acid biosynthesis within brassicales. PNAS, 122(29), e2506170122. (www)

  @article{ , abstract = {Salicylic acid (SA) is a major defense phytohormone. In Arabidopsis thaliana , the isochorismate (IC) pathway is the primary route for pathogen-induced SA biosynthesis. First, the IC synthase (ICS) catalyzes the isomerization of chorismate to IC in chloroplasts. Second, the chloroplast-localized MATE transporter EDS5 appears to transport IC from chloroplasts to the cytosol. Cytosolic IC is then further converted to SA via the GH3 amino acid-conjugating enzyme PBS3. While this pathway is genetically well-characterized in A. thaliana , its evolutionary origin and conservation remain controversial. In this study, through comprehensive phylogenetic, structural, and functional analyses, we demonstrate that the IC pathway emerged within the Brassicales order in a time span between the divergence of Carica papaya and Capparis spinosa . The evolution of the IC pathway was driven by three key adaptations during the time span: 1) enhancement of ICS activity, 2) neofunctionalization of EDS5 after duplication of its ancestral gene, and 3) evolution of a PBS3 , whose activity is specialized for glutamate-conjugation to IC. Structural modeling and functional assays reveal that an enhanced salt bridge network in ICS enhanced its activity. One of the duplicated genes, EDS5, acquired key amino acid substitutions in the C-lobe, which contributed to the EDS5 neofunctionalization. In addition, the functional PBS3 clade, including A. thaliana PBS3 , is restricted to a Brassicales clade. Taken together, this study addresses the evolutionary trajectory of IC-based SA biosynthesis.}, archive = {J_PNAS}, author = {Hong, Kunqi and Nakano, Masahito and Tang, Ying and Jeanguenin, Linda and Kang, Wenshang and Wang, Yongliang and Zuo, Lu and Li, Pengyue and He, Jingjng and Jiang, Wanqing and Huang, Ruidong and Matsui, Hidenori and Wang, Yiming and Nakagami, Hirofumi and Li, Bo and Li, Xia and Xie, Kabin and Fukushima, Kenji and Guo, Liang and Han, Xiaowei and Katagiri, Fumiaki and Hattori, Motoyuki and Tsuda, Kenichi}, doi = {10.1073/pnas.2506170122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2506170122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Emergence of isochorismate-based salicylic acid biosynthesis within brassicales}, volume = {122}, year = {2025}, }
• (2025). Infectious disease outbreaks drive political mistrust. PNAS, 122(29), e2506093122. (www)

  @article{ , abstract = {The COVID-19 pandemic has renewed attention to the far-reaching social implications of emerging infectious diseases, an issue with historical parallels in the transformative effects of the Black Plague and Spanish Flu. However, the potential for epidemics to reshape political trust and fuel instability has remained underexplored. This study leverages a novel dataset on zoonotic disease outbreaks—including Ebola, Marburg, H1N1, and the Black Plague—and geolocated Afrobarometer survey data from dozens of African states to investigate whether exposure to these deadly outbreaks alters public confidence in political institutions. Estimating the average-treatment-effect-in-the-treated with coarsened exact matching, we find that individuals with an infectious disease outbreak experience significant declines in trust toward the political establishment, especially the president, parliament, and ruling party (reductions of 0.2, 0.18, and 0.22 points, respectively, on a four-point scale). These findings, consistent across various spatial and temporal windows, provide robust empirical evidence that deadly infectious disease outbreaks can exacerbate political polarization and undermine political stability. The study emphasizes the critical need for policy strategies that integrate public health preparedness with efforts to preserve and rebuild institutional trust during outbreaks.}, archive = {J_PNAS}, author = {Koren, Ore and Weidmann, Nils B.}, doi = {10.1073/pnas.2506093122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2506093122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Infectious disease outbreaks drive political mistrust}, volume = {122}, year = {2025}, }
• (2025). Human and climate impacts on the alpine critical zone over the past 10,000 y. PNAS, 122(29), e2506030122. (www)

  @article{ , abstract = {Agropastoral activities have impacted the habitable part of our planet—the “Critical Zone”—for thousands of years, triggering a major increase in soil erosion in mountain environments. Understanding and quantifying the impact of these activities on soil is central to the well-being of our societies. Here, we investigate the isotope ratios of the trace element lithium in detrital sediments of Lake Bourget, European Alps, and provide a reconstruction of the impact of human activities on the evolution of alpine soil during the Holocene. We demonstrate that during the Early Holocene, soil formation was altered by the development of pastoralism followed by tillage. This led to three major erosive surges (3.8 to 3.0, 2.8 to 1.6, and 1.6 ky cal BP to modern times), thinning soils down to a state close to that of their early development 10,000 y ago. The detailed study of the lithium detrital signal reveals the appearance of an altitudinal decoupling in the response of the Critical Zone in the Alps following the development of the agropastoral activities during the Iron Age. The onset of agropastoral activities disrupted the balance between soil formation and erosion, leading to erosion rates 3 to 10 times faster than soil production since the end of the Ice Age.}, archive = {J_PNAS}, author = {Rapuc, William and Guinoiseau, Damien and Arnaud, Fabien and Dellinger, Mathieu and Sabatier, Pierre and Gaillardet, Jérôme and Poulenard, Jérôme and Bouchez, Julien}, doi = {10.1073/pnas.2506030122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2506030122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Human and climate impacts on the alpine critical zone over the past 10,000 y}, volume = {122}, year = {2025}, }
• (2025). Reactive mixing enables enzymatic depolymerization of recalcitrant or unsortable polyester wastes. PNAS, 122(29), e2505611122. (www)

  @article{ , abstract = {Enzyme-catalyzed depolymerization allows efficient recycling of poly(ethylene terephthalate) (PET) bottles, which are easy to sort and made of slowly crystallizing PET. However, because crystalline phases are recalcitrant to enzymatic hydrolysis, this technology fails for rapidly crystallizing polyester wastes such as poly(butylene terephthalate) (PBT), unsortable mixed polyesters, or heterogeneous formulated PET waste streams. We show that melt transesterification and vitrimerization of mixtures of rapidly crystallizing polyester wastes, leveraging catalysts already present, produce copolyesters that crystallize slowly and are readily depolymerized. For example, reactive blending of a rapidly crystallizing postindustrial PET nonwoven waste with PBT improves depolymerization yields from 20% (PET nonwoven) and 1% (PBT) to 90%. Synergistic mixing can replace sorting, extending the scope of enzymatic recycling to recalcitrant, heterogeneous, and unsortable wastes.}, archive = {J_PNAS}, author = {Garate, Hernan and Freymond, Clément and Breloy, Louise and Schindler, Michael and Pallis, Jack and Gibbs, Benjamin and Mansaku, Brian and Rondelez, Yannick and Creton, Costantino and Griffiths, Andrew D. and Leibler, Ludwik}, doi = {10.1073/pnas.2505611122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2505611122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reactive mixing enables enzymatic depolymerization of recalcitrant or unsortable polyester wastes}, volume = {122}, year = {2025}, }
• (2025). Unusual bone bed reveals a vertebrate community with pterosaurs and turtles in equatorial pangaea before the end-triassic extinction. PNAS, 122(29), e2505513122. (www)

  @article{ , abstract = {Temporally constrained microvertebrate bone beds are powerful tools for understanding continent-scale biotic change. Such sites are rare globally in nonmarine settings during the 12 million years (Ma) preceding the end-Triassic extinction (ETE; ~201.5 Ma), obscuring patterns of faunal change across this interval. A vertebrate assemblage from Arizona, USA, provides unique insights into community composition and ecology prior to the ETE. PFV 393 is a macro- and microvertebrate bone bed preserved in a volcaniclastic fluvial channel-fill with a high-precision U-Pb zircon age of 209.187 ± 0.083 Ma. The fossil assemblage consists of three-dimensionally preserved, delicate, and small skeletal elements of known and new taxa that document a local paleocommunity including hybodontiformes, actinopterygians, actinistians, metoposaurids, salientians, synapsids, lepidosaurs, testudinatans, trilophosaurids, Vancleavea , doswelliids, Revueltosaurus , loricatans, phytosaurs, and pterosaurs. The new early-diverging pterosaur is one of the few Triassic pterosaurs found outside of Europe and the only one with a documented precise radioisotopic age. The testudinatan material shows the rapid dispersal of terrestrial stem-turtles across the Pangaean supercontinent in the Norian and refines temporal constraints on the origin of the turtle shell. The presence of vertebrate lineages endemic to the Triassic highlights their persistence in a mesic, fluvial paleocommunity through a prolonged phase of environmental change preceding the ETE. These lineages coexisted with frogs, lepidosaurs, turtles, and pterosaurs- all key elements of post–Triassic Mesozoic communities. The arrival of turtles and pterosaurs in west-central Pangaea therefore may have been driven by the northward drift of Laurentia from humid equatorial conditions into more arid subtropical latitudes.}, archive = {J_PNAS}, author = {Kligman, Ben T. and Whatley, Robin L. and Ramezani, Jahandar and Marsh, Adam D. and Lyson, Tyler R. and Fitch, Adam J. and Parker, William G. and Behrensmeyer, Anna K.}, doi = {10.1073/pnas.2505513122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2505513122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unusual bone bed reveals a vertebrate community with pterosaurs and turtles in equatorial pangaea before the end-triassic extinction}, volume = {122}, year = {2025}, }
• (2025). α-glucan remodeling by GH13-domain enzymes shapes fungal cell wall architecture. PNAS, 122(29), e2505509122. (www)

  @article{ , abstract = {Cell walls are critical structures of fungi, bacteria, and plants, providing mechanical strength, maintaining shape, and protecting cells from environmental stress. In the fission yeast Schizosaccharomyces pombe , the α-glucan synthase Ags1 produces α-1,3-glucan chains essential for cell wall integrity, but how these chains are further assembled into mature polymers is not understood. Here, we identify two conserved glycosylphosphatidylinositol-anchored α-amylase-like enzymes, Aah1 and Aah3, which act redundantly as key contributors to α-glucan network formation. Cells lacking both enzymes exhibit severe growth and morphological defects, including rounded shape, delayed division, and cell clumping. Using solid-state NMR spectroscopy of intact cells, we show that the double mutant cell walls have dramatically reduced α-1,3-glucan and galactomannan content, with a compensatory increase in β-glucans driven by the activation of the cell integrity pathway. These changes correlate with cell wall thickening, increased rigidity, and reduced polymer mobility and hydration. We also uncover in vivo polymorphic forms of α- and β-glucans, some of which are selectively lost or gained in the mutant cells. Our data suggest that Aah1 and Aah3 function as GH13-family transglycosylases that collaborate nonredundantly with the α-glucan synthase to build a properly organized α-glucan matrix. These findings highlight a previously unrecognized layer of complexity in fungal cell wall biosynthesis and point to GH13-family enzymes as potential antifungal targets given that related enzymes are found in many fungi.}, archive = {J_PNAS}, author = {Jacob, Anand and Willet, Alaina H. and Igarashi, Maya G. and El Hariri El Nokab, Mustapha and Turner, Lesley A. and Alsanad, Abdulrahman Khalid A. and Wang, Tuo and Gould, Kathleen L.}, doi = {10.1073/pnas.2505509122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2505509122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {α-glucan remodeling by GH13-domain enzymes shapes fungal cell wall architecture}, volume = {122}, year = {2025}, }
• (2025). Sleeping upside-down: Knockdown of a sleep-associated gene induces daytime sleep in the jellyfish cassiopea. PNAS, 122(29), e2505074122. (www)

  @article{ , abstract = {The conservation of sleep among diverse animals provides clear evidence for its physiological importance, but the extent of its regulatory conservation is unknown. The upside-down jellyfish Cassiopea xamachana sleeps, and this behavior is controlled by radially spaced marginal ganglia. After defining a sleep–wake threshold, we compared gene expression profiles of ganglia from animals deprived of sleep and found differential expression in many sleep-related genes including GABAergic, melatonergic, and cholinergic receptors. In particular, a nicotinic acetylcholine receptor alpha subunit-like (Chrnal-E) was strongly differentially expressed in sleep deprived animals. Animals deprived of sleep under both mechanical and light perturbations suggested chrnal-E as a key gene regulating sleep. We found that chemical cholinergic neuromodulators regulate pacemaker activity. Visualization of chrnal-E mRNA revealed it is expressed primarily within the ganglia, and that the area of expression expands after sleep deprivation. In order to confirm the functional role of chrnal-E , we developed RNAi for use in Cassiopea and determined that Chrnal-E promotes wakefulness. Finally, we field-sampled control and sleep deprived animals and found chrnal-E has lowest expression late at night in controls, while in sleep deprived animals, chrnal-E peaks at this time, supporting a link to wakefulness. Our finding that Cassiopea sleep is regulated by the cholinergic-like system underscores that some components of sleep regulation are deeply conserved even in an animal with a distributed nervous system.}, archive = {J_PNAS}, author = {Abrams, Michael J. and Ohdera, Aki and Francis, Diana A. and Donayre, Owen and Chen, Henry and Lu, Kevin and Hsu, Celeste Y. and Zeigler, Hannah and Harland, Richard M.}, doi = {10.1073/pnas.2505074122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2505074122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sleeping upside-down: Knockdown of a sleep-associated gene induces daytime sleep in the jellyfish cassiopea}, volume = {122}, year = {2025}, }
• (2025). Climate-linked biogeography of mycorrhizal fungal spore traits. PNAS, 122(29), e2505059122. (www)

  @article{ , abstract = {Climate-driven variation in traits is crucial for predicting ecological responses to environmental change, yet global patterns and drivers of microbial trait variation remain poorly understood. Using global datasets of arbuscular mycorrhizal (AM) fungal observations linked to spore morphological traits, we show that climate shapes spore trait variation and functional diversity. Larger spore volumes were more prevalent in warm, wet climates but were associated with smaller species range sizes, suggesting a trade-off between persistence and dispersal potential. Similarly, ornamented spores were more common in warm, wet climates and were associated with narrower range sizes. Cell wall investment (i.e., wall thickness relative to volume) decreased in warmer, wetter climates compared to cooler, drier ones and was the strongest predictor of species range size, with intermediate investment associated with larger geographic distributions. Spore shape and color (i.e., melanin pigmentation) also exhibited climate-driven patterns, with spherical spores and greater pigmentation more common in warm, wet climates. Phylogenetic analyses revealed high conservatism for spore ornamentation, moderate for volume, low for color, and none for shape and cell wall investment. Additionally, functional diversity analyses showed that warm, wet climates promote higher within-community trait richness but lower trait divergence, while broader climatic variability drives higher beta diversity. These findings support growing evidence that trait–environment relationships extend to microbial communities, reflecting ecological principles such as environmental filtering, evolutionary constraint, and dispersal–persistence trade-offs. Incorporating microbial traits improves predictions of biogeographic shifts and their cascading effects on plant–microbe interactions and ecosystem stability under climate change.}, archive = {J_PNAS}, author = {Pehim Limbu, Smriti and Stürmer, Sidney L. and Zahn, Geoffrey and Aguilar-Trigueros, Carlos A. and Rogers, Noah and Chaudhary, V. Bala}, doi = {10.1073/pnas.2505059122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2505059122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Climate-linked biogeography of mycorrhizal fungal spore traits}, volume = {122}, year = {2025}, }
• (2025). Surface tension between coexisting phases of active brownian particles. PNAS, 122(29), e2505010122. (www)

  @article{ , abstract = {The confliction between the stable interface in phase-separated active Brownian particles and its negative surface tension, obtained mechanically via the active pressure, has sparked considerable debate about the formula of active surface tension. Based on the intrinsic pressure of active system, we here derive a mechanical expression of active surface tension by calculating the work required to create a differential interface area, while remaining the interfacial profiles of intensive quantities invariant (not considered previously). Our expression yields a significantly positive surface tension that increases with the particle activity, which is further supported by mechanical stability analysis of both steady-state droplet and fluctuating interface. Our work is thus promising to resolve the contradiction related to active surface tension.}, archive = {J_PNAS}, author = {Li, Longfei and Sun, Zihao and Yang, Mingcheng}, doi = {10.1073/pnas.2505010122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2505010122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Surface tension between coexisting phases of active brownian particles}, volume = {122}, year = {2025}, }
• (2025). A gentle palette of plasma membrane dyes. PNAS, 122(29), e2504879122. (www)

  @article{ , abstract = {Plasma membrane (PM) stains are important organelle markers for monitoring membrane morphology and dynamics. The state-of-the-art PM stains are bright, specific, fluorogenic, and compatible with superresolution imaging. However, when recording membrane dynamics using advanced fluorescence microscopes, PM is prone to photodynamic damage introduced by dyes due to its phospholipid bilayer nature. Here, we introduce PK Mem dyes tailored for time-lapse fluorescence imaging. By integrating triplet-state quenchers into the MemBright dyes featuring cyanine chromophores and amphiphilic zwitterion anchors, PK Mem dyes exhibited a three-fold reduction in phototoxicity and a more than four-fold improvement in photostability in imaging experiments compared to MemBright prototypes. These dyes enable 2D and 3D imaging of live or fixed cancer cell lines and a wide range of primary cells, at the same time pair well with various fluorescent markers. PK Mem dyes can be applied to neuronal imaging in brain slices and in vivo two-photon imaging. The gentle nature of PK Mem palette enables ultralong-term recording of cell migration, cardiomyocyte beating, spermiogenesis, and axonal growth cone dynamics, which are prohibitively challenging using traditional PM dyes. Notably, PK Mem dyes are optically compatible with STED/SIM imaging, which can handily upgrade the routine of time-lapse neuronal imaging, such as growth cone tracking and mitochondrial transportations, into nanoscopic resolutions.}, archive = {J_PNAS}, author = {Ling, Jing and Liu, Yitong and Dumoulin, Alexandre and Sheng, Danli and Fu, Yunzhe and Liu, Shuzhang and Ding, Ling and Huang, Lulu and Xi, Peng and Tang, Hongyun and Stoeckli, Esther T. and Chen, Zhixing}, doi = {10.1073/pnas.2504879122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2504879122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A gentle palette of plasma membrane dyes}, volume = {122}, year = {2025}, }
• (2025). Training and retraining liquid crystal elastomer metamaterials for pluripotent functionality. PNAS, 122(29), e2504304122. (www)

  @article{ , abstract = {Training has emerged as a promising materials design technique in which function can be achieved through repeated physical modification of an existing material rather than by direct chemical functionalization, cutting, or reprocessing. This work investigates both the ability to train for function and then to erase that function on-demand in macroscopic metamaterials made from liquid crystal elastomers. We first show that the Poisson’s ratio of these disordered arrays can be tuned via directed aging to induce an auxetic response. We then show that the arrays can be reset and retrained for another local mechanical function, allostery, thus demonstrating pluripotent functionality.}, archive = {J_PNAS}, author = {Gowen, Savannah D. and Ghimire, Elina and Lindberg, Charlie A. and Appen, Ingrid S. and Rowan, Stuart J. and Nagel, Sidney R.}, doi = {10.1073/pnas.2504304122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2504304122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Training and retraining liquid crystal elastomer metamaterials for pluripotent functionality}, volume = {122}, year = {2025}, }
• (2025). Wireless arm-worn bioimpedance sensor for continuous assessment of whole-body hydration. PNAS, 122(29), e2504278122. (www)

  @article{ , abstract = {Assessment of whole-body hydration (WBH) is crucial for health management and disease diagnosis. Traditional methods are invasive or require bulky equipment, making them impractical for mobile, continuous sensing. We present a wearable bioimpedance sensor with strategic electrode placement across the arm for noninvasive, continuous, and mobile WBH monitoring. Although whole-body bioimpedance is a proven method for indicating WBH, the effectiveness of local bioimpedance measurement has been unclear. Our finite element analysis demonstrated that with an optimized cross-arm sensing configuration, a strong linear relationship exists between arm bioimpedance and muscle electrical resistivity, confirming the utility of arm bioimpedance for assessing WBH given the well-established relationship between muscle electrical resistivity and body water. Our IRB-approved diuretic-induced dehydration study demonstrated a strong linear correlation between the increase of arm bioimpedance and the decrease in body weight due to water loss, with a Pearson correlation coefficient of 0.956 ± 0.033 among eight participants. Arm and whole-body demonstrated strong alignment, suggesting that arm bioimpedance measurements can reflect not only changes in WBH but also potentially absolute WBH status when compared against established population reference data. In a 24-h free-living experiment, the wireless, dry electrode-based, arm-conformable bioimpedance sensor continuously tracked dehydration and rehydration despite motions associated with daily activities. These results suggest that properly measured arm bioimpedance can serve as a surrogate for WBH, offering a reliable and accessible solution. The potential uses of this wearable technology range from improving personal wellness to enhancing professional sports and occupational safety.}, archive = {J_PNAS}, author = {Jankovic, Matija and Kang, Seungmin and Bhattacharya, Sarnab and Kashanchi, Jordon and Wang, Jieting and Deoli, Kanika and Huang, Tianda and Johnson, Alex and Ambani, Karina and Kim, Sangjun and Wang, Pulin and Coyle, Edward and Lu, Nanshu}, doi = {10.1073/pnas.2504278122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2504278122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Wireless arm-worn bioimpedance sensor for continuous assessment of whole-body hydration}, volume = {122}, year = {2025}, }
• (2025). Norms emerge through iterated learning. PNAS, 122(29), e2504178122. (www)

  @article{ , abstract = {Injunctive norms are universal: Every culture has rules that specify what actions are forbidden, obligatory, or permitted. Where do all of these norms come from? In this paper, we identify a mechanism of cultural transmission that can explain the emergence of injunctive norms. In particular, we develop an iterated learning account that shows how weak biases in pedagogy and inference can drive norm emergence through cultural transmission. Using transmission chain studies, we confirm the core predictions of the iterated learning account. In five studies ( N = 3,688), an initial generation of participants learn about an action that is merely inadvisable and teach a new generation of participants about that action. After this learning process repeats iteratively, participants in later generations reliably judge that the action is impermissible and subject to punishment. We find this inadvisable -to- impermissible effect is elicited across a wide range of initial conditions. Overall, then, our results support the idea that iterated learning can drive the emergence of injunctive norms across a wide range of contexts.}, archive = {J_PNAS}, author = {Partington, Scott and Kamtekar, Rachana and Nichols, Shaun}, doi = {10.1073/pnas.2504178122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2504178122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Norms emerge through iterated learning}, volume = {122}, year = {2025}, }
• (2025). Deletion of p63 exon 13 in mice reveals C-terminal isoform–specific functions in epithelial development. PNAS, 122(29), e2503866122. (www)

  @article{ , abstract = {The transcription factor p63 is an essential regulator of epithelial development. Yet, the complexity at the 3′UTR, which gives rise to the three distinct C-terminal protein isoforms (α, β, and γ), remains unresolved and opens an investigation on the in vivo role of the C-terminus. This region, codified by exon 13, harbors genetic mutations leading to AEC syndrome. Here, we generated a mouse with a deletion of p63 exon 13 in keratin-14-expressing tissues and employed transcriptome, genome-wide occupancy, and interactome studies to characterize the role of the p63 C-terminus in vivo. In this model mouse, the p63 protein is expressed at the correct level in time and space but predominantly as the β isoform instead of the α isoform, thereby providing insights into the function of the C-terminus. We show that p63β interacts more readily with the core promoter transcription machinery and p63α-depleted isoforms bind more frequently the promoter region of target genes, resulting in inappropriate overexpression of extracellular matrix organization genes in the skin. This leads to the aberrant adhesion of epidermal keratinocytes to the basal lamina and triggers systemic inflammation, growth abnormalities, and premature death. We found a significant role of the full-length ΔNp63a isoform which cannot be substituted by the other isoforms (β or γ). Our studies highlight a crucial role for p63α in correctly orchestrating the gene expression program to ensure proper formation of epithelia.}, archive = {J_PNAS}, author = {Lena, Anna Maria and Smirnov, Artem and Mancini, Mara and Montanaro, Manuela and Ciccosanti, Fabiola and Foti, Valeria and Nardacci, Roberta and Fimia, Gian Maria and Mavilio, Mara and Federici, Massimo and Mauriello, Alessandro and Piacentini, Mauro and Melino, Gerry and Candi, Eleonora}, doi = {10.1073/pnas.2503866122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2503866122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deletion of p63 exon 13 in mice reveals C-terminal isoform–specific functions in epithelial development}, volume = {122}, year = {2025}, }
• (2025). Elevated CO2 alters relative belowground carbon investment for nutrient acquisition in a mature temperate forest. PNAS, 122(29), e2503595122. (www)

  @article{ , abstract = {Forests are potential carbon (C) sinks that partially offset anthropogenic carbon dioxide (CO 2 ) emissions via enhanced C assimilation and productivity. However, the question remains whether mature trees will express sufficient plasticity in nutrient acquisition strategies to support enhanced growth under elevated CO 2 (eCO 2 ). Trees may sustain growth by investing C belowground to enhance nutrient acquisition, e.g., by increasing root absorptive surfaces for greater soil available resource exploration (a “do-it-yourself” strategy) or utilizing C exudation or mycorrhizal associations as priming mechanisms for nutrient acquisition (“outsourcing”). We show that 4 y of eCO 2 (+140 ± 38 ppm; i.e., +35% above ambient) altered the relative belowground C investment strategies of mature oak ( Quercus robur L.) in a 180-y-old temperate forest. Fine-root branching frequency increased 73% under eCO 2 . Specific root C exudation was enhanced under eCO 2 (63%), particularly outside the peak growing season, and the exudate C to nitrogen (N) ratio was increased (28%). Ectomycorrhizal (ECM) biomass production increased during leaf fall (17%) while ECM turnover increased almost fourfold under eCO 2 . The exudate and root metabolome composition were considerably altered during the late growing season under eCO 2 . We find, therefore, that a broad suite of nutrient acquisition strategies are upregulated under eCO 2 , with dynamic shifting between different outsourcing and do-it-yourself elements at different times of the year. These belowground changes support the increase in net primary productivity observed in this forest, with implications for the role of mature temperate forests in the global carbon sink.}, archive = {J_PNAS}, author = {Reay, Michaela K. and Sayer, Emma J. and Smith, Andrew and Pastor, Victoria and Kourmouli, Angeliki and Marshall, Miles and Grzesik, Robert T. and Evans, Iwan and Rumeau, Manon and Hart, Kris and Ma, Jiaojiao and Norby, Richard J. and MacKenzie, A. Robert and Hamilton, R. Liz and Hartley, Iain P. and Ullah, Sami}, doi = {10.1073/pnas.2503595122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2503595122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Elevated CO2 alters relative belowground carbon investment for nutrient acquisition in a mature temperate forest}, volume = {122}, year = {2025}, }
• (2025). Unveiling organ-specific metabolism of citrus clementina. PNAS, 122(29), e2503406122. (www)

  @article{ , abstract = {Understanding plant response to environmental factors such as temperature, drought, diseases, and carbon-to-nitrogen (C:N) ratio is essential for crop resilience, quality, and adaptation to climate change. Here, we present i Citrus2616, a high-resolution organ-specific genome-scale metabolic model for Citrus clementina , comprising 2,616 genes, 8,653 metabolites, and 10,654 reactions. The model integrates organ-specific metabolomics data, i.e., leaf, stem, and root, and predicts plant responses to different conditions with high accuracy. Lower C:N ratios showed higher growth rates compared to higher C:N ratios, suggesting an inverse relationship between growth and C:N ratios. Simulations show that polymers such as starch and hemicellulose increased 4-fold under mixotrophic compared to phototrophic conditions, contributing to enhanced rigidity of cell walls, thus improving mechanical and drought stress. Furthermore, i Citrus2616 revealed higher production of specialized metabolites such as flavonoids in the presence of specific nutrients. Additionally, transcriptomics data from symptomatic and asymptomatic leaf and root tissues across four seasons (winter, spring, fall, and summer) during Huanglongbing infection (citrus greening) were integrated into the model. This integration revealed tissue-specific metabolic adaptations, including shifts in energy allocation, secondary metabolite production, and stress-response pathways under biotic stress. These findings underscore the utility of i Citrus2616 in elucidating the metabolic underpinnings of biotic and abiotic stress resilience and could aid in improving crop productivity and quality, thereby meeting escalating market demands.}, archive = {J_PNAS}, author = {Passi, Anurag and Tec-Campos, Diego and Kumar, Manish and Tibocha-Bonilla, Juan D. and Zuñiga, Cristal and Peacock, Beth and Hale, Amanda and Santibáñez-Palominos, Rodrigo and Borneman, James and Zengler, Karsten}, doi = {10.1073/pnas.2503406122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2503406122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unveiling organ-specific metabolism of citrus clementina}, volume = {122}, year = {2025}, }
• (2025). Amplification through local critical behavior in the mammalian cochlea. PNAS, 122(29), e2503389122. (www)

  @article{ , abstract = {Hearing hinges upon the ear’s ability to enhance its responsiveness by means of an energy-expending active process that amplifies the very mechanical inputs that it detects. This process is defined by four properties that, although seemingly unrelated, consistently occur together: amplification, sharp frequency tuning, compressive nonlinearity, and spontaneous otoacoustic emission. In nonmammal tetrapods, the active process is evident in individual hair cells. The hair bundles of the bullfrog, for example, exhibit all four attributes by operating near a Hopf bifurcation—a critical regime in which these properties naturally coalesce. In mammals, however, the delicate nature of the cochlea has restricted the evidence for an active process to studies in vivo, where it is generally attributed to the collective effort of the outer hair cells that energize the traveling wave along the cochlear spiral. As a result, the cellular mechanisms that underlie the properties of mammalian hearing remain contested, with uncertainty about whether criticality plays a role in the cochlea’s active process. Here we show that, when placed in a recording chamber that closely mimics the in vivo physiological environment, a segment of the mammalian cochlea ex vivo displays the features of the active process—amplification, frequency tuning, compressive nonlinearity, and the generation of distortion products. We show that this process operates locally, independently of traveling waves, and that the sensory epithelium achieves active amplification by operating near criticality at a Hopf bifurcation. The results reveal the existence of a unified biophysical principle that underlies auditory processing across species and even phyla.}, archive = {J_PNAS}, author = {Alonso, Rodrigo G. and Gianoli, Francesco and Fabella, Brian and Hudspeth, A. J.}, doi = {10.1073/pnas.2503389122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2503389122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Amplification through local critical behavior in the mammalian cochlea}, volume = {122}, year = {2025}, }
• (2025). NEDD4L induces mitochondrial dysfunction and neurodegeneration by promoting LIPT2 degradation in huntington’s disease. PNAS, 122(29), e2503342122. (www)

  @article{ , abstract = {Impairment of mitochondrial protein stability is associated with neurodegeneration in Huntington’s disease (HD). However, the E3 ligase responsible for maintaining mitochondrial protein homeostasis in HD remains poorly understood. In this study, we demonstrate that NEDD4L protein levels are elevated in human striatal organoids (hSOs) derived from induced pluripotent stem cells of patients as well as in a mouse model of HD. Overexpression of NEDD4L leads to degeneration and cell death of medium spiny neurons (MSNs), along with a reduction in motor activities. Conversely, deletion of NEDD4L restores abnormal MSN morphology, corrects deficits in calcium signaling, alleviates neurodegeneration in HD-hSOs, and improves motor dysfunction observed in YAC128 mice. Mechanistically, NEDD4L disrupts mitochondrial function by binding to lipoyl(octanoyl) transferase 2 (LIPT2) and promoting its degradation through ubiquitination and lysosomal pathways. This process impairs lipoic acid biosynthesis and the lipoylation of E2 subunits of alpha-ketoglutarate dehydrogenase (α-KGDH E2). Furthermore, either overexpressing LIPT2 or administering lipoic acid mitigates neurodegeneration and rectifies deficits in motor coordination activity. These findings unveil a molecular mechanism underlying the regulation of lipoic acid metabolism and underscore the potential therapeutic role of protein lipoylation in the treatment of HD.}, archive = {J_PNAS}, author = {Fan, Pan and Liu, Yaqing and Liu, Chunyue and Yao, Hao and Xu, Shibo and Jiang, Yueqing and Wu, Yang and Liu, Yan and Guo, Xing}, doi = {10.1073/pnas.2503342122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2503342122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {NEDD4L induces mitochondrial dysfunction and neurodegeneration by promoting LIPT2 degradation in huntington’s disease}, volume = {122}, year = {2025}, }
• (2025). Ciprofloxacin-driven purifying selection on viral genomes accelerates soil N2O production. PNAS, 122(29), e2503199122. (www)

  @article{ , abstract = {Viruses are ubiquitous regulators of microbial dynamics and may thus greatly influence global microbial-driven greenhouse gas emissions. Anthropogenic stressors, such as chemical contamination, are likely to amplify these viral contributions; however, their global significance and underlying mechanisms remain elusive. Utilizing 15 N tracing, metagenomics, and laboratory assays, we explore soil viral communities and their evolutionary potential under the stress from antibiotic ciprofloxacin (CIP), focusing on their roles in regulating nitrogen cycling and N 2 O production. Through isolation and reinoculation of soil viruses, we demonstrate that CIP stimulates soil denitrification-derived N 2 O production, with 18 to 29% of the increase attributed to viral activity. Under CIP stress, soil viruses shift toward a lysogenic lifestyle, promoting mutualism with denitrifiers by horizontally transferring viral denitrification-related auxiliary metabolic genes (AMGs). The observed synonymous mutations in these AMGs, driven by CIP, suggest enhanced purifying selection, likely optimizing codon usage to align with host preferences. This optimization likely enhances the expression of denitrifying AMGs and increases N 2 O production. This study provides insights into the overlooked role of viral dynamics and genomic mutations in modulating N 2 O production under stressful environments, highlighting their evolutionary significance and impact on biogeochemical cycles in the Anthropocene.}, archive = {J_PNAS}, author = {Fang, Linfa and Lakshmanan, Prakash and Zhang, Hailin and Deng, Yue and Xiao, Ran and Wen, Teng and Ma, Bin and Ge, Tida and Müller, Christoph and Zhang, Jinbo and Chen, Xinping and Zhu, Yongguan and Su, Xiaoxuan}, doi = {10.1073/pnas.2503199122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2503199122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ciprofloxacin-driven purifying selection on viral genomes accelerates soil N2O production}, volume = {122}, year = {2025}, }
• (2025). Glycolipids implicated as mediators of clinically visible retinal pigment epithelial migration in age-related macular degeneration. PNAS, 122(29), e2503191122. (www)

  @article{ , abstract = {The retinal pigment epithelium (RPE) is the metabolic gatekeeper to the photoreceptors, thus playing many essential roles in healthy vision. Under certain conditions, RPE cells may transdifferentiate and migrate from the RPE layer. Ectopic RPE cells are potential signal sources for hyperreflective foci, prominent clinically visible biomarkers in age-related macular degeneration, which causes central vision loss globally. Applying multiple imaging modalities including ex vivo optical coherence tomography, autofluorescence microscopy, and imaging mass spectrometry (IMS) to human retina tissue, we compared lipid profiles in ectopic and orthotopic RPE cells. Our results showed that ectopic RPE cells share some molecular signatures with normal RPE cells as revealed through autofluorescence imaging and IMS. In both orthotopic and ectopic RPE cells, IMS detected phosphatidylglycerol, PG 36:2, and several triacylglycerols containing long-chain fatty acids. GM3 gangliosides (40:1, 42:1, and 42:2) were also detected in ectopic RPE cells with differences in abundance in different populations of ectopic RPE cells. Lactosylceramide (LacCer 44:5) and glucosylceramide (GlcCer 44:5) were found exclusively in ectopic RPE cells. In contrast, ectopic RPE did not exhibit signals of phosphatidylinositols (PI) (PI32:0, PI32:1, PI34:1, and PI34:2) normally detected in RPE cells. Near-single-cell resolution IMS results suggest that RPE transdifferentiation, with loss of normal functions and gain of new functions like migration, may be linked to altered metabolism of glycosphingolipids and PIs.}, archive = {J_PNAS}, author = {Wang, Zhen and Anderson, David M. G. and Messinger, Jeffrey D. and Curcio, Christine A. and Schey, Kevin L.}, doi = {10.1073/pnas.2503191122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2503191122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Glycolipids implicated as mediators of clinically visible retinal pigment epithelial migration in age-related macular degeneration}, volume = {122}, year = {2025}, }
• (2025). Bistable random momentum transfer in a linear on-chip resonator. PNAS, 122(29), e2502921122. (www)

  @article{ , abstract = {Optical switches and bifurcation rely on the nonlinear response of materials. Here, we demonstrate linear temporal bifurcation responses in a passive multimode microresonator, with strongly coupled chaotic and whispering gallery modes (WGMs). In microdisks, the chaotic modes exhibit broadband transfer within the deformed cavities, but their transient response is less explored and yields a random output of the analog signal distributed uniformly from “0” to “1.” Here, we build chaotic states by perturbing the multimode microring resonators with densely packed silicon nanocrystals on the waveguide surface. In vivo measurements reveal random and “digitized” output that ONLY populates around 0 and 1 intensity levels. The bus waveguide mode couples first to chaotic modes, then either dissipates or tunnels into stable WGMs. This binary pathway generates high-contrast, digitized outputs. The fully passive device enables real-time conversion of periodic clock signals into binary outputs with contrasts exceeding 12.3 dB, data rates of up to 10 7 · bits per second, and 20 dB dynamic range.}, archive = {J_PNAS}, author = {Gu, Tingyi and Chang, Lorry and Wu, Jiagui and Wu, Lijun and Lee, Hwaseob and Chen, Young-Kai and Rahim, Masudur and Dong, Po and Wong, Chee Wei}, doi = {10.1073/pnas.2502921122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2502921122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bistable random momentum transfer in a linear on-chip resonator}, volume = {122}, year = {2025}, }
• (2025). The apportionment of dietary diversity in wildlife. PNAS, 122(29), e2502691122. (www)

  @article{ , abstract = {Evaluating species’ roles in food webs is critical for advancing ecological theories on competition, coexistence, and biodiversity but is complicated by pronounced dietary variability within species and overlap across species. We combined dietary DNA metabarcoding, GPS tracking, and a machine-learning algorithm to cluster and compare dietary profiles within and among five migratory large-herbivore species from Yellowstone National Park. Interspecific niche partitioning was weak, but statistically significant (PERMANOVA: pseudo- F 4,498 = 14.7, R 2 = 0.11, P ≤ 0.001), such that some diet profiles from different species were as similar as those from within one species. Instead of affirming species’ identity as a primary determinant of diet composition, we found three statistically different clusters of diet profiles—one concentrated on graminoids and forbs, another on forbs and deciduous shrubs, and a third on gymnosperms—each including samples from all herbivore species. Clusters did not reflect traditional diet classification schemes such as the grazer-browser continuum that is often used to distinguish species by percent grass consumption or use of grassland habitat in African savannas. Instead, clusters in Yellowstone reflected seasonal dietary variation within species that often equaled or exceeded niche differences between species, contributing to our growing understanding of why environmental variability may favor generalist foraging strategies at temperate latitudes, whereas specialized grazer and browser guilds appear to predominate in tropical savannas. Data-driven strategies that untangle complex trophic networks without relying on a priori groupings can offer new insights into wildlife diets, with potential applications in resource management and environmental monitoring.}, archive = {J_PNAS}, author = {Hoff, Hannah K. and Littleford-Colquhoun, Bethan L. and Kartzinel, Rebecca Y. and Anderson, Heidi M. and Geremia, Chris and McGarvey, Lauren M. and Segal, Carlisle and Kartzinel, Tyler R.}, doi = {10.1073/pnas.2502691122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2502691122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The apportionment of dietary diversity in wildlife}, volume = {122}, year = {2025}, }
• (2025). Targeting PBK with small-molecule 1-O-acetyl-4R,6S-britannilactone for the treatment of neuroinflammation. PNAS, 122(29), e2502593122. (www)

  @article{ , abstract = {Neuroinflammation is a complex immunological phenomenon characterized by a dysregulated inflammatory response in the central nervous system (CNS) that can be triggered by various pathological injuries, such as toxins, which are involved in Parkinson’s and Alzheimer’s diseases (PD and AD), therefore, suppressing neuroinflammation serves as an effective treatment for CNS diseases. Herein, we found that natural soluble epoxide hydrolase (sEH) inhibitor 1- O -acetyl-4 R ,6 S -britannilactone (AB) regulated mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways to suppress the microglial activation by regulating inflammation and autophagy in vitro and in vivo, contributing to the improvement of lipopolysaccharide (LPS)-mediated neuroinflammation. Protein microarray analysis indicated that AB could selectively target PDZ binding kinase (PBK) through covalently binding to C70, exhibiting a dissociation constant (Kd) of 0.62 μM, which was corroborated by subsequent chemical biology experiments. We gained a deeper understanding of the mechanistic by which AB interfered PBK function, specifically by disrupting its interaction with tumor necrosis factor alpha-induced protein-8 like-2 (TIPE2), blocking the serine 3 (S3) phosphorylation-mediated ubiquitylation and degradation of TIPE2. Additionally, our study revealed that PBK genetic deletion alleviated the course of LPS-mediated neuroinflammation in vitro and in vivo, and AB did not exhibit any extra effects in LPS-mediated PBK -/- mice. These findings first offered broader prospects for treating neuroinflammation by targeting PBK to repress inflammation and activate autophagy, suggesting that AB had the potential to serve as a direct inhibitor in the PBK–TIPE2 interaction.}, archive = {J_PNAS}, author = {Zhang, Juan and Zhang, Hui-Lin and Xu, Xin-Rong and Feng, Yan-Li and Zhu, Qi-Meng and Morisseau, Christophe and Qiu, Feng and Hammock, Bruce D. and Sun, Cheng-Peng}, doi = {10.1073/pnas.2502593122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2502593122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Targeting PBK with small-molecule 1-O-acetyl-4R,6S-britannilactone for the treatment of neuroinflammation}, volume = {122}, year = {2025}, }
• (2025). N-acetyltransferases required for iron uptake and aminoglycoside resistance promote virulence lipid production in mycobacterium marinum. PNAS, 122(29), e2502577122. (www)

  @article{ , abstract = {Phagosomal lysis is essential for mycobacterial infection of macrophages. Acetylation is a protein modification mediated enzymatically by N-acetyltransferases (NATs) that impacts bacterial pathogenesis and physiology. To identify NATs required for lytic activity, we leveraged Mycobacterium marinum, a nontubercular pathogen and a model for Mycobacterium tuberculosis. M. marinum hemolysis is a proxy for phagolytic activity. We generated M. marinum strains with deletions in conserved NAT genes and screened for hemolytic activity. Several conserved lysine acetyltransferases (KATs) contributed to hemolysis, which is mediated by the ESX-1 secretion system and by the virulence lipid phthiocerol dimycocerosate (PDIM). Using thin-layer chromatography, we found that MbtK, a conserved acyl-transferase required for mycobactin siderophore synthesis and virulence, was required for PDIM and phenolic glycolipid (PGL) production. Exogenous addition of sodium propionate or Mycobactin J restored PDIM/PGL production in the Δ mbtK strain. The Δ mbtK M. marinum strain was attenuated in macrophage and Galleria mellonella infection models. Constitutive expression of either eis or papA5, which encode a KAT required for aminoglycoside resistance and a PDIM/PGL biosynthetic enzyme, rescued PDIM/PGL production, and virulence of the ∆ mbtK strain. Eis N-terminally acetylated PapA5 in vitro, providing a plausible mechanism for restored lipid production. Overall, our study establishes connections between the MbtK and Eis NATs, and between iron uptake and PDIM and PGL synthesis in M. marinum . Our findings underscore the multifunctional nature of mycobacterial NATs and their connection to key virulence pathways.}, archive = {J_PNAS}, author = {Jones, Bradley S. and Pareek, Vikram and Hu, Daniel D. and Weaver, Simon D. and Syska, Camille and Galfano, Grace and Champion, Matthew M. and Champion, Patricia A.}, doi = {10.1073/pnas.2502577122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2502577122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {N-acetyltransferases required for iron uptake and aminoglycoside resistance promote virulence lipid production in mycobacterium marinum}, volume = {122}, year = {2025}, }
• (2025). A quantitative imaging framework for lithium morphology: Linking deposition uniformity to cycle stability in lithium metal batteries. PNAS, 122(29), e2502518122. (www)

  @article{ , abstract = {Characterizing the morphology of lithium (Li) is crucial for developing long-lasting lithium metal batteries. It is well established that more uniform Li deposition correlates with better cell performance. Li morphology is often characterized through qualitative analysis of scanning electron microscopy (SEM) images; however, there are no widely accepted metrics to quantitatively describe deposition uniformity. Here, we propose a framework to quantify uniformity through SEM image analysis via the index of dispersion ( ID ) metric, which is defined and presented in the context of Li metal batteries. We also explore experimental impacts of sampling protocols on ID measurements. Our results demonstrate that the ID metric is highly sensitive to variations in deposition uniformity, including the coexistence and uniformity of multiple morphologies, uniformity within a single morphology, and particle size distribution uniformity. Furthermore, it is demonstrated that uniformity, as measured by the ID , can be related to the average potential of Li||Li symmetric cells over cycling. Higher capacity cycling leads to more pronounced changes in both ID and average cell potential. Local minima/maxima are found consistently in both ID and average cell potential immediately before cells short-circuit, which we suggest may indicate a collapse of the microstructure prior to failure. We put forward this framework as a more robust approach to quantify Li deposition uniformity, advancing the development of Li metal batteries that are safer and longer lasting.}, archive = {J_PNAS}, author = {Nicolas, Jenny R. and Hui, Zeyu and Miao, Qiushi and Lin, Haichen and Davidson, Michael R. and Liu, Ping}, doi = {10.1073/pnas.2502518122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2502518122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A quantitative imaging framework for lithium morphology: Linking deposition uniformity to cycle stability in lithium metal batteries}, volume = {122}, year = {2025}, }
• (2025). MtKO: A dedicated guide RNA library for mitochondria research. PNAS, 122(29), e2502285122. (www)

  @article{ , abstract = {Mitochondria are multifunctional organelles central to both physiological and pathological processes. In malignant cancer cells, mitochondrial reprogramming establishes the metabolic foundation to meet cellular demands, which is particularly important in tumor cells with existing metabolic perturbations. To identify key mitochondrial pathways supporting cancer development, we developed mitochondria Knockout (mtKO), a robust and unbiased CRISPR screening platform to pinpoint critical mitochondria-associated pathways. The mtKO screen revealed that the mitochondrial antioxidant enzyme SOD2 is essential for cells harboring IDH1 mutations. Mechanistically, SOD2 activity determines the disease manifestation of IDH1-mutated cancers, through maintaining redox homeostasis and mitochondrial fitness. This study introduces a powerful functional genomic tool to identify mitochondrial-centered pathways and reveals the selective mitochondrial vulnerability in Krebs cycle-deficient cancers for future therapeutic intervention.}, archive = {J_PNAS}, author = {Kaur, Karambir and Zaheer, Javeria and Lang, Fengchao and Ribeiro, Diego Luis and Zhang, Meili and Song, Hua and Zhang, Wei and Chari, Raj and Alkaissi, Hussam and Yang, Chunzhang}, doi = {10.1073/pnas.2502285122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2502285122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MtKO: A dedicated guide RNA library for mitochondria research}, volume = {122}, year = {2025}, }
• (2025). Dissociable glucocorticoid and noradrenergic effects on parochial cooperation and competition in intergroup conflict. PNAS, 122(29), e2502257122. (www)

  @article{ , abstract = {Stress changes social behavior, yet its effects remain contradictory. Traditionally, stress was thought to trigger an antagonistic fight-or-flight response aimed at eliminating the stressor. However, recent studies have revealed the opposite response, tend-and-befriend, where individuals prosocially invest in their social network in exchange for support and mutual protection. We hypothesize that stress does not promote one response over the other; instead, it stimulates both behaviors, dissociable on the neuropharmacological level and moderated by social context. In a placebo-controlled, double-blind psychopharmacological study, we administered hydrocortisone and yohimbine—alone or in combination—to manipulate the actions of the main stress hormone cortisol and the arousal transmitter noradrenaline. Participants then made decisions in an intergroup conflict task. They teamed up with others to form an in-group and played against multiple out-groups. Notably, out-group members initiated financial harm to in-group participants before these responded. Participants then chose either to 1) maximize their own payoff, 2) cooperatively increase the payoff of their in-group, or 3) increase the in-group’s payoff while competitively decreasing that of the out-group. Consistent with our hypotheses, glucocorticoid activation increased generosity toward the in-group, whereas noradrenergic activation increased parochial competition, i.e., prosocial in-group support combined with hostility toward the out-group. These findings challenge the dichotomy between fight-or-flight and tend-and-befriend, suggesting stress-related behavior is neither static nor one-directional, but shaped by the relative dominance of cortisol versus noradrenaline in the neurohormonal stress response and by intergroup dynamics. We highlight broader societal implications, offering a potential biological mechanism underlying the self-perpetuating cycle of intergroup conflict.}, archive = {J_PNAS}, author = {Dashti, Damon and Lüpken, Luca M. and Seidisarouei, Mohammad and Forbes, Paul A. G. and Schnitzler, Alfons and Kalenscher, Tobias}, doi = {10.1073/pnas.2502257122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2502257122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dissociable glucocorticoid and noradrenergic effects on parochial cooperation and competition in intergroup conflict}, volume = {122}, year = {2025}, }
• (2025). Microscopic and structural observations of actin filament capping and severing by cytochalasin d. PNAS, 122(29), e2502164122. (www)

  @article{ , abstract = {Cytochalasin D (CytoD), a widely used actin inhibitor, is typically employed in cell studies as a simple barbed end capper. However, accumulating evidence suggests broader effects on actin dynamics. We addressed this by observing single actin filaments using total internal reflection fluorescence microscopy. Our depolymerization assay confirmed that, at nanomolar concentrations, CytoD tightly caps barbed ends. The K 1/2 for inhibition was 4.1 nM, consistent with previous bulk measurements, and our approach revealed a capping duration of ~2 min. In polymerization assays, nanomolar CytoD completely suppressed barbed end elongation. Interestingly, at subnanomolar concentrations, CytoD caps barbed ends only transiently, rapidly associating and dissociating under both polymerizing and depolymerizing conditions. We interpreted this contradictory behavior as arising from differences in binding modes: capping one strand (fast dissociation) or both strands (slow dissociation). CytoD severs actin filaments at micromolar levels, a concentration range commonly used in cell biological studies. Although the severing rate is slower than cofilin, its higher frequency leads to filament fragmentation. Severing activity was suppressed by inorganic phosphate or cofilin. Our crystal structure of CytoD bound to filamentous conformation (F-form) actin showed that CytoD fits better in the hydrophobic cleft of F-form actin than monomeric conformation actin, explaining its preference for barbed end subunits. CytoD prevents barbed end depolymerization by stabilizing the terminal subunits in the F-form, which is supported by our MD simulations. These findings reveal the molecular mechanisms by which CytoD modulates actin dynamics and highlight the need for careful dosage control when treating cells with CytoD.}, archive = {J_PNAS}, author = {Mitani, Takahiro and Takeda, Shuichi and Oda, Toshiro and Narita, Akihiro and Maéda, Yuichiro and Honda, Hajime and Fujiwara, Ikuko}, doi = {10.1073/pnas.2502164122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2502164122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Microscopic and structural observations of actin filament capping and severing by cytochalasin d}, volume = {122}, year = {2025}, }
• (2025). Inference of human pigmentation from ancient DNA by genotype likelihoods. PNAS, 122(29), e2502158122. (www)

  @article{ , abstract = {Light eyes, hair, and skins probably evolved several times as Homo sapiens dispersed from Africa. In areas with lower UV radiation, light pigmentation alleles increased in frequency because of their adaptive advantage and of other contingent factors such as migration and drift. However, the tempo and mode of their spread is not known. Phenotypic inference from ancient DNA is complicated, both because these traits are polygenic and because of low sequence depth. We evaluated the effects of the latter by randomly removing reads in three high-coverage ancient samples, the Paleolithic Ust’-Ishim from Russia, the Mesolithic SF12 from Sweden, and the Neolithic I5077 from current Croatia. We could thus compare three approaches to pigmentation inference, concluding that for suboptimal levels of coverage (<8×), a probabilistic method estimating genotype likelihoods leads to the most robust predictions. We then applied that protocol to 348 ancient genomes from Eurasia, describing how skin, eye, and hair color evolved over the past 45,000 y. The shift toward lighter pigmentations turned out to be all but linear in time and place, and slower than expected, with half of the individuals showing dark or intermediate skin colors well into the Bronze and Iron ages. We also observed a peak of light eye pigmentation in Mesolithic times, and an accelerated change during the spread of Neolithic farmers over Western Eurasia, although localized processes of gene flow and admixture, or lack thereof, also played a significant role.}, archive = {J_PNAS}, author = {Perretti, Silvia and Santos, Patrícia and Vizzari, Maria Teresa and Tassani, Enrico and Benazzo, Andrea and Ghirotto, Silvia and Barbujani, Guido}, doi = {10.1073/pnas.2502158122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2502158122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inference of human pigmentation from ancient DNA by genotype likelihoods}, volume = {122}, year = {2025}, }
• (2025). Paleobiome dynamics shaped a large gondwanan plant radiation. PNAS, 122(29), e2502129122. (www)

  @article{ , abstract = {Theories of adaptive radiation propose predictable trajectories in which diversity accumulates rapidly in newly formed or colonized environments with underexploited niche space and few competing species, before slowing down as competition intensifies, and speciation and extinction rates approach equilibrium. This historical perspective on diversity may be more important than current environmental variation for explaining today’s biodiversity, but this has been difficult to determine because of the complexity of diversification dynamics and the challenges of relating diversification processes to past environmental change. Here we unravel the complex and heterogenous diversification dynamics of Proteaceae (subfamily Grevilleoideae), a large Gondwanan plant clade, to investigate how the expansion and contraction of biomes since the Cretaceous has shaped its current megadiversity across the Sahul region (Australia and New Guinea). We modeled paleobiome dynamics over a 120 Ma period and produced a nuclear phylogenomic dataset of 458 loci for ~700 species (~74%) to show that historical diversification rates across the Grevilleoideae phylogeny are closely associated with ecological opportunity provided by emerging and expanding biomes. Diversification is rapid in emerging and expanding biomes, while long-occupied biomes tend to have higher species richness but lower diversification rates, as expected if these biomes have approached equilibrium diversity. Our results reveal a strong and heterogeneous legacy of climatic and geological history on today’s floristic diversity and explain why diversity is often decoupled from expectations based on measures of ecological “carrying capacity” such as the area or climate of present-day biomes.}, archive = {J_PNAS}, author = {Skeels, Alexander and Sauquet, Hervé and Mast, Austin and Weston, Peter H. and Olde, Peter M. and Jordan, Gregory J. and Carpenter, Raymond J. and Fenker, Jéssica and Reynolds, Zoe K. M. and Lemmon, Alan R. and Lemmon, Emily Moriarty and Pichardo-Marcano, Fritz J. and Cardillo, Marcel}, doi = {10.1073/pnas.2502129122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2502129122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Paleobiome dynamics shaped a large gondwanan plant radiation}, volume = {122}, year = {2025}, }
• (2025). Amyloid-β modulates the phase separation and aggregation of α-synuclein. PNAS, 122(29), e2501987122. (www)

  @article{ , abstract = {The aggregation of amyloid-β (Aβ) and α-synuclein (αSyn) into insoluble proteinaceous deposits is a hallmark of Alzheimer’s and Parkinson’s diseases. Recent evidence suggests that these amyloidogenic proteins act in synergy, with their coaggregation frequently observed in these disorders. In this study, we investigate the interaction of Aβ and αSyn using various biophysical tools. In particular, we explore the cocondensation of Aβ with αSyn, elucidating the pathways through which Aβ modulates αSyn phase separation. We studied different variants of Aβ, focusing on the most prominent species, namely Aβ42 and Aβ40. We found that Aβ42 and Aβ40 have fundamentally different mechanistic effects on the kinetics of αSyn condensation. Aβ42 initially forms large aggregates that act as heterogeneous nucleation sites which initiate the phase separation of αSyn. In contrast, Aβ40 is sequestered into αSyn condensates where it accelerates the liquid-to-solid transition of αSyn into amyloid aggregates. All other Aβ variants we probed fell into one of these two mechanistic pathways, with Aβ37, Aβ39, and Aβ35-25 exhibiting similar behavior to Aβ40, whereas Aβ43 triggered nucleation processes similar to Aβ42. Given the complexity behind amyloid formation, it is key to understand how molecular partners can interact with one another. Our results thus illustrate the extreme sensitivity of protein mixtures and shed light on some of the mechanisms involved in the cocondensation and aggregation of Aβ with αSyn.}, archive = {J_PNAS}, author = {Röntgen, Alexander and Toprakcioglu, Zenon and Morris, Owen M. and Vendruscolo, Michele}, doi = {10.1073/pnas.2501987122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2501987122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Amyloid-β modulates the phase separation and aggregation of α-synuclein}, volume = {122}, year = {2025}, }
• (2025). Representational drift and learning-induced stabilization in the piriform cortex. PNAS, 122(29), e2501811122. (www)

  @article{ , abstract = {The brain encodes external stimuli through patterns of neural activity, forming internal representations of the world. Increasing experimental evidence showed that neural representations for a specific stimulus can change over time in a phenomenon called “representational drift” (RD). However, the underlying mechanisms for this widespread phenomenon remain poorly understood. Here, we study RD in the piriform cortex of the olfactory system with a realistic neural network model that incorporates two general mechanisms for synaptic weight dynamics operating at two well-separated timescales: spontaneous multiplicative fluctuations on a scale of days and spike-timing-dependent plasticity (STDP) effects on a scale of seconds. We show that the slow multiplicative fluctuations in synaptic sizes, which lead to a steady-state distribution of synaptic weights consistent with experiments, can induce RD effects that are in quantitative agreement with recent empirical evidence. Furthermore, our model reveals that the fast STDP learning dynamics during presentation of a given odor drives the system toward a low-dimensional representational manifold, which effectively reduces the dimensionality of synaptic weight fluctuations and thus suppresses RD. Specifically, our model explains why representations of already “learned” odors drift slower than unfamiliar ones, as well as the dependence of the drift rate with the frequency of stimulus presentation—both of which align with recent experimental data. The proposed model not only offers a simple explanation for the emergence of RD and its relation to learning in the piriform cortex, but also provides a general theoretical framework for studying representation dynamics in other neural systems.}, archive = {J_PNAS}, author = {Morales, Guillermo B. and Muñoz, Miguel A. and Tu, Yuhai}, doi = {10.1073/pnas.2501811122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2501811122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Representational drift and learning-induced stabilization in the piriform cortex}, volume = {122}, year = {2025}, }
• (2025). A fire-safe li metal battery via smart gas management. PNAS, 122(29), e2501549122. (www)

  @article{ , abstract = {Lithium (Li) metal batteries offer high energy density but face significant safety challenges due to gas evolution under thermal abuse conditions. At the anode, the reduction of organic carbonate-based electrolytes generates flammable gases (e.g., H 2 , CH 4 ), while the poor thermal stability of the cathode results in the release of O 2 , CO, and CO 2 . The accumulation of these gases contributes to mechanical rupture, and their migration further exacerbates thermal runaway. To address these challenges, we propose a smart gas management strategy that constructs continuous flame-retardant interfaces (FRIs) by incorporating flame-retardant polymers (FRPs) into the cathode. Smart gas management is defined as the ability to suppress gas production, alter gas composition to reduce flammability, and mitigate internal pressure buildup, thereby preventing thermal runaway. The FRIs significantly enhance the thermal stability of the cathode by suppressing oxygen release and minimizing electrolyte oxidation caused by active oxygen species. Additionally, the FRP releases flame-retardant radicals that diffuse into the electrolyte, interrupting reactions that generate flammable gases at the anode. This dual-action mechanism reduces gas production and mitigates the risks associated with thermal runaway, forming the foundation of a smart gas management strategy. With this strategy, we demonstrate zero thermal runaway in a 0.58-Ah Li||NCM811 pouch cell with 100% state of charge under thermal abuse conditions. This approach is highly compatible with current manufacturing processes, offering a scalable solution for improving the safety of high-energy-density Li metal batteries. This work provides a promising pathway toward fire-safe Li metal batteries for electric vehicles and other energy storage applications.}, archive = {J_PNAS}, author = {Guo, Jun-Chen and Chai, Cong-Zheng and Wang, Ya-Hui and Zhao, Yao and Xin, Sen and Zhang, Ying and Guo, Yu-Guo and Bai, Chunli}, doi = {10.1073/pnas.2501549122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2501549122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A fire-safe li metal battery via smart gas management}, volume = {122}, year = {2025}, }
• (2025). Metabolic traits are shaped by phylogenetic conservatism and environment, not just body size. PNAS, 122(29), e2501541122. (www)

  @article{ , abstract = {Metabolic rate dictates life’s tempo, yet how ecological and environmental factors integrate to shape metabolic traits remains contentious. Considering metabolic traits of 114 species of ants from seven subfamily clades along a 1,500 km climatic and soil phosphorus availability gradient in Australia, we tested four hypotheses relating to variation in metabolic rate due to niche conservatism, temperature, aridity, and ecological stoichiometry. We also tested the contested hygric hypothesis, which predicts that insect ventilation patterns can be modified to reduce water loss in arid environments. Mass-independent metabolic rate was phylogenetically conserved. The ant clade Myrmecia had metabolic rates 3 to 10× higher than other species, likely related to their large eye size, a correlate of cognitive complexity. Metabolic rate was higher in ants from warm, arid sites relative to those from wet, cool sites. A weak positive interaction between soil phosphorus and body mass indicated that, at sites with low soil phosphorus, smaller ants respired at higher rates than expected based on their mass—consistent with ecological stoichiometry theory. Larger ants, regardless of clade, were more likely to exhibit discontinuous gas exchange (DGC) with increasing aridity, likely reflecting a water conservation strategy. Phylogenetic conservatism of metabolic rate and a moderate influence of environment suggest that, in addition to biophysical geometric constraints, metabolic rate has evolved to match the energetic demands required of ecological strategies to address environmental stressors. For larger insect species confronting their metabolic limits, DGC may promote resilience in a world that is becoming hotter and more arid.}, archive = {J_PNAS}, author = {Leahy, Lily and Chown, Steven L. and Riskas, Hannah L. and Wright, Ian J. and Carlesso, Amelia G. and Hammer, Ian J. and Sanders, Nathan J. and Bishop, Tom R. and Parr, Catherine L. and Gibb, Heloise}, doi = {10.1073/pnas.2501541122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2501541122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Metabolic traits are shaped by phylogenetic conservatism and environment, not just body size}, volume = {122}, year = {2025}, }
• (2025). Classical BSE emergence from nor98/atypical scrapie: Unraveling the shift vs. selection dichotomy in the prion field. PNAS, 122(29), e2501104122. (www)

  @article{ , abstract = {Prion diseases can manifest with distinct phenotypes in a single species, a phenomenon known as prion strains. Upon cross-species transmission, alterations in the disease phenotype can occur, interpreted as the emergence of a new strain. Two main and non–mutually exclusive evolutionary hypotheses have been proposed to explain this phenomenon: the “conformational shift” or “deformed templating” and the “conformational selection.” The conformational shift hypothesis proposes that the introduction of a new host prion protein (PrP C ) forces a change in the conformation of the pathological prion protein (PrP Sc ), causing the new prion strain emergence. On the contrary, the conformational selection model postulates that prion isolates are a conglomerate of PrP Sc conformations with relative distribution frequencies, wherein the species barrier acts as a filter selecting the one fittest for the new species environment. Previous studies reported the emergence of the classical bovine spongiform encephalopathy agent (c-BSE) upon transmission of Nor98/atypical scrapie (AS) onto a bovine PrP. This study investigates the evolutionary dichotomy of this c-BSE emergence by using prion strain thermostability combined with protein misfolding cyclic amplification to distinguish between both strains. Our results suggest that the conformational shift could be the principal mechanism responsible for the c-BSE emergence. Furthermore, the selection model was dismissed as the key mechanism based on the analysis of an artificial c-BSE and AS mixture. The ability of the AS conformers to shift conformation to a c-BSE one supports the hypothesis that the epidemic c-BSE prion may have originated from the transmission of AS in cattle.}, archive = {J_PNAS}, author = {Canoyra, Sara and Marín-Moreno, Alba and Espinosa, Juan Carlos and Fernández-Borges, Natalia and Vidal, Enric and Orge, Leonor and Benestad, Sylvie L. and Andréoletti, Olivier and Torres, Juan María}, doi = {10.1073/pnas.2501104122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2501104122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Classical BSE emergence from nor98/atypical scrapie: Unraveling the shift vs. selection dichotomy in the prion field}, volume = {122}, year = {2025}, }
• (2025). Water content modulation enables selective ion transport in 2D MXene membranes. PNAS, 122(29), e2501017122. (www)

  @article{ , abstract = {Separation membranes are critical for a range of processes, including but not limited to water desalination, chemical and fuel production, and recycling and recovery applications. Fundamentally, there are intrinsic trade-offs between permeability and selectivity. Local water organization and content can impact membrane structure (short- and long-range) in laminar transition metal carbide (MXene) membranes and impact selective ion permeation. Intercalation of chaotropic cesium (Cs + ) ions within the layers reduces the water content in the membrane and at the surface which cannot be found in the intercalation of other ions. Additionally, 3D imaging using focused ion beam scanning electron microscopy showed fewer defects in the Cs-MXene membrane, due to reduced local water content, leading to more efficient ion sieving. X-ray diffraction and density functional theory calculations on the nanochannel structure demonstrated that the chaotropic ion results in the smallest nanochannel size and induces a stronger resistance to water-induced nanochannel swelling. With a narrower nanochannel, the Cs-MXene membrane limits ion transport pathways, resulting in more selective transport of lithium over other metal cations, as evidenced in both experiment and molecular dynamics simulations. Our findings highlight the potential for controlling the structural organization of 2D MXene membranes to enable on-demand transport of ions for diverse applications.}, archive = {J_PNAS}, author = {Zhu, Yaguang and Xiong, Qinsi and Jeon, Woo Cheol and Blum, Monika and Camino, Fernando and Schatz, George C. and Hatzell, Kelsey B.}, doi = {10.1073/pnas.2501017122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2501017122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Water content modulation enables selective ion transport in 2D MXene membranes}, volume = {122}, year = {2025}, }
• (2025). Foxn3 is required to suppress aberrant ciliogenesis in nonphotoreceptor retinal neurons. PNAS, 122(29), e2500871122. (www)

  @article{ , abstract = {The retinal photoreceptors possess specialized sensory cilia critical for phototransduction while the nonphotoreceptor cells typically exhibit simpler primary cilia or lack them altogether. This dichotomy in ciliary architecture underpins the functional specialization of retinal cell types, but how this dichotomy arises and is maintained remains elusive. This study explores the role of the transcription factor Foxn3 in establishing and maintaining this divergence. We generated retina-specific Foxn3 conditional knockout (Foxn3CKO) mice, which show that Foxn3 is essential for repressing ciliary gene expression in nonphotoreceptor cells, such as bipolar and amacrine cells. Foxn3CKO mice exhibit significant reductions in electroretinogram b-wave amplitudes and oscillatory potentials, indicating functional impairments in inner retinal neurons. Loss of Foxn3 leads to ectopic ciliary gene expression and abnormal ciliogenesis in nonphotoreceptor neurons, without affecting retinal cell specification and differentiation. Single-Cell RNA Sequencing, chromatin profiling, and transcription assays reveal that Foxn3 directly binds to and represses the promoters of ciliary genes and their transactivators, including Foxj1 and Rfx family members. Our data together highlight Foxn3 as a key transcriptional repressor that may function to ensure the proper ciliary architecture of retinal neurons by preventing nonphotoreceptor neurons from adopting photoreceptor-like ciliary features and provide insights into the molecular mechanisms governing retinal development and ciliopathies.}, archive = {J_PNAS}, author = {Liu, Shuting and Chen, Junyao and Chen, Haiqiao and Guo, Yanan and Yuan, Fa and Xiao, Dongchang and Xiang, Mengqing}, doi = {10.1073/pnas.2500871122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2500871122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Foxn3 is required to suppress aberrant ciliogenesis in nonphotoreceptor retinal neurons}, volume = {122}, year = {2025}, }
• (2025). Explaining and predicting the southern hemisphere eddy-driven jet. PNAS, 122(29), e2500697122. (www)

  @article{ , abstract = {The summertime eddy-driven jet (EDJ) in the Southern Hemisphere is a critical mediator between regional climate and large-scale phenomena, guiding synoptic systems that shape weather patterns. Uncertainties in global climate models (GCMs)-particularly in projecting changes in remote drivers like tropical warming, stratospheric polar vortex strengthening, and asymmetric tropical Pacific warming-hinder predictions of EDJ trends and associated regional outcomes. In this study, we develop a causal framework that combines observations, reanalysis datasets, and storylines estimated from the Coupled Model Intercomparison Project (CMIP) projections to attribute past EDJ changes and predict plausible future trajectories. Our findings indicate that tropical warming has evolved along the low end of plausible CMIP trajectories, while the stratospheric polar vortex shows robust strengthening, both strongly influencing observed EDJ trends. Our results suggest that 50% of the observed EDJ latitude shift can be directly attributed to global warming (GW), and the remaining 50% to remote drivers whose attribution to GW remains uncertain. Importantly, GCMs appear to accurately estimate the observed latitudinal shifts but underestimate the observed strengthening of the EDJ, while the proposed storylines are able to capture the observed trend. By integrating causal inference with climate storylines, our approach narrows the divide between attribution and prediction, offering a physically grounded method to estimate plausible pathways of future climate change.}, archive = {J_PNAS}, author = {Mindlin, Julia and Shepherd, Theodore G. and Osman, Marisol and Vera, Carolina S. and Kretschmer, Marlene}, doi = {10.1073/pnas.2500697122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2500697122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Explaining and predicting the southern hemisphere eddy-driven jet}, volume = {122}, year = {2025}, }
• (2025). Electrokinetic propulsion for electronically integrated microscopic robots. PNAS, 122(29), e2500526122. (www)

  @article{ , abstract = {Semiconductor microelectronics are emerging as a powerful tool for building smart, autonomous sub-millimeter robots. Yet a number of existing microrobot platforms, despite significant advantages in speed, robustness, power consumption, or ease of fabrication, have no clear path toward electronics integration, limiting their potential for intelligence. Here, we show how to upgrade a class of self-propelled particles into electronically integrated microrobots, reaping the best of both platforms in a single design. Inspired by electrokinetic micromotors, these robots generate electric fields in a surrounding fluid, and by extension propulsive electrokinetic flows. The underlying physics is captured by a model in which robot speed is proportional to applied current, making design and control straightforward. As proof, we build basic robots at the 100-micron scale that use rudimentary, on-board photovoltaic circuits and a closed-loop optical control scheme to navigate waypoints and move in coordinated swarms at speeds of up to one body length per second. Broadly, the unification of micromotor propulsion with on-robot electronics invites future work to realize robust, fast, easy to manufacture, electronically programmable microrobots that remain operationally viable for months to years.}, archive = {J_PNAS}, author = {Hanson, Lucas C. and Reinhardt, William H. and Shrager, Scott and Sivakumar, Tarunyaa and Miskin, Marc Z.}, doi = {10.1073/pnas.2500526122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2500526122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electrokinetic propulsion for electronically integrated microscopic robots}, volume = {122}, year = {2025}, }
• (2025). Predictive processes shape individual musical preferences. PNAS, 122(29), e2500494122. (www)

  @article{ , abstract = {Current models suggest that musical pleasure is tied to the intrinsic reward of learning, as it relies on predictive processes that challenge our minds. According to predictive coding, optimal learning, which maximizes epistemic value, depends on balancing predictability and uncertainty, implying that musical pleasure should also reflect this equilibrium. We tested this idea in two independent large samples using a novel decision-making paradigm, where participants indicated preferences for melodies varying in surprise and entropy. Consistent with prior research, we found an inverted U-shaped relationship between predictability and preference. Moreover, our results revealed an interaction between predictability and entropy, with smaller surprises preferred in low-entropy melodies and larger surprises favored in high-entropy music, consistent with predictive coding principles. Computational models incorporating this interaction predicted individuals’ genre preferences and pleasure responses to real compositions, highlighting its applicability to real-world music experiences. These findings advance our understanding of the cognitive mechanisms driving music preferences and the role of predictive processes in affective responses.}, archive = {J_PNAS}, author = {Mas-Herrero, Ernest and Marco-Pallarés, Josep}, doi = {10.1073/pnas.2500494122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2500494122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Predictive processes shape individual musical preferences}, volume = {122}, year = {2025}, }
• (2025). An enzyme-based approach for highly efficient self-replication of DNA origami dimers. PNAS, 122(29), e2500160122. (www)

  @article{ , abstract = {Self-replication and exponential growth are essential to all living things, the driving force for Darwinian evolution, and potentially useful in nanotechnology for large-scale production of nanoscopic materials. An artificial (nonliving) self-replication system has been shown to exhibit exponential growth and selection using DNA monomer origami tiles templated on a dimer seed. That system purposefully avoided the use of enzymes to get a hint of how self-replication might have evolved in a prebiotic world by using CNV K and UV light to crosslink complementary DNA single strands. For further investigations into competition and extinction and for potential applications involving biocompatibility, we wanted to investigate enzymatic ligation to replace the chemical photo crosslinking step. Here, we present a system which uses thermotolerant T4 DNA ligase and no UV. This system has several additional advantages including a much faster cycling time, yielding 2,000,000 amplifications in 12 h. We also introduce competition to study the possibility of Darwinian-like evolution. Two pairs of DNA origami tiles compete for the same connection strands and show different growth rates under different connection strand concentrations. This system has the potential to combine with other enzymes, such as RNA polymerase to support feedback, allowing us to fine-tune replication dynamics and achieve sophisticated, life-like behaviors. The highly efficient self-replication and exponential growth of DNA origami dimers demonstrated in this work not only enhances our understanding of Darwinian evolution in nature but also opens the door to applications ranging from synthetic biology to smart materials.}, archive = {J_PNAS}, author = {Zhang, Lei and Sha, Ruojie and Chaikin, Paul}, doi = {10.1073/pnas.2500160122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2500160122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An enzyme-based approach for highly efficient self-replication of DNA origami dimers}, volume = {122}, year = {2025}, }
• (2025). T lymphocyte–specific deletion of SHP1 and SHP2 promotes activation-induced cell death of CD4+ t cells and impairs antitumor response. PNAS, 122(29), e2427254122. (www)

  @article{ , abstract = {SHP1 (PTPN6) and SHP2 (PTPN11) are closely related protein-tyrosine phosphatases (PTPs), which are autoinhibited until their SH2 domains bind paired tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory/switch motifs (ITIMs/ITSMs). These PTPs bind overlapping sets of ITIM/ITSM-bearing proteins, suggesting that they might have some redundant functions. By studying T cell–specific single and double knockout mice, we found that SHP1 and SHP2 redundantly restrain naïve T cell differentiation to effector and central memory phenotypes, with SHP1 playing the dominant role. Surprisingly, loss of SHP2 alone in T cells enhanced the antitumor effects of anti-PD-1 antibodies, whereas there was no effect of SHP1 deletion. Also unexpectedly, the absence of both PTPs resulted in poorer tumor control and failure to respond to Programmed Cell Death Protein 1 (PD-1) blockade, associated with reduced frequency and activation of T cells and dendritic cells. Mechanistic studies revealed that CD4 + , but not CD8 + , T cells lacking SHP1 and SHP2 show increased activation-induced cell death upon anti-CD3/CD28 stimulation. Adoptive transfer of antigen-specific CD4 + T cells restored normal levels of tumor control in mice lacking both PTPs. Together, our results demonstrate that SHP1 or SHP2 is required to prevent activation-induced cell death of CD4 + T cells and is critical for tumor immunity, raising the possibility that inhibition of SHP2 might augment the therapeutic efficacy of PD-1-based immune therapy.}, archive = {J_PNAS}, author = {Foster, Connor J. R. and Du, Jasper and Pundel, Oscar and Geer, Mitchell J. and Ripert, Ryan C. and Liu, Jia and Heim, Taylor A. and Araki, Kiyomi Y. and Lund, Amanda W. and Wang, Jun and Neel, Benjamin G.}, doi = {10.1073/pnas.2427254122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2427254122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {T lymphocyte–specific deletion of SHP1 and SHP2 promotes activation-induced cell death of CD4+ t cells and impairs antitumor response}, volume = {122}, year = {2025}, }
• (2025). In vivo generation of CAR macrophages via the enucleated mesenchymal stem cell delivery system for glioblastoma therapy. PNAS, 122(29), e2426724122. (www)

  @article{ , abstract = {Glioblastoma multiforme (GBM) is one of the most aggressive intracranial tumors for which there is no effective treatment. Chimeric antigen receptor macrophage (CAR-M) therapies have demonstrated impressive therapeutic efficacy in solid tumors; however, the cost and rigor associated with manufacturing engineered macrophages ex vivo can be prohibitive. Here, we utilized enucleated mesenchymal stem cells (MSCs) as vehicles for the targeted delivery of CAR-encoding plasmid to reprogram glioma-associated microglia/macrophages (GAM), thereby achieving CAR-M preparation in vivo. Specifically, we observed that the enucleated cells retained the key organelle function and membrane integrity, and actively homed to glioma tissue. Interestingly, enucleated MSCs underwent intrinsic apoptosis due to the absence of the nucleus, which subsequently triggered macrophage-specific endocytosis, thereby achieving precise delivery of CAR-plasmids to GAM. Compared with lipid nanoparticles, this strategy specifically generated sufficient numbers of CAR-M in glioma situ to achieve GBM therapy. Moreover, this process altered the immune cell profiles within the tumor by increasing cytotoxic T cells and M1-like macrophages with antitumor activity. When combined with CD47-blocking therapies, tumor growth was completely suppressed in the GBM orthotopic mouse model, resulting in a 90-d survival rate of 83%. Collectively, our strategy provides a viable platform technology for CAR-M generation in vivo, which is expected to provide an approach for GBM therapy.}, archive = {J_PNAS}, author = {Zhou, Lei and Song, Qingying and Zhang, Xin and Cao, Mengnian and Xue, Dayu and Sun, Yiwen and Mao, Meihua and Li, Xinling and Zhang, Zhenzhong and Liu, Junjie and Shi, Jinjin}, doi = {10.1073/pnas.2426724122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2426724122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In vivo generation of CAR macrophages via the enucleated mesenchymal stem cell delivery system for glioblastoma therapy}, volume = {122}, year = {2025}, }
• (2025). Diverse and dynamic influences of saccades on visual representations in the mouse superior colliculus. PNAS, 122(29), e2425788122. (www)

  @article{ , abstract = {How do sensory systems account for stimuli generated by natural behavior? We addressed this question by examining how an ethologically relevant class of saccades modulates visual representations in the mouse superior colliculus (SC), a key region for sensorimotor integration. Leveraging the conserved natural tendency to make saccades that reset the eye-head angle to a default position via the optokinetic reflex, we developed an efficient and unbiased “white noise” approach to study the modulation of representations of visual stimuli by stochastically timed resetting saccades in large neuronal populations in awake, untrained head-fixed mice. Extracellular Neuropixels recordings revealed that saccades significantly impacted population representations of the visual probes in the SC, with early enhancement that began prior to saccade initiation and pronounced suppression for several hundred milliseconds following saccades, independent of units’ visual response properties or directional tuning. To determine whether visual or motor signals are responsible for saccadic modulation, we presented fictive saccades—rapid translations of the visual scene—that simulated the visual experience during saccades in the absence of motor output. Some units exhibited similar modulation by fictive and real saccades, suggesting a sensory-driven origin of saccadic modulation, while others had dissimilar modulation, indicating a motor contribution. These findings establish a simple and robust mouse model to study how movements affect sensory representations and advance our understanding of the neural basis of natural visual coding across species and behaviors.}, archive = {J_PNAS}, author = {Hunt, Joshua B. and Buteau, Anna and Barreto, Joe and Hanson, Spencer and Scholl, Benjamin and Poleg-Polsky, Alon and Felsen, Gidon}, doi = {10.1073/pnas.2425788122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2425788122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Diverse and dynamic influences of saccades on visual representations in the mouse superior colliculus}, volume = {122}, year = {2025}, }
• (2025). Optomechanical reservoir computing. PNAS, 122(29), e2424991122. (www)

  @article{ , abstract = {Nonlinear dynamics are pervasive phenomena in natural and synthetic material systems, where time-varying signals from different physical stimuli in the environment influence the material system behavior. Physical reservoir computing leverages these nonlinear dynamics to produce complex input–output mappings by interpreting the dynamical system as a physical recurrent neural network. A source of physical nonlinearity is crucial for enabling the reservoir to predict nonlinear relationships. Despite the significance of nonlinearity, most physical reservoirs leverage only a single source of nonlinearity. Furthermore, there exists a gap between analyses that examine fundamental capabilities of reservoir computers and those that evaluate the practical performance of reservoir computers. In this study, an optomechanical reservoir is introduced that combines both the nonlinear dynamics from bilinear springs and nonlinear sensing from optical fibers. Both the nonlinear springs and the optical fibers are shown to contribute significantly to the range of nonlinear frequency content produced by the optomechanical reservoir. A novelty search of simulated reservoirs highlights the range of performance exhibited by the optomechanical reservoir, and several high performing designs are validated experimentally. Additionally, a frequency content metric is introduced to characterize the nature of a given reservoir’s nonlinearity, highlighting what kinds of frequencies the reservoir can and cannot produce. This analysis is an important step toward the rational design of reservoir computers as it allows one to match reservoir computers with computational tasks. The development of both analytical techniques and multiphysics designs lays the groundwork for more effective embodied intelligence in dynamic systems.}, archive = {J_PNAS}, author = {Kiyabu, Steven and Nelson, Daniel and Thomson, John and Schultz, Benjamin and Vincent, Timothy and Hertlein, Nathan and Gillman, Andrew and Criner, Amanda and Buskohl, Philip R.}, doi = {10.1073/pnas.2424991122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2424991122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Optomechanical reservoir computing}, volume = {122}, year = {2025}, }
• (2025). A population genetic analysis of the nematode strongyloides stercoralis in asia shows that human infection is not a zoonosis from dogs. PNAS, 122(29), e2424630122. (www)

  @article{ , abstract = {Gut nematode worms are important parasites of people and other animals. The parasitic nematode Strongyloides stercoralis infects an estimated 600 million people worldwide and is one of the soil-transmitted helminthiases, a WHO-defined neglected tropical disease. It has long been suggested that human S. stercoralis infection may be a zoonosis from dogs. We investigated this by whole genome sequence analysis of S. stercoralis from sympatric human and dog populations in Asia. We find that human- and dog-derived S. stercoralis have genetically distinct nuclear genomes, but we also find evidence of rare cross-infection. Analysis of the S. stercoralis mitochondrial genome reveals evidence of historical introgression between human- and dog-derived parasites. Based on these data, we suggest that S. stercoralis was originally a parasite of canids, that began to infect humans when people domesticated dogs, since when human- and dog-derived parasites have differentiated, but have not become separate species.}, archive = {J_PNAS}, author = {Liu, Yuchen and Sarker, A. H. M. Raihan and Sripa, Banchob and Tangkawattana, Sirikachorn and Khieu, Virak and Nevin, William and Paterson, Steve and Viney, Mark}, doi = {10.1073/pnas.2424630122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2424630122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A population genetic analysis of the nematode strongyloides stercoralis in asia shows that human infection is not a zoonosis from dogs}, volume = {122}, year = {2025}, }
• (2025). Synergy between membrane topography and domains to control signaling protein localization in mast cells facilitates their activation. PNAS, 122(29), e2424427122. (www)

  @article{ , abstract = {Similar to T cells and B cells, mast cell surfaces are dominated by microvilli, and like these other immune cells we showed with microvillar cartography (MVC) that key signaling proteins for RBL mast cells localize to these topographical features. Although stabilization of ordered lipid nanodomains around antigen-crosslinked IgE-FcεRI is known to facilitate necessary coupling with Lyn tyrosine kinase to initiate transmembrane signaling in these mast cells, the relationship of ordered-lipid nanodomains to membrane topography had not been determined. With nanoscale resolution provided by MVC, standard error of the mean (SEM), and colocalization probability (CP) analysis, we found that FcεRI and Lyn kinase are positioned primarily on the microvilli of resting mast cells in separate nano-assemblies. Upon antigen-activation, FcεRI and Lyn merge into overlapping populations together with the LAT scaffold protein, accompanied by merger of microvilli into ridge-like ruffles. With selective lipid probes, we further found that ordered-lipid nanodomains preferentially occupy microvillar membranes, contrasting with localization of disordered lipids to flatter regions. With this proximity of signaling proteins and ordered lipid nanodomains in microvilli, the mast cells are poised to respond sensitively and efficiently to antigen but only in the presence of this stimulus. Use of a short chain ceramide to disrupt ordered-lipid regions of the plasma membrane and evaluation with MVC, CP, and flow cytometry provided strong evidence that the microvillar selective localization of signaling proteins and membrane environments is facilitated by the interplay between ordered-lipid nanodomains and actin attachment proteins, ERM (ezrin, radixin, moesin), and cofilin.}, archive = {J_PNAS}, author = {Ghosh, Shirsendu and Wagenknecht-Wiesner, Alice and Desai, Shriya and Vyphuis, Jada and Ramos, Mariena Silvestry and Grazul, John L. and Baird, Barbara A.}, doi = {10.1073/pnas.2424427122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2424427122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synergy between membrane topography and domains to control signaling protein localization in mast cells facilitates their activation}, volume = {122}, year = {2025}, }
• (2025). Inactivation of PI3K-c2α deregulates cell death pathways and sensitizes to endotoxic shock. PNAS, 122(29), e2423358122. (www)

  @article{ , abstract = {The organismal roles of the class II PI3K isoform PI3K-C2α remain poorly understood. Recent studies have found PI3K-C2α to promote arterial thrombosis and breast cancer metastasis, generating interest in this kinase as a drug target, with small molecule PI3K-C2α inhibitors now available. However, the consequences of systemic PI3K-C2α inactivation in the nondiseased, postnatal state are largely unknown. Here, we show that induction of genetic PI3K-C2α inactivation in adult mice is well tolerated, without adverse effects on normal physiology. Surprisingly, however, mice with inactive PI3K-C2α display strong sensitization to challenge with bacterial lipopolysaccharide (LPS), a model of endotoxic shock. This sensitization is recapitulated by vascular endothelial-specific deletion of PI3K-C2α. Furthermore, sensitization to LPS can be fully rescued by disabling extrinsic induction of cell death by combined caspase-8- and RIPK3 deficiency. These observations validate the tolerability of systemic PI3K-C2α inhibition in principle but reveal an unexpected role for PI3K-C2α in the regulation of extrinsic cell death pathways.}, archive = {J_PNAS}, author = {Posor, York and Conduit, Sarah E. and Pearce, Wayne and Morelli, Daniele and Constantinou, Georgia and Whitehead, Maria and Sebire, Neil J. and Scudamore, Cheryl L. and Peltzer, Nieves and Walczak, Henning and Vanhaesebroeck, Bart}, doi = {10.1073/pnas.2423358122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2423358122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inactivation of PI3K-c2α deregulates cell death pathways and sensitizes to endotoxic shock}, volume = {122}, year = {2025}, }
• (2025). Complementary genetic and epigenetic changes facilitate rapid adaptation to multiple global change stressors. PNAS, 122(29), e2422782122. (www)

  @article{ , abstract = {To persist under unprecedented rates of global change, populations can adapt or acclimate. However, how these resilience mechanisms interact, particularly the role of epigenetic variation in long-term adaptation, is unknown. To address this gap, we experimentally evolved the foundational marine copepod Acartia tonsa for 25 generations under ocean acidification, warming, and their combination and then measured epigenomic, genomic, and transcriptomic responses. We observed clear and consistent epigenomic and genomic divergence between treatments, with epigenomic divergence concentrated in genes related to stress response and the regulation of transposable elements. However, epigenetic and genetic changes were inversely related and occurred in different regions of the genome; levels of genetic differentiation (F ST ) were up to 2.5× higher in regions where methylation did not differ between treatments compared to regions with significant methylation changes. This negative relationship between epigenetic and genetic divergence could be driven by local inhibition of one another or distinct functional targets of selection. Finally, epigenetic divergence was positively, though weakly, associated with gene expression divergence, suggesting that epigenetic changes may facilitate phenotypic change. Taken together, these results suggest that unique, complementary genetic and epigenetic mechanisms promote resilience to global change.}, archive = {J_PNAS}, author = {Brennan, Reid S. and deMayo, James A. and Finiguerra, Michael and Baumann, Hannes and Dam, Hans G. and Pespeni, Melissa H.}, doi = {10.1073/pnas.2422782122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2422782122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Complementary genetic and epigenetic changes facilitate rapid adaptation to multiple global change stressors}, volume = {122}, year = {2025}, }
• (2025). Dynamic neuroplasticity of language networks: The intersection of bilingualism and epilepsy. PNAS, 122(29), e2422742122. (www)

  @article{ , abstract = {Are bilingual language networks flexible enough to dynamically adapt to neurological insult? We examined language lateralization in 24 bilingual and 46 monolingual adults with temporal lobe epilepsy using functional MRI. In a group of primarily early sequential bilingual patients, the first acquired language (L1) showed more bilateral lateralization than in monolingual patients, with no effect of seizure onset laterality. In contrast, the second-acquired language (L2) was more bilateral in the presence of left hemisphere epilepsy and more left-lateralized in right hemisphere epilepsy. Most notably, in left hemisphere epilepsy, seizure onset closer to L2 acquisition was associated with more right-lateralized L2 representation. These findings suggest a compensatory process in which L2 networks strengthen in the hemisphere opposite the seizure focus, potentially reflecting neural adaptation in early bilingualism. Conversely, L1 appears to have less dynamic reorganization in response to neurological insult. Together, these findings highlight the importance of timing in both language experience and neurological stress in shaping language network organization. They support the view that the bilingual brain is not simply the sum of two monolingual systems, but a dynamic and unique system marked by high interindividual variability, in which divergence between languages may emerge under certain experience- and context-dependent conditions.}, archive = {J_PNAS}, author = {Stasenko, Alena and Kaestner, Erik and Schadler, Adam J. and Reyes, Anny and Urbanic, Clare and Helm, Jonathan L. and Saldana, Daniel and Carollo-Duprey, Giselle and Połczyńska, Monika and Benjamin, Christopher and Sepeta, Leigh N. and Gollan, Tamar H. and Cavanagh, Lucia and McDonald, Carrie R.}, doi = {10.1073/pnas.2422742122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2422742122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic neuroplasticity of language networks: The intersection of bilingualism and epilepsy}, volume = {122}, year = {2025}, }
• (2025). Mutualisms within light microhabitats are associated with sensory convergence in a mimetic butterfly community. PNAS, 122(29), e2422397122. (www)

  @article{ , abstract = {Niche partitioning within variable habitats can expose species to distinct sensory information. Vision is the primary sensory modality used by many animals to interact with their habitat. However, the role of terrestrial light environment properties in shaping species assemblages and visual system evolution is not fully understood. By studying a diverse, sympatric community of mimetic butterflies, we demonstrate that forest architecture creates a mosaic of light microhabitats that drive adaptive sensory convergence and divergence in both peripheral and central sensory systems. Our results show that across the visual system, predictable patterns of evolution characterize how species adapt to the availability of sensory information within their preferred light microhabitat. Our study provides an example of how visual systems consistently respond to their external sensory world, and illustrates the wide-reaching consequences of interspecific mutualisms, such as Müllerian mimicry, on organismal evolution.}, archive = {J_PNAS}, author = {Wainwright, J. Benito and Loupasaki, Theodora and Ramírez, Francisco and Penry-Williams, Iestyn L. and England, Sam J. and Barker, Annalie and Meier, Joana I. and How, Martin J. and Roberts, Nicholas W. and Troscianko, Jolyon and Montgomery, Stephen H.}, doi = {10.1073/pnas.2422397122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2422397122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mutualisms within light microhabitats are associated with sensory convergence in a mimetic butterfly community}, volume = {122}, year = {2025}, }
• (2025). De novo design of a fusion protein tool for GPCR research. PNAS, 122(29), e2422360122. (www)

  @article{ , abstract = {G protein–coupled receptors (GPCRs) play pivotal roles in cellular signaling and represent prominent drug targets. Structural elucidation of GPCRs is crucial for drug discovery efforts. However, structural studies of GPCRs remain challenging, particularly for inactive-state structures, which often require extensive protein engineering. Here, we present a de novo design strategy termed “click fusion” for generating fusion proteins to facilitate GPCR structural studies. Our method involves the rational design of structurally stable protein domains rigidly linked to GPCRs. The resulting fusion protein enhances the thermostability of the target GPCR and aids in determining GPCR structures via cryoelectron microscopy (cryo-EM). We further demonstrate that the designed fusion protein can be transferred among structurally similar GPCRs with minor adjustments to the linker region. Our study introduces a promising approach for facilitating GPCR structural studies and advancing drug discovery efforts.}, archive = {J_PNAS}, author = {Gao, Kaixuan and Zhang, Xin and Nie, Jia and Meng, Hengyu and Zhang, Weishe and Tian, Boxue and Liu, Xiangyu}, doi = {10.1073/pnas.2422360122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2422360122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {De novo design of a fusion protein tool for GPCR research}, volume = {122}, year = {2025}, }
• (2025). Energy expenditure and obesity across the economic spectrum. PNAS, 122(29), e2420902122. (www)

  @article{ , abstract = {Global economic development has been associated with an increased prevalence of obesity and related health problems. Increased caloric intake and reduced energy expenditure are both cited as development-related contributors to the obesity crisis, but their relative importance remains unresolved. Here, we examine energy expenditure and two measures of obesity (body fat percentage and body mass index, BMI) for 4,213 adults from 34 populations across six continents and a wide range of lifestyles and economies, including hunter-gatherer, pastoralist, farming, and industrialized populations. Economic development was positively associated with greater body mass, BMI, and body fat, but also with greater total, basal, and activity energy expenditure. Body size–adjusted total and basal energy expenditures both decreased approximately 6 to 11% with increasing economic development, but were highly variable among populations and did not correspond closely with lifestyle. Body size–adjusted total energy expenditure was negatively, but weakly, associated with measures of obesity, accounting for roughly one-tenth of the elevated body fat percentage and BMI associated with economic development. In contrast, estimated energy intake was greater in economically developed populations, and in populations with available data (n = 25), the percentage of ultraprocessed food in the diet was associated with body fat percentage, suggesting that dietary intake plays a far greater role than reduced energy expenditure in obesity related to economic development.}, archive = {J_PNAS}, author = {McGrosky, Amanda and Luke, Amy and Arab, Leonore and Bedu-Addo, Kweku and Bonomi, Alberto G. and Bovet, Pascal and Brage, Soren and Buchowski, Maciej S. and Butte, Nancy and Camps, Stefan G. and Casper, Regina and Cummings, Daniel K. and Krupa Das, Sai and Deb, Sanjoy and Dugas, Lara R. and Ekelund, Ulf and Forrester, Terrence and Fudge, Barry W. and Gillingham, Melanie and Goris, Annelies H. and Gurven, Michael and Hambly, Catherine and Joosen, Annemiek and Katzmarzyk, Peter T. and Kempen, Kitty P. and Kraus, William E. and Kriengsinyos, Wantanee and Kuriyan, Rebecca and Kushner, Robert F. and Lambert, Estelle V. and Larsson, Christel L. and Leonard, William R. and Lessan, Nader and Löf, Marie and Martin, Corby K. and Medin, Anine C. and Neuhouser, Marian L. and Pietilainen, Kirsi H. and Plasqui, Guy and Prentice, Ross L. and Racette, Susan B. and Raichlen, David A. and Ravussin, Eric and Redman, Leanne and Reynolds, Rebecca M. and Rimm, Eric B. and Roberts, Susan and Rosinger, Asher Y. and Samuels, Mary H. and Sinha, Srishti and Snodgrass, J. Josh and Stice, Eric and Uauy, Ricardo and Urlacher, Samuel S. and Verbunt, Jeanine A. and Wolfe, Bruce and Wood, Brian and Zhang, Xueying and Murphy-Alford, Alexia J. and Loechl, Cornelia J. and Rood, Jennifer and Sagayama, Hiroyuki and Schoeller, Dale A. and Westerterp, Klaas R. and Wong, William W. and Yamada, Yosuke and Speakman, John R. and Pontzer, Herman and null, null and Andersen, Lene F. and Bandini, Linda and Branth, Stephan and De Bruin, Niels C. and Cooper, Richard and Dutman, Alice E. and Ebbeling, Cara B. and Fogelholm, Mikael and Harris, Tamara and Heijligenberg, Rik and Jorgensen, Hans U. and Ludwig, David S. and Matsiko, Eric and McCloskey, Margaret and Meijer, Gerwin A. and Pannemans, Daphne L. and Philippaerts, Renaat M. and Plange-Rhule, Jacob and Rothenberg, Elisabet M. and Schulz, Sabine and Stunkard, Albert and Subar, Amy and Tanskanen, Minna and Van den Berg-Emons, Rita and van Etten, Ludo M. and Van Gemert, Wim G. and Velthuis-te Wierik, Erica J. and Verboeket-van de Venne, Wilhelmine W. and Willett, Walter C.}, doi = {10.1073/pnas.2420902122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2420902122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Energy expenditure and obesity across the economic spectrum}, volume = {122}, year = {2025}, }
• (2025). ADPact: A versatile sensor for ADP-F-actin. PNAS, 122(29), e2420467122. (www)

  @article{ , abstract = {The dynamic organization of the actin cytoskeleton, crucial for numerous cellular processes, is intricately regulated by the nucleotide state of actin filaments (F-actin). Visualization tools for specifically detecting ADP-bound F-actin, however, remain limited. Here, we introduce ADPact, a 20-amino-acid peptide that selectively binds to ADP-F-actin. ADPact allows for the precise visualization of ADP-F-actin structures both in vitro and in eukaryotic cells, particularly under energy stress conditions where ADP-/ATP-actin ratio increases. Importantly, ADPact and its fluorescent fusion variant, ADPact-GFP, do not disrupt actin dynamics, ensuring accurate monitoring of cytoskeletal reorganization. Our findings provide a powerful tool for studying actin dynamics and offer fresh insights into the regulation of the cytoskeleton under physiological and pathological conditions.}, archive = {J_PNAS}, author = {Ma, Qianqian and Han, Xiao and Zhu, Kexin and Ng, Cai Xin and He, Danxia and Miao, Yansong}, doi = {10.1073/pnas.2420467122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2420467122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ADPact: A versatile sensor for ADP-F-actin}, volume = {122}, year = {2025}, }
• (2025). Resource-use plasticity governs the causal relationship between traits and community structure in model microbial communities. PNAS, 122(29), e2419275122. (www)

  @article{ , abstract = {Resolving the relationship between species’ traits and their relative abundance is a central challenge in ecology. Current hypotheses assume relative abundances either result from or are independent of traits. However, despite some success, these hypotheses do not integrate the feedback interactions between traits and abundances to predictions of community structure such as relative abundance distributions and trait–abundance relationships. Here, we study how plasticity in resource-use traits governs the causal relationship between traits and relative abundances. We adopt a consumer–resource model that incorporates resource-use plasticity that operates to optimize organism growth, underpinned by investment constraints in physiological machinery for the acquisition of resources. We first show how plasticity in a single species in a community allows all other nonplastic species to coexist, a case of facilitation emerging from competitive interactions. Here, resource-use optimization by the plastic species results in a trade-off between minimizing its similarity with competitors while maximizing its resource-use efficiency in its environment. We apply this trade-off to predict trait–abundance relationships and reveal, unexpectedly, that initial traits are better predictors of equilibrium abundances than equilibrium traits. We then demonstrate that the rate of plasticity controls the coupling strength between trait and abundance dynamics, predicting species’ equilibrium relative abundances. This result highlights the importance of transient dynamics in driving species sorting despite the emergence of “ecological equivalence” at equilibrium. Thus, our study explains the unexpected co-occurrence at equilibrium of emergent neutrality and strong trait–abundance relationships. We propose trait–abundance feedback as an ecoevolutionary mechanism linking community structure and assembly, highlighting trait plasticity’s role in driving community dynamics.}, archive = {J_PNAS}, author = {McGuinness, Brendon and Weber, Stephanie C. and Guichard, Frederic}, doi = {10.1073/pnas.2419275122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2419275122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Resource-use plasticity governs the causal relationship between traits and community structure in model microbial communities}, volume = {122}, year = {2025}, }
• (2025). Dynamic forces drive cell and organ morphology changes during embryonic development. PNAS, 122(29), e2418111122. (www)

  @article{ , abstract = {Cells, tissues, and organs must change shape in precise ways during embryonic development to execute their functions. Multiple mechanisms including biochemical signaling pathways and biophysical forces help drive these morphology changes, but it has been difficult to tease apart their contributions, especially from tissue-scale dynamic forces that are typically ignored. We use a combination of mathematical models and in vivo experiments to study a simple organ in the zebrafish embryo called Kupffer’s vesicle (KV). Modeling indicates that dynamic forces generated by tissue movements in the embryo produce shape changes in KV that are observed during development. Laser ablations in the zebrafish embryo that alter these forces result in altered organ shapes matching model predictions. These results demonstrate that dynamic forces sculpt cell and organ shape during embryo development.}, archive = {J_PNAS}, author = {Manna, Raj Kumar and Retzlaff, Emma M. and Hinman, Anna Maria and Lan, Yiling and Abdel-Razek, Osama and Bates, Mike and Hehnly, Heidi and Amack, Jeffrey D. and Manning, M. Lisa}, doi = {10.1073/pnas.2418111122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2418111122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic forces drive cell and organ morphology changes during embryonic development}, volume = {122}, year = {2025}, }
• (2025). Different folding mechanisms in prion proteins from mammals with different disease susceptibility observed at the single-molecule level. PNAS, 122(29), e2416191122. (www)

  @article{ , abstract = {Misfolding of the protein PrP causes prion diseases in mammals. Disease susceptibility varies widely among species, despite PrP sequences differing by only a few amino acids. How these differences alter PrP folding and misfolding remains unclear. We compared the folding dynamics of single PrP molecules from three species with different disease susceptibility: dogs (immune), hamsters (susceptible), and bank voles (extremely susceptible). Measurements with optical tweezers revealed important differences between the folding cooperativity, pathways, energy barriers, and kinetics of these proteins. In contrast to the two-state folding of hamster PrP, dog PrP always folded through multiple intermediates. However, both featured rapid native folding, homogeneous energy barriers, and no readily observable misfolding. Bank vole PrP also folded via intermediates, but more slowly and via inhomogeneous barriers. Most notably, it formed several metastable misfolded states starting from the unfolded state. Analyzing the sequence of intermediates seen in pulling curves, we found significant differences in the folding pathways for dog and bank vole PrP, implying that sequence mutations altered energy barriers so as to redirect folding pathways. These results show that subtle differences in PrP sequence between species produce profound changes in folding behavior, providing insight into the factors underlying misfolding propensity.}, archive = {J_PNAS}, author = {Anand, Uttam and Patra, Shubhadeep and Sekar, Rohith Vedhthaanth and Garen, Craig R. and Woodside, Michael T.}, doi = {10.1073/pnas.2416191122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2416191122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Different folding mechanisms in prion proteins from mammals with different disease susceptibility observed at the single-molecule level}, volume = {122}, year = {2025}, }
• (2025). A versatile immunomodulated nanoCRISPR converter augments the susceptibility and visibility of tumors to the immune system. PNAS, 122(29), e2415100122. (www)

  @article{ , abstract = {Immune checkpoint blockade (ICB) has potential in alleviating cytotoxic T lymphocyte (CTL) exhaustion. However, resistance that impaired major histocompatibility complex class I (MHC-I) expression on tumors can be developed in many patients after ICB treatment, resulting in insufficient antigen presentation to CTLs. Herein, we rationally design a ver s atile and po w erful i mmunomodula t ed hierar ch ical nanoCRISPR converter (SWITCH) targeting PD-L1 and PCSK9 loci to convert the immune-resistance state of tumors with high PD-L1 and low MHC-I expression for augmenting the susceptibility and visibility of tumors to the immune system. SWITCH possesses enhanced blood circulation and tumor-targeting capacity through PEGylation, acid-triggered pH low insertion peptides (pHLIPs), and interaction of hyaluronan with CD44 receptors. With the assistance of hyaluronidase and preternatural oxidative stress within tumor cells, SWITCH undergoes enzyme-responsive disassembly, charge reversal, rapid lysosomal escape, and efficient disruption of PD-L1 and PCSK9 orderly. This dual-action mechanism simultaneously blocks PD-1/PD-L1 immunosuppression while restoring MHC-I-mediated antigen presentation, resulting in enhanced the susceptibility and visibility of tumors to the immune system. Our results demonstrate SWITCH's remarkable efficacy in suppressing primary, contralateral, and recurrent tumor growth. Taken together, our study provides an encouraging strategy for relieving tumor immune resistance and further potentiating the efficacy of ICB.}, archive = {J_PNAS}, author = {Li, Yingjie and Zhou, Shiyao and Fu, Wangxian and Li, Xinchao and Chen, Tao and Le, Hao and Xu, Yangsong and Tang, Yuting and Mi, Peng and Gao, Huile and Wu, Qinjie and Gong, Changyang}, doi = {10.1073/pnas.2415100122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2415100122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A versatile immunomodulated nanoCRISPR converter augments the susceptibility and visibility of tumors to the immune system}, volume = {122}, year = {2025}, }
• (2025). Robust single-trial decoding of physical self-motion from hemodynamic signals in the brain measured by functional ultrasound imaging. PNAS, 122(29), e2414354122. (www)

  @article{ , abstract = {Physical self-motion frequently happens in daily life, during which our vestibular system is critical in various important functions including balance and visual stability maintenance, postural and motor control, locomotion, spatial perception, and path integration-based navigation. Conventional noninvasive methods for studying vestibular functions include functional MRI (fMRI) that conveniently measures brain-wide signals; however, subjects are required to be physically restricted in the scanner. In such cases, caloric or galvanic vestibular stimulation is applied to stimulate peripheral vestibular organs, suffering a loss of precise stimulation of peripheral vestibular organs as during physical motion conditions. In this study, we adopted functional ultrasound (fUS) imaging, a newly emerging minimally invasive technique with high spatiotemporal resolution, to measure vestibular related signals in primates under passive, physical self-motion conditions that selectively activate vestibular organs. We found that robust fUS signals were evoked in brain-wide regions. While many areas overlapped with those previously reported by fMRI or electrophysiology, significant activations were also seen in areas that were not clearly identified previously including area 5, 1-2, M1, V3A, and 7 m. Importantly, using a linear discriminant analysis algorithm, physical self-motion information, including both translation directions, and translation-vs.-rotation, could be reliably decoded from fUS signals on a single-trial basis. In addition to vestibular-related activity, many areas also exhibited visual-motion response, indicating possible multisensory interactions. Our findings suggest that fUS imaging holds a promising tool for studying vestibular functions in tasks under physical self-motion conditions, as well as interactions with visual or motor systems.}, archive = {J_PNAS}, author = {Liu, Bingyu and Luo, Qingyang and Liang, Zhifeng and He, Hua and Gu, Yong}, doi = {10.1073/pnas.2414354122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2414354122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Robust single-trial decoding of physical self-motion from hemodynamic signals in the brain measured by functional ultrasound imaging}, volume = {122}, year = {2025}, }
• (2025). A genetically defined pontine nucleus essential for ingestion in mice. PNAS, 122(29), e2411174122. (www)

  @article{ , abstract = {The first phase of feeding consists in the procurement of solid foods from the environment by biting, and their preparation for swallowing by chewing. These actions require the precise coordination of tens of orofacial muscles for the jaw and tongue. The seat for this motor patterning is known to reside in the reticular formation, a complex and poorly mapped region of the hindbrain, but the neuron groups involved are still elusive. Here, we characterize a group of excitatory reticular interneurons located in the supratrigeminal area that express the homeodomain transcription factor Phox2b . This nucleus—Sup5 Phox2b —is premotor to both jaw-closing and jaw-opening motoneurons and receives direct input from cranial sensory afferents, motor cortex, and satiation related nuclei. Its activity differentially tracks lapping, biting, and chewing movements, suggesting its involvement in the elaboration of distinct orofacial motor patterns in vivo. Acute global activation or inhibition of Sup5 Phox2b by optogenetics interrupt volitional feeding sequences. Thus, Sup5 Phox2b is an obligatory subcortical node, topologically and genetically defined, in the neural circuits that control the oral phase of feeding in mice.}, archive = {J_PNAS}, author = {Sungeelee, Selvee and Mailhes-Hamon, Caroline and Chettouh, Zoubida and Bokiniec, Phillip and Eymael, Annaliese and McMullan, Simon and Léna, Clément and Dempsey, Bowen and Brunet, Jean-François}, doi = {10.1073/pnas.2411174122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2411174122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A genetically defined pontine nucleus essential for ingestion in mice}, volume = {122}, year = {2025}, }
• (2025). Systemic delivery of biotherapeutic RNA to the myocardium transiently modulates cardiac contractility in vivo. PNAS, 122(29), e2409266122. (www)

  @article{ , abstract = {Lipid nanoparticles (LNP) represent a versatile platform for improving delivery of therapeutic nucleic acids. Yet, delivery to the myocardium remains a formidable challenge due to local barriers in the heart and systemic hindrances. In particular, plasma apolipoprotein E (apoE) directs LNP to the liver, limiting potential extrahepatic delivery. Here, we report a cardiotropic LNP (cLNP), which within 30 min post–intravenous injection accumulates in the heart of ApoE knockout ( Apoe −/− ) mice. The findings were confirmed for Apoe −/− rats and for wild-type mice after siRNA-mediated plasma apoE ablation. To test cardiac-specific functional effects as a proof of concept, we used cLNP loaded with siRNA to ATP2A2, encoding the sarcoplasmic-endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2A). This cardiomyocyte-specific protein is a key regulator of contractility and relaxation. Intravenous administration of cLNP/siRNA-ATP2A2 in Apoe −/− mice led to near-complete ablation of SERCA2A in the myocardium and a potent modulation of contractility of the cardiomyocytes obtained from these mice. In summary, cardiotropic nanocarriers may allow the delivery and effect of RNA and other agents to the myocardium. Achieving this unmet medical need promises new types of treatment for heart diseases, which remains the leading cause of death worldwide.}, archive = {J_PNAS}, author = {Shuvaev, Vladimir V. and Tam, Ying K. and Lee, Benjamin W. and Myerson, Jacob W. and Herbst, Alan and Kiseleva, Raisa Yu. and Glassman, Patrick M. and Parhiz, Hamideh and Alameh, Mohamad-Gabriel and Pardi, Norbert and Muramatsu, Hiromi and Shuvaeva, Tea I. and Arguiri, Evguenia and Marcos-Contreras, Oscar A. and Hood, Elizabeth D. and Brysgel, Taylor V. and Nong, Jia and Papp, Tyler E. and Eaton, Deborah M. and Riley, Rachel and Palanki, Rohan and Musunuru, Kiran and Brenner, Jacob S. and Mitchell, Michael J. and Ferrari, Victor A. and Mui, Barbara L. and Semple, Sean C. and Weppler, Sherry A. and Atluri, Pavan and Margulies, Kenneth B. and Weissman, Drew and Muzykantov, Vladimir R.}, doi = {10.1073/pnas.2409266122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2409266122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Systemic delivery of biotherapeutic RNA to the myocardium transiently modulates cardiac contractility in vivo}, volume = {122}, year = {2025}, }
• (2025). How to design better incentives for carbon capture and storage in the united states. PNAS, 122(29), e2404677122. (www)

  @article{ , archive = {J_PNAS}, author = {Olmstead, Sheila M. and Leibowicz, Benjamin D. and Mason, Charles F. and Waxman, Andrew R. and Grubert, Emily and Huber-Rodriguez, HR and Stemmler, Joseph}, doi = {10.1073/pnas.2404677122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2404677122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How to design better incentives for carbon capture and storage in the united states}, volume = {122}, year = {2025}, }
• (2025). Indigenous critiques and recommendations for reclaiming nature-based solutions. PNAS, 122(29), e2315917121. (www)

  @article{ , abstract = {Indigenous peoples have long histories and diverse contemporary practices of caring for and enhancing biodiversity at different scales, in rural and urban contexts. As has been researched and documented by the Convention on Biological Diversity and others, Indigenous peoples globally only constitute 5% of the world’s population and control and care for just 20% of the Earth’s surface yet protect nearly 80% of the world’s remaining biodiversity. Indigenous peoples have forms of biodiversity conservation that could be characterized as “nature-based solutions” (NbS), or would they be culture-based solutions? Given the extraordinary diversity of Indigenous peoples globally, there will never be a “one size fits all” solution. Yet there are general principles that have been articulated in the United Nations Declaration on the Rights of Indigenous Peoples that articulate global concepts of Indigenous Knowledge Systems (IKS) and Traditional Ecological Knowledge (TEK). IKS, TEK, and Native ways of knowing and caring for biodiversity can find both resonance and conflict with what is currently being called NbS. This article articulates Indigenous concerns and critiques of the conceptual and ontological framework of NbS, demonstrating that Indigenous Peoples’ knowledge systems include a similar framework but extend it to include a distinctly biocultural and relational orientation that does not make an artificial division between nature and culture. Different Indigenous perspectives and approaches to sustainability will be highlighted, including two case stories. We conclude with recommendations for respectful, just, decolonial, and transparent ways to explore greater resonance between NbS and Indigenous peoples’ rights.}, archive = {J_PNAS}, author = {Nelson, Melissa K. and Reed, Graeme}, doi = {10.1073/pnas.2315917121}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2315917121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Indigenous critiques and recommendations for reclaiming nature-based solutions}, volume = {122}, year = {2025}, }
• (2025). Empowering cities globally: Four levers for transformative urban adaptation with nature-based solutions. PNAS, 122(29), e2315912121. (www)

  @article{ , abstract = {The latest report of the Intergovernmental Panel on Climate Change showed that upcoming decades are likely to be accompanied with an increase in climate impacts in urban areas, thereby stressing the need for empowering cities to help them address the challenges ahead by closing the urban adaptation gap. The lock-in systems in which cities are often trapped create resistance to change and leads to missed opportunities to cocreate better futures. Putting nature at the center of urban adaptation agenda is a promising vision that nature-based solutions can help realize if city leaders are adequately supported in accessing the knowledge and resources they need to take action. Despite their proven potential, important barriers to the planning, implementation, and management of nature-based solutions (NbS) for urban climate adaptation persist and need to be urgently addressed. We highlight key barriers related to knowledge gaps and dissemination, policy incentives, and financial autonomy faced by city leaders trying to integrate NbS into policy and planning. In this perspective, we propose four levers of transformative adaptation which build on examples from Europe, the United States, Africa, and Latin America and which have proven successful in supporting cities adopting nature-based adaptation actions, including to 1) produce, assess and share knowledge; 2) adopt incentive-based policies and regulations; 3) facilitate access to multiple sources of funding; and 4) create reflexive monitoring mechanisms. If these steps are taken with the goal of addressing vulnerabilities on the ground, they can unleash the potential of NbS to engage on a path of transformative adaptation.}, archive = {J_PNAS}, author = {Diep, Loan and McPhearson, Timon}, doi = {10.1073/pnas.2315912121}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2315912121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Empowering cities globally: Four levers for transformative urban adaptation with nature-based solutions}, volume = {122}, year = {2025}, }
• (2025). Inter- and transdisciplinary knowledge is critical for nature-based solutions to contribute to just urban transformations. PNAS, 122(29), e2315911121. (www)

  @article{ , abstract = {Nature-based solutions (NBS) are used to transform existing unsustainable and undesirable path dependencies in cities. For NBS to contribute to just urban transformations, a stronger inter- and transdisciplinary knowledge base is needed. This knowledge base is essential to engage with six complex yet crucial questions about NBS, including “for what?,” “which nature?,” “where?,” “how?,” “when,” and “for whom?.” To address these questions, we identify two critical opportunities to advance the knowledge of NBS. First, we argue for solidifying interdisciplinary approaches to examine how NBS can be designed, planned, and implemented for multifunctionality. Second, we argue that researchers need to work transdisciplinarily with diverse stakeholders to ensure the design, siting, and planning of NBS are appropriate to the context. In both critical opportunities, justice should be a core guiding principle from the beginning of planning the NBS, starting with the foundational understanding that NBS are not inherently just or unjust. Instead, their value depends on a holistic examination of the context in which they operate and the institutional logic that guides their planning. To center justice in the inter- and transdisciplinary research and practice of NBS, a knowledge shift from epistemological injustice to epistemological inclusivity is a critical way forward.}, archive = {J_PNAS}, author = {Frantzeskaki, Niki and Wijsman, Katinka and Kabisch, Nadja and McPhearson, Timon}, doi = {10.1073/pnas.2315911121}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2315911121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inter- and transdisciplinary knowledge is critical for nature-based solutions to contribute to just urban transformations}, volume = {122}, year = {2025}, }
• (2025). Global synthesis and regional insights for mainstreaming urban nature-based solutions. PNAS, 122(29), e2315910121. (www)

  @article{ , abstract = {Nature-based solutions (NbS) have emerged as a key strategy for sustainably addressing multiple urban challenges, with rapidly increasing knowledge production requiring synthesis to better understand whether and how NbS work in different social, ecological, economic, or governance contexts. Insights in this Perspective are drawn from a thematic review of 61 NbS review articles supported by an expert assessment of NbS knowledge in seven global regions to examine key challenges, fill gaps in Global South assessment, and provide insights for scaling up NbS for impact in cities. Eight NbS challenges emerged from our review of NbS reviews including conceptual, thematic, geographic, ecological, inclusivity, health, governance, and systems challenges. An additional expert assessment reviewing literature and cases in seven global regions further revealed the following: 1) Local context-based ecological knowledge is essential for NbS success; 2) Improved technical knowledge is required for planning and designing NbS; 3) NbS need to be included in all levels of planning and governance; 4) Putting justice and equity at the center of urban NbS approaches is critical, and 5) Inclusive and participatory governance processes will be key to long-term success of NbS. We synthesized findings from the NbS review results and regional expert assessments to offer four critical pathways for scaling up NbS: 1) foster new NbS research, technological innovation, and learning, 2) build a global NbS alliance for sharing knowledge, 3) ensure a systems approach to NbS planning and implementation, and 4) increase financing and political will for diverse NbS implementation.}, archive = {J_PNAS}, author = {McPhearson, Timon and Frantzeskaki, Niki and Ossola, Alessandro and Diep, Loan and Anderson, Pippin M. L. and Blatch, Timothy and Collier, Marcus J. and Cook, Elizabeth M. and Culwick Fatti, Christina and Grabowski, Zbigniew J. and Grimm, Nancy B. and Haase, Dagmar and Herreros-Cantis, Pablo and Kavonic, Jessica and Lin, Brenda B. and Lopez Meneses, Duván H. and Matsler, A. Marissa and Moglia, Magnus and Morató, Jordi and O’Farrell, Patrick and Roy, Parama and Singh, Chandni and Wang, Jing and Zhou, Weiqi}, doi = {10.1073/pnas.2315910121}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2315910121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global synthesis and regional insights for mainstreaming urban nature-based solutions}, volume = {122}, year = {2025}, }
• (2025). Nature-based solutions for urban sustainability. PNAS, 122(29), e2315909122. (www)

  @article{ , archive = {J_PNAS}, author = {Cook, Elizabeth M. and Kim, Yeowon and Grimm, Nancy B. and McPhearson, Timon and Anderson, Pippin and Bulkeley, Harriet and Collier, Marcus J. and Diep, Loan and Morató, Jordi and Zhou, Weiqi}, doi = {10.1073/pnas.2315909122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {29}, pages = {e2315909122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nature-based solutions for urban sustainability}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(28), eiti2825122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti2825122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {eiti2825122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for kim et al., signaling axis involving hedgehog, notch, and scl promotes the embryonic endothelial-to-hematopoietic transition. PNAS, 122(28), e2516068122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2516068122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2516068122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for kim et al., signaling axis involving hedgehog, notch, and scl promotes the embryonic endothelial-to-hematopoietic transition}, volume = {122}, year = {2025}, }
• (2025). Correction for zhu et al., population size interacts with reproductive longevity to shape the germline mutation rate. PNAS, 122(28), e2515950122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2515950122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2515950122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for zhu et al., population size interacts with reproductive longevity to shape the germline mutation rate}, volume = {122}, year = {2025}, }
• (2025). Noncoding RNAs have a key role in butterfly speciation. what about other flora and fauna?. PNAS, 122(28), e2515930122. (www)

  @article{ , archive = {J_PNAS}, author = {Bolakhe, Saugat}, doi = {10.1073/pnas.2515930122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2515930122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Noncoding RNAs have a key role in butterfly speciation. what about other flora and fauna?}, volume = {122}, year = {2025}, }
• (2025). QnAs with janet b. pierrehumbert. PNAS, 122(28), e2515539122. (www)

  @article{ , archive = {J_PNAS}, author = {Ravindran, Sandeep}, doi = {10.1073/pnas.2515539122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2515539122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {QnAs with janet b. pierrehumbert}, volume = {122}, year = {2025}, }
• (2025). Political and biological reality checks. PNAS, 122(28), e2515272122. (www)

  @article{ , archive = {J_PNAS}, author = {Berenbaum, May R.}, doi = {10.1073/pnas.2515272122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2515272122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Political and biological reality checks}, volume = {122}, year = {2025}, }
• (2025). What you c is what you get. PNAS, 122(28), e2513611122. (www)

  @article{ , archive = {J_PNAS}, author = {Holland, Patrick L.}, doi = {10.1073/pnas.2513611122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2513611122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {What you c is what you get}, volume = {122}, year = {2025}, }
• (2025). Reply to dablander et al.: Identifying interventions that change intentions lays a valuable foundation for behavior change. PNAS, 122(28), e2513159122. (www)

  @article{ , archive = {J_PNAS}, author = {Sinclair, Alyssa H. and Cosme, Danielle and Lydic, Kirsten and Reinero, Diego A. and Mann, Michael E. and Falk, Emily B.}, doi = {10.1073/pnas.2513159122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2513159122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to dablander et al.: Identifying interventions that change intentions lays a valuable foundation for behavior change}, volume = {122}, year = {2025}, }
• (2025). Subterranean salamanders lean into mechanical sense following vision loss. PNAS, 122(28), e2512732122. (www)

  @article{ , archive = {J_PNAS}, author = {Hanken, James}, doi = {10.1073/pnas.2512732122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2512732122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Subterranean salamanders lean into mechanical sense following vision loss}, volume = {122}, year = {2025}, }
• (2025). Ancient forests help document the long-term impacts of climate change. PNAS, 122(28), e2512729122. (www)

  @article{ , archive = {J_PNAS}, author = {Anderson, David G.}, doi = {10.1073/pnas.2512729122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2512729122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ancient forests help document the long-term impacts of climate change}, volume = {122}, year = {2025}, }
• (2025). Expressing intentions is not climate action. PNAS, 122(28), e2512457122. (www)

  @article{ , archive = {J_PNAS}, author = {Dablander, Fabian and Lange, Florian and Brick, Cameron and Aron, Adam R.}, doi = {10.1073/pnas.2512457122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2512457122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Expressing intentions is not climate action}, volume = {122}, year = {2025}, }
• (2025). Reply to pang et al.: Generalizable ability to track beliefs could be the most parsimonious explanation. PNAS, 122(28), e2511485122. (www)

  @article{ , archive = {J_PNAS}, author = {Kosinski, Michal}, doi = {10.1073/pnas.2511485122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2511485122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to pang et al.: Generalizable ability to track beliefs could be the most parsimonious explanation}, volume = {122}, year = {2025}, }
• (2025). Noncanonical action of circadian clock genes controls winter diapause entry via the NuA4/TIP60 complex in harmonia axyridis. PNAS, 122(28), e2510550122. (www)

  @article{ , abstract = {To adapt to seasonal changes, many animals, particularly insects, enter a dormancy-like condition known as diapause, which is primarily accomplished by sensing photoperiodic signals. The circadian clock, which is driven by positive regulators Clock (CLK) and Cycle (CYC), and negative regulators Period and Timeless, is thought to mediate this response. However, it remains unclear whether diapause induction involves a canonical rhythmic mechanism or occurs independently of their traditional roles in timekeeping. Using the ladybug Harmonia axyridis as a model for short-day-induced winter diapause, we demonstrate that knockdown of Clk and cyc , but not per or tim , disrupted entry into reproductive diapause. This finding demonstrated that Clk-cyc regulates diapause independently of per and tim . We further show that the DNA methyltransferase 1-associated protein 1 (DMAP1)-mediated Nucleosome Acetyltransferase of H4 (NuA4)/TIP60 histone acetyltransferase complex impinges on diapause regulation by acting simultaneously as a downstream effector and a physical interactor of CLK-CYC. Application of the juvenile hormone (JH) receptor agonist methoprene effectively rescued the diapause phenotypes caused by Clk , cyc , and dmap1 knockdowns, highlighting the central role of the CLK-CYC-NuA4/TIP60 complex in JH production. Additionally, using a corpora allata (CA)-specific driver in Drosophila melanogaster , we demonstrate that this complex functions locally in the CA to mediate JH biosynthesis. Collectively, our findings identify a previously unrecognized pathway by which circadian clock proteins interact with an epigenetic regulator to specifically govern JH biosynthesis in a critical endocrine tissue, thereby regulating diapause entry independently of canonical circadian clock mechanisms.}, archive = {J_PNAS}, author = {Gao, Qiao and Dai, Yi-Fei and Zhao, Yu-Lian and Li, Xue and An, Hao-Min and King-Jones, Kirst and Wang, Jia-Lu and Wang, Xiao-Ping and Liu, Wen}, doi = {10.1073/pnas.2510550122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2510550122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Noncanonical action of circadian clock genes controls winter diapause entry via the NuA4/TIP60 complex in harmonia axyridis}, volume = {122}, year = {2025}, }
• (2025). Glycogen supports glycolytic plasticity in neurons. PNAS, 122(28), e2509003122. (www)

  @article{ , abstract = {Glycogen is the largest energy reserve in the brain, but the specific role of glycogen in supporting neuronal energy metabolism in vivo is not well understood. We established a system in Caenorhabditis elegans to dynamically probe glycolytic states in single cells of living animals via the use of the glycolytic sensor HYlight and determined that neurons can dynamically regulate glycolysis in response to activity or transient hypoxia. We performed an RNAi screen and identified that PYGL-1, an ortholog of the human glycogen phosphorylase, is required in neurons for glycolytic plasticity. We determined that neurons employ at least two mechanisms of glycolytic plasticity: glycogen-dependent glycolytic plasticity (GDGP) and glycogen-independent glycolytic plasticity. We uncover that GDGP is employed under conditions of mitochondrial dysfunction, such as transient hypoxia or in mutants for mitochondrial function. We find that the loss of GDGP impairs glycolytic plasticity and is associated with defects in synaptic vesicle recycling during hypoxia. Together, our study reveals that, in vivo, neurons can directly use glycogen as a fuel source to sustain glycolytic plasticity and synaptic function.}, archive = {J_PNAS}, author = {Singh, Milind and Wolfe, Aaron D. and Vishwanath, Anjali A. and Tsives, Anastasia and Gonzalez, Ian J. and Emerson, Sarah E. and Goodman, Richard and Colón-Ramos, Daniel}, doi = {10.1073/pnas.2509003122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2509003122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Glycogen supports glycolytic plasticity in neurons}, volume = {122}, year = {2025}, }
• (2025). Cell-to-cell translocation of florigen is inhibited by low ambient temperature through abscisic acid signaling in arabidopsis thaliana. PNAS, 122(28), e2507987122. (www)

  @article{ , abstract = {In Arabidopsis thaliana , the FLOWERING LOCUS T ( FT ) gene encodes florigen, a floral stimulus that integrates multiple environmental cues to optimize the timing of flowering, which is crucial for reproductive success. The FT protein is synthesized in the phloem companion cells of leaves but exerts its function in the shoot apical meristem (SAM) to initiate floral morphogenesis. While the environment-dependent regulation of FT transcription in leaves is well studied, the mechanisms underlying FT transport, particularly its cell-to-cell translocation within the SAM, remain poorly understood. In this study, we employed an in vivo bimolecular fluorescence complementation assay to elucidate the molecular mechanisms regulating FT intercellular translocation in the SAM. We demonstrate that low ambient temperature inhibits the cell-to-cell movement of FT in the SAM through abscisic acid signaling pathways, resulting in flowering delay. We further show that the permeability of plasmodesmata (PD) is involved in FT transport; in particular, CALLOSE SYNTHASE ( CalS ) 1 and CalS7 are induced at low temperature, leading to reduced permeability of PD and inhibition of symplastic FT translocation in the SAM. Collectively, our findings provide insights into the molecular mechanisms that regulate the intercellular translocation of FT in the SAM in response to environmental conditions and lead to a framework for the understanding of flowering.}, archive = {J_PNAS}, author = {Murata, Yusuke and Nagata, Kenji and Abe, Mitsutomo}, doi = {10.1073/pnas.2507987122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2507987122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cell-to-cell translocation of florigen is inhibited by low ambient temperature through abscisic acid signaling in arabidopsis thaliana}, volume = {122}, year = {2025}, }
• (2025). CDKN1B (p27/kip1) enhances drug-tolerant persister CTCs by restricting polyploidy following mitotic inhibitors. PNAS, 122(28), e2507203122. (www)

  @article{ , abstract = {The mitotic inhibitor docetaxel (DTX) is often used to treat endocrine-refractory metastatic breast cancer, but initial responses are mitigated as patients develop disease progression. Using a cohort of ex vivo cultured circulating tumor cells (CTCs) from patients with heavily pretreated breast cancer (n=18), we find distinct patterns of response to DTX, which are intrinsic and independent of past clinical treatment with taxanes. In some CTC cultures, treatment with a single dose of DTX results in complete cell killing, associated with accumulation of nonviable polyploid (≥8 N) cells arising from endomitosis. In other CTC cultures, a transient viable drug-tolerant persister (DTP) population emerges, ultimately enabling renewed proliferation of CTCs with preserved parental cell ploidy and restored DTX sensitivity identical to that of the pretreated culture. In these CTCs, efficient cell cycle exit generates a ≤4 N drug-tolerant state dependent on CDKN1B (p27/kip1). Exposure to DTX triggers stabilization of CDKN1B through AKT-mediated phosphorylation at serine 10. Suppression of CDKN1B reduces the number of persister CTCs, increases ≥8 N mitotic cells and abrogates regrowth after DTX exposure. Thus, CDKN1B-mediated suppression of endomitosis contributes to the initiation of a reversible drug-tolerant persister state following mitotic inhibitors in advanced patient-derived breast cancer cells.}, archive = {J_PNAS}, author = {Horwitz, Elad and Dubash, Taronish D. and Szabolcs, Annamaria and Wittner, Ben S. and Kreuzer, Johannes and Morris, Robert and Bardia, Aditya and Chirn, Brian and Wiley, Devon and Che, Dante and Russell, Hunter C. and Herrera Lopez, Xcanda Ixchel and Fox, Douglas B. and Antmen, Ezgi and Burr, Risa and Ting, David T. and Haas, Wilhelm and Sade-Feldman, Moshe and Maheswaran, Shyamala and Haber, Daniel A.}, doi = {10.1073/pnas.2507203122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2507203122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CDKN1B (p27/kip1) enhances drug-tolerant persister CTCs by restricting polyploidy following mitotic inhibitors}, volume = {122}, year = {2025}, }
• (2025). Do large language models have a theory of mind?. PNAS, 122(28), e2507080122. (www)

  @article{ , archive = {J_PNAS}, author = {Pang, Damian K. F. and Pang, Severin K. Y. and Broeker, Marianne D. and Hibble, Alix}, doi = {10.1073/pnas.2507080122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2507080122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Do large language models have a theory of mind?}, volume = {122}, year = {2025}, }
• (2025). Thalamic CGRP neurons define a spinothalamic pathway for affective pain. PNAS, 122(28), e2505889122. (www)

  @article{ , abstract = {Pain is both a sensory and emotional experience caused by various harmful stimuli. While numerous studies have explored peripheral and central pain mechanisms, the specific neural circuits linking the spinal cord to the brain remain poorly defined. In this study, we demonstrate the involvement of calcitonin gene-related peptide (CGRP)-positive neurons in the parvicellular part of the subparafascicular nucleus (SPFp) in pain. Tracing revealed that CGRP neurons in the SPFp (CGRP SPFp ) receive projections from the dorsal horn. Increased calcium activity was observed in CGRP SPFp neurons during mechanical, thermal, and inflammatory stimuli. Genetic silencing of these neurons resulted in reduced pain responses in animals. Furthermore, optogenetic activation of CGRP SPFp neurons induced aversive memory but did not alter mechanical or thermal pain thresholds. This study reveals a distinct neural circuit involving CGRP SPFp neurons that mediates pain, which differs from CGRP neurons in the parabrachial nucleus. Understanding these circuits could lead to better pain treatments with fewer side effects.}, archive = {J_PNAS}, author = {Kang, Sukjae J. and Liu, Shijia and Kim, Jong-Hyun and Kim, Dong-Il and Oh, Tae Gyu and Peng, Jiahang and Ye, Mao and Lee, Kuo-Fen and Evans, Ronald M. and Goulding, Martyn and Han, Sung}, doi = {10.1073/pnas.2505889122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2505889122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Thalamic CGRP neurons define a spinothalamic pathway for affective pain}, volume = {122}, year = {2025}, }
• (2025). A chemoreceptor conformational equilibrium controlled by signaling inputs. PNAS, 122(28), e2505872122. (www)

  @article{ , abstract = {In chemotaxis, motile bacteria recognize external molecules and move toward favorable concentrations. Chemoreceptors form complexes that perform transmembrane signaling, control a histidine kinase, and undergo posttranslational adaptational modifications. Chemoreceptors are thought to function by switching between two signaling states: kinase-off, favored by ligand occupancy, and kinase-on, favored by adaptational modification. Many structural and biochemical features of the two states have been identified, but little is known about the equilibrium between them and the response of that equilibrium to signaling inputs. Using single-molecule Förster resonance energy transfer, we monitored helical separations in the Escherichia coli aspartate chemoreceptor Tar for the two pairs of helices that form the cytoplasmic four-helix coiled coil bundle. Rather than the commonly assumed switch between two conformations in response to signaling inputs, we identified two separations in each helical pair that were present under all conditions but with variation in relative occupancy. Ligand occupancy and adaptational modification were found to differentially impact the conformational equilibria, rather than reversing the same conformational response, as previously thought. Ligand occupancy changed symmetrical packing in the four-helix bundle into rhomboid packing, whereas adaptational modification determined which helical pair was central in the rhombus. Thus, the structural consequence of ligand binding was not stabilization of a specific helical conformation but instead the collective geometry of all helices in the bundle. Such changes in helical geometry may play a role in conformational signaling by other transmembrane receptors.}, archive = {J_PNAS}, author = {Hoffman, Mikaila C. and Li, Mingshan and Hazelbauer, Gerald L. and Schlau-Cohen, Gabriela S.}, doi = {10.1073/pnas.2505872122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2505872122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A chemoreceptor conformational equilibrium controlled by signaling inputs}, volume = {122}, year = {2025}, }
• (2025). A conserved editing mechanism for the fidelity of bacterial cell wall biosynthesis. PNAS, 122(28), e2505676122. (www)

  @article{ , abstract = {Peptidoglycan (PG), a defining feature of the bacterial cell envelope, is crucial for cell integrity and morphology. PG is a macromolecular mesh consisting of glycan polymers crosslinked by short peptides encasing the cytoplasmic membrane. PG peptides contain two to five amino acids of both L- and D-configuration, with a conserved L-alanine residue at the first position in most bacteria. We previously identified a β-lactam hypersensitive mutant of Escherichia coli lacking yfiH (renamed pgeF ) that shows incorporation of L-serine or glycine instead of L-alanine. Here, we demonstrate that PgeF is an editing enzyme that imparts fidelity to the biosynthesis of PG peptides across bacterial genera. Using extensive mass spectrometry, we find accumulation of misincorporated cytoplasmic PG precursors in the absence of pgeF . Detailed biochemical analysis of several bacterial PgeF homologs reveals that PgeF specifically cleaves serine or glycine but not alanine from the PG precursors. Additionally, expression of heterologous ligases that incorporate L-serine or glycine is lethal in the absence of pgeF , indicating that L-alanine at the first position is crucial for wall integrity. Interestingly, PgeF is selectively conserved in bacteria and vertebrates; however, we find that the PG editing activity is exclusive to bacterial homologs. Furthermore, homologs from both taxa were previously characterized as purine nucleoside phosphorylases (PNP). Here, we find that they indeed have a weak PNP activity, but with no physiological relevance in bacterial systems. Overall, our study demonstrates the existence of a conserved proofreading pathway that is fundamental to the integrity of the bacterial cell wall.}, archive = {J_PNAS}, author = {Garde, Shambhavi and Selvaraj, Harikrishnan and Chandramouli, Aakash and Reddy, Gundlapally S. and Bahety, Devesh and Chodisetti, Pavan Kumar and Kamat, Siddhesh S. and Reddy, Manjula}, doi = {10.1073/pnas.2505676122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2505676122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A conserved editing mechanism for the fidelity of bacterial cell wall biosynthesis}, volume = {122}, year = {2025}, }
• (2025). The prefusion structure of the HERV-K (HML-2) env spike complex. PNAS, 122(28), e2505505122. (www)

  @article{ , abstract = {The human endogenous retrovirus K (HERV-K) is a retrovirus that got assimilated into the human genome in ancient times and has been inherited in our germline ever since. It enters cells using a class-I spike protein (Env) that mediates receptor recognition and membrane fusion. On top of having a biological role during development, HERV-K is activated in amyotrophic lateral sclerosis, various cancers, and other pathological conditions. Antibodies that target the HERV-K spike complex have therapeutic value, flagging the spike as a novel drug target. Here, we use cryo-EM to determine the trimeric structure of the HERV-K spike. The spike presents a distinct structure, which substantially differs from other class-I fusogens. Nevertheless, some general architectural features suggest a common origin with other retroviruses. The ability to structurally characterize the HERV-K spike may facilitate the development of antibody-based therapies.}, archive = {J_PNAS}, author = {Shaked, Ron and Katz, Michael and Cohen-Dvashi, Hadas and Diskin, Ron}, doi = {10.1073/pnas.2505505122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2505505122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The prefusion structure of the HERV-K (HML-2) env spike complex}, volume = {122}, year = {2025}, }
• (2025). Environmental variability shapes the representational format of cultural learning. PNAS, 122(28), e2505283122. (www)

  @article{ , abstract = {Cumulative culture requires learning mechanisms that are both efficient and flexible in the face of environmental change. We examine models of this learning mechanism that emphasize teaching what to do (causally opaque procedures) and those that foreground what to aim for and why (goals and causal reasoning). Learning procedures is cheap but inflexible; learning goals is more flexible to changing circumstance, but requires expensive individual learning about how to achieve them. In an iterated learning experiment, we demonstrate that cultural learning adapts in precisely this way: Microcultures more often instruct future generations to follow procedures when the world is stable, but they tend to share information about valuable outcomes and causal relations when the world is variable.}, archive = {J_PNAS}, author = {Roberts-Gaal, Xavier and Bolic, Marija and Cushman, Fiery A.}, doi = {10.1073/pnas.2505283122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2505283122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Environmental variability shapes the representational format of cultural learning}, volume = {122}, year = {2025}, }
• (2025). Sustainable synthesis of polymer-grade ethylene via electrified acetylene semihydrogenation. PNAS, 122(28), e2505151122. (www)

  @article{ , abstract = {The electrocatalytic semihydrogenation of acetylene (C 2 H 2 ), powered by renewable electricity, provides an energy- and cost-efficient alternative to conventional thermocatalytic methods for purifying crude ethylene (C 2 H 4 ) streams. This approach provides a more sustainable route to polymer-grade C 2 H 4 by reducing greenhouse gas emissions, yet its commercial potential remains limited by the scarcity of high-performance catalysts and the absence of comprehensive techno-economic analyses for large-scale implementation. In this study, we conduct an extensive screening and evaluation of monodisperse metal nanoparticle (NP) catalysts (Cu, Ag, Au, Pd, Bi) with tunable particle sizes and morphologies for the electrocatalytic semihydrogenation of C 2 H 2 in flow reactors. Among these candidates, 45 nm Cu nanocubes and 8 nm Ag NPs exhibited the highest performance. In a simulated crude ethylene stream (C 2 H 2 : C 2 H 4 = 1:80), Cu nanocubes achieved 99.7% C 2 H 2 removal at room temperature with a specific selectivity of 86.7% for C 2 H 4 and maintained stability for 120 h. Meanwhile, 8 nm Ag NPs exhibited a high specific selectivity of 98.9%, with 96.7% conversion and 24-h stability under the same conditions. A detailed techno-economic analysis confirms the feasibility of electrocatalytic systems for industrial-scale crude ethylene treatment, with an optimal conversion cost of $0.74 per kg of C 2 H 2 , compared to $1.34 per kg for the optimized thermocatalytic system. Furthermore, our life cycle assessment highlights the environmental benefits of the electrocatalytic pathway with a carbon emission reduction of over 50%. Our electrified, efficient C 2 H 2 semihydrogenation in C 2 H 4 crude streams minimizes environmental impact and optimizes resource use, contributing to a more sustainable future.}, archive = {J_PNAS}, author = {Yan, Zihao and Xu, Libang and Zhu, Huiyuan}, doi = {10.1073/pnas.2505151122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2505151122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sustainable synthesis of polymer-grade ethylene via electrified acetylene semihydrogenation}, volume = {122}, year = {2025}, }
• (2025). Kinetic mechanisms for the sequence dependence of transcriptional errors. PNAS, 122(28), e2505040122. (www)

  @article{ , abstract = {The fidelity of template-dependent mRNA synthesis during transcription elongation is the primary determinant of accurate gene expression and the maintenance of functional RNA transcripts. However, the mechanisms governing transcription fidelity remain incompletely understood. While previous studies have characterized how error rates vary with nucleotide identity at upstream and downstream positions from the incorporation site, the comprehensive microscopic explanation of this sequence dependence has not been elucidated. In this study, we develop a theoretical approach that integrates transcription proofreading mechanisms and inhomogeneous DNA sequence effects. Using first-passage analysis validated by Monte Carlo simulations, we quantitatively characterize nucleotide-specific error rates during RNA polymerase II transcription. The model accurately reproduces experimental error rates and predicts kinetic parameters influencing transcriptional fidelity. Analysis reveals nucleotide incorporation rates follow the hierarchy U<C<G<A, consistent with independent experimental observations. Notably, our model not only explains how the error rates depend on the nature of the base immediately downstream (+1) but also predicts that the identity of the nucleotide at the second downstream position (+2) also plays an important role. Pyrimidines at position +2 contribute to lower error rates than purines, whereas the third downstream base (+3) has no effect. These previously unreported correlations are corroborated by bioinformatic analysis of existing datasets. In addition, using the BRCA1 gene as an example, we explore the physiological implications of sequence-dependent error rates, identifying an increased likelihood of premature stop codon errors. These findings clarify how DNA sequence context modulates nucleotide incorporation kinetics, advancing our understanding of transcriptional fidelity and its functional consequences.}, archive = {J_PNAS}, author = {Midha, Tripti and Kolomeisky, Anatoly B. and Igoshin, Oleg A.}, doi = {10.1073/pnas.2505040122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2505040122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Kinetic mechanisms for the sequence dependence of transcriptional errors}, volume = {122}, year = {2025}, }
• (2025). WT1 directs normal progesterone receptor–chromatin binding essential for uterine receptivity at peri-implantation. PNAS, 122(28), e2504361122. (www)

  @article{ , abstract = {Progesterone receptor (PR)-mediated progesterone (P4) signaling plays a crucial role in the establishment of uterine receptivity which is the prerequisite for successful embryo implantation in mammals. However, detailed molecular mechanisms underlying PR–chromatin binding and transcriptional activity in the uterus remain largely elusive. Here, combining the P4-administrated ovariectomized mouse model and PR–chromatin immunoprecipitation sequencing, we identified transcription factor WT1 as a potential cooperator of PR in the uterus. WT1 was specifically expressed in uterine stromal cells. Uterine deletion of Wt1 resulted in implantation failure due to attenuated P4 responsiveness in stromal cells and aberrant uterine receptivity. Mechanistically, WT1 physically interacted with PR in stromal cells, and exhibited genome-wide co-occupancy with PR. Furthermore, WT1 was indispensable for directing PR onto the chromatin via corecruitment and tethering manners, and facilitated PR to activate the transcription of target genes that were critical for uterine receptivity. Collectively, our study provided substantial evidence that WT1 served as a functional partner of PR in uterine stromal cells, thus guaranteeing P4 responsiveness conducive to uterine receptivity.}, archive = {J_PNAS}, author = {Ni, Zhangli and Guo, Chuanhui and Liu, Xiaojing and Li, Gaizhen and Tang, Yedong and Cai, Han and Huang, Weiyu and Gao, Fei and Tu, Zhaowei and Wang, Chao and Wang, Haibin and Kong, Shuangbo and Bao, Haili}, doi = {10.1073/pnas.2504361122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2504361122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {WT1 directs normal progesterone receptor–chromatin binding essential for uterine receptivity at peri-implantation}, volume = {122}, year = {2025}, }
• (2025). AI-driven design of multiprincipal element alloys for optimal water splitting. PNAS, 122(28), e2504226122. (www)

  @article{ , abstract = {Water splitting for hydrogen production is essential in advancing the hydrogen economy. Multiprincipal element alloys offer promising opportunities for optimizing this process, yet their vast compositional space and the presence of local minima pose significant challenges for experimental and AI-driven exploration. To overcome these challenges, an AI framework is developed by integrating Gaussian Process Regression with a configuration entropy–based acquisition function for screening and a design of experiments (DoE) for data-efficient overpotential mapping. Through Bayesian optimization across 16.2 million chemical compositions, this entropy-screened and DoE dataset–trained AI identifies Fe 12 Co 28 Ni 33 Mo 17 Pd 5 Pt 5 as the best composition for water splitting within its search space. The alloy exhibits ultralow overpotentials of 24 mV for hydrogen evolution and 204 mV for oxygen evolution at 10 mA·cm −2 with robust stability, surpassing state-of-the-art non-noble and noble metal electrocatalysts including Pt/C+IrO 2 , Pt 35 Ru 65 , and Ru–VO 2 —demonstrating remarkable performance beyond reach by contemporary experimental and AI frameworks.}, archive = {J_PNAS}, author = {Kim, Jihoon and Kim, Dong Won and Choi, Jong Hui and Goddard, William A. and Kang, Jeung Ku}, doi = {10.1073/pnas.2504226122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2504226122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {AI-driven design of multiprincipal element alloys for optimal water splitting}, volume = {122}, year = {2025}, }
• (2025). Piezo2+ mechanosensory neurons orchestrate postnatal development through mechano-chemo-transduction of PDGFA signaling. PNAS, 122(28), e2504103122. (www)

  @article{ , abstract = {Mechanical forces are ubiquitous and essential during vertebrate development, yet how these forces are translated into biochemical signals and regulate development during postnatal organogenesis remains poorly understood. While early embryogenesis relies on cell-autonomous mechanotransduction, the role of sensory innervation—abundant in postnatal stages—has been overlooked. Here, using the postnatal mouse molar development model, a system experiencing sustained mechanical forces and extensive innervation during tooth root formation, we first identify a subpopulation of Piezo2 + mechanosensory neurons in the trigeminal ganglia and reveal these neurons specifically detect tooth root-associated mechanical forces and orchestrate tooth root development via paracrine signaling. Critically, we show that Piezo2 in neurons—not in dental cells—is essential for tooth root morphogenesis, revealing sensory neurons as unexpected master regulators of mesenchymal cell fate. Mechanistically, Piezo2 activation triggers the calcium-dependent secretion of platelet-derived growth factor A, defining the neuronal mechanotransduction pathway that directly converts force into biochemical signals to drive organogenesis. Taken together, our findings demonstrate that Piezo2 + mechanosensory neurons primarily orchestrate mechanical-force-regulated processes during postnatal development. The identification of the PIEZO2–calcium–PDGF axis provides important insight into mechanotransduction by introducing sensory neurons as active architects of tissue development. This work establishes a paradigm in developmental biology, revealing how mechanosensation bridges biomechanics and neurobiology to regulate postnatal organogenesis, with implications for tissue regeneration strategies.}, archive = {J_PNAS}, author = {Meng, Lin and Feng, Jifan and Guo, Tingwei and Zhang, Mingyi and Cha, Sa and Chen, Peng and Ziaei, Heliya and Harouni, Aaron and Ho, Thach-Vu and Chai, Yang}, doi = {10.1073/pnas.2504103122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2504103122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Piezo2+ mechanosensory neurons orchestrate postnatal development through mechano-chemo-transduction of PDGFA signaling}, volume = {122}, year = {2025}, }
• (2025). HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise. PNAS, 122(28), e2504080122. (www)

  @article{ , abstract = {The regulation of metabolism in peripheral tissues is intricately linked to circadian rhythms, with hypoxia-inducible factor-1α (HIF1α) implicated in modulating time-of-day-specific exercise responses. To investigate this relationship, we generated a skeletal muscle-specific HIF1α knockout (KO) mouse model and performed extensive metabolic phenotyping and transcriptomic profiling under both basal conditions and following acute exercise during early rest (ZT3) and active (ZT15) phases. Our findings reveal that HIF1α drives a more robust transcriptional and glycolytic response to exercise at ZT3, promoting glucose oxidation and mannose-6-phosphate production while potentially sparing fatty acid oxidation. In the absence of HIF1α, skeletal muscle metabolism shifts toward oxidative pathways at ZT3, with notable alterations in glucose fate. These results establish HIF1α as an important regulator of time-of-day-specific metabolic adaptations, integrating circadian and energetic signals to optimize substrate utilization. This work highlights the broader significance of HIF1α in coordinating circadian influences on metabolic health and exercise performance.}, archive = {J_PNAS}, author = {Ehrlich, Amy M. and MacGregor, Kirstin A. and Ashcroft, Stephen P. and Small, Lewin and Altıntaş, Ali and Chibalin, Alexander V. and Anagho-Mattanovich, Matthias and Stocks, Ben and Moritz, Thomas and Treebak, Jonas T. and Zierath, Juleen R.}, doi = {10.1073/pnas.2504080122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2504080122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise}, volume = {122}, year = {2025}, }
• (2025). Competition for hfq drives kinetic selection of mRNA targets by escherichia coli small noncoding RNAs. PNAS, 122(28), e2503747122. (www)

  @article{ , abstract = {Small noncoding RNAs (sRNAs) regulate gene expression in Escherichia coli bacteria in response to diverse stimuli in the environment and the host. Most sRNAs regulate mRNA expression by directly base pairing with complementary sites in the target mRNA with the help of the chaperone protein Hfq. sRNAs and Hfq must rapidly search hundreds of candidate mRNAs for matched (cognate) targets while discriminating against noncognate targets. Here, we use single-molecule fluorescence microscopy to directly observe how cognate and noncognate mRNAs bind immobilized sRNA–Hfq. The results show that initially unstable sRNA–Hfq–mRNA complexes either dissociate within seconds by ejecting one of the two RNAs, depending on their interactions with Hfq, or are stabilized by sRNA–mRNA base pairing. Cognate mRNAs are more likely to form long-lived sRNA–Hfq–mRNA complexes, even in the presence of competing RNA. Active competition for the mutual Hfq chaperone introduces a kinetic barrier to RNA colocalization that is resolved by base pairing, driving the accumulation of cognate sRNA–mRNA interactions while eliminating noncognate interactions.}, archive = {J_PNAS}, author = {Roca, Jorjethe and Chen, Yi-Lan and Woodson, Sarah A.}, doi = {10.1073/pnas.2503747122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2503747122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Competition for hfq drives kinetic selection of mRNA targets by escherichia coli small noncoding RNAs}, volume = {122}, year = {2025}, }
• (2025). GSK3β phosphorylated tau filaments are probably not like those from AD brains. PNAS, 122(28), e2503730122. (www)

  @article{ , archive = {J_PNAS}, author = {Scheres, Sjors H. W.}, doi = {10.1073/pnas.2503730122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2503730122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {GSK3β phosphorylated tau filaments are probably not like those from AD brains}, volume = {122}, year = {2025}, }
• (2025). Herbarium specimens reveal a constrained seasonal climate niche despite diverged annual climates across a wildflower clade. PNAS, 122(28), e2503670122. (www)

  @article{ , abstract = {Quantifying species’ niches across a clade reveals how environmental tolerances evolve, and offers insights into present and future distributions. We use herbarium specimens to explore climate niche evolution across 14 annual species of the Streptanthus ( s.l. ) clade (Brassicaceae), which originated in deserts and diversified into cooler, moister areas. To understand how climate niches evolved, we used historical climate records to estimate each species’ 1) classic annual climate niche, averaged over specimen collection sites; 2) growing season niche, from estimated specimen germination date to collection date, averaged across specimens (specimen-specific niche); and 3) standardized seasonal niche based on average growing seasons of all species (clade-seasonal niche). In addition to estimating how phenological variation maps onto climate niche evolution, we explored how spatial refugia shape the climate experienced by species by 1) analyzing how field soil texture changes relative to the climate space that species occupy and 2) comparing soil water holding capacity from each specimen locality to that of surrounding areas. Specimen-specific niches exhibited less clade-wide variation in climatic water deficit (CWD) than did annual or clade-seasonal niches, and specimen-specific temperature niches showed no phylogenetic signal, in contrast to annual and clade-seasonal temperature niches. Species occupying cooler regions tracked hotter and drier climates by growing later into the summer, and by inhabiting refugia on drought-prone soils. These results underscore how phenological shifts, spatial refugia, and germination timing shape “lived” climate. Despite occupying a large range of annual climates, we found these species are constrained in the conditions under which they thrive.}, archive = {J_PNAS}, author = {Bontrager, Megan and Worthy, Samantha J. and Cacho, N. Ivalú and Leventhal, Laura and Maloof, Julin N. and Gremer, Jennifer R. and Schmitt, Johanna and Strauss, Sharon Y.}, doi = {10.1073/pnas.2503670122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2503670122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Herbarium specimens reveal a constrained seasonal climate niche despite diverged annual climates across a wildflower clade}, volume = {122}, year = {2025}, }
• (2025). Decoding and engineering temperature-sensitive lethality in ceratitis capitata for pest control. PNAS, 122(28), e2503604122. (www)

  @article{ , abstract = {The Sterile Insect Technique (SIT) is a species-specific and environmentally friendly method for effectively controlling pest insect populations based on releasing reared, sterile insects into infested areas. Sex sorting in rearing facilities, enabling male-only releases, is necessary to ensure SIT programs are efficient, cost-effective and, in case of mosquito control, also safe. This can be greatly facilitated by genetic sexing strains (GSS), exhibiting sex-specific phenotypic markers. However, the development of GSS remains challenging. The construction of a temperature-sensitive lethal ( tsl )-based GSS in the Mediterranean fruit fly ( Ceratitis capitata ) over three decades ago was considered a major breakthrough for SIT programs but was never successfully replicated in other pests. After over 30 y of research, we have pinpointed a specific mutation in the C. capitata lysine--tRNA ligase ( Lysyl-tRNA synthetase , LysRS ) gene responsible for the tsl phenotype. Introducing this specific mutation into a wild-type strain produced full embryonic lethality under heat stress, replicating the original mutant phenotype. The random integration of a LysRS minigene reversed this effect. The high conservation of LysRS among insects suggests that tsl-based GSS could be expanded to multiple pest species and extend applications of SIT programs for disease prevention and the protection of agriculture.}, archive = {J_PNAS}, author = {Aumann, Roswitha A. and Gouvi, Georgia and Gregoriou, Maria-Eleni and Rehling, Tanja and Sollazzo, Germano and Bourtzis, Kostas and Schetelig, Marc F.}, doi = {10.1073/pnas.2503604122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2503604122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Decoding and engineering temperature-sensitive lethality in ceratitis capitata for pest control}, volume = {122}, year = {2025}, }
• (2025). Orientation fields predict human perception of 3D shape from shading. PNAS, 122(28), e2503088122. (www)

  @article{ , abstract = {How the brain recovers the three-dimensional structure of surfaces and objects from 2D retinal images remains mysterious. Shading patterns provide one of the most powerful—yet least understood—visual depth cues. Most theories assume the brain infers surface normals from luminance values. However, this seems unlikely as visual neurons are broadly insensitive to luminance. To identify alternative cues, we measured responses of model orientation-selective cell populations to images of shaded objects. We found a surprising statistical relationship between image orientations and surface curvature properties, suggesting a way to estimate shape from shading. We find that the orientation-based cues not only predict striking illusions of shape perception when lighting varies, but also the impressive robustness of shape perception when large image modifications are introduced to directly pit luminance and image orientation cues against one another. The findings resolve the longstanding question of which image measurements drive shape from shading perception.}, archive = {J_PNAS}, author = {Aubuchon, Celine and Vergne, Romain and Cholewiak, Steven A. and Kunsberg, Benjamin and Holtmann-Rice, Daniel and Zucker, Steven W. and Fleming, Roland W.}, doi = {10.1073/pnas.2503088122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2503088122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Orientation fields predict human perception of 3D shape from shading}, volume = {122}, year = {2025}, }
• (2025). Genetic ancestry shapes dengue virus infection in human skin explants. PNAS, 122(28), e2502793122. (www)

  @article{ , abstract = {Dengue is the most prevalent arthropod-borne viral disease of humans, with over half the world’s population at risk. Infection with any of the four dengue virus (DENV) serotypes is most often self-limiting, but a significant number of cases present with severe dengue characterized by vascular leakage that may be fatal. African ancestry is associated with protection against severe dengue, but the mechanisms are unknown. Using skin explants from genetically defined donors, we show that European ancestry skin has a much stronger inflammatory response to DENV than African ancestry skin, eliciting markedly increased infiltration, infection and migration of resident Langerhans cells, macrophages, and dendritic cells. The effect was seen with all dengue serotypes and Zika virus and in the presence of heterotypic immune serum. Genetic pathways associated with inflammation, interferon (IFN)-α, and inflammatory cytokine signaling were enriched in European relative to African ancestry skin following infection. Infiltration and infection of macrophages in African ancestry skin increased to that of European skin after blocking IFN-α and providing interleukin-1β. Polymorphic variants in RXRA , OAS1-3, and TGFB1 genes that were more frequent in European donors were associated with increased virus replication. Paradoxically, European ancestry skin cells had increased expression of OAS3 in response to virus and type I IFN. Thus, the limited inflammatory response of African ancestry skin to infection restricts replication and spread of dengue and other flaviviruses. Genetic ancestry should be considered when predicting a patient’s likelihood of severe dengue, and when assessing efficacy and adverse events associated with dengue vaccines.}, archive = {J_PNAS}, author = {Castanha, Priscila M. S. and Martí, Michelle M. and Duangkhae, Parichat and Taddonio, Jocelyn M. and Cooper, Kristine L. and Wallace, Megan and Kettenburg, Gwenddolen and Erdos, Geza and Chavva, Hasitha and Alex, Aleena and Rubin, J. Peter and Watkins, Simon C. and Falo, Louis D. and Marques, Ernesto T. A. and Martinson, Jeremy J. and Barratt-Boyes, Simon M.}, doi = {10.1073/pnas.2502793122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2502793122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genetic ancestry shapes dengue virus infection in human skin explants}, volume = {122}, year = {2025}, }
• (2025). EDNRB2 regulates fate, migration, and maturation of hair cell precursors in regenerating avian auditory epithelium explants. PNAS, 122(28), e2502713122. (www)

  @article{ , abstract = {The mammalian cochlea loses its ability to regenerate hair cells (HCs) after birth. In contrast, in the avian auditory epithelium, the basilar papilla (BP), supporting cells (SCs) retain the capability for HC regeneration throughout life. Our previous study using single-cell RNA sequencing indicated a stepwise fate conversion of SCs to HCs via a precursor state, in which endothelin receptor type B2 ( EDNRB2 ) exhibited specifically high expression during HC regeneration in chick BP. This study aimed to reveal the distinct role of EDNRB2 in HC regeneration in the chick BP. During HC regeneration in chick BP explant cultures, EDNRB2 expression was observed in some ATOH1 -expressing SCs immediately after HC loss and decreased as the HC regeneration process progressed. In the embryonic chick BP, EDNRB2 expression was specifically detected in the precursor cell state, confirming that mature SCs were reprogrammed to the precursor state in response to HC loss. Pharmacological inhibition of EDNRB signaling decreases the number of regenerated HCs in chick BP explant cultures. RNA sequencing revealed that EDNRB signaling inhibition downregulated genes involved in HC differentiation and maturation as well as genes involved in cell migration. Histological assessments clarified the deterioration of HC precursor migration and the delay in HC regeneration due to EDNRB signaling inhibition. These results indicate that EDNRB2 expression contributes to the fate determination of HCs, and its signaling regulates the migration and maturation of HC precursors during chick HC regeneration.}, archive = {J_PNAS}, author = {Takeuchi, Marie and Matsunaga, Mami and Kita, Tomoko and Nishimura, Koji and Tona, Yosuke and Omori, Koichi and Katsuno, Tatsuya and Nakagawa, Takayuki}, doi = {10.1073/pnas.2502713122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2502713122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {EDNRB2 regulates fate, migration, and maturation of hair cell precursors in regenerating avian auditory epithelium explants}, volume = {122}, year = {2025}, }
• (2025). Asymptotic theory of in-context learning by linear attention. PNAS, 122(28), e2502599122. (www)

  @article{ , abstract = {Transformers have a remarkable ability to learn and execute tasks based on examples provided within the input itself, without explicit prior training. It has been argued that this capability, known as in-context learning (ICL), is a cornerstone of Transformers’ success, yet questions about the necessary sample complexity, pretraining task diversity, and context length for successful ICL remain unresolved. Here, we provide a precise answer to these questions in an exactly solvable model of ICL of a linear regression task by linear attention. We derive sharp asymptotics for the learning curve in a phenomenologically rich scaling regime where the token dimension is taken to infinity; the context length and pretraining task diversity scale proportionally with the token dimension; and the number of pretraining examples scales quadratically. We demonstrate a double-descent learning curve with increasing pretraining examples, and uncover a phase transition in the model’s behavior between low and high task diversity regimes: in the low diversity regime, the model tends toward memorization of training tasks, whereas in the high diversity regime, it achieves genuine ICL and generalization beyond the scope of pretrained tasks. These theoretical insights are empirically validated through experiments with both linear attention and full nonlinear Transformer architectures.}, archive = {J_PNAS}, author = {Lu, Yue M. and Letey, Mary and Zavatone-Veth, Jacob A. and Maiti, Anindita and Pehlevan, Cengiz}, doi = {10.1073/pnas.2502599122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2502599122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Asymptotic theory of in-context learning by linear attention}, volume = {122}, year = {2025}, }
• (2025). Chlorophyll trends are negative for lakes but positive for estuarine–coastal waters. PNAS, 122(28), e2502289122. (www)

  @article{ , abstract = {Nutrient (nitrogen and phosphorus) pollution is an environmental problem of global concern because overenrichment of water bodies increases phytoplankton biomass and ecosystem metabolism, depletes oxygen in bottom waters, and increases the frequency and intensity of harmful algal blooms. These responses to nutrient pollution have motivated policies to reduce anthropogenic nutrient inputs. However, these policies have not been universally implemented and their success at reducing phytoplankton biomass is confounded by other components of global change that regulate the conversion of nutrients into biomass. These regulating processes themselves are changing in the Anthropocene. Our study is an assessment of changing phytoplankton biomass over the period 2000–2019, using chlorophyll a trends measured in 191 lakes and 159 estuarine-coastal sites. Our results show that phytoplankton biomass has decreased in most lakes, increased in most coastal sites, and the largest trends have been predominantly negative for lakes and positive for coastal sites. These results provide evidence of opposing directions of phytoplankton biomass change between lakes and coastal sites in this recent period of unprecedented global change. Nutrient pollution is a knotty environmental problem, and our study indicates that it might be a particularly challenging problem for ecosystems situated in densely populated landscapes where freshwater and sea water meet. Success at overcoming this challenge will require deeper scientific understanding of changes in processes that regulate the conversion of nutrients into phytoplankton biomass, substantial investments of time and resources to reduce nutrient inputs, and a flexible strategy designed to anticipate and adapt to a changing world.}, archive = {J_PNAS}, author = {Cloern, James E. and Jassby, Alan D.}, doi = {10.1073/pnas.2502289122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2502289122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chlorophyll trends are negative for lakes but positive for estuarine–coastal waters}, volume = {122}, year = {2025}, }
• (2025). Revealing the structure of snowflakes using acoustic levitation. PNAS, 122(28), e2502112122. (www)

  @article{ , archive = {J_PNAS}, author = {Mason, Nigel John}, doi = {10.1073/pnas.2502112122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2502112122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Revealing the structure of snowflakes using acoustic levitation}, volume = {122}, year = {2025}, }
• (2025). Strong strain dependence of friction in graphene kirigami allows engineering a negative coefficient of friction. PNAS, 122(28), e2501728122. (www)

  @article{ , abstract = {The friction force typically increases linearly with normal load with a constant of proportionality called the coefficient of friction. Most materials exhibit a positive friction coefficient, so that an increase in the normal load leads to an increase in the friction force. Recently, materials with negative friction coefficients have been observed at meticulously constructed interfaces due to an interplay between superstructures at heterojunctions, out-of-plane buckling, or the ordering of thin water films. However, the magnitude of the negative friction coefficient is typically much less than 10 − 2 , the geometries are highly restrictive, and the mechanisms are difficult to scale to larger systems. Here, we show that a friction coefficient of − 0.08 can be obtained for a graphene sheet modified with kirigami-inspired cuts when inducing sheet tension through a normal load coupling. We use molecular dynamics simulations to show that the frictional behavior of kirigami cut sheets exhibits a strong nonmonotonic dependence on in-plane strain, while only weakly influenced by normal loading. We argue that the strong influence of strain arises from changes in commensurability between the graphene sheet and the substrate when the sheet deforms and buckles out of plane. We propose a simple nanomachine design that couples normal loading and sheet tension which enables the realization of different frictional laws, including a negative coefficient of friction. This represents a unique approach to creating tunable frictional surfaces and opens up applications in sheet-like systems across scales.}, archive = {J_PNAS}, author = {Juel, Mikkel Metzsch and Malthe-Sørenssen, Anders and Sveinsson, Henrik Andersen}, doi = {10.1073/pnas.2501728122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2501728122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Strong strain dependence of friction in graphene kirigami allows engineering a negative coefficient of friction}, volume = {122}, year = {2025}, }
• (2025). Acyl-CoA-binding protein as a driver of pathological aging. PNAS, 122(28), e2501584122. (www)

  @article{ , abstract = {The tissue hormone acyl coenzyme A–binding protein (ACBP, encoded by the gene diazepam-binding inhibitor , DBI) has been implicated in various facets of pathological aging. Here, we show that ACBP plasma concentrations are elevated in (close-to-)centenarians (mean ± SD age 99.5 ± 4.5 y) commensurate with their health deterioration, correlating with a reduced glomerular filtration rate and a surge in senescence-associated cytokines. ACBP neutralization by means of a monoclonal antibody (mAb) improved health span in a strain of progeroid mice. In a mouse model of chronic kidney injury induced by cisplatin, anti-ACBP mAb administration counteracted both histopathological and functional signs of organ failure. ACBP inhibition also prevented the senescence of tubular epithelial cells and glomerular podocytes induced by cisplatin or doxorubicin, respectively, as measurable by the immunohistochemical detection of cyclin-dependent kinase inhibitor 1A (CDKN1A, best known as p21). Senescence was also prevented by anti-ACBP mAb treatment in additional mouse models of accelerated aging. This applied to liver damage induced by a combination of high-fat diet and carbon tetrachloride, where hepatic cells become senescent. Moreover, administration of anti-ACBP mAb prevented natural and doxorubicin-accelerated cardiomyocyte senescence. We performed single-nucleus RNA sequencing to study the transcriptome of hearts that had been exposed to doxorubicin and/or anti-ACBP in vivo. In cardiomyocytes, doxorubicin caused an anti-ACBP-reversible dysregulation of mRNAs coding for cardioprotective proteins involved in autophagy, fatty acid oxidation, mitochondrial homeostasis, and oxidative phosphorylation. Altogether, these findings plead in favor of a broad age-promoting effect of ACBP across different organ systems.}, archive = {J_PNAS}, author = {Montégut, Léa and Lambertucci, Flavia and Moledo-Nodar, Lucas and Fiuza-Luces, Carmen and Rodríguez-López, Carlos and Serra-Rexach, Jose Antonio and Lachkar, Sylvie and Motiño, Omar and Abdellatif, Mahmoud and Durand, Sylvère and Aprahamian, Fanny and Carbonnier, Vincent and Le Corre, Delphine and Mouillet-Richard, Sophie and Chen, Hui and Sauvat, Allan and Dong, Yanbing and Li, Sijing and Rong, Yan and Pietrocola, Federico and Laurent-Puig, Pierre and López-Otín, Carlos and Martins, Isabelle and Barcena, Clea and Lucia, Alejandro and Kroemer, Guido}, doi = {10.1073/pnas.2501584122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2501584122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Acyl-CoA-binding protein as a driver of pathological aging}, volume = {122}, year = {2025}, }
• (2025). Monensin suppresses EMT-driven cancer cell motility by inducing golgi pH–dependent exocytosis of GOLIM4. PNAS, 122(28), e2501347122. (www)

  @article{ , abstract = {Despite extensive efforts to develop strategies to inhibit cancer metastasis—the leading cause of cancer-related deaths—progress has been limited in recent decades. Epithelial-to-mesenchymal transition (EMT) initiates metastasis by enhancing the migratory capacity and plasticity of cancer cells, enabling them to escape the primary tumor site. Identifying vulnerabilities unique to mesenchymal cancer cells is, therefore, critical for developing effective antimetastatic therapies. Our prior research has highlighted the crucial role of the Golgi apparatus in EMT-driven cancer cell motility and metastasis. In this study, we investigated the antimigratory effects of various Golgi-disrupting compounds and identified Monensin, a polyether ionophore antibiotic, as a potent migration suppressor in mesenchymal non–small cell lung cancer (NSCLC) cells. Monensin treatment increases the pH within the Golgi lumen, inducing rapid exocytosis of the promigratory Golgi scaffold protein Golgi Integral Membrane Protein 4 (GOLIM4). GOLIM4 plays a key role in regulating cell motility and adhesion by modulating the post-Golgi trafficking of Talin 1 (TLN1), an essential focal adhesion component. Furthermore, we found that both GOLIM4 and TLN1 are highly expressed in mesenchymal cancer cells and are direct targets of microRNA-200b, a microRNA that is suppressed during EMT. Treatment with Monensin or depletion of GOLIM4 or TLN1 significantly impaired the migratory activity of mesenchymal NSCLC cells. In summary, this study demonstrates that Monensin exhibits potential antimetastatic activity by disrupting the promigratory GOLIM4–TLN1 axis in mesenchymal NSCLC cells.}, archive = {J_PNAS}, author = {Tan, Xiaochao and Cardin, Derrick L. and Wang, Shike and Xu, Yuting and Russell, William K.}, doi = {10.1073/pnas.2501347122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2501347122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Monensin suppresses EMT-driven cancer cell motility by inducing golgi pH–dependent exocytosis of GOLIM4}, volume = {122}, year = {2025}, }
• (2025). Active contacts control sliding friction. PNAS, 122(28), e2501169122. (www)

  @article{ , abstract = {Sliding friction between two dry surfaces is commonly described by the speed-independent Amonton–Coulomb friction force law. However, there are many situations where multiple frictional contact points between two surfaces are “active” and each can move at a different relative speed. Here, we study the sliding friction properties of a system with multiple active contacts each with independent and controllable speed. We demonstrate that multiple active contacts can produce controllable speed-dependent sliding friction forces, despite each individual contact exhibiting a speed-independent friction. We study in experiment a rotating carousel with ten speed-controlled wheels in frictional contact with the ground. We first vary the contact speeds and demonstrate that the equilibrium system speed is the median of the active contact speeds. Next we directly measure the sliding friction forces and observe how the contact speeds can control the force–speed curve of the system. In the final experiments, we demonstrate how control of the force–speed curve can create sliding friction with a controllable effective viscosity and controllable sliding friction coefficient. Surprisingly, we are able to demonstrate that frictional contacts can create near frictionless sliding with appropriate force–speed control. By revealing how active contacts can shape the force–speed behavior of dry sliding friction systems, we can better understand animal and robot locomotion and furthermore open up opportunities for new engineered surfaces to control sliding friction.}, archive = {J_PNAS}, author = {Shah, Rohan and Gravish, Nick}, doi = {10.1073/pnas.2501169122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2501169122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Active contacts control sliding friction}, volume = {122}, year = {2025}, }
• (2025). Human milk IgA promotes normal immune development by limiting th17-inducing erysipelatoclostridium ramosum in the infant gut. PNAS, 122(28), e2501030122. (www)

  @article{ , abstract = {The gut microbiota is highly dynamic during the first year of life and plays a crucial role in immune development. Breastfeeding is known to support infant health, but the contributions of the numerous breastmilk components to gut microbiota and immune maturation remain unclear. Secretory IgA (SIgA), the most abundant antibody in human milk, is a key modulator of gut microbiota composition. We have shown previously that mouse milk SIgA protects against asthma by limiting segmented filamentous bacteria in mice. The present study uncovers a similar mechanism in humans. Using human milk from the CHILD Cohort Study, we define a relationship between human milk SIgA and infant gut microbiota composition. This leads to the identification of Erysipelatoclostridium ramosum as a key player in immune development, which is controlled by milk SIgA. Cell culture modeling demonstrates that SIgA restricts the capacity of E. ramosum to adhere to the intestinal epithelium and to induce Th17 responses, which are implicated in allergic and other chronic diseases.}, archive = {J_PNAS}, author = {Donald, Katherine and Serapio-Palacios, Antonio and Bozorgmehr, Tahereh and Ma, Mandi and Garcia, Ma Andrea Isabelle and Petersen, Charisse and Mandhane, Piushkumar and Subbarao, Padmaja and Moraes, Theo J. and Simons, Elinor and Turvey, Stuart and Azad, Meghan B. and Finlay, B. Brett}, doi = {10.1073/pnas.2501030122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2501030122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Human milk IgA promotes normal immune development by limiting th17-inducing erysipelatoclostridium ramosum in the infant gut}, volume = {122}, year = {2025}, }
• (2025). Including the gender dimension of migration is essential to avoid systematic bias in migration predictions. PNAS, 122(28), e2500874122. (www)

  @article{ , abstract = {This study examines the theoretical and methodological limitations of migration research in understanding gender-specific trends of migration. In particular, theory-driven methods suffer from the gender blindness of migration theories, while data-driven methods suffer from the scarcity of gender disaggregated migration data. This research aims to evaluate how these dual limitations affect the accuracy of commonly used migration prediction models. By analyzing migration flows disaggregated by gender, the study compares the performance of deterministic methods and probabilistic gravity-type models in predicting migrant flows with varying gender compositions. The findings reveal significant differences in the predictive performance of gravity-type models based on the gender composition of migration flows. Drawing on migration theories and case studies, the study contextualizes these findings, concluding that the lack of robust theoretical frameworks and the limited availability of gender-specific migration data have critically undermined the accuracy of current prediction and forecasting methods. The implications of this research highlight the urgent need for a critical reassessment of migration theories and methodologies through the lens of gender biases, paving the way for more inclusive and accurate migration predictions.}, archive = {J_PNAS}, author = {Anastasiadou, Athina and Zagheni, Emilio and de Valk, Helga A. G.}, doi = {10.1073/pnas.2500874122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2500874122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Including the gender dimension of migration is essential to avoid systematic bias in migration predictions}, volume = {122}, year = {2025}, }
• (2025). The eisenstein ideal at prime-square level has constant rank. PNAS, 122(28), e2500729122. (www)

  @article{ , abstract = {Let N and p be prime numbers with p ≥ 5 such that p ∣ ∣ ( N + 1 ) . In a previous paper, we showed that there is a cuspform f of weight 2 and level Γ 0 ( N 2 ) whose ℓ -th Fourier coefficient is congruent to ℓ + 1 modulo a prime above p for all primes ℓ . In this paper, we prove that this form f is unique up to Galois conjugacy, and the extension of Z p generated by the coefficients of f is exactly Z p [ ζ p + ζ p − 1 ] . We also prove similar results when a higher power of p divides N + 1 .}, archive = {J_PNAS}, author = {Lang, Jaclyn and Wake, Preston}, doi = {10.1073/pnas.2500729122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2500729122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The eisenstein ideal at prime-square level has constant rank}, volume = {122}, year = {2025}, }
• (2025). Controlling t cell–tumor cell interaction with a biomimetic physical barrier for cancer immunotherapy. PNAS, 122(28), e2500589122. (www)

  @article{ , abstract = {Cancer immunotherapy has shown tremendous promise in various cancers. However, current strategies, such as immune checkpoint blockade, primarily restore exhausted T cells but provide only transient efficacy, as the rapid clearance of antibodies. Their limited durability is further hindered by persistent T cell-tumor cell interactions that accelerate T cell exhaustion. To prevent T cells from sustained exposure to these interactions, we present a hydrogel-based biomimetic physical barrier (BPB) here to create a “protective zone” for T cells. The BPB temporarily blocks T cell-tumor cell interactions and shields T cells from inactivation and exhaustion, allowing them to accumulate and maintain their functional activity in the tumor microenvironment. After sufficient T cell accumulation, the dismantling of BPB triggered by near-infrared light irradiation-induced gel-sol transition will restore the interaction between T cells and tumor cells. This controlled re-exposure allows the accumulated T cells to attack the tumor cells in a more activated and anti-exhaustion state, maximizing their tumor-killing potential. Moreover, BPB not only enhances immediate tumor regression but also triggers systemic immune activation and durable memory responses, enabling long-term protection against tumor rechallenge and effective control of multifocal tumors. Collectively, our BPB for modulating the T cell-tumor cell interaction has great prospects for advancing cancer immunotherapy.}, archive = {J_PNAS}, author = {Zhang, Yuxuan and Wang, Jinjin and Qing, Guangchao and Wang, Yongchao and Li, Xianlei and Luo, Ting and Wang, Yi-Feng and Liu, Lu and Wang, Yufei and Ni, Qiankun and Li, Shuyi and Chen, Junge and Li, Fangzhou and Guo, Weisheng and Zhang, Jinchao and Gong, Ningqiang and Liang, Xing-Jie}, doi = {10.1073/pnas.2500589122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2500589122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Controlling t cell–tumor cell interaction with a biomimetic physical barrier for cancer immunotherapy}, volume = {122}, year = {2025}, }
• (2025). P63 and ZNF148 cooperate to regulate head and neck squamous cell carcinoma. PNAS, 122(28), e2500579122. (www)

  @article{ , abstract = {Head and neck squamous cell carcinoma (HNSCC) is a common and aggressive malignancy. While significant advances have been made in the management of low-grade cancer, treatment of advanced HNSCC remains challenging. Here, we used a proteomic approach to find binding partners of the oncogene p63, the most frequently amplified transcription factor in HNSCC. We identified a zinc finger protein, ZNF148, which is coexpressed and physically binds p63 in carcinoma cells. Genome occupancy analyses identified a functional transcribed enhancer-derived RNA (eRNA) upstream of the CCND1 gene occupied by both factors. Mechanistically, p63 and ZNF148 control transcription of this eRNA, leading to overexpression of cyclin D1 to reinforce tumor cell proliferation. Importantly, this axis is specific for cancer cells and remains inactive in normal epithelial cells. The expression levels of these factors and the eRNA are positively correlated in cancer and associated with advanced stage and metastasis. Collectively, our data reveal a molecular pathway controlling HNSCC progression and identify potential selective targets for cancer treatment.}, archive = {J_PNAS}, author = {Pecorari, Rosalba and Mancini, Mara and Smirnov, Artem and Corleone, Giacomo and Novelli, Flavia and Lena, Anna Maria and Franzese Canonico, Mariacristina and Montanaro, Manuela and Cappello, Angela and Sacconi, Andrea and Misso, Gabriella and Falco, Michela and Tammaro, Chiara and Ciccosanti, Fabiola and Piacentini, Mauro and Scimeca, Manuel and Caraglia, Michele and Blandino, Giovanni and Mauriello, Alessandro and Fanciulli, Maurizio and Melino, Gerry and Candi, Eleonora}, doi = {10.1073/pnas.2500579122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2500579122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {P63 and ZNF148 cooperate to regulate head and neck squamous cell carcinoma}, volume = {122}, year = {2025}, }
• (2025). The evolution of male–female dominance relations in primate societies. PNAS, 122(28), e2500405122. (www)

  @article{ , abstract = {Historically, it was widely assumed that males dominate females socially in most mammals. However, recent studies revealed significant variation within and among species, opening new possibilities to explore the extent and drivers of sex biases in dominance relations. This study uses quantitative data from 253 populations across 121 primate species to investigate the distribution of, and factors associated with, sex biases in the outcome of male–female contests. We first showed that male–female contests are common (around half of all contests) and that males win >90% of these contests in less than 20% of populations. We next tested five hypotheses to explain sex biases in dominance relations. We found that female-biased dominance primarily occurs in primate societies where females have substantial reproductive control, as in monogamous, sexually monomorphic, and arboreal species. Female-biased dominance is also frequent in societies where female–female competition is intense, as in solitary or pair-living species where females are intolerant of each other, as well as in species where females face lower reproductive costs and are philopatric. Conversely, male-biased dominance is common in polygynous, dimorphic, terrestrial, and group-living species and often relies on physical superiority. In contrast, female empowerment hinges on alternative strategies, such as leveraging reproductive control. Our study highlights that male–female dominance relationships are highly variable and identifies the traits associated with the emergence of female- versus male-biased dominance in primate evolutionary history, which may also deepen our understanding of the origins of gender roles in early human societies.}, archive = {J_PNAS}, author = {Huchard, Elise and Kappeler, Peter M. and Smit, Nikolaos and Fichtel, Claudia and Lukas, Dieter}, doi = {10.1073/pnas.2500405122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2500405122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The evolution of male–female dominance relations in primate societies}, volume = {122}, year = {2025}, }
• (2025). Mycophenolic acid treatment drives the emergence of novel SARS-CoV-2 variants. PNAS, 122(28), e2500276122. (www)

  @article{ , abstract = {Mycophenolic acid (MPA) is commonly used in immunosuppressive regimens following solid organ transplantation. We demonstrate that MPA treatment reproducibly inhibits the replication of a range of viruses, including severe respiratory syndrome coronavirus 2 (SARS-CoV-2). Mechanistically, we identified cellular guanosine triphosphate pool depletion as a key mediator of this antiviral effect. Strikingly, this inhibition can be overcome which was correlated with the emergence of three breakthrough mutations in the SARS-CoV-2 genome (S P812R, ORF3 Q185H, and E S6L). Subsequent analyses confirmed that the combination of these mutations conferred accelerated replication kinetics, higher viral titers, and more rapid onset of cytopathic effects, but not MPA resistance. Comparison of global transcriptional responses to infection highlighted dysregulation of specific cellular gene programs under MPA treatment prior to breakthrough mutation emergence. Together, these findings identify viral and host drivers of variant emergence under immunosuppression. They also advocate for close monitoring of immunosuppressed patients, where emergence of novel viral variants with a fitness advantage may arise.}, archive = {J_PNAS}, author = {Meister, Toni Luise and Nocke, Maximilian K. and Heinen, Natalie and Burkard, Thomas L. and Brüggemann, Yannick and Westhoven, Saskia and Trüeb, Bettina and Ebert, Nadine and Thomann, Lisa and Lubieniecki, Krzysztof P. and Lubieniecka, Joanna M. and Döring, Kristina and Herrmann, Maike and Haid, Sibylle and Pietschmann, Thomas and Wiegmann, Bettina and Tao, Ronny and Pfefferle, Susanne and Addo, Marylyn M. and Thiel, Volker and Drexler, Ingo and Babel, Nina and Phuc Nguyen, Huu and Brown, Richard J. P. and Todt, Daniel and Steinmann, Eike and Pfaender, Stephanie}, doi = {10.1073/pnas.2500276122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2500276122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mycophenolic acid treatment drives the emergence of novel SARS-CoV-2 variants}, volume = {122}, year = {2025}, }
• (2025). SARS-CoV-2 infection induces ZBP1-dependent PANoptosis in bystander cells. PNAS, 122(28), e2500208122. (www)

  @article{ , abstract = {Virus-induced excessive inflammatory response is a key contributor to pathology in respiratory viral infections. However, the underlying mechanisms by which viral infection provokes intense inflammatory reaction and how sustained inflammation leads to tissue damage are not fully understood. Using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as an example, our research demonstrates that SARS-CoV-2 infection can induce PANoptosis in bystander cells, contributing to the persistence of inflammatory responses. Specifically, the activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) in infected cells leads to the secretion of 2′3′cGMP-AMP, TNF-α, and IFN-β. These molecules activate STING-induced autophagy-mediated ADAR1 degradation, resulting in the accumulation of Z-nucleic acid, which subsequently triggers ZBP1-dependent PANoptosis in bystander cells. Additionally, inhibiting the cGAS pathway or knocking out STING effectively reduces PANoptosis and alleviates the pathology associated with SARS-CoV-2 and influenza A virus infection in mouse models. Overall, our findings reveal the unexpected role of PANoptosis in bystander cells during SARS-CoV-2 infection as a mechanism driving pathological damage and persistent inflammatory responses. Targeting this process may offer a promising strategy to mitigate tissue damage in COVID-19 as well as other viral infections and inflammatory conditions.}, archive = {J_PNAS}, author = {Yang, Bo and Hu, Ao and Wang, Tiantian and Chen, Xiaolin and Ma, Caina and Yang, Xinyue and Deng, Kai}, doi = {10.1073/pnas.2500208122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2500208122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SARS-CoV-2 infection induces ZBP1-dependent PANoptosis in bystander cells}, volume = {122}, year = {2025}, }
• (2025). TaHSP18.6 and TaSRT1 interact to confer resistance to fusarium crown rot by regulating the auxin content in common wheat. PNAS, 122(28), e2500029122. (www)

  @article{ , abstract = {Fusarium crown rot (FCR) is one of the most serious soil-borne diseases in common wheat and has caused major wheat yield losses worldwide. Here, we identified an 18.6 kDa heat shock protein gene ( TaHSP18.6 ) through combining a transcriptome analysis and a genome-wide association study. We verified the positive role of TaHSP18.6 in regulating wheat FCR resistance using ethyl methanesulfonate (EMS) mutants and genetic transformation. Next, we screened a lysine deacetylase sirtuin-like (TaSRT1) to determine its potential interaction with TaHSP18.6. We demonstrated that TaSRT1 deacetylated TaHSP18.6 and thereby inhibited TaHSP18.6 protein accumulation. Haplotype analysis revealed that the K171M substitution of TaHSP18.6 generated a susceptible haplotype TaHSP18.6 M171 in wheat, and mass spectrometry results implied that K171 is a key lysine acetylation site. We confirmed the differential acetylation level between TaHSP18.6 K171 and TaHSP18.6 M171 by TaSRT1. Analysis of overexpression lines and EMS mutants showed that TaSRT1 negatively regulated wheat FCR resistance. Meanwhile, we identified that TaHSP18.6 interacted with an auxin-responsive protein IAA1 (TaIAA1) that negatively regulated FCR resistance. TaHSP18.6 overexpression and TaSRT1 mutation significantly increased the auxin content. Exogenous application of auxin substantially enhanced wheat FCR resistance. Taken together, we proposed a TaSRT1–TaHSP18.6 model regulating FCR resistance possibly through mediating TaIAA1 to change the endogenous auxin content in wheat plants.}, archive = {J_PNAS}, author = {Zhang, Ning and Liu, Lu and Li, Songgang and Wei, Yuhui and Ren, Wanting and Li, Mengyao and Zhao, Simin and Sun, Zhipeng and Yang, Xia and Ren, Yan and Yang, Mei and He, Guangming and Deng, Xing Wang and Chen, Feng}, doi = {10.1073/pnas.2500029122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2500029122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TaHSP18.6 and TaSRT1 interact to confer resistance to fusarium crown rot by regulating the auxin content in common wheat}, volume = {122}, year = {2025}, }
• (2025). OMT and tensor SVD–based deep learning model for segmentation and predicting genetic markers of glioma: A multicenter study. PNAS, 122(28), e2500004122. (www)

  @article{ , abstract = {Glioma is the most common primary malignant brain tumor and preoperative genetic profiling is essential for the management of glioma patients. Our study focused on tumor regions segmentation and predicting the World Health Organization (WHO) grade, isocitrate dehydrogenase (IDH) mutation, and 1p/19q codeletion status using deep learning models on preoperative MRI. To achieve accurate tumor segmentation, we developed an optimal mass transport (OMT) approach to transform irregular MRI brain images into tensors. In addition, we proposed an algebraic preclassification (APC) model utilizing multimode OMT tensor singular value decomposition (SVD) to estimate preclassification probabilities. The fully automated deep learning model named OMT-APC was used for multitask classification. Our study incorporated preoperative brain MRI data from 3,565 glioma patients across 16 datasets spanning Asia, Europe, and America. Among these, 2,551 patients from 5 datasets were used for training and internal validation. In comparison, 1,014 patients from 11 datasets, including 242 patients from The Cancer Genome Atlas (TCGA), were used as independent external test. The OMT segmentation model achieved mean lesion-wise Dice scores of 0.880. The OMT-APC model was evaluated on the TCGA dataset, achieving accuracies of 0.855, 0.917, and 0.809, with AUC scores of 0.845, 0.908, and 0.769 for WHO grade, IDH mutation, and 1p/19q codeletion, respectively, which outperformed the four radiologists in all tasks. These results highlighted the effectiveness of our OMT and tensor SVD–based methods in brain tumor genetic profiling, suggesting promising applications for algebraic and geometric methods in medical image analysis.}, archive = {J_PNAS}, author = {Zhu, Zhengyang and Wang, Han and Li, Tiexiang and Huang, Tsung-Ming and Yang, Huiquan and Tao, Zhennan and Tan, Zhong-Heng and Zhou, Jianan and Chen, Sixuan and Ye, Meiping and Zhang, Zhiqiang and Li, Feng and Liu, Dongming and Wang, Maoxue and Lu, Jiaming and Zhang, Wen and Li, Xin and Chen, Qian and Jiang, Zhuoru and Chen, Futao and Zhang, Xin and Lin, Wen-Wei and Yau, Shing-Tung and Zhang, Bing}, doi = {10.1073/pnas.2500004122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2500004122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {OMT and tensor SVD–based deep learning model for segmentation and predicting genetic markers of glioma: A multicenter study}, volume = {122}, year = {2025}, }
• (2025). Osteoinductive low-dose 3D porous calcium phosphate graphene oxide–integrated matrices enhance osteogenesis and mechanical properties. PNAS, 122(28), e2427124122. (www)

  @article{ , abstract = {Bone regeneration continues to be a challenge due to the complex nature of the tissue. Identifying new materials that stimulate regeneration while providing mechanical properties is an active area of research. One class of promising material in bone regeneration is graphene and its derivatives including graphene oxide (GO), the oxidized form of graphene. Recently, calcium phosphate graphene (CaPG), synthesized from GO, has been proven to have osteoinductive properties in vivo. However, CaPG is a powder, and therefore, processing is difficult. Here, we present a method for creating porous CaPG matrices by incorporating it in poly(lactic-co-glycolic acid) (PLGA). This research has comprehensively evaluated CaPG-encapsulated PLGA-based microspheres for localized delivery of osteoinductive inducerons, calcium, and phosphate ions for bone regenerative engineering. CaPG distribution improved mechanical properties and matrix hydrophilicity. CaPG-integrated matrices successfully supported cell viability, proliferation, and enhanced osteogenic differentiation of MC3T3-E1 cells assessed by alkaline phosphatase activity and calcium deposition. Major osteogenic gene expression significantly increased, including Sp7, bone gamma-carboxyglutamate protein, COL1A1, bone sialoprotein, and dentin matrix protein1. The CaPG-containing matrices induced the endogenous canonical Wnt/β-catenin signaling pathway, with no significant difference when treated with DKK1 inhibition, demonstrating its possible selective activation mechanism. The increased protein expression of pathway-specific target genes, Bone morphogenic protein-2 (BMP-2) and WNT-1-inducible-signaling pathway protein 1 (WISP-1), further confirmed endogenous activation of canonical Wnt/β-catenin signaling. These results suggest that CaPG-modified matrices improve the cellular osteogenic differentiation via the canonical Wnt/β-catenin signaling pathway. This study provides further mechanistic insights into the nature of crosstalk between cells and inducerons-rich functionalized matrices for osteoblastic differentiation and improved bone regeneration.}, archive = {J_PNAS}, author = {Hosseini, Fatemeh S. and Whitfield, Taraje and Orlando, Jason D. and Deng, Chenyun and Abedini, Amir A. and Argyrou, Chrysoula and Kan, Ho-Man and Ghosh, Debolina and Maye, Peter F. and Lo, Kevin W.-H. and Nair, LakshmiS. and Sydlik, Stefanie A. and Laurencin, Cato T.}, doi = {10.1073/pnas.2427124122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2427124122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Osteoinductive low-dose 3D porous calcium phosphate graphene oxide–integrated matrices enhance osteogenesis and mechanical properties}, volume = {122}, year = {2025}, }
• (2025). Patient-reported treatment outcomes in ME/CFS and long COVID. PNAS, 122(28), e2426874122. (www)

  @article{ , abstract = {Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are persistent multisystem illnesses affecting many patients. With no known effective FDA-approved treatments for either condition, patient-reported outcomes of treatments may prove helpful in identifying management strategies that can improve patient care and generate new avenues for research. Here, we present the results of an ME/CFS and long COVID treatment survey with responses from 3,925 patients. We assess the experiences of these patients with more than 150 treatments in conjunction with their demographics, symptoms, and comorbidities. Treatments with the greatest perceived benefits are identified. Patients with each condition who participated in the study shared similar symptom profiles, including all the core symptoms of ME/CFS, e.g., 89.7% of ME/CFS and 79.4% of long COVID reported postexertional malaise (PEM). Furthermore, treatment responses between these two patient groups were significantly correlated (R 2 = 0.68). Patient subgroups, characterized by distinct symptom profiles and comorbidities, exhibited increased responses to specific treatments, e.g., a POTS-dominant cluster benefiting from autonomic modulators and a cognitive-dysfunction cluster from CNS stimulants. This study underscores the symptomatic and therapeutic similarities between ME/CFS and long COVID and highlights the commonalities and nuanced complexities of infection-associated chronic diseases and related conditions. While this study does not provide recommendations for specific therapies, in the absence of approved treatments, insights from patient-reported experiences provide urgently needed real-world evidence for developing targeted patient care therapies and future clinical trials.}, archive = {J_PNAS}, author = {Eckey, Martha and Li, Peng and Morrison, Braxton and Bergquist, Jonas and Davis, Ronald W. and Xiao, Wenzhong}, doi = {10.1073/pnas.2426874122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2426874122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Patient-reported treatment outcomes in ME/CFS and long COVID}, volume = {122}, year = {2025}, }
• (2025). SHANK2 establishes auditory hair bundle architecture essential for mammalian hearing. PNAS, 122(28), e2426646122. (www)

  @article{ , abstract = {The mammalian auditory system relies on the precise architecture of the hair cell stereociliary bundle for effective sound transduction. Each bundle consists of approximately 100 actin-filled stereocilia arranged in a three-row staircase pattern, forming a linear shape in inner hair cells (IHCs) and a V-shape in outer hair cells (OHCs), the latter geometry being a hallmark of the mammalian cochlea. While the initial development from uniformly distributed microvilli into stereociliary bundles is guided by lateral migration of the kinocilium, the mechanisms that establish the characteristic bundle architecture and its functional significance remain unclear. Here, we show that SHANK2, a protein implicated in synaptic function and autism spectrum disorders, is a critical regulator of bundle architecture. SHANK2 localizes to the medial apical surface of developing hair cells. This localization is regulated by the small GTPase RAP1, independently of known lateral (Gαi, GPSM2) or medial (aPKCζ, PARD6B) proteins. Hair cell-specific ablation of Shank2 or Rap1 disrupts bundle architecture while preserving key features essential for mechanotransduction. In particular, OHCs lose their unique bundle geometry and show impaired amplification, especially at high frequencies. Longitudinal studies further reveal that this architectural disruption leads to progressive bundle degeneration and hearing loss. These findings suggest that the characteristic bundle architecture, particularly the V-shaped geometry of OHCs, is essential for high-frequency hearing and long-term bundle integrity in the mammalian cochlea.}, archive = {J_PNAS}, author = {Choi, Han Seul and Park, Hyeyoung and Min, Hyehyun and Kim, Kwan Soo and Kim, Soo Min and Li, Jinan and Liu, Chang and Ko, Hyuk Wan and Lee, Min Goo and Song, Lei and Zhao, Bo and Bok, Jinwoong}, doi = {10.1073/pnas.2426646122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2426646122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SHANK2 establishes auditory hair bundle architecture essential for mammalian hearing}, volume = {122}, year = {2025}, }
• (2025). Oxidative stress is a shared characteristic of ME/CFS and long COVID. PNAS, 122(28), e2426564122. (www)

  @article{ , abstract = {Over 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition marked by fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). With no clinically approved treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions. By studying bioenergetic characteristics of peripheral blood lymphocytes in 25 healthy controls, 27 ME/CFS, and 20 LC donors, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, especially in the memory subset. Using a combination of flow cytometry, RNA-seq, mass spectrometry, and systems chemistry analysis, we observed aberrations in reactive oxygen species (ROS) clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase protein levels, and glutathione peroxidase 4–mediated lipid oxidative damage. Strikingly, these redox pathways changes show sex-specific trends. While ME/CFS females exhibit higher total ROS and mitochondrial calcium levels, males have normal ROS levels, with pronounced mitochondrial lipid oxidative damage. In females, these higher ROS levels correlate with T cell hyperproliferation, consistent with the known role of elevated ROS in initiating proliferation. This hyperproliferation can be attenuated by metformin, suggesting this Food and Drug Administration (FDA)-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients. Moreover, these results suggest a shared mechanistic basis for the systemic phenotypes of ME/CFS and LC, which can be detected by quantitative blood cell measurements, and that effective, patient-tailored drugs might be discovered using standard lymphocyte stimulation assays.}, archive = {J_PNAS}, author = {Shankar, Vishnu and Wilhelmy, Julie and Curtis, Ellis J. and Michael, Basil and Cervantes, Layla and Mallajosyula, Vamsee and Davis, Ronald W. and Snyder, Michael and Younis, Shady and Robinson, William H. and Shankar, Sadasivan and Mischel, Paul S. and Bonilla, Hector and Davis, Mark M.}, doi = {10.1073/pnas.2426564122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2426564122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Oxidative stress is a shared characteristic of ME/CFS and long COVID}, volume = {122}, year = {2025}, }
• (2025). Optimization of a sarbecovirus llama nanobody–antigen binding interface via a combined computational and phage display protein engineering approach. PNAS, 122(28), e2426438122. (www)

  @article{ , abstract = {Single-domain antibodies, such as variable heavy domain of heavy chain (VHH) domains from camelids, are an attractive platform for therapeutic purposes. VHHs have a smaller size than traditional antibodies, which harbors certain advantages such as tissue penetration or accessing epitopes that may be shielded by protein domains. However, the smaller size of VHHs typically involves a smaller binding site, which can limit the scope of related antigens they are able to bind and, in the specific case of antiviral VHHs, render them susceptible to escape by a single point mutation. Here, we present a combined computational and experimental protein engineering approach to broaden the reactivity of SARS-CoV-1 receptorbinding domain (RBD)-specific VHH-72 for SARS-CoV-2 and Delta. Our strategy focuses on increasing the size of the binding site by imparting “second site” interactions toward heterologous antigens. We utilized the residue-based pharmacophore modeling approach, Protein-ligandinterface design (ProtLID), to identify potential productive side chain interactions in this second site and then encoded the ProtLID-predicted restricted diversity into a VHH-72-based phage library, which we then screened for cross-reactive SARS-CoV-1/2 RBD clones. Based on sequence analysis from the resulting population of functional VHH clones, we identified a VHH-72 triple mutant (T60P.D61P.D100eY), which maintained high affinity for SARS-CoV-1 RBD but was enhanced by 18- and 20-fold for RBDs from SARS-CoV-2 and Delta relative to WT VHH-72. These results highlight the potential of computationally customizing phage display diversity for single-domain binding proteins and provide a strategy for designing extension of protein binding interfaces.}, archive = {J_PNAS}, author = {Ramos, Kevin E. and Nandigrami, Prithviraj and Najafian, Ahmad and Lai, Jonathan R. and Fiser, Andras}, doi = {10.1073/pnas.2426438122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2426438122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Optimization of a sarbecovirus llama nanobody–antigen binding interface via a combined computational and phage display protein engineering approach}, volume = {122}, year = {2025}, }
• (2025). The pathogenic factor of ZC4H2-associated rare disorder is a postsynaptic regulator for synaptic activity and cognitive function. PNAS, 122(28), e2426375122. (www)

  @article{ , abstract = {The maintenance of excitatory synaptic activity is crucial for cognitive function and genetic mutations are responsible for the pathogenesis of related brain disorders. However, the roles of these pathogenic factors in synaptic dysregulation and cognitive malfunction are still poorly understood. In this study, a conditional knockout mouse model lacking ZC4H2 —an X-linked gene implicated in ZC4H2-associated rare disorder (ZARD) —in forebrain excitatory neurons is generated and these mice exhibit cognitive malfunction, recapitulating the intellectual disability manifestation of ZARD. Mechanistically, ZC4H2 harbors a protein interaction network with key excitatory synaptic regulators and ZC4H2 interacts directly with AMPA receptors (AMPARs) and regulates their ubiquitination at the postsynaptic sites, thereby maintaining AMPARs protein stability and synaptic expression. ZC4H2 deficiency specifically and aberrantly increases AMPAR-mediated excitatory synaptic transmission and impairs synaptic plasticity of long-term potentiation. More importantly, pharmacological treatment with perampanel, an AMPAR-specific antagonist, successfully restores the excitatory synaptic activity and cognitive function of ZC4H2-deficient mice. Together, we establish that ZC4H2 is a postsynaptic regulator for AMPARs and excitatory synaptic activity and highlight that the dysregulation of these biological processes is a crucial etiology underlying ZARD-associated intellectual disability.}, archive = {J_PNAS}, author = {Wan, Li Pear and Li, Yuwei and Zhao, Shuhua and Zhao, Shiping and Song, Ning-Ning and Yuan, Kai-Ming and Yang, Cuiping and Ding, Yu-Qiang and Mao, Bingyu and Sheng, Nengyin and Tao, Wucheng and Ma, Pengcheng}, doi = {10.1073/pnas.2426375122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2426375122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The pathogenic factor of ZC4H2-associated rare disorder is a postsynaptic regulator for synaptic activity and cognitive function}, volume = {122}, year = {2025}, }
• (2025). Summer and nonsummer climatic signals in speleothem δ18O revealed by loess microcodium δ18O in east asia. PNAS, 122(28), e2425565122. (www)

  @article{ , abstract = {Speleothem δ 18 O records from central southern China have long been regarded as a key benchmark for Asian summer monsoon intensity. However, the similar δ 18 O minima observed among precession minima and their link to seasonal precipitation mixing remains unclear. Here, we present a 400,000-y record of summer precipitation δ 18 O from loess microcodium, which captures distinct precession cycles similar to those seen in speleothem δ 18 O records, particularly during glacial periods. Notably, our microcodium δ 18 O record reveals very low-δ 18 O values during precession minima at peak interglacials, a feature absent in speleothem δ 18 O records from central southern China. This discrepancy suggests that the mixed summer and nonsummer climatic signals substantially influence the speleothem δ 18 O records from central southern China. Proxy-model comparisons indicate that the lack of very low-δ 18 O values in speleothem δ 18 O records is due to an attenuated summer signal contribution, resulting from a lower summer-to-annual precipitation ratio in southern China at strong monsoon intervals. Our findings offer a potential explanation for the long-standing puzzle of the absence of 100- and 41-kyr cycles in speleothem δ 18 O records and underscore the critical role of seasonality in interpreting paleoclimatic proxies in central southern China. These insights also have broader implications for interpreting speleothem δ 18 O records globally, advocating for a more multiseason interpretive framework.}, archive = {J_PNAS}, author = {Zhang, Zeke and Liu, Zhengyu and Li, Gaojun and Cai, Yanjun and Wen, Qin and Cheng, Hai and Lawrence Edwards, R. and Lei, Jing and Liu, Heng and Jing, Zhaowei and Li, Tao and Clemens, Steven C. and Wang, Yongjin and Sun, Youbin and Shi, Zhengguo and Tan, Liangcheng and Kang, Shugang and Wang, Xulong and Jin, Zhangdong and Zhou, Weijian and An, Zhisheng}, doi = {10.1073/pnas.2425565122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2425565122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Summer and nonsummer climatic signals in speleothem δ18O revealed by loess microcodium δ18O in east asia}, volume = {122}, year = {2025}, }
• (2025). Electrochemically controlled switching of dyes for enhanced superresolution optical fluctuation imaging (EC-SOFI). PNAS, 122(28), e2425390122. (www)

  @article{ , abstract = {In superresolution optical fluctuation imaging (SOFI), molecules spaced closer than the diffraction limit can be separated through spatial and temporal correlation analysis of the fluorescence intensity fluctuations. The resolution and speed of SOFI imaging greatly depend on the characteristics of these fluorescence fluctuations. Fluorophores with stochastic and rapid fluorescence fluctuations are favorable for improving SOFI imaging resolution and speed, especially in high-order cumulant analysis. Stochastic blinking of organic dyes in oxygen scavenging and thiol reducing buffers are well suited for SOFI due to their high brightness. However, the blinking rates can be too slow and nonuniform, which introduces nonlinearity in SOFI image. To address these challenges, we introduce electrochemically controlled dye switching for SOFI (EC-SOFI). By applying an oscillating electrochemical potential to a transparent electrode surface, we increase the overall dye switching rate and uniformity. Using Alexa 647 dye as an example, EC-SOFI reduces the average ON time by over threefold and switching variance by more than twofold compared to conventional photochemical switching, achieving ~60 nm spatial resolution in 6th order EC-SOFI image. We further demonstrate that EC-SOFI achieves ~130 nm and ~80 nm resolution with 100 and 300 frames, respectively, enabling fast, large-area tile-scan superresolution imaging. This advancement in EC-SOFI significantly enhances the practical potential of the SOFI technique.}, archive = {J_PNAS}, author = {Yang, Ying and Ma, Yuanqing and Tilley, Richard D. and Gooding, J. Justin}, doi = {10.1073/pnas.2425390122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2425390122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electrochemically controlled switching of dyes for enhanced superresolution optical fluctuation imaging (EC-SOFI)}, volume = {122}, year = {2025}, }
• (2025). Resolving the structure and dynamics of the disordered c terminus of human cardiac troponin t and effects of cardiomyopathic mutations. PNAS, 122(28), e2425343122. (www)

  @article{ , abstract = {The C-terminal tail of cardiac troponin T (C-cTnT) inhibits thin filament activation and is a hotspot for cardiomyopathic mutations and variants. The mechanism whereby this region limits activation is not well understood. The last 16 C-terminal residues form a highly flexible and disordered domain and thus have been poorly resolved in studies to date. Using Time-Resolved fluorescence resonance energy transfer (TR-FRET) we resolved the structure of the disordered C-cTnT and studied the structural and dynamic effects of cardiomyopathic mutations on the region. For wildtype (WT) thin filaments, our data revealed a repositioning of cTnT-274 closer to cTnC when bound with calcium and myosin, while cTnT-283 did not move relative to cTnC. Myosin binding decreased the flexibility of cTnT-274 while having no effect on cTnT-283. We found that hypertrophic cardiomyopathy mutation cTnT-K273E decreased flexibility and placed the C-cTnT in an activated position in the blocked and closed states, resulting in increased actomyosin interactions in the absence of calcium; while dilated cardiomyopathy mutation cTnT-D270N increased flexibility and decreased the ability of the C-cTnT to reach its activated position in the open state but had no effect on actomyosin interactions. Our results demonstrate the WT C-cTnT undergoes a disordered to ordered transition upon myosin binding that is directly altered in the presence of cardiomyopathic mutations. These data provide a structural framework for the coupling of TR-FRET with high-resolution molecular dynamics as a tool for interrogating intermolecular interactions of intrinsically disordered proteins and protein complexes.}, archive = {J_PNAS}, author = {Crosby, Garrett S. and Hei, Bai and Lynn, Melissa L. and Chakraborti, Ananya and Schwartz, Steven D. and Tardiff, Jil C.}, doi = {10.1073/pnas.2425343122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2425343122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Resolving the structure and dynamics of the disordered c terminus of human cardiac troponin t and effects of cardiomyopathic mutations}, volume = {122}, year = {2025}, }
• (2025). A meta-analysis of the effectiveness of gratitude interventions on well-being across cultures. PNAS, 122(28), e2425193122. (www)

  @article{ , abstract = {Gratitude practice is a popular strategy for promoting happiness worldwide. However, is it equally effective for people from different cultural backgrounds? To answer this question, we conducted a preregistered meta-analysis on the effectiveness of gratitude interventions on well-being across cultures. Using data from 145 papers, 163 samples, 727 effect sizes, and 24,804 participants from 28 countries, we found that gratitude interventions led to small overall increases in well-being, Hedges’ g = 0.19, 95% CI [0.15, 0.22]. Moderation analyses revealed significant between-country differences in the effects of gratitude interventions. However, we found no significant evidence of moderators explaining such cross-cultural variability, highlighting the need for more primary research in this domain. Subsequent analyses indicated that three methodological characteristics moderated the effects: well-being outcomes, intervention types, and randomization. The effectiveness of gratitude interventions was greater when well-being outcomes were measured as positive affect, when multiple types of gratitude interventions were combined, and when randomized controlled trials were employed. Overall, the results appeared to be robust against publication bias and the presence of influential cases. These findings contribute to a deeper understanding of the effectiveness of gratitude interventions on well-being across cultural contexts and methodological characteristics.}, archive = {J_PNAS}, author = {Choi, Hyewon and Cha, Youngjae and McCullough, Michael E. and Coles, Nicholas A. and Oishi, Shigehiro}, doi = {10.1073/pnas.2425193122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2425193122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A meta-analysis of the effectiveness of gratitude interventions on well-being across cultures}, volume = {122}, year = {2025}, }
• (2025). A noncanonical cGAS–STING pathway drives cellular and organismal aging. PNAS, 122(28), e2424666122. (www)

  @article{ , abstract = {Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. Stimulator of interferon genes (STING) protein translates the sensing of cytosolic DNA by cyclic-GMP-AMP synthase (cGAS) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS–STING pathway leads to aging remain poorly understood. We show that STING does not follow the canonical pathway of activation in human fibroblasts passaged (aging) in culture, senescent fibroblasts, or progeria fibroblasts (from Hutchinson–Gilford progeria syndrome patients). Despite cytosolic DNA buildup, features of the canonical cGAS–STING pathway like increased cGAMP production, STING phosphorylation, and STING trafficking to perinuclear compartment are not observed in progeria/senescent/aging fibroblasts. Instead, STING localizes at endoplasmic reticulum, nuclear envelope, and chromatin. Despite the nonconventional STING behavior, aging/senescent/progeria cells activate inflammatory programs such as the senescence-associated secretory phenotype and the interferon response, in a cGAS and STING-dependent manner, revealing a noncanonical pathway in aging. Importantly, progeria/aging/senescent cells are hindered in their ability to activate the canonical cGAS–STING pathway with synthetic DNA, compared to young cells. This deficiency is rescued by activating vitamin D receptor signaling, unveiling mechanisms regulating the cGAS–STING pathway in aging. Significantly, in HGPS, inhibition of the noncanonical cGAS–STING pathway ameliorates cellular hallmarks of aging, reduces tissue degeneration, and extends the lifespan of progeria mice. Our study reveals that a new feature of aging is the progressively reduced ability to activate the canonical cGAS–STING pathway in response to cytosolic DNA, triggering instead a noncanonical pathway that drives senescence/aging phenotypes.}, archive = {J_PNAS}, author = {Cancado de Faria, Rafael and Silva, Lilian N. D. and Teodoro-Castro, Barbara and McCommis, Kyle S. and Shashkova, Elena V. and Gonzalo, Susana}, doi = {10.1073/pnas.2424666122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2424666122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A noncanonical cGAS–STING pathway drives cellular and organismal aging}, volume = {122}, year = {2025}, }
• (2025). Stress-mediated growth determines escherichia coli division site morphogenesis. PNAS, 122(28), e2424441122. (www)

  @article{ , abstract = {In order to proliferate, bacteria must remodel their cell wall at the division site. The division process is driven by the enzymatic activity of peptidoglycan synthases and hydrolases around the constricting Z-ring. We introduce a morphoelastic model that correctly reproduces the shape of the division site during the constriction and septation phases of Escherichia coli . In the model, mechanical stress directs the transformation of the bacterial wall. The two constants associated with growth and remodeling respectively are its only adjustable parameters. Different morphologies, corresponding either to mutant or wild type cells, are recovered as a function of the remodeling parameter. In addition, a plausible range for the cell stiffness and turgor pressure was determined by comparing numerical simulations with bacterial cell plasmolysis data.}, archive = {J_PNAS}, author = {Pelech, Petr and Navarro, Paula P. and Vettiger, Andrea and Chao, Luke H. and Allolio, Christoph}, doi = {10.1073/pnas.2424441122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2424441122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stress-mediated growth determines escherichia coli division site morphogenesis}, volume = {122}, year = {2025}, }
• (2025). BIK polymorphism and proteasome regulation unveil host risk factor for severe influenza. PNAS, 122(28), e2424367122. (www)

  @article{ , abstract = {Influenza A viruses (IAVs) pose a significant public health threat, with host factors playing a crucial role in disease severity. We investigated the role of Bcl-2-interacting killer (BIK) in IAV infection using cellular and mouse models, and influenza-infected human cohort. In airway epithelial cells (AECs), BIK deficiency impaired viral replication, while BIK restoration enhanced it. Conversely, airway-specific BIK overexpression in mice increased viral load, inflammation, and mortality, whereas BIK suppression conferred protection. Critically, a genetic variation (rs738276) in the BIK gene, influencing BIK expression, correlates with altered viral replication in air–liquid interface differentiated primary normal human bronchial epithelial cells and influenza severity in humans. Mechanistically, we demonstrate that IAV nucleoprotein (NP) suppresses β5, a subunit of the proteasome, leading to increased BIK levels and enhanced viral replication. Conversely, β5 treatment dampened BIK levels and protected mice from IAV-induced morbidity and mortality. Furthermore, BIK interacts with NP, disrupting the Bcl-2/NP interaction and promoting viral replication. Our findings uncover an IAV–BIK–β5 axis that governs viral replication, suggesting that targeting BIK or β5 may offer therapeutic strategies against influenza.}, archive = {J_PNAS}, author = {Soni, Sourabh and Yildiz, Soner and Allen, Emma Kaitlynn and Petersen, Hans and Peeples, Mark and El Zahed, Sara and Rosas, Lorena and Anang, Vandana and Antonescu, Laura and Nho, Richard Seonghun and Mora, Ana Lucia and Horowitz, Jeffrey Craig and Rojas, Mauricio and Medina, Rafael Andrés and Thomas, Paul Glyndwr and García-Sastre, Adolfo and Tesfaigzi, Yohannes and Mebratu, Yohannes Afework}, doi = {10.1073/pnas.2424367122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2424367122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {BIK polymorphism and proteasome regulation unveil host risk factor for severe influenza}, volume = {122}, year = {2025}, }
• (2025). Motilin stimulates food intake linked to gastric motility in suncus murinus: Simultaneous recordings of food intake and gastric motility in the conscious state. PNAS, 122(28), e2424363122. (www)

  @article{ , abstract = {The intestinal-derived hormone motilin, a peptide belonging to the ghrelin family, induces strong gastric contractions and hunger sensations. However, whether motilin regulates food intake and its association with gastric motility remains unclear. Rodents are unsuitable for animal studies of motilin function, as both the motilin and motilin-receptor genes exist only as pseudogenes in their genomes. In this study, we investigated the role of motilin on food intake by simultaneously monitoring gastric contractions and their central mechanisms in the house musk shrew ( Suncus murinus ), a small mammal that produces motilin. In the interdigestive state, plasma motilin concentrations were elevated during spontaneous phase III contractions of the migrating motor complex (MMC) than during phase I contractions. Food intake during spontaneous phase III contractions was higher than that during phase I contractions. Intravenous motilin administration stimulated food intake during phase I, although its effect was weaker than that of ghrelin. Motilin-induced food intake was abolished in vagotomized suncus. Additionally, motilin increased c-Fos expression in tyrosine hydroxylase (TH) neurons in the area postrema and nucleus of the solitary tract of the brain stem, as well as in activated neuropeptide Y and TH neurons in the arcuate nucleus of the hypothalamus. These results revealed that motilin stimulated feeding linked to gastric motility through the vagus nerve and activated brain regions associated with food intake. Our findings provide evidence that motilin regulates food intake, highlighting its potential as a therapeutic strategy for appetite disorders.}, archive = {J_PNAS}, author = {Huang, Jin and Watanabe, Ayumi and Kanaya, Moeko and Gomi, Ayano and Yokoyama, Haruka and Ishii, Hikari and Nakamura, Yusuke and Azuma, Morio and Konno, Norifumi and Kaiya, Hiroyuki and Sakai, Takafumi and Sakata, Ichiro}, doi = {10.1073/pnas.2424363122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2424363122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Motilin stimulates food intake linked to gastric motility in suncus murinus: Simultaneous recordings of food intake and gastric motility in the conscious state}, volume = {122}, year = {2025}, }
• (2025). Genome analyses suggest recent speciation and postglacial isolation in the norwegian lemming. PNAS, 122(28), e2424333122. (www)

  @article{ , abstract = {The Norwegian lemming ( Lemmus lemmus ) is a small rodent distributed across the Fennoscandian mountain tundra and the Kola Peninsula. The Norwegian lemming likely evolved during the Late Pleistocene and inhabited Fennoscandia shortly prior to the Last Glacial Maximum. However, the exact timing and origins of the species, and its phylogenetic position relative to the closely related Siberian lemming ( Lemmus sibiricus ) remain disputed. Moreover, the presence of ancient or contemporary gene flow between both species is largely untested. The Norwegian lemming displays characteristic phenotypic and behavioral adaptations (e.g., coat color, aggression) that are not present in other Lemmus species. We generated a de novo genome assembly for the Norwegian lemming and resequenced nine modern and two ancient Lemmus spp. genomes. We show that all Lemmus species form distinct monophyletic clades, with concordant topology between the mitochondrial and nuclear genome phylogenies. The Siberian lemming is divided into two distinct but paraphyletic clades, one in the east and one in the west, where the western clade represents a sister taxon to the Norwegian lemming. We estimate that the Norwegian and western Siberian lemming diverged shortly before the Last Glacial Maximum, making the Norwegian lemming one of the youngest known mammalian species. We did not find any indication of gene flow between L. lemmus and L. sibiricus , suggesting postglacial isolation of L. lemmus . Furthermore, we identify species-specific genomic differences in genes related to coat color and fat transport, which are likely associated with the distinctive coloration and overwintering behavior observed in the Norwegian lemming.}, archive = {J_PNAS}, author = {Lord, Edana and Feinauer, Isabelle S. and Soares, André E. R. and Lagerholm, Vendela K. and Näsvall, Karin and Ersmark, Erik and Olsen, Remi-André and Prost, Stefan and Kuzmina, Elena A. and Smirnov, Nickolay G. and Stewart, John R. and Knul, Monika V. and Noiret, Pierre and Germonpré, Mietje and Ehrich, Dorothee and Pokrovsky, Ivan and Fedorov, Vadim B. and Goropashnaya, Anna V. and Dalén, Love and Díez-del-Molino, David}, doi = {10.1073/pnas.2424333122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2424333122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genome analyses suggest recent speciation and postglacial isolation in the norwegian lemming}, volume = {122}, year = {2025}, }
• (2025). Regulation of Na/Ca exchange by cytoplasmic protons modifies intracellular calcium dynamics and the cardiac response to ischemia. PNAS, 122(28), e2423203122. (www)

  @article{ , abstract = {The cardiac sodium–calcium exchanger (NCX1) is a critical regulator of intracellular calcium (Ca) in cardiomyocytes. Although strongly regulated by pH, the role of NCX1 pH sensitivity in cardiac function and intracellular Ca regulation is not understood. We used CRISPR/Cas9 to produce a pH-resistant NCX1 mouse by replacing histidine 165 with alanine (H165A). H165A mice live into adulthood and are fertile. Comparative studies in isolated ventricular myocytes demonstrated that NCX1 current (I NCX ) was significantly inhibited by lowering pH i to ~6.5 in the wild type (WT) but was unaffected in myocytes from pH-resistant H165A mice. Similarly, in WT cardiomyocytes loaded with the Ca indicator fura-2 AM, Ca transient amplitude increased dramatically during field stimulation when pH i was lowered to 6.5, consistent with impaired Ca efflux caused by proton-mediated NCX1 inhibition. In contrast, Ca transients were unchanged by low pH i in H165A myocytes, indicating effective Ca efflux by the mutant exchanger despite acidosis. When we subjected H165A mouse hearts to ischemia/reperfusion, where cellular injury is thought to result in part from Ca accumulation and inhibition of NCX1 by ischemic acidosis, there was reduced injury and improved recovery of function compared to WT. These results reveal that maintaining NCX1 activity during ischemia, and presumably maintaining Ca extrusion, is a powerful approach to protect or precondition the heart against injury that would otherwise occur subsequently during reperfusion. We conclude that allosteric regulation of NCX1 by protons is a highly relevant physiological process that takes place in clinical settings associated with abnormally low pH, such as cardiac ischemia.}, archive = {J_PNAS}, author = {Zhang, Rui and Wu, Xiaokang and Kim, Seho and Kim, Brian and Xie, Catherine and Gonzalez, Devina and Norris, Raven and Chin, Nicholas and Li, Liang and John, Scott and Philipson, Kenneth D. and Ottolia, Michela and Goldhaber, Joshua I.}, doi = {10.1073/pnas.2423203122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2423203122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Regulation of Na/Ca exchange by cytoplasmic protons modifies intracellular calcium dynamics and the cardiac response to ischemia}, volume = {122}, year = {2025}, }
• (2025). Multiorgan transcriptomics in mice identifies immunoglobulin heavy constant mu (Ighm) as a tissue-level aging biomarker. PNAS, 122(28), e2423142122. (www)

  @article{ , abstract = {Identifying aging-associated biomarkers applicable for multiple tissues is challenging but crucial for assessing tissue aging. Here, we obtained and analyzed 456 transcriptomes on 17 organs from 30 C57BL/6 J mice with different ages, revealing the consistently upregulated mRNAs of Ighm , C4b , and Ccl8 in most aged organs. This finding received support from independent transcriptomic and proteomic datasets and was further validated through western blot, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence, arguing for both Ighm mRNA and protein as tissue-level aging biomarkers, at least in mice. Its sensitivity to antiaging interventions further emphasizes the significance of Ighm in assessing tissue aging in mice.}, archive = {J_PNAS}, author = {Yin, Fan-Qian and Wang, Xia-Yan and Li, Yong-Xuan and Li, Kai-Jing and Ma, Si-Yu and Lv, Meng-Jiao and Liu, Zhen-Hua and Zhong, Wei-Xia and Liu, Yan and Tang, Chuan-Fang and Liu, Hong-Shi and Li, Yuze and Xiao, Fu-Hui and Kong, Qing-Peng}, doi = {10.1073/pnas.2423142122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2423142122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multiorgan transcriptomics in mice identifies immunoglobulin heavy constant mu (Ighm) as a tissue-level aging biomarker}, volume = {122}, year = {2025}, }
• (2025). Diffusion of complex contagions is shaped by a trade-off between reach and reinforcement. PNAS, 122(28), e2422892122. (www)

  @article{ , abstract = {How does social network structure amplify or stifle behavior diffusion? Existing theory suggests that when social reinforcement makes the adoption of behavior more likely, it should spread more—both farther and faster—on clustered networks with redundant ties. Conversely, if adoption does not benefit from social reinforcement, it should spread more on random networks which avoid such redundancies. We develop a model of behavior diffusion with tunable probabilistic adoption and social reinforcement parameters to systematically evaluate the conditions under which clustered networks spread behavior better than random networks. Using simulations and analytical methods, we identify precise boundaries in the parameter space where one network type outperforms the other or they perform equally. We find that, in most cases, random networks spread behavior as far or farther than clustered networks, even when social reinforcement increases adoption. Although we find that probabilistic, socially reinforced behaviors can spread farther on clustered networks in some cases, this is not the dominant pattern. Clustered networks are even less advantageous when individuals remain influential for longer after adopting, have more neighbors, or need more neighbors before social reinforcement takes effect. Under such conditions, clustering tends to help only when adoption is nearly deterministic, which is not representative of socially reinforced behaviors more generally. Clustered networks outperform random networks by a 5% margin in only 22% of the parameter space under its most favorable conditions. This pattern reflects a fundamental trade-off: Random ties enhance reach, while clustered ties enhance social reinforcement.}, archive = {J_PNAS}, author = {Wan, Allison and Riedl, Christoph and Lazer, David}, doi = {10.1073/pnas.2422892122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2422892122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Diffusion of complex contagions is shaped by a trade-off between reach and reinforcement}, volume = {122}, year = {2025}, }
• (2025). Temperature-invariant crystal–glass heat conduction: From meteorites to refractories. PNAS, 122(28), e2422763122. (www)

  @article{ , abstract = {The thermal conductivities of crystals and glasses vary strongly and with opposite trends upon heating, decreasing in crystals and increasing in glasses. Here, we show that the dominant conduction mechanisms of crystals (particle-like propagation) and glasses (wave-like tunneling) can compensate in materials with crystalline bond order and nearly glassy bond geometry, yielding a hybrid crystal–glass conductivity that is constant from the quantum to the classical regime (i.e., from below to above the Debye temperature). We showcase these arguments with a combined theoretical and experimental study on meteoritic silica (a tridymite carved from a sample found in Steinbach, Germany, in 1724) and on a geometrically amorphous tridymite phase found in refractory bricks used in furnaces for steel smelting. Our results prove that temperature-invariant conductivities are not limited to the classical regime, and pave the way to understand or control heat-transport phenomena in solids exposed to extreme temperature variations, ranging from planetary cooling to heating protocols to reduce the carbon footprint of industrial furnaces.}, archive = {J_PNAS}, author = {Simoncelli, Michele and Fournier, Daniele and Marangolo, Massimiliano and Balan, Etienne and Béneut, Keevin and Baptiste, Benoit and Doisneau, Béatrice and Marzari, Nicola and Mauri, Francesco}, doi = {10.1073/pnas.2422763122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2422763122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Temperature-invariant crystal–glass heat conduction: From meteorites to refractories}, volume = {122}, year = {2025}, }
• (2025). Hippocampal blood oxygenation predicts choices about everyday consumer experiences: A deep-learning approach. PNAS, 122(28), e2421905122. (www)

  @article{ , abstract = {This research investigates the neurophysiological mechanisms of experiential versus monetary choices under risk. While ventral striatum and insula activity are instrumental in predicting monetary choices, we find that hippocampal activity plays a key role in predicting experiential choices, which we theorize is due to its role in retrieving autobiographical memories. This neurophysiological differentiation clarifies observed variations in risk preferences between experiential and monetary prospects and highlights the importance of domain-specific neurophysiological processes in shaping human decision-making.}, archive = {J_PNAS}, author = {Basavaraj, Chinmai and Reimann, Martin and Barnard, Kobus and Nadel, Lynn}, doi = {10.1073/pnas.2421905122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2421905122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hippocampal blood oxygenation predicts choices about everyday consumer experiences: A deep-learning approach}, volume = {122}, year = {2025}, }
• (2025). Autophagic stress activates distinct compensatory secretory pathways in neurons. PNAS, 122(28), e2421886122. (www)

  @article{ , abstract = {Autophagic dysfunction is a hallmark of neurodegenerative disease, leaving neurons vulnerable to the accumulation of damaged organelles and aggregated proteins. However, the late onset of diseases suggests that compensatory quality control mechanisms may be engaged to delay these deleterious effects. Neurons expressing common familial Parkinson’s disease-associated mutations in the leucine-rich repeat kinase 2 (LRRK2) exhibit defective autophagy. Here, we demonstrate that both primary murine neurons and human induced Pluripotent Stem Cells (iPSC)-derived neurons harboring pathogenic LRRK2 upregulate the secretion of extracellular vesicles. We used unbiased proteomics to characterize the secretome of LRRK2 G2019S neurons and found that autophagic cargos including mitochondrial proteins were enriched. Based on these observations, we hypothesize that autophagosomes are rerouted toward secretion when cell-autonomous degradation is compromised to mediate clearance of undegraded cellular waste. Immunoblotting confirmed the release of autophagic cargos and live-cell imaging demonstrated that secretory autophagy is upregulated in LRRK2 G2019S neurons. We also found that LRRK2 G2019S neurons upregulate the release of exosomes containing microRNAs. Live-cell imaging confirmed that this upregulation of exosomal release is dependent on hyperactive LRRK2 activity, while pharmacological experiments indicate that this release staves off apoptosis. Finally, we show that markers of both vesicle populations are upregulated in plasma from mice expressing pathogenic LRRK2. In sum, we find that neurons expressing pathogenic LRRK2 upregulate secretory autophagy and the compensatory release of exosomes to mediate waste disposal and transcellular communication, respectively. We propose that this increased secretion contributes to the maintenance of cellular homeostasis, delaying neurodegenerative disease progression over the short term while potentially contributing to neuroinflammation over the longer term.}, archive = {J_PNAS}, author = {Palumbos, Sierra D. and Popolow, Jacob and Goldsmith, Juliet and Holzbaur, Erika L. F.}, doi = {10.1073/pnas.2421886122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2421886122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Autophagic stress activates distinct compensatory secretory pathways in neurons}, volume = {122}, year = {2025}, }
• (2025). Structure-based discovery of positive allosteric modulators of the a1 adenosine receptor. PNAS, 122(28), e2421687122. (www)

  @article{ , abstract = {Allosteric modulation of G protein–coupled receptors (GPCRs) is an exciting strategy for developing new therapeutic agents, and it has several advantages over more commonly used orthosteric drugs. Recently determined GPCR structures have revealed allosteric pockets facing the lipid bilayer, enabling rational drug design. Here, we develop a virtual screening strategy to discover ligands of extrahelical binding pockets and apply this approach to the adenosine A 1 receptor (A 1 R). The A 1 R is a high-value therapeutic target for ischemia–reperfusion injury and chronic neuropathic pain. Developing effective A 1 R therapeutics remains challenging due to high structural conservation across orthosteric binding sites and on-target unwanted effects stimulated by prototypical A 1 R agonists, such as bradycardia and atrioventricular block. However, A 1 R positive allosteric modulators (PAMs) acting through spatially distinct allosteric sites can fine-tune A 1 R activity with high subtype selectivity and spatiotemporal specificity, thereby overcoming current limitations. A chemical library of 160 million compounds was computationally docked to the allosteric pocket identified in a cryo-EM structure of the A 1 R, and a set of 26 top-ranked compounds were selected for experimental evaluation. Pharmacological evaluation of these, and structure-guided hit optimization, led to the discovery of subtype-selective A 1 R PAMs. These compounds demonstrated minimal allosteric agonism and negligible impact on A 1 R-mediated beat rate of an orthosteric agonist. The discovered PAMs pave the way for potential treatments for neuropathic pain and ischemia–reperfusion injury without accompanying side effects. Our results demonstrate the utility of a synergistic computational and experimental approach in GPCR drug discovery.}, archive = {J_PNAS}, author = {Nguyen, Anh T. N. and Panel, Nicolas and Vo, Duc Duy and Thai, Bui San and Chia, Ling Yeong and Lu, Cam Sinh and Hellyer, Shane D. and Langiu, Monica and Jörg, Manuela and Gregory, Karen J. and Kihlberg, Jan and White, Paul J. and Scammells, Peter J. and Christopoulos, Arthur and Carlsson, Jens and May, Lauren T.}, doi = {10.1073/pnas.2421687122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2421687122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure-based discovery of positive allosteric modulators of the a1 adenosine receptor}, volume = {122}, year = {2025}, }
• (2025). Strength and weakness of disease-induced herd immunity in networks. PNAS, 122(28), e2421460122. (www)

  @article{ , abstract = {When a fraction of a population becomes immune to an infectious disease, the population-wide infection risk decreases nonlinearly due to collective protection, known as herd immunity. Some studies based on mean-field models suggest that natural infection in a heterogeneous population may induce herd immunity more efficiently than homogeneous immunization. However, we theoretically show that this is not necessarily the case when the population is modeled as a network instead of using the mean-field approach. We identify two competing mechanisms driving disease-induced herd immunity in networks: the biased distribution of immunity toward socially active individuals enhances herd immunity, while the topological localization of immune individuals weakens it. The effect of localization is stronger in networks embedded in a low-dimensional space, which can make disease-induced immunity less effective than random immunization. Our results highlight the role of networks in shaping herd immunity and call for a careful examination of model predictions that inform public health policies.}, archive = {J_PNAS}, author = {Hiraoka, Takayuki and Ghadiri, Zahra and Rizi, Abbas K. and Kivelä, Mikko and Saramäki, Jari}, doi = {10.1073/pnas.2421460122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2421460122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Strength and weakness of disease-induced herd immunity in networks}, volume = {122}, year = {2025}, }
• (2025). The WWP1–JARID1B axis sustains acute myeloid leukemia chemoresistance. PNAS, 122(28), e2421159122. (www)

  @article{ , abstract = {To uncover substrates mediating the oncogenic activity of WWP1 in acute myeloid leukemia (AML), we performed a proteomic analysis that identified the histone demethylase KDM5B /JARID1B as a candidate target. Of note, JARID1B is indispensable for efficient recruitment of several DNA damage repair factors and for damage resolution, thus negatively influencing the sensitivity of cancer cells to chemo- and radiation therapies. Validation of JARID1B as a substrate of WWP1 revealed a positive regulation of JARID1B half-life by WWP1 through the establishment of K63-linked polyubiquitin chains. As a result, downregulation of JARID1B rising from WWP1 inactivation was associated with higher H3K4me3 enrichment at JARID1B target genes in WWP1-depleted relatively to control AML cells. Integration of RNA-seq and H3K4me3 ChIP-seq data uncovered a highly significant overlap between upregulated gene expression and enriched H3K4me3 peaks after shWWP1 inactivation. We confirmed transcriptional activation of JARID1B targets in WWP1-depleted cells, supporting a role for WWP1 in regulating JARID1B activity. Coherently, upon WWP1 inactivation, we observed a defective recruitment of repair proteins after DNA damage, with subsequent reduced DNA damage repair efficiency and enhanced sensitization of AML cells to the cytotoxic activity of chemotherapeutic drugs. All together, these data identify JARID1B as a bona fide target of WWP1 and imply that WWP1-mediated regulation of JARID1B impacts its ability to modify chromatin and to recruit DNA damage repair factors, thus ultimately affecting chemosensitivity of AML cells.}, archive = {J_PNAS}, author = {Fierro, Claudia and Giovannini, Sara and Moriconi, Valeria and Fiorilli, Claudia and Panatta, Emanuele and Frezza, Valentina and Corigliano, Federica and Pecorari, Rosalba and Li, Yanan and Zhou, Ji and Delvecchio, Vincenza Simona and Smirnov, Artem and Manteiga, Jose Manuel Garcia and Brendolan, Andrea and Zhang, Jinping and Shi, Yufang and Amelio, Ivano and Candi, Eleonora and Melino, Gerry and Bernassola, Francesca}, doi = {10.1073/pnas.2421159122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2421159122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The WWP1–JARID1B axis sustains acute myeloid leukemia chemoresistance}, volume = {122}, year = {2025}, }
• (2025). Multiarea processing in body patches of the primate inferotemporal cortex implements inverse graphics. PNAS, 122(28), e2420287122. (www)

  @article{ , abstract = {Stimulus-driven, multiarea processing in the inferotemporal (IT) cortex is thought to be critical for transforming sensory inputs into useful representations of the world. What are the formats of these neural representations and how are they computed across the nodes of the IT networks? A growing literature in computational neuroscience focuses on the computational-level objective of acquiring high-level image statistics that supports useful distinctions, including between object identities or categories. Here, inspired by classic theories of vision, we suggest an alternative possibility. We show that inferring 3D objects may be a distinct computational-level objective of IT, implemented via an algorithm analogous to graphics-based generative models of how 3D scenes form and project to images, but in the reverse order. Using perception of bodies as a case study, we show that inverse graphics spontaneously emerges in inference networks trained to map images to 3D objects. Remarkably, this correspondence to the reverse of a graphics-based generative model also holds across the body processing network of the macaque IT cortex. Finally, inference networks recapitulate the feedforward progression across the stages of this IT network and do so better than the currently dominant vision models, including both supervised and unsupervised variants, none of which aligns with the reverse of graphics. This work suggests inverse graphics as a multiarea neural algorithm implemented within IT, and points to ways for replicating primate vision capabilities in machines.}, archive = {J_PNAS}, author = {Yilmaz, Hakan and Shah, Aalap D. and Letrou, Ariadne and Kumar, Satwant and Vogels, Rufin and Yildirim, Ilker}, doi = {10.1073/pnas.2420287122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2420287122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multiarea processing in body patches of the primate inferotemporal cortex implements inverse graphics}, volume = {122}, year = {2025}, }
• (2025). Emergence of a temporal processing gradient from naturalistic inputs and network connectivity. PNAS, 122(28), e2420105122. (www)

  @article{ , abstract = {Natural language unfolds over multiple nested timescales: Words form sentences, sentences form paragraphs, and paragraphs build into full narratives. Correspondingly, the brain exhibits a hierarchy of processing timescales, spanning from lower- to higher-order regions. During narrative comprehension, neural activation patterns have been shown to propagate along this cortical hierarchy with increasing temporal delays (lags). To investigate the mechanisms underlying this lag gradient, we systematically manipulate the structure of a recurrent reservoir network. In the biologically inspired “Limited-Canal” configuration, word embeddings are received by a limited set of sensory neurons and transmitted through a series of local connections to the distal end of the network. This configuration endows the network with an intrinsic lag gradient, inducing a cascade of activity as information propagates along the network. We found that, similar to the human brain, this intrinsic lag gradient is enhanced by naturalistic narratives. The interaction between naturalistic input and network structure becomes evident when manipulating local connectivity through the “canal width” parameter, which determines how closely the Limited-Canal model mirrors the human brain’s sensitivity to narrative structure. In addition, we found that processing cost, as a computational proxy for the BOLD signal, increases more slowly in later neurons, which can account for the emergence of the lag gradient. Our results demonstrate that narrative-driven neural dynamics can emerge from macroscale anatomical topology alone without task-specific training. These fundamental topological properties of the human cortex may have evolved to effectively process the hierarchical structures ubiquitous in the natural environment.}, archive = {J_PNAS}, author = {Chang, Claire H. C. and Nastase, Samuel A. and Hasson, Uri and Dominey, Peter Ford}, doi = {10.1073/pnas.2420105122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2420105122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Emergence of a temporal processing gradient from naturalistic inputs and network connectivity}, volume = {122}, year = {2025}, }
• (2025). Inherent instability leads to high costs of hovering in near-neutrally buoyant fishes. PNAS, 122(28), e2420015122. (www)

  @article{ , abstract = {Hovering, the ability to maintain a stationary position in fluid, is essential for many fish species during prey capture, habitat exploration, and mating. While traditionally assumed to be energetically inexpensive for fishes with a swim bladder, the metabolic costs and morphological factors influencing postural stability during hovering remain poorly understood. Hovering requires fishes to counteract small instabilities in position and orientation, often through continuous adjustments using their fins and body. To examine the energetic consequences of this active stabilization, we measured body posture, fin kinematics, and metabolic rates in 13 near-neutrally buoyant fish species during both hovering and resting. Our results show that hovering nearly doubles metabolic rates compared to resting, and species with greater separation between the center of mass and center of buoyancy and increased caudal fin activity exhibit higher energetic costs. In contrast, species with more posteriorly positioned pectoral fins and lower length-to-depth ratios show reduced hovering costs. Our findings demonstrate that, despite morphological traits that promote instability, fishes maintain posture and position through fine-scale fin control—at a significant energetic expense. This study suggests that hovering is a costly behavior that likely plays a key role in shaping the evolution of fish morphology and locomotor strategies.}, archive = {J_PNAS}, author = {Di Santo, Valentina and Qi, Xuewei and Berio, Fidji and Albi, Angela and Akanyeti, Otar}, doi = {10.1073/pnas.2420015122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2420015122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inherent instability leads to high costs of hovering in near-neutrally buoyant fishes}, volume = {122}, year = {2025}, }
• (2025). Adaptive arousal regulation: Pharmacologically shifting the peak of the Yerkes–Dodson curve by catecholaminergic enhancement of arousal. PNAS, 122(28), e2419733122. (www)

  @article{ , abstract = {Performance typically peaks at moderate arousal levels, consistent with the Yerkes–Dodson law, as confirmed by recent human and mouse pupillometry studies. Arousal states are influenced by neuromodulators like catecholamines (noradrenaline and dopamine) and acetylcholine. To investigate their contributions to this law, we pharmacologically enhanced arousal while measuring human decision-making and spontaneous arousal fluctuations via pupil size. The catecholaminergic agent atomoxetine increased overall arousal and shifted the entire arousal–performance curve, suggesting a relative arousal mechanism where performance adapts to arousal fluctuations within arousal states. In contrast, the cholinergic agent donepezil did not measurably affect arousal or the curve. We modeled these findings in a neurobiologically plausible computational framework, showing how catecholaminergic modulation alters a disinhibitory neural circuit that encodes sensory evidence for decision-making. This work suggests that performance adapts flexibly to arousal fluctuations, ensuring optimal performance in each and every global arousal state.}, archive = {J_PNAS}, author = {Beerendonk, Lola and Mejías, Jorge F. and Nuiten, Stijn A. and de Gee, Jan Willem and Zantvoord, Jasper B. and Fahrenfort, Johannes J. and van Gaal, Simon}, doi = {10.1073/pnas.2419733122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2419733122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Adaptive arousal regulation: Pharmacologically shifting the peak of the Yerkes–Dodson curve by catecholaminergic enhancement of arousal}, volume = {122}, year = {2025}, }
• (2025). Cilia dynamics create a dynamic barrier to penetration of the periciliary layer in human airway epithelia. PNAS, 122(28), e2419032122. (www)

  @article{ , abstract = {The ciliated epithelium of the human respiratory tract is covered by the airway surface liquid, a protective fluid consisting of two layers: the periciliary layer (PCL), where motile cilia reside and generate fluid flow, and an overlying mucus layer. The complex structure and stratified nature of the PCL complicate both the prediction and quantification of fluid flow at the scale of individual or small groups of cilia, making it difficult to connect microscopic flows to macroscopic clearance. To tackle this challenge, we developed a methodology that involves “uncaging” a fluorescent compound to trace the flow field within the PCL. Fluorescence is activated at micrometric spots within the cilia layer, and displacement vectors and diffusion are recorded using high-speed video. Our experiments reveal a complex fluid transport pattern, with displacement velocity along the epithelial surface varying due to a nonuniform vertical flow field. Additionally, we observed that cilia expel fluid at their tips, a mechanism likely aimed at preventing pathogen access to the epithelium. Simulations, where cilia are modeled as arrays of rigid rods with length asymmetry, support these findings and offer insights into the dynamics of fluid transport in the respiratory tract and the critical role of cilia coordination.}, archive = {J_PNAS}, author = {Causa, Erika and Das, Debasish and Feriani, Luigi and Kotar, Jurij and Cicuta, Pietro}, doi = {10.1073/pnas.2419032122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2419032122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cilia dynamics create a dynamic barrier to penetration of the periciliary layer in human airway epithelia}, volume = {122}, year = {2025}, }
• (2025). The impact of US assimilation and allotment policy on american indian mortality. PNAS, 122(28), e2418836122. (www)

  @article{ , abstract = {In contrast to earlier US policies of open war, forcible removal, and relocation to address the “Indian Problem,” the Dawes Act of 1887 focused on assimilation and land severalty—making American Indians citizens of the United States with individually titled plots of land rather than members of collective tribes with communal land. Considerable scholarship shows that the consequences of the policy differed substantially from its stated goals, and by the time of its repeal in 1934, American Indians had lost two-thirds of all native land held in 1887 (86 million acres)—and nearly two-thirds of American Indians had become landless or unable to meet subsistence needs. Complementing rich qualitative history, this paper provides quantitative evidence on the demographic impact of the Dawes Act on mortality among American Indian children and adults. Using 1900 and 1910 US population census data to study both household and tribe-level variation in allotment timing, we find that assimilation and allotment policy increased the American Indian child mortality ratio by a little more than 15%. In secondary analyses (requiring additional assumptions) focused on total mortality, we find increases among young American Indians of nearly one-third (implying a decline in life expectancy at birth of about 20%). These results confirm contemporary critics’ adamant concerns about the Dawes Act.}, archive = {J_PNAS}, author = {Miller, Grant and Shane, Jack and Snipp, C. Matthew}, doi = {10.1073/pnas.2418836122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2418836122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The impact of US assimilation and allotment policy on american indian mortality}, volume = {122}, year = {2025}, }
• (2025). An aminosterol breaks the autocatalytic cycle of aβ42 aggregation and protects cell membranes from its soluble aggregates. PNAS, 122(28), e2417944122. (www)

  @article{ , abstract = {Aberrant aggregates of the 42-residue form of the amyloid-β peptide (Aβ 42 ) are cytotoxic in Alzheimer’s disease (AD). Cost-effective and chronically safe disease-modifying therapeutics are needed to address the AD medical emergency worldwide. To increase our understanding of the mechanisms of Aβ 42 -induced cytotoxicity and to investigate clinically relevant aminosterols, we study the impact of claramine on the aggregation kinetics and properties of Aβ 42 aggregates, as well as the ability of these proteotoxic species to bind and disrupt cell membranes. Whereas previously studied aminosterols accelerated Aβ 42 aggregation, we show that claramine potently inhibits Aβ 42 amyloid fibril formation. We find that claramine stabilizes soluble Aβ 42 , speeding up primary and secondary nucleation into species with antiparallel β-sheet structure that are elongation incompetent, thereby depleting Aβ 42 monomers from the aggregation reaction. This steroid–polyamine also dissociates Aβ 42 fibrillar aggregates, resulting in the abrogation of the autocatalytic capacity of Aβ 42 fibrils, and it also inhibits the aggregation of a tau fragment relevant to AD. Upon exposure of human neuroblastoma cells to stabilized Aβ 42 oligomers, claramine effectively neutralized Aβ 42 oligomer-induced cytotoxicity by preventing their binding to cell membranes. Owing to the unique mechanism of action of aminosterols to reduce the toxicity of soluble Aβ 42 aggregates by protecting cell membranes, and the newly characterized ability of claramine to inhibit Aβ 42 fibril formation and dissociate fibrillar Aβ 42 resulting in the interruption of the positive feedback loop in Aβ 42 aggregation, our findings further emphasize the relevance of this family of natural products as potential treatments for AD and other protein misfolding diseases.}, archive = {J_PNAS}, author = {Fallot, Lucas B. and Pinc, Johnathan R. and Buselmeier, Joseph E. and Palchak, Julia C. and Shroff, Supria S. and Zang, Kaitlyn and Rinauro, Dillon J. and Bacon, Kate M. and Nguyen, Michael and Schleck, Mary Claire and Cornell, Alyssa R. and Oshidar, Alexandra and Darrell, Donald J. and Gabriel, Justus M. and Wright, Aidan K. and Sasser, Liam R. and Kreiser, Ryan P. and Burpo, F. John and Santambrogio, Alessia and Xu, Peifeng and Kubiak, Robert W. and Loverde, Joseph and Jaffett, Victor A. and Toole, Justin R. and Barbut, Denise and Zasloff, Michael and Chiti, Fabrizio and Dear, Alexander J. and Vendruscolo, Michele and Limbocker, Ryan}, doi = {10.1073/pnas.2417944122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2417944122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An aminosterol breaks the autocatalytic cycle of aβ42 aggregation and protects cell membranes from its soluble aggregates}, volume = {122}, year = {2025}, }
• (2025). Inferring coexistence likelihood in changing environments from ecological time series. PNAS, 122(28), e2417905122. (www)

  @article{ , abstract = {Inferring coexistence metrics, such as niche and fitness differences, in changing environments is key for understanding the mechanism behind species coexistence and predicting its likelihood. However, it first requires estimating the per capita interactions between organisms and their intrinsic growth rates—parameters that are typically measured by isolating organisms from their natural context. Here, we first use weighted multivariate regression on the per capita growth rates of populations to estimate these key ecological parameters directly from time-series data of species-rich communities. Second, we infer niche differences and species resistance, which are two important metrics for understanding species coexistence. Our approach allows these metrics to vary over time and under different environmental conditions. We validate our approach using synthetic data and apply it to both experimental and observational data as a proof of concept. Experimental results show an expected allocative trade-off between grazing resistance and rapid growth in algae. Moreover, coexistence likelihood decreases, and coexistence balance is disturbed under stressful environmental conditions. Observational data suggests variations in intrinsic growth rates and per capita interactions among autotrophic guilds with respect to seasonal patterns. In addition, interactions between cyanobacteria with green algae and chrysophytes might indicate a potential cause for bloom development. Our approach offers a powerful toolbox to gain insight into the mechanisms underlying ecological dynamics, species coexistence, and community structures under varying environments. Such an understanding will help us address important ecological and evolutionary questions, such as explaining biodiversity patterns and solving the problem of cyanobacteria bloom.}, archive = {J_PNAS}, author = {Nguyen, Phuong L. and Pomati, Francesco and Rohr, Rudolf P.}, doi = {10.1073/pnas.2417905122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2417905122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inferring coexistence likelihood in changing environments from ecological time series}, volume = {122}, year = {2025}, }
• (2025). Arylsulfamates inhibit colonic bacteroidota growth through a sulfatase-independent mechanism. PNAS, 122(28), e2414331122. (www)

  @article{ , abstract = {Excessive degradation of the colonic mucin layer by Bacteroides within the human gut microbiota drives inflammatory bowel disease (IBD) in mice. Bacterial carbohydrate sulfatases are key enzymes in gut colonization, and they are elevated in human IBD and correlate with disease severity. Selective inhibitors of carbohydrate sulfatases could function as sulfatase-selective drugs, allowing precise control of sulfatase activity while preserving these otherwise beneficial bacteria. Arylsulfamates are covalent inhibitors that target a catalytic formylglycine residue of steroid sulfatases, a residue that is also conserved in carbohydrate sulfatases. Here, we find that a library of aryl- and carbohydrate sulfamates is ineffective against carbohydrate sulfatases, yet can inhibit human gut microbiota (HGM) species grown on sulfated glycans. Leveraging thermal proteome profiling (TPP), we identify a lipid kinase as the target responsible for these effects. This work highlights the imperative for developing specific inhibitors targeting carbohydrate sulfatases and reveals the adverse effects that arylsulfamates have on Bacteroides species of the HGM.}, archive = {J_PNAS}, author = {Crawford, Conor J. and Tomlinson, Charles W. E. and Gunawan, Christian and Chen, Zongjia and Byrne, Dominic P. and Darby, Cosette and Conti, Martina L. G. and Larson, Tony and Luis, Ana S. and Elli, Stefano and Yates, Edwin A. and Bolam, David N. and van der Post, Sjoerd and Williams, Spencer J. and Cartmell, Alan}, doi = {10.1073/pnas.2414331122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2414331122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Arylsulfamates inhibit colonic bacteroidota growth through a sulfatase-independent mechanism}, volume = {122}, year = {2025}, }
• (2025). DNA2 protein destruction dictates DNA hyperexcision, cGAS–STING activation, and innate immune response in CDK12-deregulated cancers. PNAS, 122(28), e2413732122. (www)

  @article{ , abstract = {CDK12 primarily functions as a transcription regulatory cyclin-dependent kinase (CDK) that controls mRNA elongation, splicing, and polyadenylation. The CDK12 gene is implicated in human cancers since it is frequently mutated and/or deleted in prostate and ovarian cancer but paradoxically amplified in breast cancer. Here, we demonstrate that CDK12 promotes serine-933 phosphorylation of DNA2, a nuclease/helicase critical for replication fork stress regulation, and the phosphorylation subsequently facilitates DNA2 polyubiquitination and degradation mediated by the APC/C CDC20 E3 ubiquitin ligase. CDK12 inactivation induces but amplification suppresses genome-wide expression of interferon response and antigen processing and presentation machinery genes in ovarian and breast cancer cells, respectively. Besides causing aberrant DNA2 stabilization, replication stress, genomic instability, and cytosolic double-stranded DNA (dsDNA) accumulation, CDK12 loss also triggers cGAS–STING activation and innate immune response, which can be reversed by forced expression of replication protein A (RPA) subunits or DNA2 depletion. Our findings identify DNA2 as a phosphorylation substrate of CDK12, connecting CDK12 to cell cycle regulation. These data also reveal DNA2 protein destruction as a critical mechanism that dictates genomic instability, cGAS–STING signaling activation, and innate immune response in CDK12-deregulated cancers.}, archive = {J_PNAS}, author = {Sun, Rui and Jiang, Peng and Wang, Zhijun and Yan, Binyuan and Zhu, Shouhai and Huang, Zhenlin and Zhang, Jianong and Ding, Donglin and Li, Xiang and Wang, Liguo and Lou, Zhenkun and Jin, Baiye and Pang, Jun and Huang, Haojie and Xia, Dan}, doi = {10.1073/pnas.2413732122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2413732122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {DNA2 protein destruction dictates DNA hyperexcision, cGAS–STING activation, and innate immune response in CDK12-deregulated cancers}, volume = {122}, year = {2025}, }
• (2025). Confinement of ions within graphene oxide membranes enables neuromorphic artificial gustation. PNAS, 122(28), e2413060122. (www)

  @article{ , abstract = {Introducing neuromorphic computing paradigms into taste-sensing technology will bring unprecedented opportunities for developing new hardware architectures with perceptual intelligence. Constructing the biomimetic gustatory system, however, remains a challenge due to the scarcity of suitable components operating under wet conditions. Here, we report that ion confinement within the layered graphene oxide membranes can be used to develop a memristive device capable of implementing both synaptic function and chemical sensing. The continuum model and ion dynamics characterizations demonstrate that interfacial adsorption–desorption slows down ion transport and leads to memristive behavior. Based on this nanofluidic device, we built an artificial gustatory system in the physiological environment, which can efficiently classify different flavors according to the reservoir computing algorithm. Our results suggest a paradigm for in-sensor computing in liquid.}, archive = {J_PNAS}, author = {Zhang, Yuchun and Liu, Lin and Qiao, Yu and Yao, Tian and Zhao, Xing and Yan, Yong}, doi = {10.1073/pnas.2413060122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2413060122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Confinement of ions within graphene oxide membranes enables neuromorphic artificial gustation}, volume = {122}, year = {2025}, }
• (2025). Declining winter snowpack offsets carbon storage enhancement from growing season warming in northern temperate forest ecosystems. PNAS, 122(28), e2412873122. (www)

  @article{ , abstract = {Northeastern US temperate forests are currently net carbon (C) sinks and play an important role offsetting anthropogenic C emissions, but projected climatic changes, including increased temperatures and decreased winter snowpack, may influence this C sink over the next century. Past studies show that growing season warming increases forest C storage through greater soil nutrient availability that contributes to greater rates of net photosynthesis, while reduced winter snowpack induces soil freeze/thaw cycles that reduce tree root vitality, nutrient uptake, and forest C storage. The year-round effects of climate change on this C sink are not well understood. We report here decade-long results from the Climate Change Across Seasons Experiment (CCASE) at the Hubbard Brook Experimental Forest, which determines the combined effects of growing season warming and a smaller winter snowpack on C storage in northern temperate forests. We found after a decade of treatments that growing season warming increases cumulative tree stem biomass C by 63%. However, winter soil freeze/thaw cycles offset half of this growing season warming effect. The amount of C stored in stem biomass of trees experiencing both growing season warming plus smaller winter snowpack is only 31% higher than the reference plots, but this difference is not significant. Our results suggest that current Earth system models are likely to overestimate the C sink capacity of northern temperate forests because they do not incorporate the negative impacts of a shrinking snowpack and increased frequency of soil freeze/thaw cycles on C uptake and storage by trees.}, archive = {J_PNAS}, author = {Conrad-Rooney, Emerson and Reinmann, Andrew B. and Templer, Pamela H.}, doi = {10.1073/pnas.2412873122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2412873122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Declining winter snowpack offsets carbon storage enhancement from growing season warming in northern temperate forest ecosystems}, volume = {122}, year = {2025}, }
• (2025). Unveiling the charge transport blockade in the d2 branch of the photosystem II reaction center. PNAS, 122(28), e2405023122. (www)

  @article{ , abstract = {Photosynthesis, the fundamental process sustaining life on Earth, depends on the photosystem II (PSII) reaction center’s ability to initiate the charge transport process. In this study, we have investigated this charge transport process with a focus on the dissimilarity between the two branches of the PSII reaction center, D1 and D2. Utilizing Marcus theory, we have calculated the reorganization energies and activation barriers for all the key steps involved in the charge transport process. Our analysis reveals that while both D1 and D2 branches exhibit similarities in the initial stages, the rate-determining step in the D2 branch has a significantly higher activation barrier (0.2 eV) than D1 branch (0.1 eV), suggesting a much less favorable energetic landscape. Further, the calculation of current–voltage (I-V) characteristics confirms the higher resistance in the D2 branch compared to the D1 branch, emphasizing its nonconductive nature. This comprehensive approach combining energetic and kinetic considerations provides valuable insights into the asymmetry of charge transport in PSII that may be important in optimizing PSII functionality.}, archive = {J_PNAS}, author = {Mandal, Aditya Kumar and Basera, Shubham and Goddard, William A. and Maiti, Prabal K.}, doi = {10.1073/pnas.2405023122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2405023122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unveiling the charge transport blockade in the d2 branch of the photosystem II reaction center}, volume = {122}, year = {2025}, }
• (2025). Common inherited loss-of-function mutations in the innate sensor NOD2 contribute to exceptional immune response to cancer immunotherapy. PNAS, 122(28), e2314258122. (www)

  @article{ , abstract = {Lung cancers and melanomas have many somatically mutated self-proteins that would be expected to trigger an immune rejection response, yet therapeutic responses can only be induced in a subset of patients. Here, we investigated the possibility that inherited differences in immune tolerance checkpoints contribute to variability in outcomes. Whole genome sequencing revealed biallelic germline loss-of-function (LOF) mutations in the immune tolerance checkpoint gene, NOD2 , in an exceptional immune responder to targeted radiotherapy for metastatic melanoma. In 40 exceptional immune responders to anti-PD1 monotherapy for non–small cell lung cancer (NSCLC), genome sequencing showed 30% had inherited a NOD2 LOF variant, more than twice the population frequency ( P = 0.0021). Conversely, a gain-of-function RIPK2 allele known to increase NOD2 signaling was inherited by 61% of nonresponders from the same cohort, compared to 10% of exceptional responders and much higher than the population frequency ( P < 0.0001). Within the overall recruited cohort of 144 NSCLC anti-PD1 patients, individuals with immune-related adverse events (irAE) had better overall survival, further improved in those with NOD2 LOF. In independent anti-PD1 monotherapy cohorts with a range of cancers, inherited NOD2 LOF was associated with complete or partial response ( P = 0.0107). Experimental validation in mice showed germline Nod2 LOF enhanced therapeutic immune responses elicited by anti-PD1 monotherapy against a high mutation burden colorectal cancer, increasing tumor infiltration by effector memory CD8 T cells. Collectively these results reveal common inherited human variation in an immune tolerance checkpoint is a determinant of cancer immune responses elicited by pharmacological inhibition of another checkpoint.}, archive = {J_PNAS}, author = {Barnet, Megan B. and Jackson, Katherine J. L. and Masle-Farquhar, Etienne and Russell, Amanda and Burnett, Deborah L. and Chye, Adrian and Jara, Chris J. and Faulks, Megan and Mawson, Amanda and Peters, Timothy J. and Brink, Robert and Wright, Katherine and Allen, India and Junankar, Simon and Davis, Ian D. and Heller, Gillian and Khan, Zia and Bruce, Jeffrey and Yang, Cindy and Prokopec, Stephenie and Pugh, Trevor and Behren, Andreas and Hold, Georgina L. and Zhang, Fan and Cooper, Wendy A. and Gao, Bo and Nagrial, Adnan and Joshua, Anthony M. and John, Thomas and Peters, Geoffrey and Hui, Rina and Boyer, Michael and Blinman, Prunella L. and Kao, Steven C. and Cebon, Jonathan and Goodnow, Christopher C.}, doi = {10.1073/pnas.2314258122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {28}, pages = {e2314258122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Common inherited loss-of-function mutations in the innate sensor NOD2 contribute to exceptional immune response to cancer immunotherapy}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(27), eiti2725122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti2725122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {eiti2725122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Retraction for ruby and novick, plasmid interactions in staphylococcus aureus: Nonadditivity of compatible plasmid DNA pools. PNAS, 122(27), e2515266122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2515266122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2515266122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Retraction for ruby and novick, plasmid interactions in staphylococcus aureus: Nonadditivity of compatible plasmid DNA pools}, volume = {122}, year = {2025}, }
• (2025). Correction for napora et al., subfossil bald cypress trees suggest localized, enduring effects of major climatic episodes on the southeast atlantic coast of the united states. PNAS, 122(27), e2515237122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2515237122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2515237122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for napora et al., subfossil bald cypress trees suggest localized, enduring effects of major climatic episodes on the southeast atlantic coast of the united states}, volume = {122}, year = {2025}, }
• (2025). Correction for hoshikawa et al., formation of giant ER sheets by pentadecanoic acid causes lipotoxicity in fission yeast. PNAS, 122(27), e2514200122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2514200122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2514200122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for hoshikawa et al., formation of giant ER sheets by pentadecanoic acid causes lipotoxicity in fission yeast}, volume = {122}, year = {2025}, }
• (2025). A molecular tango between chromatin and metabolites orchestrates a feedback switch for alcohol consumption. PNAS, 122(27), e2512733122. (www)

  @article{ , archive = {J_PNAS}, author = {Schmidt, Heidi M. and Tarling, Elizabeth J. and Vallim, Thomas Q. de Aguiar}, doi = {10.1073/pnas.2512733122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2512733122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A molecular tango between chromatin and metabolites orchestrates a feedback switch for alcohol consumption}, volume = {122}, year = {2025}, }
• (2025). Building confidence in models for complex barrier systems for radionuclides. PNAS, 122(27), e2511885122. (www)

  @article{ , abstract = {The modeling and simulation of the Cement–clay Interaction–Diffusion field (CI-D) experiment at the Mont Terri site in Switzerland presented here demonstrates that it is possible to capture the multiscale physical and chemical features of natural and engineered barrier systems for radionuclides. The simulations are successfully carried out with the newly developed CrunchODiTi high-performance computing software that accounts for multiple continua, including a continuum representing the electrical double layer (EDL) developed along negatively charged clay particles in clay rock. The simulation also accounts for both the complex three-dimensional (3D) geometry, expected as the norm in a geological waste repository, and the anisotropy of the geological formation. In addition, the high resolution of the model makes it possible to include “skin effects” developed at the interface between highly reactive materials, in this case between the high pH cement and the circumneutral but electrostatic Opalinus Clay. The successful history matching with the field experiment demonstrates that the distinct geochemical and physical properties of the cement and the Opalinus Clay in the CI-D experiment can be accounted for. Such analyses are essential for developing a defensible safety case for the underground storage of radioactive waste.}, archive = {J_PNAS}, author = {Sarsenbayev, Dauren and Tournassat, Christophe and Steefel, Carl I. and Wainwright, Haruko M.}, doi = {10.1073/pnas.2511885122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2511885122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Building confidence in models for complex barrier systems for radionuclides}, volume = {122}, year = {2025}, }
• (2025). Preservation bias obscures gradual ordovician reef evolution. PNAS, 122(27), e2511406122. (www)

  @article{ , abstract = {The fossil record often creates an illusion of sudden evolutionary bursts, which may reflect preservation biases rather than actual biological events. The Great Ordovician Biodiversification Event (GOBE) appears to mark the abrupt rise of diverse reef-building metazoans during the late Darriwilian (~460 Ma), seemingly contradicting gradual evolutionary models. Here, we demonstrate this apparent burst is largely an artifact of a global sea-level fall (~475 to 460 Ma) that produced widespread unconformities. Integrated stratigraphic and fossil occurrence data reveal early reef-builders likely appeared earlier than the late Middle Ordovician, but their record was erased by sea-level-driven erosion. During the peak of this sea-level fall (Dapingian Stage, 471 to 469 Ma), both carbonate deposition and fossil occurrences were minimal, with significant correlation between carbonate preservation and reef-builder occurrences. The subsequent transgression enabled these already-diversified organisms to recolonize shallow-water environments simultaneously across multiple regions, generating a misleading impression of sudden diversification. This “Sppil–Rongis effect” biased our understanding of the GOBE in reef ecosystems, illustrating how stratigraphic incompleteness can distort evolutionary patterns. Rather than a discrete evolutionary event, the GOBE reflects a continuous trajectory, interrupted and reshaped by sea-level fluctuations.}, archive = {J_PNAS}, author = {Jeon, Juwan and Li, Qi-Jian and Lee, Jeong-Hyun}, doi = {10.1073/pnas.2511406122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2511406122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Preservation bias obscures gradual ordovician reef evolution}, volume = {122}, year = {2025}, }
• (2025). The earliest domestic pigs in neolithic china were closely managed. PNAS, 122(27), e2511400122. (www)

  @article{ , archive = {J_PNAS}, author = {Rowley-Conwy, Peter}, doi = {10.1073/pnas.2511400122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2511400122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The earliest domestic pigs in neolithic china were closely managed}, volume = {122}, year = {2025}, }
• (2025). 15-PGDH inhibition preserves blood–brain barrier integrity and cognition. PNAS, 122(27), e2511399122. (www)

  @article{ , archive = {J_PNAS}, author = {van Egmond, Daisy M. and Lygeroudi, Anita and Kooij, Gijs}, doi = {10.1073/pnas.2511399122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2511399122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {15-PGDH inhibition preserves blood–brain barrier integrity and cognition}, volume = {122}, year = {2025}, }
• (2025). Advanced synchrotron method reveals early molecular decomposition steps in a high-energy material. PNAS, 122(27), e2511225122. (www)

  @article{ , archive = {J_PNAS}, author = {Huotari, Simo}, doi = {10.1073/pnas.2511225122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2511225122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Advanced synchrotron method reveals early molecular decomposition steps in a high-energy material}, volume = {122}, year = {2025}, }
• (2025). Reply to ju et al.: Mechanisms of deeper soil organic carbon loss. PNAS, 122(27), e2510690122. (www)

  @article{ , archive = {J_PNAS}, author = {Zhoua, Zhenghu and Xu, Minggang and Cai, Andong}, doi = {10.1073/pnas.2510690122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2510690122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to ju et al.: Mechanisms of deeper soil organic carbon loss}, volume = {122}, year = {2025}, }
• (2025). Downward movement of nitrate stimulates losses of soil organic carbon in deeper soil layers. PNAS, 122(27), e2510350122. (www)

  @article{ , archive = {J_PNAS}, author = {Ju, Xiaotang and Zhang, Chong and Tian, Xue}, doi = {10.1073/pnas.2510350122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2510350122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Downward movement of nitrate stimulates losses of soil organic carbon in deeper soil layers}, volume = {122}, year = {2025}, }
• (2025). Patchy harmonic functional connectivity of the mouse auditory cortex. PNAS, 122(27), e2510012122. (www)

  @article{ , abstract = {Analyzing the functional connectivity of the brain is an enormous challenge, as deciphering functional connectivity requires knowledge of functional responses and connections. One promising strategy is analyzing the spatial pattern of activity correlations across cell populations. In the primary auditory cortex (A1), cells respond to different sound features. On the large scale, there exists a tonotopic map, which is fractured at the small scale, raising the question of whether functional connections are spatially ordered or disordered. To test whether functional connectivity on a local and a global scale is also disordered, we first designed a robust statistical model to estimate parameters and test for the significance of the estimated correlation maps. We developed an inference method that allows efficient model fitting and statistical testing to project the correlation maps to 2D space. We then performed in vivo two-photon calcium imaging in layer 2/3 of A1 with pure tones (PT) or a combination of two tones (TT; harmonically related or not). We found that the spatial patterns of signal correlations (SCs) depend on the type of sound stimuli that were presented. The functional 2D maps of PT-driven SCs are more restricted to local neurons than TT signal correlations which showed more global textures. 2D SC patterns for harmonic stimuli showed spatially distinct relationships. TT SCs revealed spatially precise functional connectivity between harmonically related neurons. Thus, even though the frequency preference of neighboring neurons in A1 is functionally diverse, the functional connection pattern of these neurons is functionally precise and harmonically related.}, archive = {J_PNAS}, author = {Jendrichovsky, Peter and Khosravi, Sahar and Rupasinghe, Anuththara and Maximov, Katherine and Guo, Pinyue and Babadi, Behtash and Kanold, Patrick O.}, doi = {10.1073/pnas.2510012122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2510012122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Patchy harmonic functional connectivity of the mouse auditory cortex}, volume = {122}, year = {2025}, }
• (2025). The global persistence of work from home. PNAS, 122(27), e2509892122. (www)

  @article{ , abstract = {Work from home (WFH) surged worldwide during the COVID-19 pandemic, then partially receded as the pandemic subsided. Using our Global Survey of Working Arrangements covering dozens of countries, we find that average WFH rates among college-educated employees stabilized after 2022. The average number of WFH days per week is steady at roughly 1 d per week globally from 2023 through early 2025. Cross-country variation persists: WFH is about twice as common in advanced English-speaking economies as in much of Asia. These results show how the pandemic-driven shift to remote work has persisted and reached a new equilibrium with implications for urban economies, workforce flexibility, and future research on labor markets.}, archive = {J_PNAS}, author = {Aksoy, Cevat Giray and Barrero, Jose Maria and Bloom, Nicholas and Davis, Steven J. and Dolls, Mathias and Zarate, Pablo}, doi = {10.1073/pnas.2509892122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2509892122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The global persistence of work from home}, volume = {122}, year = {2025}, }
• (2025). FcγRIIIa is a noncanonical costimulatory molecule for CD8 t cells. PNAS, 122(27), e2509016122. (www)

  @article{ , abstract = {A critical component of the function of IgG antibodies is their capacity to engage specialized cellular receptors, Fcγ receptors (FcγRs), expressed on effector leukocytes. Highlighting the importance of FcγR-mediated signaling in the regulation of the fate, activation, and differentiation status of leukocytes, FcγRs are ubiquitously expressed by nearly all leukocyte populations. Here, we report that while at steady state, T cells are negative for all classes of FcγRs, CD8 T cells specifically induce the expression of the activating FcγR, FcγRIIIa, in response to viral infection in cohorts of COVID-19 and dengue patients, as well as in virus infection models using FcγR humanized mouse strains. In in vivo mechanistic studies, we demonstrate that induction of FcγRIIIa expression on effector CD8 T cells follows a well-defined trajectory that closely tracks the course and magnitude of the immune response, while immune resolution is characterized by receptor downregulation. Uniquely to these CD8 T cells, FcγRIIIa crosslinking alone is paradoxically insufficient to elicit T cell activation and cytotoxicity. However, when coupled with T cell receptor (TCR) stimulation, it results in synergistic cellular activation and, compensates for the downregulation of canonical costimulatory molecules on terminal effector CD8 T cells. These results reveal a previously unappreciated role for FcγRIIIa as a unique costimulatory molecule that synergizes with TCR signaling to lower the effective threshold required for CD8 T cell activation, highlighting the role of virally induced antibodies in modulating CD8 effector cell responses.}, archive = {J_PNAS}, author = {Kao, Kevin S. and Pihlstrom, Nicole L. and Niejadlik, Emily G. and Cantaert, Tineke and Ahmed, Rafi and Ravetch, Jeffrey V. and Bournazos, Stylianos}, doi = {10.1073/pnas.2509016122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2509016122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {FcγRIIIa is a noncanonical costimulatory molecule for CD8 t cells}, volume = {122}, year = {2025}, }
• (2025). In silico evolution of globular protein folds from random sequences. PNAS, 122(27), e2509015122. (www)

  @article{ , abstract = {The origin and evolution of protein folds are among the most challenging, long-standing problems in biology. We developed Protein Fold Evolution Simulator (PFES), a computational approach that simulates evolution of globular folds from random amino acid sequences with atomistic details. PFES introduces random mutations in a population of protein sequences, evaluates the effect of mutations on protein structure, and selects a new set of proteins for further evolution. Iteration of this process allows tracking the evolutionary trajectory of a changing protein fold that evolves under selective pressure for protein fold stability, interaction with other proteins, or other features shaping the fitness landscape. We employed PFES to show how stable, globular protein folds could evolve from random amino acid sequences as monomers or in complexes with other proteins. The simulations reproduce the evolution of many simple folds of natural proteins as well as emergence of distinct folds not known to exist in nature. We show that evolution of small globular protein folds from random sequences, on average, takes 1.15 to 3 amino acid replacements per site, depending on the population size, with some simulations yielding stable folds after as few as 0.2 replacements per site. These values are lower than the characteristic numbers of replacements in conserved proteins during the time since the Last Universal Common Ancestor, suggesting that simple protein folds can evolve from random sequences relatively easily and quickly. PFES tracks the complete evolutionary history from simulations and can be used to test hypotheses on protein fold evolution.}, archive = {J_PNAS}, author = {Sahakyan, Harutyun and Babajanyan, Sanasar G. and Wolf, Yuri I. and Koonin, Eugene V.}, doi = {10.1073/pnas.2509015122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2509015122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In silico evolution of globular protein folds from random sequences}, volume = {122}, year = {2025}, }
• (2025). Reply to izuma and kakinuma: Conversation aligns self-views above and beyond noise reduction. PNAS, 122(27), e2508437122. (www)

  @article{ , archive = {J_PNAS}, author = {Welker, Christopher and Wheatley, Thalia and Meyer, Meghan}, doi = {10.1073/pnas.2508437122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2508437122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to izuma and kakinuma: Conversation aligns self-views above and beyond noise reduction}, volume = {122}, year = {2025}, }
• (2025). Experimental determination of tripartite quantum discord. PNAS, 122(27), e2507467122. (www)

  @article{ , abstract = {Quantum discord is a measure of nonclassical correlations in quantum systems. While the bipartite version of quantum discord is experimentally well-studied, the multipartite version has never been convincingly measured. In this study, we experimentally investigate tripartite quantum discord using an NMR quantum information processor. Building on a theoretical framework for conditional projective measurements and quantum conditional mutual information, we quantify the tripartite quantum discord and its contributions in different three-qubit states such as the Greenberger-Horne-Zeilinger (GHZ) and Werner (W) states as well as classical mixtures of biseparable Bell states, and classical mixtures of product states. The experiments employed full quantum state tomography and temporal averaging to prepare mixed states, achieving fidelities exceeding 95%. Our results confirm that quantum discord persists even in the absence of entanglement, highlighting its utility as a broader indicator of quantum correlations. Furthermore, we validate the nonconvexity of discord, confirming that classical mixtures of zero-discord states can exhibit nonzero discord. This experimentally confirms that quantum discord does not fit into the framework of resource theory. This work establishes a robust methodology for measuring quantum discord, illuminating the structure and distribution of quantum correlations in multipartite systems.}, archive = {J_PNAS}, author = {Gulati, Vaishali and Bhowmick, Shaileyee and Byrnes, Tim and Radhakrishnan, Chandrashekar and Dorai, Kavita}, doi = {10.1073/pnas.2507467122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2507467122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Experimental determination of tripartite quantum discord}, volume = {122}, year = {2025}, }
• (2025). The highly conserved C-terminal end segment of troponin t binds tropomyosin and actin to function in modulating contractile kinetics. PNAS, 122(27), e2507107122. (www)

  @article{ , abstract = {The troponin (Tn) complex plays a central role in regulating striated muscle contraction and relaxation. Troponin T (TnT) and troponin I (TnI) are two of the three subunits of Tn, which have evolved from a TnI-like ancestor gene. Proteolytic removal of the evolutionarily added N-terminal variable region of cardiac TnT, as occurs in acute ventricular contractility-afterload mismatch, brings back a TnI-like molecular conformation and function to reduce ventricular systolic velocity, elongates ejection time, and sustains stroke volume. Investigating the underlying mechanism found in addition to the two previously known tropomyosin (Tm)-binding sites another Tm-binding site in the highly conserved C-terminal end segment of TnT, which is also an F-actin binding site. Its functionality is retained in the form of free peptide with an effect on cardiac muscle contractile kinetics. Hypertrophic cardiomyopathy mutations in this segment significantly decrease Tm-binding affinity. The finding of a third Tm-binding site and localizing the actin-binding site of TnT revise our understanding of the dynamic interactions between Tn and actin thin filament with physiological and pathophysiological implications.}, archive = {J_PNAS}, author = {Cao, Tianxin and Feng, Han-Zhong and Jayasundar, Jayant James and Jin, J.-P.}, doi = {10.1073/pnas.2507107122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2507107122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The highly conserved C-terminal end segment of troponin t binds tropomyosin and actin to function in modulating contractile kinetics}, volume = {122}, year = {2025}, }
• (2025). A transcriptomic, proteomic, and functional genetic atlas dissects neurofibromin function in the peripheral nervous system. PNAS, 122(27), e2506823122. (www)

  @article{ , abstract = {The NF1 tumor suppressor gene is recurrently mutated in human cancers and is associated with the neurofibromatosis type 1 (NF-1) cancer predisposition syndrome. NF1 encodes neurofibromin, a Ras guanosine triphosphate (GTPase) activating protein that negatively regulates Ras signaling. NF1 mutation accordingly leads to Ras misactivation and downstream activation of RAF/MEK/ERK signaling, leading to the approval of the MEK inhibitor selumetinib for NF-1 associated peripheral nervous system (PNS) tumors. However, how NF1 loss modifies response to selumetinib and the utility of targeting additional upstream inputs or downstream outputs of Ras these tumors remain unclear. Here, we perform RNA-sequencing, phosphoproteomic, pharmacologic, and proximal proteomic analysis across a panel of CRISPR interference immortalized peripheral nerve (iPN) cells to systematically dissect the function of neurofibromin loss. Small guide NF1 (sg NF1 ) repression is sufficient to increase Ras GTP levels and alter gene expression to promote cell proliferation and dedifferentiation, with sg NF1 iPNs showing decreased sensitivity to selumetinib due to altered feedback regulation to Ras/RAF/MEK/ERK. Upstream small guide PTPN11 (sg PTPN11 ) repression leads to the inverse gene expression signature, decreasing cell proliferation and promoting differentiation, and sg PTPN11 iPNs are more sensitive to selumetinib. However, upstream sonof sevenless 1 inhibition shows limited efficacy in iPNs due to compensation by SOS2. Finally, proximal proteomics reveals Kirsten rat sarcoma virus (KRAS), but not Harvey rat sarcoma virus (HRAS) or neuroblastoma Ras viral oncogene homolog (NRAS), associates with neurofibromin in iPN cells, and pan-KRAS inhibition is sufficient to block ERK activation and CDK1/2 activation in NF1 mutant cells, suggesting blocking KRAS may be a therapeutic approach for NF1 mutant PNS tumors.}, archive = {J_PNAS}, author = {Vasudevan, Harish N. and Arang, Nadia and Sacconi Nunez, Maria and Kennedy, Patrick and Payne, Emily and Mohabeer, Sarah and Chien, Julian and Wright, Aaron and Sale, Matthew J. and Krogan, Nevan J. and Forget, Antoine and McCormick, Frank}, doi = {10.1073/pnas.2506823122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2506823122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A transcriptomic, proteomic, and functional genetic atlas dissects neurofibromin function in the peripheral nervous system}, volume = {122}, year = {2025}, }
• (2025). Cosmic ray–driven electron-induced reaction theory quantifies spatiotemporal variations in lower-stratospheric ozone and temperature. PNAS, 122(27), e2506469122. (www)

  @article{ , abstract = {Cosmic rays (CRs) play an important role in affecting planetary and interstellar climate and environment. Here, we apply the CR–driven electron-induced reaction (CRE) theory of ozone depletion to obtain a quantitative understanding of spatiotemporal variations in Earth’s lower-stratospheric ozone (LSO) and temperature, which provide fingerprints for the mechanisms of ozone depletion and examine the impact of nonhalogen greenhouse gases on the ozone layer. We first show from observations that both LSO and temperature display pronounced 11-y cyclic variations over Antarctica and mid-latitudes, while weak (no apparent) cyclic variations over the tropics. These observations are consistent with the prediction by the CRE theory. Second, our no-parameter CRE theoretical calculations give the vertical profile of ozone loss in perfect agreement with observations at the Antarctic Syowa station and reproduce well the time-series variations of both LSO and temperature in the polar, mid-latitude, and tropical regions, including the previously reported large ozone depletion in the lower stratosphere over the tropics. The results also demonstrate that both LSO and temperature are controlled by CRs and ozone-depleting substances (ODSs) only. Moreover, CRE calculations exhibit complex phenomena in future trends of LSO and temperature, which are strongly affected by the future trend of CR fluxes. The latter might even lead to almost no recovery of the ozone hole over Antarctica and no returning to the 1980 level over the tropics by 2100. This study greatly improves quantitative understanding of ozone depletion and climate in the global lower stratosphere and offers predictions on future trends.}, archive = {J_PNAS}, author = {Lu, Qing-Bin}, doi = {10.1073/pnas.2506469122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2506469122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cosmic ray–driven electron-induced reaction theory quantifies spatiotemporal variations in lower-stratospheric ozone and temperature}, volume = {122}, year = {2025}, }
• (2025). The sediment transport mechanics driving lateral accretion in muddy meanders. PNAS, 122(27), e2506462122. (www)

  @article{ , abstract = {The discovery of paleo-meanders on Mars and debates about the occurrence of meandering on prevegetation early Earth have stimulated field studies of channel morphology and deposit stratigraphy in arid environments. They show that mud can provide the cohesive strength to retard outer bank erosion, enabling inner bank lateral accretion (including mud deposition) to keep pace and thus sustain meandering. The process by which mud is deposited in the lateral accretion deposits, however, is poorly known. Building on previous fieldwork in the muddy meandering Quinn River, we use Delft3D and the Partheniades–Krone model for cohesive sediment transport to predict erosion and deposition patterns in a 2,300 m long reach. While flocculation of mud increases the settling velocity and hence the likelihood of deposition, the standard metric for distinguishing washload from suspended load, (i.e. settling velocity to shear velocity ratio), does not indicate relative deposition rate. Mud deposition is driven by the product of settling velocity times basal concentration: w s c b . Relatively low w s but high c b can induce deposition. We show that with sufficiently high basal concentrations, significant net lateral accretion deposition occurs in areas where elevated flocculation settling velocities are > 100 times lower than the local shear velocity. Observed grain size distributions of lateral accretion deposits are predicted. Just by introducing a period of elevated mud load with no change in discharge creates a distinct muddy interbed. Our model points to multiple ways lateral accretion deposits can vary sedimentologically, including creating mud-sand couplets, and lead to single thread, active meandering channels in muddy rivers.}, archive = {J_PNAS}, author = {Miao, Runze and Howard, Alan D. and Dietrich, William E.}, doi = {10.1073/pnas.2506462122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2506462122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The sediment transport mechanics driving lateral accretion in muddy meanders}, volume = {122}, year = {2025}, }
• (2025). Fundamental toughening landscape in soft–hard composites: Insights from a minimal framework. PNAS, 122(27), e2506071122. (www)

  @article{ , abstract = {Soft–hard composite strategy is a highly general yet powerful approach to overcome the inherent trade-off between strength and toughness in material design. However, the underlying toughening mechanisms, veiled by nonlinearities and complex network interactions, remains unclear. Here, we employ a three-dimensional soft–hard composite (SH- com ) framework by arranging randomly distributed linear-elastic soft and hard elements to explore the toughening mechanisms of soft–hard composites, while shielding the influence of complex nonlinearities and network architectures. Key features observed in soft–hard composites, including mechanical hysteresis, sacrificial bond-driven toughening, and brittle-to-ductile (BTD) transitions, are successfully reproduced, suggesting that the simplest model captures the essence of toughening in soft–hard composites. Visualization of internal fracture reveals distinct fracture patterns associated with the BTD transition, while numerical and theoretical analyses elucidate its mechanical origins. Furthermore, we identify an optimal toughening composition governed by a unified scaling relation linked to the fracture toughness ratio between soft and hard components. A fundamental toughening phase diagram is also established in terms of strength and toughness. This work sheds light on the underlying toughening landscape of soft–hard composite systems.}, archive = {J_PNAS}, author = {Tian, Fucheng and Sato, Katsuhiko and Zheng, Yong and Lu, Feixue and Gong, Jian Ping}, doi = {10.1073/pnas.2506071122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2506071122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fundamental toughening landscape in soft–hard composites: Insights from a minimal framework}, volume = {122}, year = {2025}, }
• (2025). Not only self-views but also any ratings converge without conversations due to reduced noise bias. PNAS, 122(27), e2505968122. (www)

  @article{ , archive = {J_PNAS}, author = {Izuma, Keise and Kakinuma, Kyosuke}, doi = {10.1073/pnas.2505968122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2505968122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Not only self-views but also any ratings converge without conversations due to reduced noise bias}, volume = {122}, year = {2025}, }
• (2025). In vivo directed evolution of an ultrafast rubisco from a semianaerobic environment imparts oxygen resistance. PNAS, 122(27), e2505083122. (www)

  @article{ , abstract = {Carbon dioxide (CO 2 ) assimilation by the enzyme Ribulose-1,5-bisphosphate Carboxylase/Oxygenase (Rubisco) underpins biomass accumulation in photosynthetic bacteria and eukaryotes. Despite its pivotal role, Rubisco has a slow carboxylation rate ( k cat CO 2 ) and is competitively inhibited by oxygen (O 2 ). These traits impose limitations on photosynthetic efficiency, making Rubisco a compelling target for improvement. Interest in Form II Rubisco from Gallionellaceae bacteria, which comprise a dimer or hexamer of large subunits, arises from their nearly fivefold higher k cat CO 2 than the average Rubisco enzyme. As well as having a fast k cat CO 2 (25.8 s − 1 at 25 °C), we show that Gallionellaceae Rubisco (GWS1B) is extremely sensitive to O 2 inhibition, consistent with its evolution under semianaerobic environments. We therefore used an in vivo mutagenesis-mediated screening pipeline to evolve GWS1B over six rounds under oxygenic selection, identifying three catalytic point mutants with improved ambient carboxylation efficiency: Thr-29-Ala (T29A), Glu-40-Lys (E40K), and Arg-337-Cys (R337C). Full kinetic characterization showed that each substitution enhanced the CO 2 affinity of GWS1B under oxygenic conditions by subduing oxygen affinity, leading to 25% (E40K), 11% (T29A), and 8% (R337C) enhancements in carboxylation efficiency under ambient O 2 at 25 °C. By contrast, under the near anaerobic natural environment of Gallionellaceae , the carboxylation efficiency of each mutant was impaired ~16%. These findings demonstrate the efficacy of artificial directed evolution to access distinctive regions of catalytic space in Rubisco.}, archive = {J_PNAS}, author = {McDonald, Julie L. and Shapiro, Nathan P. and Mengiste, Amanuella A. and Kaines, Sarah and Whitney, Spencer M. and Wilson, Robert H. and Shoulders, Matthew D.}, doi = {10.1073/pnas.2505083122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2505083122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In vivo directed evolution of an ultrafast rubisco from a semianaerobic environment imparts oxygen resistance}, volume = {122}, year = {2025}, }
• (2025). Akt isoform specificity drives intrinsic immune regulation during HSV-1 infection. PNAS, 122(27), e2504962122. (www)

  @article{ , abstract = {Akt isoforms are generally considered functionally redundant, contributing to total Akt activity. However, during HSV-1 infection, Akt1 and Akt2 knockout animals exhibited distinct antiviral responses. Unexpectedly, in the absence of Akt1, Akt2 played a unique role in regulating cytokine production and inactivating proapoptotic transcription factor FoxO3a, a mechanism not shared by Akt1. These findings provide the clearest in vivo evidence yet that Akt isoforms are not functionally redundant, revealing distinct immune-regulatory roles for each isoform and suggesting a broader principle for fine-tuning immunity and cell death across diverse pathological settings.}, archive = {J_PNAS}, author = {Suryawanshi, Rahul K. and Patil, Chandrashekhar D. and Borase, Hemant and Shukla, Deepak}, doi = {10.1073/pnas.2504962122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2504962122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Akt isoform specificity drives intrinsic immune regulation during HSV-1 infection}, volume = {122}, year = {2025}, }
• (2025). Metabolic engineering of bacillus subtilis for the production of active hemoglobins and myoglobins by improving heme supply. PNAS, 122(27), e2504795122. (www)

  @article{ , abstract = {Hemoglobins (Hb) and myoglobins (Mb) are important hemoproteins with broad applications in food and medicine. Microbial cell factory is a promising approach for the green and sustainable production of hemoproteins. However, current microbial hosts face the challenges of safety and insufficient heme supply. Here, we report a global regulation strategy, “push–restrain–pull–block,” to enhance heme supply for producing various active Hb and Mb in food-grade Bacillus subtilis . Initially, the insufficient supply of the precursor 5-aminolevulinate was overcome by relieving feedback inhibition and mitigating the negative effects of HemX on HemA. Next, HemD was identified as the primary uroporphyrinogen III synthase and self-assembled with HemC to minimize the formation of the uroporphyrinogen I by-product. Additionally, the coproporphyrin-dependent pathway was selected as the superior downstream route for heme synthesis, and crucial rate-limiting steps were subsequently enhanced. Moreover, heme consumption was blocked by eliminating protoheme IX farnesyltransferase. Finally, through the combination and fine-tuned expression of key genes, a 221-fold improvement of heme supply was achieved in the engineered strain. Using this stable prokaryotic chassis, we achieved production of 0.81, 0.82, 1.11, and 1.01 g L −1 of soybean Hb, clover Hb (C-Hb), bovine Mb (B-Mb), and porcine Mb, respectively, through fermentation, marking the highest reported titers in prokaryotic systems. These hemoproteins exhibit properties similar to natural standards. Furthermore, the synthesized C-Hb and B-Mb demonstrated superior effects for preparing plant-based meat analogs as colorants and flavoring agents. This work provides a universal platform for producing other high-value hemoproteins, promising future advancements in food processing and biocatalysis.}, archive = {J_PNAS}, author = {Wang, Song and Zhou, Jingwen and Li, Jianghua and Chen, Jian and Du, Guocheng and Li, Zhengqiang and Lee, Sang Yup and Zhao, Xinrui}, doi = {10.1073/pnas.2504795122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2504795122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Metabolic engineering of bacillus subtilis for the production of active hemoglobins and myoglobins by improving heme supply}, volume = {122}, year = {2025}, }
• (2025). Regulation of the ordinal DNA translocation cycle in bacteriophage Φ29 through trans-subunit interactions. PNAS, 122(27), e2504780122. (www)

  @article{ , abstract = {Certain viruses such as tailed bacteriophages and herpes simplex virus package double-stranded DNA into empty procapsids via powerful, ring-shaped molecular motors. High-resolution structures and force measurements on the DNA packaging motor of bacteriophage Φ29 revealed that its five ATPase subunits coordinate ATP hydrolysis with each other to maintain the proper cyclic sequence of DNA translocation steps about the ring. Here, we explore how the Φ29 motor regulates translocation by timing key events, namely ATP binding/hydrolysis and DNA gripping, through trans-subunit interactions. We used subunit dimers bound to DNA as our model system, a minimal system that still captures the conformation and trans-subunit interactions of the full pentameric motor complex. Molecular dynamics simulations of all-ATP and mixed ATP–ADP dimers revealed that the nucleotide occupancy of one subunit strongly affects the ability to hydrolyze ATP in the adjacent subunit by altering the free energy landscape of its catalytic glutamate approaching the gamma phosphate of ATP. Specifically, one ATP-bound subunit donates residues in trans that sterically block the neighboring subunit’s catalytic glutamate. This steric hindrance is resolved when the first subunit hydrolyzes ATP and is ADP bound. This obstructive mechanism is supported by functional mutagenesis and appears to be conserved across several Φ29 relatives. Mutual information analysis of our simulations revealed intersubunit signaling pathways, via the trans-acting obstructive residues, that allow for sensing and communication between the binding pockets of adjacent subunits. This work reveals how the sequential order of DNA translocation events among subunits is preserved through trans-subunit interactions and pathways.}, archive = {J_PNAS}, author = {Dargis, Rokas and Pajak, Joshua and Ariyawansa, Pavan and Morais, Marc C. and Jardine, Paul J. and Arya, Gaurav}, doi = {10.1073/pnas.2504780122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2504780122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Regulation of the ordinal DNA translocation cycle in bacteriophage Φ29 through trans-subunit interactions}, volume = {122}, year = {2025}, }
• (2025). The growth and collapse of autonomy at work. PNAS, 122(27), e2504419122. (www)

  @article{ , abstract = {Humans hate being monitored. Autonomy is prized—including by research scientists. Yet little is known about a fundamental issue in the modern world: What is happening to job autonomy in today’s workplaces as people move from youth on to middle age and then on to older ages? It would be natural to believe that individuals in the second half of their careers would be the senior ones with high autonomy. We provide evidence that such a belief is wrong. This study uses longitudinal data on hundreds of thousands of randomly sampled individuals, in three rich countries, who are followed through their working lives (n > 400,000). Workers’ feelings of job autonomy trace out a smooth concave parabola, increasing up to midlife, until approximately the surprisingly early age of 40, and then collapsing over the ensuing twenty to 30 y of a person’s working life. This is apparently not an illusion. We show that objective measures of autonomy —signified by managerial and supervisory job titles, for example—behave in a matching, hump-shaped way. As a further check, consistent qualitative evidence is given: a survey we ran asking managers about their experiences. We believe this paper’s results represent a foundational, essentially unknown, and intrinsically cross-disciplinary puzzle.}, archive = {J_PNAS}, author = {Mujcic, Redzo and Oswald, Andrew J.}, doi = {10.1073/pnas.2504419122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2504419122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The growth and collapse of autonomy at work}, volume = {122}, year = {2025}, }
• (2025). A circular RNA overcomes acquired resistance to BET inhibitors by antagonizing IGF2BP2-mediated c-MYC translation in TNBC. PNAS, 122(27), e2504320122. (www)

  @article{ , abstract = {Bromodomain-and-extraterminal-domain (BET) proteins are promising therapeutic targets for refractory solid tumors, including triple-negative breast cancer (TNBC). However, acquired resistance to BET inhibitors (BETi) remains a significant clinical challenge. Elucidation of the underlying mechanisms of BETi resistance is therefore of critical importance. In this study, we identified the RNA-binding protein IGF2BP2 as a key driver of acquired BETi resistance in TNBC, primarily through its role in enhancing the translation of c-MYC mRNA. Given that IGF2BP2 is not an ideal target for small-molecular drugs, we performed RNA immunoprecipitation sequencing (RIP-Seq) and found circRNA-BISC as a potent IGF2BP2 repressor. BISC effectively inhibited both c-MYC translation and BETi resistance. Notably, BISC contains a “CAC-linker-XGGX” motif that specifically binds IGF2BP2 rather than to IGF2BP1 and IGF2BP3. The efficacy and selectivity of BISC in targeting IGF2BP2 prompted further exploration of BISC-based RNA therapeutics for TNBC. In vitro transcribed and circularized BISC, when combined with the BETi OTX-015, demonstrated impressive tumor regression in BETi-resistant TNBC models without detectable toxicity. These findings establish BISC as a potent IGF2BP2 repressor and highlight the feasibility of circRNA-based therapeutic strategies to overcome BETi resistance in TNBC.}, archive = {J_PNAS}, author = {Guo, Jiawei and Li, Ke and Ming, Yue and Pan, Yitong and Tan, Shuangyan and Ma, Hulin and Chen, Shuang and Duan, Yingying and Peng, Yong}, doi = {10.1073/pnas.2504320122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2504320122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A circular RNA overcomes acquired resistance to BET inhibitors by antagonizing IGF2BP2-mediated c-MYC translation in TNBC}, volume = {122}, year = {2025}, }
• (2025). PI(4)P recruits CIDE proteins to promote the formation of unilocular lipid droplets during adipogenesis and hepatic steatosis. PNAS, 122(27), e2504219122. (www)

  @article{ , abstract = {Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. The composition of LD surface phospholipids and their impact on LD growth and function remain to be defined. Phosphoinositides mark cellular organelles and regulate organellar function. Here, we demonstrate that PI(4)P decorates a subset of LDs to recruit and activate CIDE proteins. Enhanced expression of ORP2 and ORP5, LD-associated lipid transfer proteins that remove PI(4)P from LDs, abolished the localization and function of CIDE proteins. Blocking the synthesis of PI(4)P on the LD surface via knocking down PI4K2A also impaired the localization and function of CIDE proteins. In adipocytes, depleting PI(4)P dramatically reduced the size of LDs, as well as adipose tissue mass. In severe steatotic liver, depleting PI(4)P impeded LD enlargement. Our results thus identify a key function of LD surface PI(4)P under physiological conditions and unveil how CIDE proteins are recruited to LDs.}, archive = {J_PNAS}, author = {Wu, Jin and Gao, Mingming and Wu, Xiaoqin and Liu, Yang and Zhang, Taiping and Liang, Yan and Yang, Haixia and Ma, Chengxin and Ye, Youpi and Chang, Chunmei and Li, Peng and Chen, Feng-Jung and Yang, Hongyuan}, doi = {10.1073/pnas.2504219122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2504219122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PI(4)P recruits CIDE proteins to promote the formation of unilocular lipid droplets during adipogenesis and hepatic steatosis}, volume = {122}, year = {2025}, }
• (2025). The epigenetic impacts of pubertal acceleration following early caregiver disruptions. PNAS, 122(27), e2504216122. (www)

  @article{ , abstract = {A stable caregiving environment early in life is essential for children’s development, and disruptions have the potential to impact biological processes. Using data from the Bucharest Early Intervention Project, we examined a developmental cascade model in which shifts in pubertal tempo following early caregiving disruptions come at an epigenetic cost. Among 115 individuals, all of whom experienced severe deprivation early in life, we tracked caregiving disruptions across childhood; assessed pubertal timing and tempo across adolescence; and quantified the pace of cellular aging via telomere erosion across the second decade of life. We demonstrate that a greater number of caregiving disruptions is associated with delayed pubertal timing and an acceleration of pubertal tempo. In turn, accelerations in pubertal tempo are associated with significantly greater telomere erosion across time. A formal mediation model indicated that greater caregiving disruptions during childhood predicted greater telomere erosion through an acceleration of pubertal tempo. By documenting the impact of caregiving disruptions on pubertal development and ultimately biological aging, these findings highlight the importance of the stability of the caregiving context and the critical need to ensure that organizations caring for vulnerable children establish programs and policies to minimize unnecessary disruptions.}, archive = {J_PNAS}, author = {Jopling, Ellen and Drury, Stacy S. and Fox, Nathan A. and Zeanah, Charles H. and Nelson, Charles A.}, doi = {10.1073/pnas.2504216122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2504216122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The epigenetic impacts of pubertal acceleration following early caregiver disruptions}, volume = {122}, year = {2025}, }
• (2025). Prehistoric archives reveal evidence of predator loss and prey release in caribbean reef fish communities. PNAS, 122(27), e2503986122. (www)

  @article{ , abstract = {Understanding how humans have altered coral reef food webs remains challenging due to the absence of prehistoric baselines. Here, we use fish remains preserved in fossil and archaeological deposits from Panamá and the Dominican Republic to explore how Caribbean reef fish mortality patterns have changed over millennia. By quantifying accumulation rates of shark dermal denticles (scales) and bony fish otoliths (ear stones) in reef sediments, we assess relative fish abundance, while otolith size serves as a proxy for body size at death. Comparisons of these death assemblages suggest a 75% decline in shark-derived material and a 22% reduction in the sizes of human-targeted fishes—consistent with historical exploitation. This evidence of decline in large-bodied, higher trophic level fish remains coincided with a doubling in prey fish otolith accumulation and a 17% increase in their reconstructed body sizes. These patterns in time-averaged death assemblages align with effects of release from predation, documenting an often assumed (but rarely shown) cascading effect. In contrast, otoliths of predator-sheltered cryptobenthic fishes showed no change in either accumulation or size, suggesting that ‘‘bottom–up”environmental factors were not responsible for the observed changes. Together, these data indicate that pre-exploitation predator communities strongly controlled exposed prey fishes, but this “top–down” effect diminishes rapidly toward the food chain base, especially in predator-resistant groups. Understanding trophic cascades on Caribbean reefs requires studying systems before predator depletion.}, archive = {J_PNAS}, author = {O’Dea, Aaron and Dillon, Erin M. and Brandl, Simon J. and Cramer, Katie L. and Cybulski, Jonathan D. and de Gracia, Brígida and García-Méndez, Kimberly and Griswold, Katherine and Lin, Chien-Hsiang and Leray, Matthieu and Lueders-Dumont, Jessica A. and Sellers, Andrew J. and Wake, Thomas A.}, doi = {10.1073/pnas.2503986122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2503986122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prehistoric archives reveal evidence of predator loss and prey release in caribbean reef fish communities}, volume = {122}, year = {2025}, }
• (2025). Polymer sailing on rafts within lipid membranes. PNAS, 122(27), e2503203122. (www)

  @article{ , abstract = {Understanding the dynamics of macromolecules adsorbed from extracellular fluids onto cell membranes is crucial for elucidating basic cellular processes and advancing applications in biotechnology, such as biosensing, therapeutics, and synthetic biology. However, this is complicated by the interplay between membrane heterogeneity, macromolecule conformation, and fluid hydrodynamics. We investigate the dynamics of linear polymers on binary lipid membranes using hydrodynamics simulations and single-molecule tracking experiments. We find that the preferential adsorption of nanosized polymer onto the raft-forming component of the membrane induces and stabilizes a single lipid raft that colocalizes with the polymer. This lipid raft, in turn, imposes dynamic confinement on the polymer, resulting in swollen yet restricted 2D conformations and Saffman–Delbrück-type diffusivity. These effects lead to an unusual scaling for polymer interfacial diffusion, D ∼ N − ν D with ν D ≈ 0.5 . Normal mode analysis further reveals that the relaxation time of the polymer’s slowest mode surprisingly follows the prediction of Zimm model for a 3D chain in a good solvent, irrespective of whether the polymer’s hydrodynamics are dominated by the 3D solvent or 2D fluid membrane. We also identify two diffusive modes: Saffman–Delbrück-type for polymer on heterogeneous membranes and Stokes–Einstein-like for polymer on homogeneous membranes, demonstrating the potential of polymer adsorbates as biosensors for membrane heterogeneity. Our study provides insights into polymer dynamics on biological membranes and suggests that polymer adsorbates can modulate lipid rafts, influencing raft-related cellular processes.}, archive = {J_PNAS}, author = {Gao, Jie and Shen, Yiyang and Komura, Shigeyuki and Hu, Wenbing and Shen, Lei and Hu, Jinglei}, doi = {10.1073/pnas.2503203122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2503203122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Polymer sailing on rafts within lipid membranes}, volume = {122}, year = {2025}, }
• (2025). Comparing conventional and alternative mechanisms of discovering and accessing the scientific literature. PNAS, 122(27), e2503051122. (www)

  @article{ , abstract = {This study compares the bibliographic and full-text coverage of 15 conventional and alternative discovery/access mechanisms: two multidisciplinary library databases (Scopus and the Web of Science Core Collection), five single-subject databases, the integrated library search (ILS) mechanism of Manhattan University, a scholarly search engine (Google Scholar), two web-based scholarly databases (Dimensions and OpenAlex), two academic social networks (Academia.edu and ResearchGate), and two pirate sites (Anna’s Archive and Sci-Hub). The analysis is based on known-item searches for 875 target documents in chemistry, materials science, cardiology, public health, economics, education, and psychology. Overall, Google Scholar, OpenAlex, and the ILS are the most comprehensive sources of bibliographic records. Google Scholar’s coverage rate is higher than that of all the Manhattan University databases combined, and Scopus—the most comprehensive multidisciplinary library database—has a lower bibliographic coverage rate than Google Scholar, both of the web-based scholarly databases, one of the two ASNs, and one of the two pirate sites. In terms of full-text coverage, the best multidisciplinary options are the ILS, Google Scholar, and the two pirate sites. Although several of the alternative discovery/access mechanisms are deficient in terms of their user interfaces, search capabilities, and metadata, they nonetheless provide excellent bibliographic and full-text coverage of the scholarly literature. In contrast, many single-subject library databases provide very incomplete coverage of their own subject areas. These findings have implications for scholars and students as well as system-wide implications for the use, development, and evaluation of information resources.}, archive = {J_PNAS}, author = {Walters, William H.}, doi = {10.1073/pnas.2503051122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2503051122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Comparing conventional and alternative mechanisms of discovering and accessing the scientific literature}, volume = {122}, year = {2025}, }
• (2025). Onset of cavitation and vapor bubble development over hydrophilic and hydrophobic surfaces. PNAS, 122(27), e2503033122. (www)

  @article{ , abstract = {Cavitation, the formation of vapor bubbles as the liquid pressure is reduced below the saturated vapor pressure, often requires a substantial negative relative pressure in a pure liquid. Classical nucleation theory (CNT) provides an estimate for the rate of cavitation but there is often a disconnect between the predictions at the molecular scale compared to observations at the macroscale. We report on mesoscale simulations of cavitation based on many-body dissipative particle dynamics (mDPD), a coarse-grained molecular dynamics (MD), which bridges the two scales. A liquid layer is confined between smooth planar walls at a constant temperature, while the pressure is reduced slowly by expanding the wall-bounded domain. The wetting properties of the liquid are determined by the parameters of the interaction potentials. With hydrophilic walls, homogeneous nucleation is observed in the liquid bulk. As a bubble forms and grows, it creates a strong pressure pulse and oscillations that cause other bubbles that may have formed slightly later to collapse. For a nearly neutral wall with a contact angle close to 90 ° , heterogeneous nucleation occurs at the walls at a smaller negative pressure and generates weaker pressure oscillations. With hydrophobic walls or seed particles, heterogeneous nucleation readily occurs, where fluctuations and the merger of transient surface bubbles are significant.}, archive = {J_PNAS}, author = {Lin, Chensen and Maxey, Martin R. and Li, Zhen and Zhang, Kaixuan and Karniadakis, George Em}, doi = {10.1073/pnas.2503033122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2503033122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Onset of cavitation and vapor bubble development over hydrophilic and hydrophobic surfaces}, volume = {122}, year = {2025}, }
• (2025). SpecTf: Transformers enable data-driven imaging spectroscopy cloud detection. PNAS, 122(27), e2502903122. (www)

  @article{ , abstract = {Current and upcoming generations of visible-shortwave infrared (VSWIR) imaging spectrometers promise unprecedented capacity to quantify Earth system processes across the globe. However, reliable cloud screening remains a fundamental challenge for these instruments, where traditional spatial and temporal approaches are limited by cloud variability and limited temporal coverage. The Spectroscopic Transformer (SpecTf) addresses these challenges with a spectroscopy-specific deep-learning architecture that performs cloud detection using only spectral information (no spatial or temporal data are required). By treating spectral measurements as sequences rather than image channels, SpecTf learns fundamental physical relationships without relying on spatial context. Our experiments demonstrate that SpecTf significantly outperforms the current baseline approach implemented for the Earth surface Mineral dust source InvesTigation (EMIT) instrument, and performs comparably with other machine learning methods with orders of magnitude fewer learned parameters. Critically, we demonstrate SpecTf’s inherent interpretability through its attention mechanism, revealing physically meaningful spectral features the model has learned. Finally, we present SpecTf’s potential for cross-instrument generalization by applying it to a different instrument on a different platform without modifications, opening the door to instrument-agnostic data-driven algorithms for future imaging spectroscopy tasks.}, archive = {J_PNAS}, author = {Lee, Jake H. and Kiper, Michael and Thompson, David R. and Brodrick, Philip G.}, doi = {10.1073/pnas.2502903122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2502903122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SpecTf: Transformers enable data-driven imaging spectroscopy cloud detection}, volume = {122}, year = {2025}, }
• (2025). Axonal pathology differentially affects human purkinje cell subpopulations in the essential tremor cerebellum. PNAS, 122(27), e2502024122. (www)

  @article{ , abstract = {The cerebellar cortex is organized into discrete regions populated by molecularly distinct Purkinje cells (PCs), the sole cortical output neurons. While studies in animal models have shown that PC subtypes differ in their vulnerability to disease, our understanding of human PC subtype and vulnerability remains limited. Here, we demonstrate that human cerebellar regions specialized for motor vs. cognitive functions (lobule HV vs. Crus I) contain distinct PC populations characterized by specific molecular and anatomical features, which show selective vulnerability in essential tremor (ET), a cerebellar degenerative disorder. Using a known PC subtype marker, neurofilament heavy chain (NEFH), we found that motor lobule HV contains PCs with high NEFH expression, while cognitive lobule Crus I contains PCs with low NEFH expression in postmortem samples from healthy controls. In the same cerebella, PC axons in lobule HV were 2.2-fold thicker than those in Crus I. Across lobules, axon caliber positively correlated with NEFH expression. In ET cerebella, we identified motor lobule-specific PC axon pathology with a 1.5-fold reduction in caliber and increased axon variability in lobule HV, while Crus I axons were unaffected. Tremor severity and duration in ET correlated with axon diameter variability selectively in lobule HV PCs. Given that axonal caliber is a major determinant of neural signaling capacity, our results 1) suggest that disrupted cerebellar corticonuclear signaling is occurring in ET, and 2) provide evidence of region-specific PC populations in the human cerebellum and offer insight into how different PC subpopulations may contribute to the pathophysiology of cerebellar degeneration.}, archive = {J_PNAS}, author = {Widner, James and Faust, Phyllis L. and Louis, Elan D. and Fujita, Hirofumi}, doi = {10.1073/pnas.2502024122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2502024122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Axonal pathology differentially affects human purkinje cell subpopulations in the essential tremor cerebellum}, volume = {122}, year = {2025}, }
• (2025). Action-mode subnetworks for decision-making, action control, and feedback. PNAS, 122(27), e2502021122. (www)

  @article{ , abstract = {The action-mode network (AMN) is a canonical functional brain network first identified using resting-state functional connectivity (RSFC). Based on animal and human data, we have proposed that AMN supports the brain’s action mode by controlling functions required for successful goal-directed behavior. However, task fMRI averaged across groups has associated AMN regions with a variety of behaviors, contributing to uncertainty about AMN function. Here, we investigated the AMN using an inside-out approach, in which the network architecture of the AMN is first precisely mapped within individuals and then associated with behavioral functions. Individual-specific precision functional mapping with >5 h of RSFC and task functional magnetic resonance imaging (fMRI) data revealed a replicable AMN subnetwork structure. AMN subnetworks were characterized and annotated by combining a meta-analytic network association method with RSFC, intrinsic timing, and task activation profiling. We demonstrate the existence of AMN-Decision, -Action, and -Feedback subnetworks that are distributed across lobes, forming a temporally sequential within-network processing stream by which the brain adjudicates between possible goals, sets action plans, and modifies those plans in response to feedback such as pain. A subnetwork in the pars marginalis of the cingulate was distinct from the Decision, Action, and Feedback subnetworks and may be important for the construction of the bodily self.}, archive = {J_PNAS}, author = {Badke D’Andrea, Carolina and Laumann, Timothy O. and Newbold, Dillan J. and Lynch, Charles J. and Hadji, Mohammad and Nelson, Steven M. and Nielsen, Ashley N. and Chauvin, Roselyne J. and Krimmel, Samuel R. and Snyder, Abraham Z. and Marek, Scott and Greene, Deanna J. and Raichle, Marcus E. and Dosenbach, Nico U. F. and Gordon, Evan M.}, doi = {10.1073/pnas.2502021122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2502021122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Action-mode subnetworks for decision-making, action control, and feedback}, volume = {122}, year = {2025}, }
• (2025). The transcription factor bcl11a is essential for B-1a cell maintenance during aging. PNAS, 122(27), e2501974122. (www)

  @article{ , abstract = {B-1a cells, a self-renewing B cell subset essential for innate immunity, produce natural IgM antibodies that defend against pathogens, yet mechanisms sustaining their maintenance during aging remain unclear. We report that aging B-1a cells exhibit hallmarks of decline, including DNA damage, apoptosis, and reduced proliferation, with striking sex-specific disparities: aged females retain higher B-1a cell numbers than males, correlating with enhanced glycolysis and chromatin accessibility. Motif analysis of accessible regions identified the transcription factor Bcl11a, which shows elevated chromatin accessibility and expression in aged female B-1a cells but declines in males. Bcl11a deletion reduced B-1a cell numbers, impaired viability, and increased apoptosis across sexes and ages. Mechanistically, Bcl11a sustains survival by upregulating antiapoptotic genes ( Mcl1 , Mdm2 , and Mdm4 ) to suppress p53-mediated apoptosis, as evidenced by partial rescue of viability defects in Bcl11a-deficient B-1a cells upon p53 deletion. Conversely, Bcl11a overexpression or Bcl11a-high B-1a cells from aged Bcl11a -eGFP reporter mice enhanced stress resistance. These findings establish Bcl11a as a key regulator of B-1a cell maintenance during aging and reveal its role in mitigating sex-dimorphic immune decline through transcriptional control of survival pathways.}, archive = {J_PNAS}, author = {Xu, Shasha and Huang, Liangfeng and Liu, Xingjie and Zhang, Linlin and Wang, Jing and Hu, Yifeng and Yang, Yi and Shi, Xiaojie and Liu, Chaohong and Wang, Rong and Miao, Zhichao and Yu, Yong}, doi = {10.1073/pnas.2501974122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2501974122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The transcription factor bcl11a is essential for B-1a cell maintenance during aging}, volume = {122}, year = {2025}, }
• (2025). Identification of a VPS29 isoform with restricted association to retriever and retromer accessory proteins through autoinhibition. PNAS, 122(27), e2501111122. (www)

  @article{ , abstract = {The endosomal–lysosomal network is a hub of organelles that orchestrate the dynamic sorting of hundreds of integral membrane proteins to maintain cellular homeostasis. VPS29 is a central conductor of this network through its assembly into Retromer, Retriever, and Commander endosomal sorting complexes, and its role in regulating RAB GTPase activity. Two VPS29 isoforms have been described, VPS29A and VPS29B, that differ solely in their amino-terminal sequences. Here, we identify a third VPS29 isoform, which we term VPS29C, that harbors an extended amino-terminal sequence compared to VPS29A and VPS29B. Through a combination of AlphaFold predictive modeling, in vitro complex reconstitution, mass spectrometry, and molecular cell biology, we find that the amino-terminal VPS29C extension constitutes an autoinhibitory sequence that limits access to a hydrophobic groove necessary for effector protein recruitment to Retromer, and association with Retriever and Commander. VPS29C is therefore unique in its ability to uncouple Retromer-dependent cargo sorting from the broader roles of VPS29A and VPS29B in regulating the endosomal–lysosomal network through accessory protein recruitment. Our identification and characterization of VPS29C points to additional complexity in the differential subunit assembly of Retromer, an important consideration given the increasing interest in Retromer as a potential therapeutic target in neurodegenerative diseases.}, archive = {J_PNAS}, author = {Daly, James L. and Chen, Kai-en and Butkovič, Rebeka and Guo, Qian and Healy, Michael D. and Pennink, Eva and Gamble-Strutt, Georgia and Higham, Zara and Moody, Edmund R. R. and Lewis, Philip A. and Heesom, Kate J. and Williams, Tom A. and McMillan, Kirsty J. and Collins, Brett M. and Cullen, Peter J.}, doi = {10.1073/pnas.2501111122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2501111122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identification of a VPS29 isoform with restricted association to retriever and retromer accessory proteins through autoinhibition}, volume = {122}, year = {2025}, }
• (2025). Singularity formation in 3D euler equations with smooth initial data and boundary. PNAS, 122(27), e2500940122. (www)

  @article{ , abstract = {A long-standing fundamental open problem in mathematical fluid dynamics and nonlinear partial differential equations is to determine whether solutions of the 3D incompressible Euler equations can develop a finite-time singularity from smooth, finite-energy initial data. Leonhard Euler introduced these equations in 1757 [L. Euler, Mémoires de l’Académie des Sci. de Berlin 11 , 274–315 (1757).], and they are closely linked to the Navier–Stokes equations and turbulence. While the general singularity formation problem remains unresolved, we review a recent computer-assisted proof of finite-time, nearly self-similar blowup for the 2D Boussinesq and 3D axisymmetric Euler equations in a smooth bounded domain with smooth initial data. The proof introduces a framework for (nearly) self-similar blowup, demonstrating the nonlinear stability of an approximate self-similar profile constructed numerically via the dynamical rescaling formulation.}, archive = {J_PNAS}, author = {Chen, Jiajie and Hou, Thomas Y.}, doi = {10.1073/pnas.2500940122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2500940122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Singularity formation in 3D euler equations with smooth initial data and boundary}, volume = {122}, year = {2025}, }
• (2025). UFMylation: A supervisor of the HIF1α pathway and a potential therapeutic target for anti-PD-1 combination therapy in hypoxic tumors. PNAS, 122(27), e2500562122. (www)

  @article{ , abstract = {Activation of hypoxia signaling has been identified as an innate resistance signature against anti-PD-1 therapy, suggesting its potential as a target for combination treatments. Here, we demonstrate that UFMylation modification of HIF1α stabilizes the protein by antagonizing its ubiquitination and proteasomal degradation under hypoxic conditions. Mechanistically, depletion of UFL1 or defective UFMylation increases HIF1α binding to p53, promoting its degradation. Depletion of UFL1 or UBA5 , or defective UFMylation of HIF1α, destabilizes HIF1α, significantly inhibiting tumor growth and development in vitro and in xenograft mouse models. Defective UFMylation of HIF1α enhances the response to anti-PD-1 therapy in xenograft models. Clinically, UBA5 expression is upregulated in breast cancer tissues, and a selective UBA5 inhibitor reduces UFMylation activity and HIF1α protein levels, thereby enhancing anti-PD-1 combination therapy in mouse tumor models. Our findings highlight UFMylation as a critical posttranslational modification for the HIF1α pathway and a promising therapeutic target in hypoxic tumors.}, archive = {J_PNAS}, author = {Zou, Yongkang and Wang, Zhaoxiang and Jiang, Qiang and Kong, Xia and Ma, Xiaohe and Liang, Zhengyan and Wang, Zhiguo and Chen, Beiying and Yuan, Jiao and Wen, Jiayue and Ye, Sheng and Yan, Yubin and Li, Binbin and Xiong, Xing-dong and Liu, Xin-guang and He, Zhiwei and Cai, Yafei and Zhou, Junzhi}, doi = {10.1073/pnas.2500562122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2500562122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {UFMylation: A supervisor of the HIF1α pathway and a potential therapeutic target for anti-PD-1 combination therapy in hypoxic tumors}, volume = {122}, year = {2025}, }
• (2025). Rising surface salinity and declining sea ice: A new southern ocean state revealed by satellites. PNAS, 122(27), e2500440122. (www)

  @article{ , abstract = {For decades, the surface of the polar Southern Ocean (south of 50°S) has been freshening—an expected response to a warming climate. This freshening enhanced upper-ocean stratification, reducing the upward transport of subsurface heat and possibly contributing to sea ice expansion. It also limited the formation of open-ocean polynyas. Using satellite observations, we reveal a marked increase in surface salinity across the circumpolar Southern Ocean since 2015. This shift has weakened upper-ocean stratification, coinciding with a dramatic decline in Antarctic sea ice coverage. Additionally, rising salinity facilitated the reemergence of the Maud Rise polynya in the Weddell Sea, a phenomenon last observed in the mid-1970s. Crucially, we demonstrate that satellites can now monitor these changes in real time, providing essential evidence of the Southern Ocean’s potential transition toward persistently reduced sea ice coverage.}, archive = {J_PNAS}, author = {Silvano, Alessandro and Narayanan, Aditya and Catany, Rafael and Olmedo, Estrella and González‐Gambau, Verónica and Turiel, Antonio and Sabia, Roberto and Mazloff, Matthew R. and Spira, Theo and Haumann, F. Alexander and Naveira Garabato, Alberto C.}, doi = {10.1073/pnas.2500440122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2500440122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rising surface salinity and declining sea ice: A new southern ocean state revealed by satellites}, volume = {122}, year = {2025}, }
• (2025). Vamp3/syntaxin 4 mediates the basolateral membrane fusion of TfR transcytosis across the BBB and is exploited by pathogenic e. coli. PNAS, 122(27), e2500285122. (www)

  @article{ , abstract = {Transcytosis across the blood–brain barrier (BBB), composed of brain microvascular endothelial cells (HBMECs), is tightly controlled to prevent the entry of macromolecules, microorganisms, and toxins into the brain. Transferrin receptor (TfR) transcytosis, one of the few active transcytosis pathways in HBMECs, is extensively utilized for drug transport across the BBB and employed by meningitis-causing bacteria to penetrate into the brain. However, the molecular mechanism facilitating the fusion of TfR vesicles with the basolateral membrane of HBMECs, the final step of transcytosis, has not been experimentally studied. Here, we found that the interaction between the v-SNARE protein VAMP3 on TfR vesicles and the t-SNARE protein syntaxin 4 that is limited to the basolateral membrane in HBMECs mediates the fusion. We also provided evidence that this step is critical for the efficiency of TfR transcytosis. Furthermore, we showed that neonatal meningitis Escherichia coli (NMEC) infection significantly boosts the efficiency of this transcytosis by enhancing the expression of VAMP3 and syntaxin 4 through the TLR4-TRAM-TRIF-TRAF3-IKK-IRF3 signaling pathway in HBMECs. Silence or overexpression of VAMP3 and syntaxin 4 reduces or enhances the transcytosis of transferrin and NMEC in a human BBB model in vitro . Consistently, the penetration of transferrin and NMEC into the brain was significantly inhibited in VAMP3-deficient mice. These findings provide insights for improving strategies to deliver drugs into the brain and developing effective therapy for meningitis caused by NMEC.}, archive = {J_PNAS}, author = {Liu, Bin and Su, Yingying and Sun, Hao and Yang, Bin and Wan, Lili and Li, Xiaoya and Hou, Shaobin and Ma, Guozhen and Yu, Juan Joanna and Feng, Lu and Li, Huamin Henry and Wang, Lei}, doi = {10.1073/pnas.2500285122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2500285122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Vamp3/syntaxin 4 mediates the basolateral membrane fusion of TfR transcytosis across the BBB and is exploited by pathogenic e. coli}, volume = {122}, year = {2025}, }
• (2025). A privileged ER compartment for posttranslational heteromeric assembly of an ion channel. PNAS, 122(27), e2500218122. (www)

  @article{ , abstract = {Mechanisms underlying heterotypic subunit assembly of ion channels and other oligomeric complexes are poorly understood. In the human heart, heteromeric assembly of two isoforms encoded by the human ether-à-go-go related gene ( hERG ) is essential for the normal function of cardiac I Kr in ventricular repolarization, with loss of hERG1b contributing to arrhythmias associated with long QT-syndrome (LQTS). While hERG1a homomers traffic efficiently to the plasma membrane, hERG1b homomers are retained in the endoplasmic reticulum (ER). When expressed together, the two subunits avidly associate during biogenesis. Seeking rules specifying heteromeric association, we characterized the fate of hERG1b proteins using confocal and superresolution imaging in fixed and live HeLa cells. We found hERG1b sequestered in punctate intracellular structures when expressed alone in HeLa cells. These puncta, which depend on the presence of an N-terminal “RXR” ER retention signal, represent a privileged ER subcompartment distinct from that containing ER-retained, type 2 (hERG-based) LQTS mutant proteins, which were rapidly degraded by the proteasome. Introducing hERG1a to cells with preformed hERG1b puncta dissolved these puncta by rescuing extant hERG1b. Rescue occurred by association of fully translated hERG1b with 1a, a surprising finding given previous studies demonstrating cotranslational heteromeric association. We propose that sequestration limits potentially deleterious surface expression of hERG1b homomeric channels while preserving hERG1b for an alternative mode of heteromeric hERG1a/1b channel assembly posttranslationally. These findings reveal a surprising versatility of biosynthetic pathways promoting heteromeric assembly.}, archive = {J_PNAS}, author = {Kannan, Sudharsan and Kasberg, William and Ernandez, Liliana R. and Audhya, Anjon and Robertson, Gail A.}, doi = {10.1073/pnas.2500218122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2500218122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A privileged ER compartment for posttranslational heteromeric assembly of an ion channel}, volume = {122}, year = {2025}, }
• (2025). Onset of extensive human fire use 50,000 y ago. PNAS, 122(27), e2500042122. (www)

  @article{ , abstract = {Fire is a pivotal aspect of human involvement in the carbon cycle. However, the precise timing of the large-scale human fire use remains uncertain. Here, we report a pyrogenic carbon record of East Asian fire history over the past 300,000 y from the East China Sea. This record suggests a rapid increase in fire activity since approximately 50,000 y ago, indicating a decoupling from the monsoon climate, and this pattern is consistent with fire histories in Europe, Southeast Asia, and Papua New Guinea-Australia regions. By integrating extensive archaeological data, we propose that the intensified global expansion of modern human and population growth, coupled with the rising demand for fire use during cold glacial periods, resulted in a significant increase in fire utilization from 50,000 y onward. This suggests that a measurable human imprint on the carbon cycle via fire likely predates the Last Glacial Maximum.}, archive = {J_PNAS}, author = {Jiang, Shoushu and Zhao, Debo and Kaboth-Bahr, Stefanie and Beaufort, Luc and Tu, Hua and Lu, Zhengyao and Cheng, Zhongjing and Zhang, Shanjia and Zhong, Yi and Hao, Xiudong and Pei, Wenqiang and Cui, Guangqiang and Yang, Yifei and Lin, Anni and Huang, Jie and Wan, Shiming}, doi = {10.1073/pnas.2500042122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2500042122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Onset of extensive human fire use 50,000 y ago}, volume = {122}, year = {2025}, }
• (2025). Structural state governs the mechanism of shear-band propagation in metallic glasses. PNAS, 122(27), e2427082122. (www)

  @article{ , abstract = {Shear bands (SBs) play a critical role in determining the mechanical behavior of metallic glasses (MGs). However, the rapid dynamics and highly localized nature of SB propagation present significant challenges for direct observation of their atomistic mechanisms using experimental techniques. In this study, we employ hybrid molecular dynamics/Monte Carlo simulations to investigate the atomic-scale mechanisms of SB propagation in Mg 65 Cu 25 Y 10 MGs, prepared using cooling rates as slow as 10 4 K s −1 —comparable to experimental casting conditions and significantly slower than the 10 10 K s −1 rates previously employed in atomistic simulations. Our results reveal a qualitative shift in SB propagation mechanisms as the structural state evolves with decreasing cooling rates. In hyperquenched MGs, SB propagation occurs intermittently, characterized by a “stop-and-go” motion driven by sequential activation and coalescence of multiple shear transformation zones (STZs) separated by vortex-like fields. In contrast, slowly cooled MGs exhibit continuous and rapid SB propagation, mediated by localized shear softening and the formation of large vortex fields, indicative of a more collective structural response. This transition arises from significant differences in the number density and spatial distribution of activated STZs across different structural states. These findings provide insights into the microscopic dynamics of SB initiation and propagation in MGs, highlighting how the structural state can be strategically tuned to control SB behavior. This opens up different opportunities for optimizing the mechanical performance of MGs for targeted engineering applications.}, archive = {J_PNAS}, author = {Yu, Jinhua and Zhang, Zhen and Sha, Zhendong and Ding, Jun and Greer, A. Lindsay and Ma, Evan}, doi = {10.1073/pnas.2427082122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2427082122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural state governs the mechanism of shear-band propagation in metallic glasses}, volume = {122}, year = {2025}, }
• (2025). A degradable form of polyoma small t antigen reveals the high specificity of TAZ in regulating gene expression. PNAS, 122(27), e2426862122. (www)

  @article{ , abstract = {The study of DNA tumor viruses has revolutionized cancer biology, partly by virtue of the unique capabilities of viral oncoproteins to manipulate key proteins and pathways involved in tumorigenesis. We find a high affinity and selective binding of the polyoma small T antigen (PyST) with the transcription cofactor TAZ. By engineering a degradable version of PyST, we demonstrate that, when TAZ activity is modulated by PyST, a surprisingly small number of genes have altered expression and thus are candidate transcription targets of TAZ. Notably, knocking out TAZ, or its target genes CTGF or CYR61, abolishes the growth-promoting properties of PyST that are evident upon growth factor withdrawal. Therefore, by controlling the protein abundance of PyST and consequently TAZ activity, we find that TAZ is a transcriptional coactivator that can achieve important biological effects by acting on a limited number of gene targets.}, archive = {J_PNAS}, author = {Wang, Yubao and Manokaran, Cherubin and Huang, Kevin and Schaffhausen, Brian and Roberts, Thomas M.}, doi = {10.1073/pnas.2426862122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2426862122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A degradable form of polyoma small t antigen reveals the high specificity of TAZ in regulating gene expression}, volume = {122}, year = {2025}, }
• (2025). Disentangling temperature and reynolds number effects in quantum turbulence. PNAS, 122(27), e2426598122. (www)

  @article{ , abstract = {The interplay between viscous and frictional dissipation is key to understanding quantum turbulence dynamics in superfluid 4 He. Based on a coarse-grained two-fluid description, an original scale-by-scale energy budget that identifies each scale’s contribution to energy dissipation is derived. Using the Hall-Vinen-Bekharevich-Khalatnikov (HVBK) model to further characterize mutual friction, direct numerical simulations at temperatures 1.44 K ≲ T ≲ 2.16 K indicate that mutual friction promotes intense momentum exchanges between the two fluids to maintain a joint energy cascade despite their viscosity mismatch. However, the resulting overall frictional dissipation remains small (compared to the viscous dissipation) and confined to far-dissipative scales. This remarkable feature allows us to define an effective Reynolds number for the turbulence intensity in a two-fluid system, helping to disentangle the effects of Reynolds number and temperature in quantum turbulence. Thereby, simple physical arguments predict that the distance ℓ between quantized vortices (normalized by the turbulence integral scale L 0 ) should behave as ℓ / L 0 ≈ 0.5 Re κ − 3 / 4 with the Reynolds number based on the quantum of circulation κ . This law is well supported by a large set of experimental and numerical data within the temperature range of the HVBK model. Finally, this approach offers the possibility of revisiting the ongoing controversy on intermittency in quantum turbulence. It is shown that observed changes in intermittency arise from Reynolds number effects rather than from temperature variations, as proposed in recent studies.}, archive = {J_PNAS}, author = {Polanco, Juan Ignacio and Roche, Philippe-E. and Danaila, Luminita and Lévêque, Emmanuel}, doi = {10.1073/pnas.2426598122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2426598122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Disentangling temperature and reynolds number effects in quantum turbulence}, volume = {122}, year = {2025}, }
• (2025). SpbR controls lipoteichoic acid length by directly inhibiting signal peptidase SpsB in staphylococcus aureus. PNAS, 122(27), e2426464122. (www)

  @article{ , abstract = {Staphylococcus aureus is a Gram-positive pathogen that causes life-threatening infections. Its cell envelope contains anionic polymers called teichoic acids that are required for cell viability. Teichoic acids come in two forms and are made by different biosynthetic pathways. One form, lipoteichoic acid (LTA), is anchored in the cell membrane; the other form, wall teichoic acid (WTA), is covalently linked to the peptidoglycan cell wall. Although the LTA and WTA biosynthetic pathways have been characterized, regulation of teichoic acid production is not well understood. Here, we identified SpbR ( SAOUHSC_00965 ), a polytopic membrane protein similar to a eukaryotic CAAX protease, as a factor that controls LTA levels in S. aureus cells. We show that loss of SpbR results in short LTAs and a synthetically sick phenotype when WTA biosynthesis is prevented, whereas overexpressing SpbR results in elongated LTAs. Mechanistically, we find that SpbR physically associates with the type I signal peptidase SpsB, which cleaves LtaS, the polymerase that assembles LTA on the extracellular side of the membrane, and we show that this physical interaction inhibits SpsB cleavage of LtaS both in vivo and in vitro. Although the phenotypes investigated here are dominated by SpbR’s effects on LtaS, it also inhibits cleavage of other SpsB substrates. Based on its role in regulating the activity of SpsB, we named this factor SpbR ( S ignal p eptidase b R egulator).}, archive = {J_PNAS}, author = {Park, Youngseon and Sisley, Tyler A. and Stone, Madeleine C. and Corrigan, Rebecca M. and Vickery, Christopher R. and Gründling, Angelika and Walker, Suzanne}, doi = {10.1073/pnas.2426464122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2426464122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SpbR controls lipoteichoic acid length by directly inhibiting signal peptidase SpsB in staphylococcus aureus}, volume = {122}, year = {2025}, }
• (2025). FtsZ-mediated spatial–temporal control over septal cell wall synthesis. PNAS, 122(27), e2426431122. (www)

  @article{ , abstract = {FtsZ, the tubulin-like GTPase, is the central organizer of the bacterial divisome, a macromolecular complex that synthesizes new septal cell wall (made of septal peptidoglycan, sPG) to allow cell wall constriction and cytokinesis. In Escherichia coli , it was shown that 1) FtsZ recruits all essential divisome proteins to the septum, including the core sPG synthase complex, FtsWIQLB, and its activator, FtsN; 2) FtsWIQLB must complex with FtsN to be activated to synthesize sPG under the wildtype background; and 3) the Brownian ratcheting by treadmilling FtsZ polymers drives the directional movements of sPG synthase proteins along the septum circumference; and 4) FtsZ is essential for the early stage, but dispensable for the late stage of cell wall constriction. However, it remains unclear how FtsZ spatial–temporally organizes the divisome for robust cell wall constriction during cytokinesis. Combining theoretical modeling with experiments in E. coli , we show that at the early stage during cell division, the Brownian ratcheting by FtsZ treadmilling acts both as a template to corral FtsWIQLB and FtsN into close contacts for FtsWIQLB-FtsN complex formation and as a conveyor to maximally homogenize the septal distribution of sPG synthesis activities to avoid uneven cell wall constriction. When the septum constricts progressively, the FtsN septal density increases via binding to denuded sPG (dnG) and serves as the template to activate FtsWIQLB for continued sPG synthesis, rendering FtsZ dispensable. Our work suggests an overarching framework for how FtsZ spatial–temporally regulates septal cell wall constriction, in which different bacteria species may operate in various parameter regimes to meet their distinct functional requirements.}, archive = {J_PNAS}, author = {Hu, Longhua and Perez, Amilcar J. and Nesterova, Tanya and Lyu, Zhixin and Yahashiri, Atsushi and Weiss, David S. and Xiao, Jie and Liu, Jian}, doi = {10.1073/pnas.2426431122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2426431122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {FtsZ-mediated spatial–temporal control over septal cell wall synthesis}, volume = {122}, year = {2025}, }
• (2025). Signal peptide–independent secretion of keratin-19 by pancreatic cancer cells. PNAS, 122(27), e2426218122. (www)

  @article{ , abstract = {The exclusion of T cells causes immune escape of pancreatic ductal adenocarcinoma (PDA). T cell exclusion is mediated by the interaction between CXCR4 on T cells and its ligand, CXCL12, which is complexed to keratin-19 (KRT19) on the surface of PDA cells. KRT19 secretion by PDA cells is essential to this process but is unusual because KRT19 lacks an endoplasmic reticulum (ER)-directing signal peptide (SP). By using biotinylation by an ER-restricted TurboID system and a split-GFP assay in PDA cells, we demonstrate that KRT19 enters the ER via its “head” domain. Additionally, KRT19 is shown to interact with the signal recognition particle and its secretion is sensitive to canonical protein secretion inhibitors. In vivo, mouse tumors formed with ER-TurboID-expressing PDA cells contain biotinylated KRT19. In contrast, keratin-8 (KRT8), which colocalizes with KRT19 on the surface of PDA cells, does not enter the ER. Rather, KRT8 is externalized via secretory autophagy possibly in a complex with KRT19. Thus, despite lacking a classical SP, PDA cells secrete KRT19 to capture CXCL12 and protect against immune attack.}, archive = {J_PNAS}, author = {Moresco, Philip and Kastan, Jonathan P. and Yang, Jung-in and Prabakar, Rishvanth and Kelley, Z. Larkin and Minicozzi, Francesca and Adams, Dexter W. and Cifani, Paolo and Tuveson, David A. and Fearon, Douglas T.}, doi = {10.1073/pnas.2426218122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2426218122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Signal peptide–independent secretion of keratin-19 by pancreatic cancer cells}, volume = {122}, year = {2025}, }
• (2025). Sulfur-mediated transformation from osmium nanocrystals to single atoms for efficient alkaline hydrogen evolution reaction. PNAS, 122(27), e2426207122. (www)

  @article{ , abstract = {Osmium (Os)-based catalysts, recognized for their unique chemical and electronic properties along with cost-effectiveness, hold great potential for the hydrogen evolution reaction (HER). However, their practical application has long been limited because pure Os exhibits excessively strong adsorption of intermediates and suffers from stability issues. Herein, we report the development of a highly stable catalyst achieved by implanting the sulfur (S) atom into the matrix, facilitating the transformation of Os nanocrystals into Os single atoms. The prepared atomically dispersed Os catalyst (Os-SA@SNC) demonstrates outstanding catalytic activity, requiring only a 13 mV overpotential to achieve a current density of 10 mA cm −2 in 1.0 M potassium hydroxide (KOH) solution, as well as the excellent durability. This performance surpasses that of commercial Pt/C and outperforms most of the reported state-of-the-art electrocatalysts. Theoretical simulations clarify the important role of S atoms in promoting the dispersion and diffusion of Os atoms. Moreover, density functional theory calculations indicate that S atoms adjust the local electronic structure of Os active sites, further facilitating the adsorption/dissociation of H 2 O and optimizing the hydrogen adsorption free energy (ΔG *H ), thereby accelerating the kinetics of both the Volmer and Heyrovsky steps in alkaline HER. This work revitalizes Os-based catalysts for energy conversion and paves the way for innovative HER catalyst design and application to contaminated soil/water remediation.}, archive = {J_PNAS}, author = {Xue, Wendan and Zhou, Qixing and Wang, Pengfei and Zuo, Sijin and Li, Fengxiang and Jiang, Jiwei and Mo, Fan and Yin, Chuan and Liu, Gaolei and Ban, Zhan and Wei, Yuanyuan and An, Wen and Huang, Xiulin and Wang, Hui and Zhan, Sihui}, doi = {10.1073/pnas.2426207122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2426207122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sulfur-mediated transformation from osmium nanocrystals to single atoms for efficient alkaline hydrogen evolution reaction}, volume = {122}, year = {2025}, }
• (2025). Divergent oxygen trends in ice-covered lakes driven by ice-cover decline and ecological memory. PNAS, 122(27), e2426140122. (www)

  @article{ , abstract = {Dissolved oxygen (DO) is an essential resource in ice-covered lakes, regulating water quality and biodiversity, including the survival of economically important fish species. Most of the world’s lakes seasonally freeze, often resulting in oxygen depletion as ice cover inhibits water column ventilation and snow cover limits photosynthesis while respiration continues. Widespread shortening of ice-cover duration in a warmer world might improve winter oxygenation, but this hypothesis remains untested. Here, we performed a systematic analysis of 6.6 million physical and chemical observations from 19,645 lakes in the Northern Hemisphere during 1960 to 2022. Contrary to expectations, under-ice DO trends ranged from significantly negative in small lakes (A surf <10 ha) (−0.14 ± 0.05 mg L −1 decade −1 ) to significantly positive in large lakes (≥10 4 ha) (0.11 ± 0.03 mg L −1 decade −1 ). This morphometric scaling emerged partly because ice-cover periods have shortened 2.2 times faster in large lakes compared to small lakes. Hierarchical modeling revealed that in smaller lakes, increasingly oxygen-depleted conditions in summer carried over to the ice-cover season, because fetch size limited wind-driven aeration in fall. As a result of this cross-seasonal ecological memory, under-ice hypoxic zones have expanded. Oxygen trended most negative in small eutrophic and humic lakes with high seasonal oxygen depletion rates. In larger lakes (≥10 3 ha), negligible summer deoxygenation, prolonged ventilation in fall, and shortening of the oxygen drawdown period in winter explained positive DO trends. However, in the vast majority of seasonally ice-covered lakes, which are small, continued climate warming is likely to exacerbate deoxygenation.}, archive = {J_PNAS}, author = {Jansen, Joachim and Weyhenmeyer, Gesa A. and Härkönen, Laura H. and Paterson, Andrew M. and del Giorgio, Paul A. and Prairie, Yves T.}, doi = {10.1073/pnas.2426140122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2426140122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Divergent oxygen trends in ice-covered lakes driven by ice-cover decline and ecological memory}, volume = {122}, year = {2025}, }
• (2025). TEAD-targeting small molecules induce a cofactor switch to regulate the hippo pathway. PNAS, 122(27), e2425984122. (www)

  @article{ , abstract = {TEAD proteins are the main transcriptional effectors of the Hippo signaling pathway and a clinical-stage pharmacological target in oncology. Most TEAD-targeting small molecules are designed to disrupt interaction between TEAD and the oncogenic transcriptional activators YAP and TAZ. Here, we uncover an alternative mechanism for a subset of TEAD lipid pocket-binding molecules. We report that select sulfonamide-containing TEAD-targeting compounds enhance the interaction between TEAD and the transcriptional repressor VGLL4. Chemically induced VGLL4–TEAD complexes confer an antiproliferative effect by outcompeting YAP–TEAD complexes at chromatin. This cofactor switch from YAP to VGLL4 impacts transcriptional networks, including influencing the expression of genes involved in cellular proliferation and mechanosignaling. We demonstrate that VGLL4 is required for an antiproliferative response to these sulfonamide-containing compounds by counteracting YAP. We show that VGLL4 overexpression can confer sensitivity to these compounds in Hippo-driven cell lines, and we further show that genetic deletion of VGLL4 oblates cellular responsiveness to these molecules in cells and in vivo. Our data reveal a category of TEAD inhibitors that act as “molecular glues” toward the repressive VGLL4–TEAD interaction. These findings open up understandings for curbing the oncogenic activity of Hippo pathway deregulation in cancer, and identify glue-like molecules that promote transcriptional repression.}, archive = {J_PNAS}, author = {Guarnaccia, Alissa D. and Hagenbeek, Thijs J. and Lee, Wendy and Kljavin, Noelyn and Choi, Meena and Tombling, Benjamin and Peukert, Carsten and Ulas, Gözde and Kameswaran, Vasumathi and Le, Daniel and Paul, Sayantanee and Vaidya, Samir and Zbieg, Jason R. and Crawford, James J. and Daniel, Bence and Dey, Anwesha and Lill, Jennie R.}, doi = {10.1073/pnas.2425984122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2425984122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TEAD-targeting small molecules induce a cofactor switch to regulate the hippo pathway}, volume = {122}, year = {2025}, }
• (2025). Molecular basis for substrate recognition and transport of mammalian taurine transporters. PNAS, 122(27), e2425549122. (www)

  @article{ , abstract = {The taurine transporter (TAUT) mediates cellular taurine uptake, playing a critical role in human health and longevity. In this study, we present cryogenic electron microscopy structures of both mouse and human TAUT in various conformational states. The taurine-bound, occluded forms of mouse and human TAUT reveal the substrate binding pocket and the ion binding sites. The amino group of taurine interacts with Glu406 at the binding site, constituting a key structural feature determining substrate preference. While both imidazole acetic acid and guanidinoethyl sulfonate (GES) inhibit TAUT by competing with taurine for the binding site, GES also functions as a substrate of TAUT. Moreover, mouse TAUT is captured in an inward-open apo conformation, where the tilted movement of transmembrane helix (TM) 1a opens the intracellular gate. Notably, TM6 exhibits two distinct conformational states: the canonical form consisting of two half-helices and a continuous straight helix. In the latter conformation, TM6 partially occupies the substrate binding site, likely promoting taurine release. Together, our findings provide critical insights into the molecular mechanisms by which TAUT recognizes and transports taurine.}, archive = {J_PNAS}, author = {Wang, Mingxing and He, Jin and Cai, Qianwen and Zhang, Shen-ao and She, Ji}, doi = {10.1073/pnas.2425549122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2425549122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular basis for substrate recognition and transport of mammalian taurine transporters}, volume = {122}, year = {2025}, }
• (2025). Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia. PNAS, 122(27), e2425452122. (www)

  @article{ , abstract = {Macrophages often pervade solid tumors, and clusters of macrophages sometimes associate with longer survival of patients. However, clustering mechanisms and impacts on key functions such as phagocytosis remain obscure. Here, under conditions that maximize cancer cell phagocytosis within cohesive tumors, we uncover pathways that favor dynamic clusters and find a colocalization of tumor-intrusive pseudopodia which we term “intrudopodia.” Cluster formation over hours on low-adhesion substrates occurs after macrophage induction to a state colloquially referred to as M1 after exposure to interferons and T cell–derived cytokines. Clusters prove fluid on timescales of minutes and also sort from interleukin-4-treated, so-called M2 macrophages that tend to disperse. M1 macrophages upregulate specific cell–cell adhesion receptors but suppress actomyosin contractility, with both pathways contributing to cluster formation. Decreased cortical tension was not only reflected in a low level of nuclear lamin-A that downregulates cytoskeletal targets of serum response factor and tends to soften the nucleus but was also predicted to unleash pseudopodia. Macrophage neighbors in tumor spheroids indeed coextend intrudopodia between cancer cell junctions—at least when phagocytosis conditions are maximized. Intrudopodia from neighbors help detach and individualize cancer cells for rapid engulfment. Juxtaposition of a macrophage cluster with tumor cell nests defines a broad interface that minimizes cancer cell nearest neighbor interactions and maximizes coordination of macrophage intrudopodia. Cooperative phagocytosis thus overcomes solid tumor cohesion—and might explain why the macrophage clustering factor ITGAL associates with patient survival.}, archive = {J_PNAS}, author = {Dooling, Lawrence J. and Anlaş, Alişya A. and Tobin, Michael P. and Ontko, Nicholas M. and Marchena, Tristan and Wang, Maximilian and Andrechak, Jason C. and Discher, Dennis E.}, doi = {10.1073/pnas.2425452122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2425452122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia}, volume = {122}, year = {2025}, }
• (2025). Total synthesis and biological activity of “carbamorphine”: O-to-CH2 replacement in the E-ring of the morphine core structure. PNAS, 122(27), e2425438122. (www)

  @article{ , abstract = {Morphine is a µ-opioid receptor (MOR) agonist and potent analgesic. However, it displays several side effects including respiratory depression and addiction. Here, we show that a single heavy atom replacement in the morphine core structure (O to CH 2 exchange in the E-ring) prepared through a 15-step total synthesis displays a different pharmacological profile. The total synthesis features an intramolecular inverse electron-demand Diels−Alder cycloaddition and a stereoselective Giese radical addition to construct a quaternary carbon center. Unlike morphine, where the (–)-morphine enantiomer binds the MOR, both enantiomers of this “carba” variant, which we have named carbamorphine, possess activity as agonists of the MOR. Cell-based functional assays show that (+)-carbamorphine shows reduced G-protein as well as β-arrestin efficacy at the MOR. In mouse behavioral assays, (+)-carbamorphine exhibits MOR-selective antinociception while showing reduced respiratory depression and a lack of conditioned place preference at supratherapeutic doses. Overall, through a net “single-atom” change (i.e., O to CH 2 ) in the morphine framework, different pharmacological profiles have been realized. This work provides a basis for additional syntheses and the study of morphine analogs that incorporate atom changes in the core framework.}, archive = {J_PNAS}, author = {Akiyama, Sota and Ople, Rohini S. and Kremsmair, Alexander and Ramos-Gonzalez, Nokomis and Nedungadan, Thomas and Kennedy, Brandon J. and Appourchaux, Kevin and Eans, Shainnel O. and Tsai, Bowen A. and Kraml, Christina and Huang, Xi-Ping and McLaughlin, Jay P. and Majumdar, Susruta and Sarpong, Richmond}, doi = {10.1073/pnas.2425438122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2425438122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Total synthesis and biological activity of “carbamorphine”: O-to-CH2 replacement in the E-ring of the morphine core structure}, volume = {122}, year = {2025}, }
• (2025). Tunable shear thickening, aging, and rejuvenation in suspensions of shape-memory-endowed liquid crystalline particles. PNAS, 122(27), e2425373122. (www)

  @article{ , abstract = {The morphological features of particles, notably shape anisotropy, critically influence the rheological properties of dense suspensions, spanning both natural and engineered systems. This work explores the potential of using shape memory particles to dynamically regulate suspension fluid flow through controllable shape transformations. First, we synthesize shape-memory particles with programmable anisotropy from liquid crystal elastomers, such that the stiffness and shapes of the particles can be tuned by manipulating temperature. Our findings reveal that suspensions from such particles exhibit significant tunability in shear thickening behavior, transitioning from discontinuous shear thickening to a Newtonian-like response within a narrow temperature range of 60 ° C. This capability to modulate rheological responses in situ presents an approach for addressing processing challenges in many applications where control over flow behavior is paramount. Furthermore, we also show that suspensions composed of these anisotropic particles can undergo physical aging, and evolve into a glassy state. This state can be escaped upon activation of the shape memory effect. This reversibility underscores the potential for using such materials to engineer systems that can enter or come out of kinetic arrest by leveraging internal mechanical responses to external stimuli. The insights gained here not only broaden our understanding of the interplay between particle geometry and suspension dynamics but also pave the way for leveraging ensembles of stimuli-responsive objects to precisely control collective behaviors in many-body systems.}, archive = {J_PNAS}, author = {Chen, Chuqiao and Martínez Narváez, Carina D. V. and Chang, Nina and Jimenez, Carlos Medina and Dennis, Joseph M. and Jaeger, Heinrich M. and Rowan, Stuart J. and de Pablo, Juan J.}, doi = {10.1073/pnas.2425373122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2425373122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tunable shear thickening, aging, and rejuvenation in suspensions of shape-memory-endowed liquid crystalline particles}, volume = {122}, year = {2025}, }
• (2025). Fertile androgenetic mice generated by targeted epigenetic editing of imprinting control regions. PNAS, 122(27), e2425307122. (www)

  @article{ , abstract = {Each new mammalian life begins with the fusion of an oocyte and a sperm to produce a fertilized egg containing two sets of genomes, one from the mother and one from the father. Androgenesis, a way for producing offspring solely from male genetic material, is limited in mammals, presumably due to barriers arising from genomic imprinting, an epigenetic mechanism leading to monoallelic gene expression. Here, we report adult mammalian offspring derived from the genetic material of two sperm cells. These mice, which we refer to as androgenetic mice, were produced via targeted DNA methylation editing of seven imprinting control regions (ICRs) through CRISPR-based epigenome engineering. Two sperm cells were injected into an enucleated oocyte to form putatively diploid embryos. Allele-specific epigenetic editing was achieved by injecting guide RNAs with protospacer adjacent motif (PAM) sequences designed to match one allele but not the other. The birth of androgenetic mice that were able to develop to adulthood demonstrates that mammalian androgenesis is achievable by targeted epigenetic remodeling of a few defined ICRs.}, archive = {J_PNAS}, author = {Wei, Yanchang and Yue, Tao and Wang, Yuanyuan and Yang, Yan}, doi = {10.1073/pnas.2425307122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2425307122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fertile androgenetic mice generated by targeted epigenetic editing of imprinting control regions}, volume = {122}, year = {2025}, }
• (2025). Barystatic sea level change observed by satellite gravimetry: 1993–2022. PNAS, 122(27), e2425248122. (www)

  @article{ , abstract = {Using time-variable gravity fields determined from satellite laser ranging (SLR) and the Gravity Recovery and Climate Experiment (GRACE) and GRACE Follow-On (GRACE-FO), we derive three decades of barystatic sea level (BSL) change estimates since 1993, providing a long record of satellite gravimetry-based BSL estimates comparable in duration to satellite altimetry. Over the 1993–2022 altimetry era, the BSL change rate is 1.75 ± 0.59 mm/y (2σ) as observed by SLR. The rate increases to 2.16 ± 0.59 mm/y (SLR) and 2.13 ± 0.38 mm/y (GRACE/-FO) over 2003–2022, mainly due to accelerated ice loss in Greenland since the 2000s. The remarkable agreement between SLR and GRACE/-FO estimates over the joint period cross-validates each other, suggesting that both work well in monitoring BSL changes. We also compare our satellite gravimetry estimates with the sum of individual mass change components (ice sheets, glaciers, and land water storage) obtained from multisource datasets (in situ, remote sensing and geophysical modeling). The differences are within 0.2 mm/y over the three decades, highlighting the global consistency of different techniques for observing Earth’s surface mass changes. Moreover, we reconcile the global mean sea level (GMSL) rise budget using reprocessed altimetry data and updated thermosteric sea level ensembles. From 1993 to 2022, the sum of thermosteric and SLR-based barystatic contributions (3.16 ± 0.64 mm/y) agrees well with altimetry-observed GMSL rate (3.22 ± 0.28 mm/y), suggesting that the GMSL rise budget can be closed within uncertainties over the last three decades.}, archive = {J_PNAS}, author = {Nie, Yufeng and Chen, Jianli and Xu, Guodong and Löcher, Anno}, doi = {10.1073/pnas.2425248122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2425248122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Barystatic sea level change observed by satellite gravimetry: 1993–2022}, volume = {122}, year = {2025}, }
• (2025). Gelated microvesicle–mediated delivery of mesenchymal stem cell mitochondria for the treatment of myocardial infarction. PNAS, 122(27), e2424529122. (www)

  @article{ , abstract = {Mitochondrial dysfunction is closely linked to cardiomyocyte injury following myocardial infarction (MI). While mitochondrial transplantation is a promising therapeutic strategy, challenges remain in maintaining mitochondrial structural integrity, enhancing delivery efficiency, and increasing the mitochondrial supply. Herein, we developed a gelated microvesicle–based mitochondria delivery system (Mito@Microgels) for transplanting mesenchymal stem cell mitochondria, addressing the aforementioned issues. Further decoration of phosphatidylserine on the surface of Mito@Microgels boosted cellular uptake efficiency by cardiomyocytes. These Mito@Microgels effectively deliver active mitochondria to cardiomyocytes, improving the mitochondrial network architecture and function and consequently reducing the cellular injury induced by oxidative stress. Moreover, Mito@Microgels attenuated the inflammatory phenotype of macrophages, helping resolve excessive local inflammation. In vivo animal studies using a rat MI model further validated the therapeutic efficacy of the Mito@Microgels, as evidenced by improved myocardial function, prevention of infarcted left ventricular wall thinning, and increased cardiomyocyte survival. Our study introduces an efficient mitochondrial delivery strategy with significant potential for cardiac repair post-MI and other mitochondria-related diseases.}, archive = {J_PNAS}, author = {Chu, Qi and He, Dong and Xie, Wenqi and Li, Shichun and Dong, Zixuan and Fu, Xiaoling}, doi = {10.1073/pnas.2424529122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2424529122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Gelated microvesicle–mediated delivery of mesenchymal stem cell mitochondria for the treatment of myocardial infarction}, volume = {122}, year = {2025}, }
• (2025). A mycobacterium tuberculosis secreted virulence factor rv1435c/hsr1 disrupts host snRNP biogenesis. PNAS, 122(27), e2423349122. (www)

  @article{ , abstract = {Transcriptional adaptation drives the host responses to Mycobacterium tuberculosis ( Mtb ) infection. However, Mtb alters host RNA splicing to quench host antibacterial responses, the mechanism for which remains unknown. Here, we report a mechanism whereby a secreted Mtb protein interferes with the biogenesis of key spliceosomal components. A high-throughput yeast-2-hybrid screen identified several Mtb -secreted proteins interacting with the host RNA splicing factors (SFs). Through custom-designed in-cell assays, we show that one of those proteins, Rv1435c/hsr1 (host splicing regulator 1), targets specific exon-skipping events. The Mtb Rv14345c/hsr1 facilitates direct interaction between Mtb phagosomes and U5 snRNA and SNRPF, key components of the snRNPs. Genetic deletion of Rv1435c/hsr1 reverses the specific exon-skipping events caused by WT Mtb infection. The Δ hsr1 strain shows compromised growth during ex vivo infection in macrophages and in vivo infection in mice. Tissue sections from the WT Mtb or Δhsr1 -infected mice showed significant hsr1-dependent SNRPF staining, a phenomenon also noted in the human intestinal tuberculosis (ITB) biopsies. Thus, hsr1 is a virulence factor that disrupts host snRNP biogenesis for pathogenesis. The splicing regulators from the host and pathogen are novel targets for antituberculosis therapy.}, archive = {J_PNAS}, author = {Chauhan, Komal and Datta, Dipanwita and Kapoor, Yogita and Passricha, Nishat and Dutt, Ravi and Arora, Naresh and Das, Mrinmoy and Rao, Kavya and Singh, Lakshyaveer and Gautam, Arunima and Sharma, Raman Deep and Sarkar, Binayak and Yadav, Mohit and Malakar, Basanti and Kalam, Haroon and Saini, Prince and Mehra, Lalita and Das, Prasenjit and Ahuja, Vineet and Singhal, Amit and Nandicoori, Vinay and Kumar, Dhiraj}, doi = {10.1073/pnas.2423349122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2423349122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A mycobacterium tuberculosis secreted virulence factor rv1435c/hsr1 disrupts host snRNP biogenesis}, volume = {122}, year = {2025}, }
• (2025). Spin-informed universal graph neural networks for simulating magnetic ordering. PNAS, 122(27), e2422973122. (www)

  @article{ , abstract = {The screening and discovery of magnetic materials are hindered by the computational cost of first-principles density-functional theory (DFT) calculations required to find the ground state magnetic ordering. Although universal machine-learning interatomic potentials (uMLIPs), also known as atomistic foundation models, offer high-fidelity models of many atomistic systems with significant speedup, they currently lack the inputs required for predicting magnetic ordering. In this work, we present a data-efficient, spin-informed graph neural network framework that incorporates spin degrees of freedom as inputs and preserves physical symmetries, extending the functionality of uMLIPs to simulate magnetic orderings. This framework speeds up DFT calculations through better initial guesses for magnetic moments, determines the ground-state ordering of bulk materials and even generalizes to magnetic ordering in surfaces. Furthermore, we implement a closed-loop anomaly detection approach that effectively addresses the classic “chicken-and-egg” problem of creating a high-quality dataset while developing a uMLIP, unearthing anomalies in large benchmark datasets and boosting model accuracy.}, archive = {J_PNAS}, author = {Xu, Wenbin and Sanspeur, Rohan Yuri and Kolluru, Adeesh and Deng, Bowen and Harrington, Peter and Farrell, Steven and Reuter, Karsten and Kitchin, John R.}, doi = {10.1073/pnas.2422973122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2422973122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spin-informed universal graph neural networks for simulating magnetic ordering}, volume = {122}, year = {2025}, }
• (2025). Cerebral blood flow is modulated by astrocytic cAMP elevation independently of IP3R2-mediated ca2+ signaling in mice. PNAS, 122(27), e2422069122. (www)

  @article{ , abstract = {Local neural activation drives regional increase of cerebral blood flow (CBF), in a phenomenon known as functional hyperemia. Astrocytes, which enwrap cerebral blood vessels and respond to neuronal activity through their G protein–coupled receptors (GPCRs), play a vital role in brain energy metabolism. Although astrocytic calcium (Ca 2+ ) signaling has been widely studied in relation to neurovascular coupling, the role of cyclic adenosine monophosphate (cAMP), another key second messenger of GPCRs, on CBF has not been established. In this study, we explored the effects of optogenetically induced astrocytic cAMP elevation on CBF. We engineered adeno-associated viral vectors (AAVs) to express a bacterial photoactivated adenylyl cyclase in astrocytes, which triggers an increase in cAMP upon blue light stimulation. Opto-stimulation also elevated astrocytic Ca 2+ , albeit with a delayed onset under mild stimulation. In vivo imaging of anesthetized and awake wild-type mice through a thinned skull preparation revealed that optogenetically induced astrocytic cAMP elevation led to pronounced arteriole dilation, with a latency of 1.8 s and maximal dilation reached within 10 s in the awake state and slower response under anesthesia. Mild opto-stimulation causing sensory-level cAMP elevations was sufficient to induce arteriole dilation. This effect was preserved in IP 3 receptor type 2-knockout (IP 3 R2 −/− ) mice, indicating a mechanism independent of GPCR-induced intracellular Ca 2+ elevations. These findings highlight astrocytic cAMP as a key modulator of cerebral vasodilation, contributing to our understanding of local CBF regulation. This study opens broad avenues for understanding astrocyte-mediated control of CBF and its implications in neurological diseases characterized by dysregulated blood flow.}, archive = {J_PNAS}, author = {Vittani, Marta and Herlo, Rasmus and Wang, Xiaowen and Christensen, Michala Daniela Bach and Vo, Camilla Trang and Mishima, Tsuneko and Kusk, Peter and Konno, Ayumu and Hirai, Hirokazu and Tsuboi, Takashi and Kitaguchi, Tetsuya and Kjaerby, Celia and Asiminas, Antonis and Yokoyama, Tatsushi and Sakamoto, Masayuki and Nedergaard, Maiken and Hirase, Hajime}, doi = {10.1073/pnas.2422069122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2422069122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cerebral blood flow is modulated by astrocytic cAMP elevation independently of IP3R2-mediated ca2+ signaling in mice}, volume = {122}, year = {2025}, }
• (2025). Detecting environmentally dependent developmental plasticity in fossilized individuals. PNAS, 122(27), e2421549122. (www)

  @article{ , abstract = {The fossil record provides the most powerful evidence of large-scale biodiversity change on Earth, but it does so at coarse and often idiosyncratic temporal scales. One critical problem that arises concerns the evolutionary consequences of individual environmental experience. Individuals respond to their environment instantaneously, whereas the resolution of most fossil records aggregates multiple paleoenvironments over time scales beyond individual lifespans. Therefore, the presence of phenotypic plasticity in deep time and the extent of its influence on macroevolution remain poorly understood. Using coupled computed tomography and laser ablation inductively coupled plasma mass spectrometry protocols, we studied the environmental dependence of developmental trajectories across three sister species of macroperforate planktonic foraminifera. A foraminiferal shell preserves all stages of the individual’s ontogeny, as well as the environmental state experienced throughout its lifetime. Generalized additive mixed effect (GAMM) models show that somatic growth rates differ among the three Menardella species and that these are inversely correlated with calcification temperature, as reconstructed from Mg/Ca measurements through ontogeny. This environmental dependence varies among species: The thermal sensitivity of individual chamber-to-chamber growth rates of Menardella limbata and Menardella pertenuis is double that seen in Menardella exilis . In contrast, no such environmental signal was recovered for architectural shape traits. Our integrated approach is widely applicable and demonstrates that detecting developmental plasticity in the fossil record is feasible. Extrapolating these techniques in deep time promises to revolutionize our understanding of the ways in which environmentally associated trait variation drove the diversification of life on Earth.}, archive = {J_PNAS}, author = {Brombacher, Anieke and Searle-Barnes, Alex and Mulqueeney, James M. and Standish, Christopher D. and Milton, J. Andy and Katsamenis, Orestis L. and Watson, Richard A. and Trueman, Clive and Sinclair, Ian and Wilson, Paul A. and Foster, Gavin L. and Ezard, Thomas H. G.}, doi = {10.1073/pnas.2421549122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2421549122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Detecting environmentally dependent developmental plasticity in fossilized individuals}, volume = {122}, year = {2025}, }
• (2025). Sleep duration and timing are associated with next-day physical activity: Insights from two large-scale wearable sensor studies. PNAS, 122(27), e2420846122. (www)

  @article{ , abstract = {Sleep and physical activity (PA) are pillars of health. However, the temporal dynamics between these two behaviors remain poorly understood. This research aims to examine the independent and interactive between- and within-person associations of sleep duration and sleep onset timing on next-day PA duration in two large, longitudinal samples of adults under free-living conditions. In the primary study, participants (N = 19,963; 5,995,080 person-nights) wore a validated biometric device (WHOOP) for 1 y (01/09/2021 to 31/08/2022). Objective sleep and PA metrics were derived from the wrist-worn device. Generalized additive mixed models assessed between- and within-person associations between sleep and PA variables, adjusted for age, sex, Body Mass Index, weekday/weekend, seasonal effects, biometric feedback, and autocorrelated errors. Between participants, longer sleep duration and later sleep onset timing were associated with decreased moderate-to-vigorous PA (MVPA) and overall PA duration ( ps < 0.001). Within participants, sleeping shorter-than-usual and falling asleep earlier-than-usual were associated with increased next-day MVPA and overall PA, whereas sleeping longer-than-usual, or falling asleep later-than-usual, showed the opposite relationship ( ps < 0.001). Next-day MVPA duration was highest following earlier-than-usual sleep onset timing combined with one’s typical sleep duration. Results were consistent but smaller in magnitude in the external validation study (N = 5,898; 635,477 person-nights) using Fitbit data from the All of Us Research Program. Individuals may sacrifice time in one health behavior for time in the other. Interventions promoting exercise and holistic public health messaging should consider the temporal dynamics between sleep and next-day PA outcomes.}, archive = {J_PNAS}, author = {Leota, Josh and Czeisler, Mark É. and Le, Flora and Presby, David M. and Capodilupo, Emily R. and Scott, Hannah and Wiley, Joshua F. and Drummond, Sean P. A. and Rajaratnam, Shantha M. W. and Facer-Childs, Elise R.}, doi = {10.1073/pnas.2420846122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2420846122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sleep duration and timing are associated with next-day physical activity: Insights from two large-scale wearable sensor studies}, volume = {122}, year = {2025}, }
• (2025). Jurassic constraints on the chaotic Mars–Earth eccentricity cycle linked to the volcanically induced jenkyns event. PNAS, 122(27), e2419902122. (www)

  @article{ , abstract = {Solar system gravitational interactions are embedded in Earth’s record of climate, providing a way to bypass the 60 Myr limit imposed by chaos. Presently with a 2.4 Myr period, the Mars–Earth beat cycle of orbital perihelion frequencies is particularly sensitive to chaotic diffusion, potentially varying by more than a million years. Early Mesozoic (252 to 145 Ma) strata provide some constraints on this cycle, with evidence of a swing through most of the solution space from 1.8 Myr at 210 Ma to 2.5 Myr at 190 Ma and back to 1.6 Myr at 180 Ma. However, only the 1.8 Myr cycle is corroborated by geochronologic data and the 1.6 Myr period is disputed. Here, we show that variations in land-plant-dominated stable carbon isotopic ratios (δ 13 C org ) from the lacustrine, paleo-high-latitude Sangonghe Formation (Junggar Basin, northwestern China), reveal at least three 1.6 Myr Mars–Earth beat cycles centered at 183 Ma, tracking atmospheric CO 2 isotopic composition in Earth’s exchangeable carbon reservoirs. Furthermore, the middle cycle includes the famous Jenkyns Event, expressed here by poleward migration of cheirolepidaceous conifers driven by CO 2 warming from the Karoo-Ferrar large igneous province (LIP). Our data do not, however, support major, LIP-triggered input of isotopically light carbon and instead support CO 2 amplification of local processes via warming and ecosystem change. Although requiring additional independent geochronological support, Sangonghe data help provide empirical constraints for filtering orbital solutions, tightening initial conditions, and testing gravitational models, as well as showing how extrinsic cyclical processes interact with a tectonic event, the Karoo-Ferrar LIP.}, archive = {J_PNAS}, author = {Fang, Yanan and Olsen, Paul E. and Sha, Jingeng and Whiteside, Jessica H. and Guan, Chengguo and Ikeda, Masayuki and Li, Sha and Zheng, Daran and Zhang, Haichun and Wang, Bo}, doi = {10.1073/pnas.2419902122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2419902122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Jurassic constraints on the chaotic Mars–Earth eccentricity cycle linked to the volcanically induced jenkyns event}, volume = {122}, year = {2025}, }
• (2025). Macroevolutionary changes in natural selection on codon usage reflect evolution of the tRNA pool across a budding yeast subphylum. PNAS, 122(27), e2419889122. (www)

  @article{ , abstract = {Across taxonomical domains, synonymous codons of an amino acid are found to be used at unequal frequencies within genomes. This codon usage bias (CUB) is highly variable across species. Genome-wide CUB reflects a balance between adaptive and nonadaptive microevolutionary processes within a species. Variation in microevolutionary processes results in across-species variation in CUB. As CUB is tightly linked to important molecular and biophysical processes, it is critical to understand how changes to these processes are linked to changes in microevolutionary processes. We employed a population genetics model to quantify natural selection and mutation biases on a per-codon basis across the Saccharomycotina budding yeast subphylum. We find that the strength of natural selection and mutation biases varied significantly between closely related yeasts. Across-species variation in natural selection reflected the evolution of tRNA gene copy number (tGCN). Additionally, we find that changes to tRNA modification expression can contribute to changes in natural selection across species independent of changes to tGCN. Both lines of evidence support the link between the evolution of the tRNA pool and natural selection in codon usage through changes in the translation efficiency of a codon. Furthermore, we show that changes to tGCN often reflected changes in genome-wide GC%, suggesting changes in the tRNA pool reflect changes in mutation biases. Our work establishes how changes in microevolutionary processes impact changes in molecular mechanisms, ultimately shaping the macroevolutionary variation of a trait.}, archive = {J_PNAS}, author = {Cope, Alexander L. and Shah, Premal}, doi = {10.1073/pnas.2419889122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2419889122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Macroevolutionary changes in natural selection on codon usage reflect evolution of the tRNA pool across a budding yeast subphylum}, volume = {122}, year = {2025}, }
• (2025). Tandem ssDNA in neutrophil extracellular traps binds thrombin and regulates immunothrombosis. PNAS, 122(27), e2418191122. (www)

  @article{ , abstract = {Neutrophils release neutrophil extracellular traps (NETs) to neutralize infections, a process that also contributes to immunothrombosis. While beneficial in localized infections, excessive NET formation can lead to widespread coagulopathy and organ failure. While the roles of NET-associated proteins such as histones in immunothrombosis are well characterized, NET-derived DNAs are much less known. To address this issue, we report herein the direct interaction between thrombin and DNA scaffolds and further, the identification of short tandem repeats of single-stranded (ATTCC) n in NETs that selectively bind thrombin, a crucial enzyme involved in both blood clot formation and immune response. We have also developed a strategy of selective targeting ss(ATTCC) n using antisense locked nucleic acids (LNAs), effectively disrupting NET–thrombin interactions. This finding reveals an unexplored role of single strand DNA (ssDNA) within NETs and provides a broad avenue for developing targeted therapeutic interventions for immunothrombosis-related disorders.}, archive = {J_PNAS}, author = {Guo, Weijie and Huang, Sihao and Shao, Xiangli and Wu, Yuting and Ma, Yuan and Lu, Shuya and Ren, Hanlin and Zhou, Xuening and Yang, Zhenglin and Lyu, Mingkuan and Liu, Yiwei and Gordon, Vernita and Brodbelt, Jennifer S. and Pan, Tao and Lu, Yi}, doi = {10.1073/pnas.2418191122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2418191122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tandem ssDNA in neutrophil extracellular traps binds thrombin and regulates immunothrombosis}, volume = {122}, year = {2025}, }
• (2025). Operando raman characterization of unique electroinduced molecular tautomerization in zero-gap electrolyzers promotes CO2 reduction. PNAS, 122(27), e2418144122. (www)

  @article{ , abstract = {Membrane electrode assembly (MEA) represents an advanced type of electrochemical device currently widely used in various electrocatalysis applications [e.g., electrochemical CO 2 reduction reaction (CO 2 RR)], featuring no explicit catholyte flow and a unique “solid–liquid–gas” triple-phase interface. Herein, we identify a peculiar electroinduced thiol to thione tautomerization of 4-mercaptopyridine (4MPy) molecule on Cu catalyst surfaces at this triple-phase interface driven by cathodic polarization. This leads to a significant performance improvement of CO 2 RR on Cu with a C 2+ Faradaic efficiency of over 80% with more than 60% C 2 H 4 , as well as a 300 mV reduction of cell voltage compared to bare Cu. A home-designed MEA-type operando Raman cell enables mechanistic studies directly under a current density of over 100 mA cm −2 , elucidating the intricate impacts of the 4MPy tautomerization on the local catalytic environments under real reaction conditions. Surprisingly, this tautomerization does not occur in other commonly utilized electrolyzers, e.g., flow cell and H-cell, even with the same catalyst and electrolyte conditions. The direct contact with the electrolyte in the latter cells was found to cause rapid desorption of 4MPy from the catalyst surface before its possible chemical transformation. These results highlight the opportunities of utilizing surface molecular tautomerization to promote CO 2 RR performance and using the triple phase of MEA to drive reactions that would otherwise be hard to happen in classical electrochemical devices of similar conditions.}, archive = {J_PNAS}, author = {Li, Ling and Ye, Wentao and Liu, Qiliang and Liu, Ruoxi and Lu, Xingyu and Yao, Tianbing and Wang, Linqin and Gu, Bing and Sun, Licheng and Yang, Wenxing}, doi = {10.1073/pnas.2418144122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2418144122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Operando raman characterization of unique electroinduced molecular tautomerization in zero-gap electrolyzers promotes CO2 reduction}, volume = {122}, year = {2025}, }
• (2025). How to tackle the looming challenge of solar PV panel recycling. PNAS, 122(27), e2417921122. (www)

  @article{ , archive = {J_PNAS}, author = {Xia, Siyou and Yang, Yu and Poon, Jessie P. H.}, doi = {10.1073/pnas.2417921122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2417921122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How to tackle the looming challenge of solar PV panel recycling}, volume = {122}, year = {2025}, }
• (2025). Epigenetic cellular memory in pseudomonas aeruginosa generates phenotypic variation in response to host environments. PNAS, 122(27), e2415345122. (www)

  @article{ , abstract = {Phenotypic diversification within pathogen populations can enhance survival in stressful environments, broaden niche colonization, and expand the ecological range of infectious diseases due to emerging collective pathogenicity characteristics. We describe a gene regulatory network property in the opportunistic pathogen Pseudomonas aeruginosa that generates diversity of gene expression and pathogenicity behavior at the single-cell level and that is stabilized by epigenetic cellular memory. The resulting heterogeneity in the expression of the glpD gene—an indicator of host-derived glycerol metabolism and intra-host presence—shapes adaptive processes that are subject to natural selection. Our work on how epigenetics generates phenotypic variation in response to the environment and how these changes are inherited to the next generation provides insights into phenotypic diversity and the emergence of unique functionalities at higher levels of organization. These could be crucial for controlling infectious disease outcomes.}, archive = {J_PNAS}, author = {Vatareck, Elisabeth and Rick, Tim and Oswaldo Gomez, Nicolas and Bandyopadhyay, Arnab and Kramer, Janina and Strunin, Dmytro and Erdmann, Jelena and Hartmann, Oliver and Alpers, Kathrin and Boedeker, Christian and Steffen, Anika and Sieben, Christian and Zhao, Gang and Tomasch, Jürgen and Häussler, Susanne}, doi = {10.1073/pnas.2415345122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2415345122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Epigenetic cellular memory in pseudomonas aeruginosa generates phenotypic variation in response to host environments}, volume = {122}, year = {2025}, }
• (2025). Learning predictive signals within a local recurrent circuit. PNAS, 122(27), e2414674122. (www)

  @article{ , abstract = {The predictive coding hypothesis proposes that top–down predictions are compared with incoming bottom–up sensory information, with prediction errors signaling the discrepancies between these inputs. While this hypothesis explains the presence of prediction errors, recent experimental studies suggest that prediction error signals can emerge within a local circuit, that is, from bottom–up sensory input alone. In this paper, we test whether local circuits alone can generate predictive signals by training a recurrent spiking network using local plasticity rules. Our network model replicates experimentally observed features of prediction errors, such as biphasic neural activity patterns and context dependency. Our findings shed light on how synaptic plasticity can shape prediction errors and enable the acquisition and updating of an internal model of sensory input within a recurrent neural network.}, archive = {J_PNAS}, author = {Asabuki, Toshitake and Gillon, Colleen J. and Clopath, Claudia}, doi = {10.1073/pnas.2414674122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2414674122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Learning predictive signals within a local recurrent circuit}, volume = {122}, year = {2025}, }
• (2025). Yeast centrosomes act as organizing centers to promote polo kinase–mediated adaptation to persistent DNA damage. PNAS, 122(27), e2414426122. (www)

  @article{ , abstract = {The ability of cells to overcome cell cycle arrest and adapt to the presence of unrepairable DNA damage is under the control of Polo-like kinases (PLKs) in eukaryotes. How DNA damage checkpoints are silenced or bypassed during the adaptation response is unknown, but the process requires enrichment of the Cdc5 PLK to microtubule organizing centers (MTOCs), such as the yeast centrosomes or spindle pole bodies (SPBs). Here, we found that SPBs play an active role as supramolecular organizing centers that coordinate Cdc5 recruitment and signaling to downstream effectors during the adaptation response to DNA damage. We show that SPB components Nud1, Spc110, and Spc72 are key effectors of Cdc5 recruitment to SPBs in the presence of sustained DNA damage. Following recruitment, Cdc5 transduces a phospho-signal to key structural subunits of the SPB, including Cnm67 and Mps3. We demonstrate these phosphorylation events are required to bypass cell cycle checkpoint arrest and enable effective adaptation to DNA damage. This response is specific because it cannot be recapitulated by a generic inactivation of MTOC activity. Collectively, our results indicate that centrosomes can act as supramolecular platforms to coordinate dynamic recruitment and substrate selection of PLKs during the DNA damage response (DDR).}, archive = {J_PNAS}, author = {Langlois-Lemay, Laurence and D’Amours, Damien}, doi = {10.1073/pnas.2414426122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2414426122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Yeast centrosomes act as organizing centers to promote polo kinase–mediated adaptation to persistent DNA damage}, volume = {122}, year = {2025}, }
• (2025). The cultural construction of “executive function”. PNAS, 122(27), e2407955122. (www)

  @article{ , abstract = {In cognitive science, the term “executive function” (EF) refers to universal features of the mind. Yet, almost all results described as measuring EF may actually reflect culturally specific cognitive capacities. After all, typical EF measures require forms of decontextualized/arbitrary processing which decades of cross-cultural work indicate develop primarily in “schooled worlds”–industrialized societies with universal schooling. Here, we report comparisons of performance on typical EF tasks by children inside, and wholly outside schooled worlds. Namely, children ages 5 to 18 from a postindustrial context with universal schooling (UK) and their peers in a rural, nonindustrialized context with no exposure to schooling (Kunene region, Namibia/Angola), as well as two samples with intermediate exposure to schooled worlds. In line with extensive previous work on decontextualized/arbitrary processing across such groups, we find skills measured by typical EF tasks do not develop universally: Children from rural groups with limited or no formal schooling show profound, sometimes qualitative, differences in performance compared to their schooled peers and, especially, compared to a “typical” schooled-world sample. In sum, some form of latent cognitive control capacities are obviously crucial in all cultural contexts. However, typical EF tasks almost certainly reflect culturally specific forms of cognitive development. This suggests we must decide between using the term EF to describe 1) universal capacities or 2) the culturally specific skill set reflected in performance on typical tasks. Either option warrants revisiting how we understand what has been measured as EF to date, and what we wish to measure going forward.}, archive = {J_PNAS}, author = {Kroupin, Ivan and Davis, Helen Elizabeth and Burdett, Emily and Cuata, Agustina Bani and Hartley, Vahumburuka and Henrich, Joseph}, doi = {10.1073/pnas.2407955122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2407955122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The cultural construction of “executive function”}, volume = {122}, year = {2025}, }
• (2025). Expanding the diversity of bacterial DNA partitioning: A CTP-independent ParABS system for plasmid partitioning in streptomyces. PNAS, 122(27), e2406398122. (www)

  @article{ , abstract = {The ATP- and CTP-dependent ParA-ParB- parS segrosome is a macromolecular complex that segregates chromosomes/plasmids in most bacterial species. CTP binding and hydrolysis enable ParB to slide along DNA and to bridge and condense DNA, thereby dictating the size and dynamics of the tripartite ParAB S complex. Several other evolutionarily distinct systems can also segregate DNA, although the full diversity of bacterial DNA partition systems remains unknown. Here, we identify a CTP-independent ParAB S system that maintains the conjugative plasmid SCP2 in the filamentous bacterium Streptomyces coelicolor . We demonstrate that an SCP2 ParB-like protein, ParT, loads onto DNA at an 18-bp parS site and diffuses away to the adjacent DNA despite lacking an apparent CTPase domain and detectable NTPase activity. We further show that parS DNA facilitates ParT transition from loading to a diffusing state, allowing ParT to accumulate on DNA, and that ParT activates the ATPase activity of its cognate partner protein, ParA. Additionally, we identify numerous structural homologs of ParT, suggesting that CTP-independent diffusion on DNA might be more common than previously recognized. Overall, our findings reveal a CTP-independent DNA translocation as an alternative and unexpected mechanism for assembling a bacterial DNA segregation complex and suggest that CTP binding and hydrolysis are not universal features of ParAB S -like systems.}, archive = {J_PNAS}, author = {Sukhoverkov, Kirill V. and Balaguer-Perez, Francisco and Aicart-Ramos, Clara and Tran, Ngat T. and Maqbool, Abbas and Rejzek, Martin and Chandra, Govind and Moreno-Herrero, Fernando and Le, Tung B. K.}, doi = {10.1073/pnas.2406398122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2406398122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Expanding the diversity of bacterial DNA partitioning: A CTP-independent ParABS system for plasmid partitioning in streptomyces}, volume = {122}, year = {2025}, }
• (2025). Tendencies toward triadic closure: Field experimental evidence. PNAS, 122(27), e2404590122. (www)

  @article{ , abstract = {Empirical social networks are characterized by a high degree of triadic closure (i.e., transitivity, clustering): network neighbors of the same individual are also likely to be directly connected. It is unknown to what degree this results from dispositions to form such ties (i.e., to close open triangles) per se versus other processes such as homophily and more opportunities for exposure. These mechanisms are difficult to disentangle in many settings. On social media, however, they can be decomposed - and platforms frequently make decisions that depend on these distinct processes. Here, using a field experiment on social media, we randomize the existing network structure that a user faces when they are followed by a target account that we control. We then examine whether the user reciprocates this tie formation. Being randomly assigned to have an existing tie to an account that follows the target user increases tie formation by 35%. Through multiple control conditions, we attribute this effect specifically to a minimal cue that indicates the presence of a potential mutual follower. Theory suggests that triadic closure should be especially likely in open triads of strong ties, and accordingly we find larger effects when the subject has interacted more with the existing follower. These results indicate a substantial role for tendencies toward triadic closure, but one that is substantially smaller than what might be inferred from prior observational studies. Platforms and others may rely on these tendencies in encouraging tie formation, with broader implications for network structure and information diffusion in online networks.}, archive = {J_PNAS}, author = {Mosleh, Mohsen and Eckles, Dean and Rand, David G.}, doi = {10.1073/pnas.2404590122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2404590122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tendencies toward triadic closure: Field experimental evidence}, volume = {122}, year = {2025}, }
• (2025). An agenda for science communication research and practice. PNAS, 122(27), e2400932122. (www)

  @article{ , abstract = {Science should not unilaterally dictate individuals’ decisions or public policies. Yet, it provides a vital source of information for societies and individuals that can often improve outcomes and well-being. This requires, however, the effective communication of scientific information. We identify two paradigms for science communication. One focuses on dissemination, often seeking to inform, reframe, or correct beliefs. Another emphasizes participation and engagement with the goal of improving public understanding of science and scientists’ understanding of the public’s concerns, needs, and values. We argue that participatory approaches better address contemporary challenges concerning scientific uncertainty, politicized science, artificial value neutrality, and a reactive science communication infrastructure. These approaches though need to move away from transactional partnerships toward more cocreation and coproduction of knowledge. They also need to focus more on less motivated and/or engaged populations. Investment in a participatory infrastructure is crucial given that even the most path-breaking science only matters if it can be adequately communicated to relevant stakeholders.}, archive = {J_PNAS}, author = {Druckman, James N. and Ellenbogen, Kirsten M. and Scheufele, Dietram A. and Yanovitzky, Itzhak}, doi = {10.1073/pnas.2400932122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2400932122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An agenda for science communication research and practice}, volume = {122}, year = {2025}, }
• (2025). The importance of scientists’ intellectual humility for communicating effectively across ideological and identity-based divides. PNAS, 122(27), e2400930121. (www)

  @article{ , abstract = {Growing identity-based and partisan gaps in confidence in scientists and scientific institutions call for novel approaches to science communication. In this perspectives piece, we focus on the need for greater intellectual humility (i.e., willingness to revise one’s views and admit that one might be wrong) among social scientists, who are met with particularly high levels of skepticism from the public. We begin with an overview of research demonstrating that when scientists’ identities or ideologies align (or are perceived to align) with those of the public, trust in science increases. We then highlight intellectual humility as a potential tool for cultivating trust in the social sciences even when social scientists’ and the public’s identities or ideologies do not match. Specifically, intellectual humility among social scientists predicts less bias toward one another’s research and hence may increase the diversity of perspectives to which the public is exposed and shift public perceptions of social scientists. We conclude with a discussion of how to foster intellectual humility in science communication, broadly defined.}, archive = {J_PNAS}, author = {Rios, Kimberly and Roth, Zachary C. and Coleman, Thomas J.}, doi = {10.1073/pnas.2400930121}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2400930121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The importance of scientists’ intellectual humility for communicating effectively across ideological and identity-based divides}, volume = {122}, year = {2025}, }
• (2025). Transformative community-engaged science: Strengthening relationships between science and society. PNAS, 122(27), e2400929122. (www)

  @article{ , abstract = {There is a critical need to strengthen science–society relationships—especially with historically marginalized communities—if we are to better and more equitably manage complicated, intertwined, global challenges at the intersection of environment, health, equity, and well-being. Community-engaged science, which focuses on shared leadership and mutual benefit in scientific partnership with communities, has the potential to transform science, communities, and even society. Despite this promise, however, community-engaged science is not always transformative. Presentations and discussions at the 5th National Academies Science Communication Colloquium demonstrated the importance of creating structures, practices, and a culture of science engagement that prioritizes listening and learning from communities. Based on presentations at the colloquium, research publications, and our own experiences, we share a set of evidence-informed principles that are common to successful community-engaged science across many contexts: respect, humility, listening, reciprocity, mutuality, and reflexivity. We also offer steps the scientific community can take to advance and improve the transformative practice of community-engaged science as part of a productive ecosystem of scientific activities: evolving norms and culture, integrating community science into current systems, building incentives and structures to support community-engaged science, developing a workforce skilled in community engagement, and investing in a coordinated research-to-practice agenda.}, archive = {J_PNAS}, author = {Pandya, Rajul E. and Boyd, Amanda D. and Feliú-Mójer, Mónica I. and Yanovitzky, Itzhak}, doi = {10.1073/pnas.2400929122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2400929122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transformative community-engaged science: Strengthening relationships between science and society}, volume = {122}, year = {2025}, }
• (2025). Our changing information ecosystem for science and why it matters for effective science communication. PNAS, 122(27), e2400928121. (www)

  @article{ , abstract = {Current information ecologies present unique opportunities to communicate science and engage diverse publics in science. Unfortunately, they also present unique challenges. Here, we outline how the public sphere for science is transforming as media evolve, and we connect these changes to the high-stakes issue context of COVID-19. We argue that scientific organizations’ struggles to adapt to evolving media are linked, in part, to asymmetries in which social media platforms prevent researchers from producing reliable data that could inform institutional change and improve science communication. This has been apparent in studies of echo chambers and filter bubbles. Producing a more usable evidence base, we conclude, will require that scholars a) obtain access to proprietary data, b) reconceptualize information ecologies as social systems, c) avoid ceding core research tasks to platforms, d) address ethical issues, and e) grapple with the urgency of moving forward productively.}, archive = {J_PNAS}, author = {Krause, Nicole M. and Freiling, Isabelle and Scheufele, Dietram A.}, doi = {10.1073/pnas.2400928121}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {27}, pages = {e2400928121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Our changing information ecosystem for science and why it matters for effective science communication}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(26), eiti2625122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti2625122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {eiti2625122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Editorial expression of concern for fries et al., early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. PNAS, 122(26), e2513967122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2513967122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2513967122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Editorial expression of concern for fries et al., early experience in humans is associated with changes in neuropeptides critical for regulating social behavior}, volume = {122}, year = {2025}, }
• (2025). Correction for zhang et al., dancr-BRG1 regulates nfatc1 transcription and pgc1β-dependent metabolic shifts in osteoclastogenesis. PNAS, 122(26), e2513156122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2513156122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2513156122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for zhang et al., dancr-BRG1 regulates nfatc1 transcription and pgc1β-dependent metabolic shifts in osteoclastogenesis}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for bardy et al., neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. PNAS, 122(26), e2512898122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2512898122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2512898122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for bardy et al., neuronal medium that supports basic synaptic functions and activity of human neurons in vitro}, volume = {122}, year = {2025}, }
• (2025). Correction for ewart et al., relaxation to universal non-maxwellian equilibria in a collisionless plasma. PNAS, 122(26), e2512776122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2512776122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2512776122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for ewart et al., relaxation to universal non-maxwellian equilibria in a collisionless plasma}, volume = {122}, year = {2025}, }
• (2025). Correction for chihoub et al., the evolution of robustness and fragility during long-term bacterial adaptation. PNAS, 122(26), e2512470122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2512470122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2512470122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for chihoub et al., the evolution of robustness and fragility during long-term bacterial adaptation}, volume = {122}, year = {2025}, }
• (2025). Correction for smith et al., a twist grain boundary phase in aqueous solutions of the nucleic acid tetramer GTAC. PNAS, 122(26), e2511743122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2511743122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2511743122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for smith et al., a twist grain boundary phase in aqueous solutions of the nucleic acid tetramer GTAC}, volume = {122}, year = {2025}, }
• (2025). Calcineurin targets that mediate cryptococcus thermotolerance. PNAS, 122(26), e2511623122. (www)

  @article{ , archive = {J_PNAS}, author = {Mitchell, Aaron P.}, doi = {10.1073/pnas.2511623122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2511623122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Calcineurin targets that mediate cryptococcus thermotolerance}, volume = {122}, year = {2025}, }
• (2025). Big evolutionary fireworks in tiny glass houses. PNAS, 122(26), e2511509122. (www)

  @article{ , archive = {J_PNAS}, author = {Banson, Idan and Brown, Matthew W.}, doi = {10.1073/pnas.2511509122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2511509122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Big evolutionary fireworks in tiny glass houses}, volume = {122}, year = {2025}, }
• (2025). Inhibiting nav1.8 for pain: Lessons from patients and from neurons. PNAS, 122(26), e2511228122. (www)

  @article{ , archive = {J_PNAS}, author = {Waxman, Stephen G. and Vasylyev, Dmytro V.}, doi = {10.1073/pnas.2511228122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2511228122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inhibiting nav1.8 for pain: Lessons from patients and from neurons}, volume = {122}, year = {2025}, }
• (2025). Correction for maher et al., intracranial substrates of meditation-induced neuromodulation in the amygdala and hippocampus. PNAS, 122(26), e2511043122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2511043122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2511043122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for maher et al., intracranial substrates of meditation-induced neuromodulation in the amygdala and hippocampus}, volume = {122}, year = {2025}, }
• (2025). Reply to hirbo et al.: The need for large-scale family cohorts and robust analytical frameworks of postexome study. PNAS, 122(26), e2511041122. (www)

  @article{ , archive = {J_PNAS}, author = {Wu, Xin-Rui and Yang, Liu and Wu, Bang-Sheng and Cheng, Wei and Yu, Jin-Tai}, doi = {10.1073/pnas.2511041122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2511041122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to hirbo et al.: The need for large-scale family cohorts and robust analytical frameworks of postexome study}, volume = {122}, year = {2025}, }
• (2025). On the relationship between genes and environment. PNAS, 122(26), e2510804122. (www)

  @article{ , archive = {J_PNAS}, author = {Hirbo, Jibril B. and Were, Martin C. and Jones-Paris, Celestial R.}, doi = {10.1073/pnas.2510804122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2510804122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {On the relationship between genes and environment}, volume = {122}, year = {2025}, }
• (2025). Peeling tape produces strong electric fields via stick–slip friction that drive chemical reactions. PNAS, 122(26), e2510504122. (www)

  @article{ , abstract = {Adhesive interfaces store significant energy due to interlocking molecular chain entanglement and van der Waals forces. When two adhesive surfaces are separated, triboelectric effects induce charge transfer, generating a strong electric field at the peeling interface. This effect offers different opportunities for initiating chemical reactions. Here, we report that the stick–slip friction involved in peeling tape produces electric fields on the order of 10 9 V/m, as measured by the vibrational Stark shift observed by confocal Raman spectroscopy during tape peeling. This field is sufficiently strong to ionize water and produce the H 4 O 2 + cation, a hydroxyl radical adduct with a hydronium ion. We further demonstrate that this electric field can drive a variety of electron transfer reactions. Our findings suggest that tribocharging presents a promising, energy-efficient avenue for electric-field-driven green chemistry.}, archive = {J_PNAS}, author = {Gao, Xufeng and Zhou, Peng and Yuan, Xu and Li, Xiaoxu and Li, Bowen and Xia, Yu and Meng, Yifan and Zare, Richard N. and Zheng, Tingting and Zhang, Xinxing}, doi = {10.1073/pnas.2510504122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2510504122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Peeling tape produces strong electric fields via stick–slip friction that drive chemical reactions}, volume = {122}, year = {2025}, }
• (2025). Heritable symbiont producing nonribosomal peptide confers extreme heat sensitivity and antifungal protection on its host. PNAS, 122(26), e2509873122. (www)

  @article{ , abstract = {Insects frequently form associations with maternally transmitted symbiotic bacteria. This transmission mode ensures that symbiont-conferred effects, both beneficial and negative, are passed onto offspring. Here, we report an extreme example of symbiont-mediated temperature sensitivity imposed by a vertically transmitted, defensive symbiont. Pea aphids infected with the bacterial endosymbiont, Fukatsuia symbiotica, resist infection by fungal pathogens but produce few or no offspring when moved from cool (15 °C) to mildly warmer temperatures (20 °C). This temperature-dependent reduction in host fitness is associated with increased symbiont abundance, disordered symbiont localization, and high expression of a horizontally acquired nonribosomal peptide synthetase (NRPS) locus. This NRPS operon is syntenic with the locus responsible for the production of Herbicolin A, a known antifungal produced by some plant-associated Erwiniaceae . Activity of chemical extracts from infected aphids is predictive of in vivo protection against entomopathogenic fungi, indicating that an Herbicolin A–like molecule is the likely source of Fukatsuia’s protective effects against fungal pathogens. Injection of the same chemical extracts into naive aphids partially recapitulates developmental defects observed in natural infections at 20 °C, suggesting that increased levels of this compound contribute to disrupted embryonic development. Finally, the purification of the causal agent revealed Fukatsuia produces a compound similar but not identical to Herbicolin A, that exhibits both antifungal and hemolytic activity. These results suggest that F. symbiotica infection imposes a trade-off between antifungal defense and disrupted embryonic development, mediated by a single genetic locus.}, archive = {J_PNAS}, author = {Maeda, Gerald P. and Dang, Vy and Kelly, Mary Katherine and Sundar, Aadhunik and Arnott, Ryan L. W. and Marcotte, Edward M. and Moran, Nancy A.}, doi = {10.1073/pnas.2509873122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2509873122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Heritable symbiont producing nonribosomal peptide confers extreme heat sensitivity and antifungal protection on its host}, volume = {122}, year = {2025}, }
• (2025). Promoting collective cooperation through temporal interactions. PNAS, 122(26), e2509575122. (www)

  @article{ , abstract = {Collective cooperation maintains the function of many natural and social systems, making understanding the evolution of cooperation a central question of modern science. Although human interactions involve complex contact networks, current explorations are limited to static networks, where social ties are permanent and do not change over time. In reality, human activities often involve temporal interactions, where links are impermanent, and understanding the evolution of cooperation on such temporal networks is an open problem. Here, we systematically analyze how cooperation spreads on arbitrary temporal networks, and we distill our results down to a concise condition, which integrates evolutionary game dynamics with both static and temporal interactions. We find that the emergence of cooperation is facilitated by a simple rule of thumb: Hubs (individuals with many social ties) should be temporally deprioritized in interactions. For empirical applications, we further provide a quantitative metric capturing the priority of hubs, which is validated on empirical datasets based on its effectiveness in orchestrating the ordering of interactions to best promote cooperation. Our findings unveil the fundamental advantages conferred by temporal interactions for promoting collective cooperation, transcending the specific insights gleaned from studying static networks.}, archive = {J_PNAS}, author = {Meng, Yao and McAvoy, Alex and Li, Aming}, doi = {10.1073/pnas.2509575122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2509575122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Promoting collective cooperation through temporal interactions}, volume = {122}, year = {2025}, }
• (2025). A bioinspired and degradable riboflavin-containing polypeptide as a sustainable material for energy storage. PNAS, 122(26), e2509325122. (www)

  @article{ , abstract = {Inspired by Nature, we present a polypeptide-based organic redox-active material constructed from renewable feedstocks, L-glutamic acid (an amino acid) and riboflavin (vitamin B 2 ), to address challenges with start-to-end-of-life management in energy storage systems (ESSs). The amino acid was utilized to establish a degradable polymer backbone, along which many copies of riboflavin were incorporated to serve as the redox-active pendant groups that enabled energy storage. The overall synthesis involved the ring-opening polymerization (ROP) of an l -glutamic acid-derived N- carboxyanhydride (NCA) monomer, followed by side chain activation with azides and, finally, click coupling to achieve installation of alkyne-functionalized riboflavin moieties. The steric bulkiness and rich chemical functionality of riboflavin resulted in synthetic complexities that required reaction optimization to achieve the desired polymer structure. Electrochemical characterization of the resultant riboflavin polypeptide, in organic electrolyte, showed quasireversible redox activity with a half-wave potential (E 1/2 ) of ca. −1.10 V vs. ferrocene/ferrocenium (Fc/Fc + ). Cell viability assays revealed biocompatibility, as indicated by negligible cytotoxicity for fibroblast cells. The polypeptide design, consisting of labile amide backbone linkages and side-chain ester functionalities that tethered the riboflavin units to the backbone, enabled hydrolytic degradation to recover building blocks for future upcycling or recycling. This bioinspired strategy advances the development of degradable redox-active polymers and promotes sustainable materials design for circular energy storage technologies.}, archive = {J_PNAS}, author = {Li, Shih-Guo and Mohanty, Khirabdhi T. and Easley, Alexandra D. and Rezenom, Yohannes H. and Lim, Soon-Mi and Gillett, Leyla P. and Naquin, Stone D. and Tran, David K. and Nguyen, Tan P. and Lutkenhaus, Jodie L. and Wooley, Karen L.}, doi = {10.1073/pnas.2509325122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2509325122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A bioinspired and degradable riboflavin-containing polypeptide as a sustainable material for energy storage}, volume = {122}, year = {2025}, }
• (2025). Reply to ferraro et al.: Breed-and-feed reflects inevitable trade-offs between individual longevity and population sustainability. PNAS, 122(26), e2509145122. (www)

  @article{ , archive = {J_PNAS}, author = {Clauss, Marcus and Roller, Marco and Bertelsen, Mads F. and Rudolf von Rohr, Claudia and Müller, Dennis W. H. and Schiffmann, Christian and Kummrow, Maya and Encke, Dag and Ferreira, Sam and Duvall, Ethan S. and Maré, Celesté and Abraham, Andrew J.}, doi = {10.1073/pnas.2509145122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2509145122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to ferraro et al.: Breed-and-feed reflects inevitable trade-offs between individual longevity and population sustainability}, volume = {122}, year = {2025}, }
• (2025). Photothermal catalysis of waste plastics into propionic acid and hydrogen via ni single-atom site isolation effect. PNAS, 122(26), e2508636122. (www)

  @article{ , abstract = {Currently, catalytic recycling of polyethylene (PE) into high-value chemicals using solar energy often faces poor product selectivity and low efficiency. This is mainly due to the difficulty in effectively controlling the intermediates during PE photoreforming and the long-standing challenge of inefficient charge dynamics. Here, we present a solar-driven photothermal catalytic approach for the selective conversion of PE waste into propionic acid and hydrogen under ambient conditions. Atomically dispersed Ni sites supported on CeO 2 (Ni SA /CeO 2 ) achieve a propionic acid yield of 331 μmol h –1 with 94.8% selectivity in the photothermal reaction. This performance is 1.6 times higher than that of catalysts supported by Ni clusters (Ni NP /CeO 2 ). Additionally, Ni SA /CeO 2 exhibits a hydrogen yield of 0.23 mmol h –1 with stable long-term performance. Mechanistic studies reveal that single Ni atoms form linear coordination with oxygen atoms in CeO 2 , introducing unoccupied mid-gap states that effectively capture hot electrons and enhance the photothermal effect through local hotspot formation. In contrast, Ni clusters suffer from inefficient heat accumulation due to multistep phonon scattering. Furthermore, site isolation of Ni single atoms spatially separates the reaction intermediates and suppresses dimerization of the key intermediate COOHCH 2 CH 2 *, thereby greatly improving the selectivity for propionic acid. In contrast, closely packed Ni cluster sites promote intermediate coupling and the formation of undesirable byproducts, reducing selectivity. This work provides mechanistic insights into the advantages of atomic-scale catalyst design for selective chemical transformations.}, archive = {J_PNAS}, author = {Yue, Shuai and Liu, Yixiao and Zhao, Zhiyong and Zhao, Guanshu and Yang, Mengxue and Zhang, Tao and Li, Fei and Liu, Kewang and Wang, Pengfei and Zhan, Sihui and Jia, Jinhu}, doi = {10.1073/pnas.2508636122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2508636122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Photothermal catalysis of waste plastics into propionic acid and hydrogen via ni single-atom site isolation effect}, volume = {122}, year = {2025}, }
• (2025). Trichomonas vaginalis extracellular vesicles suppress IFNε-mediated responses driven by its intracellular bacterial symbiont mycoplasma hominis. PNAS, 122(26), e2508297122. (www)

  @article{ , abstract = {Trichomonas vaginalis is a common, extracellular, sexually transmitted parasite which is often found in symbiosis with the intracellular bacterium Mycoplasma hominis (Mh), an opportunistic pathogen of the female reproductive tract. How this symbiosis affects infection outcomes and the host cell innate immune response is poorly understood. Here, we show that infection with T. vaginalis in symbiosis with M. hominis or M. hominis alone triggers a noncanonical type I interferon, interferon-epsilon (IFNε), but infection with T. vaginalis alone does not. We also demonstrate that extracellular vesicles (TvEVs) produced by the parasite downregulate host cell IFNε, counteracting this symbiont-driven response and elevating infection. We further demonstrate that IFNε, a hormonally regulated cytokine produced in the human reproductive system, is protective against T. vaginalis cytoadherence and cytolysis of host cells. These studies provide insight into how a parasite and its bacterial symbiont work in concert to regulate host cell innate immune responses to drive infection.}, archive = {J_PNAS}, author = {Kochanowsky, Joshua A. and Betts, Emma L. and Encinas, Gabriel and Amoah, Johnson and Johnson, Patricia J.}, doi = {10.1073/pnas.2508297122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2508297122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Trichomonas vaginalis extracellular vesicles suppress IFNε-mediated responses driven by its intracellular bacterial symbiont mycoplasma hominis}, volume = {122}, year = {2025}, }
• (2025). Molecular contacts in self-assembling clusters of membrane proteins. PNAS, 122(26), e2507112122. (www)

  @article{ , abstract = {Motivated by recent data pointing to the existence of homo-oligomeric assemblies of membrane proteins called higher-order transient structures, and their apparent role in connecting components of membrane signal pathways, we examine here by cryoelectron microscopy some of the protein–protein interactions that occur in cluster formation. Metabotropic glutamate receptors and HCN ion channels inside clusters contact their neighbors through structured extracellular and intracellular domains, respectively. Other ion channels, including Kv2.1 and Slo1, appear to form clusters through prominent intrinsically disordered sequences in the cytoplasm. These distinct modes of interaction are associated with clusters exhibiting varying degrees of compactness and order. We conclude that nature utilizes a variety of ways to form connections between membrane proteins in self-assembled clusters.}, archive = {J_PNAS}, author = {Mandala, Venkata Shiva and Fu, Ziao and MacKinnon, Roderick}, doi = {10.1073/pnas.2507112122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2507112122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular contacts in self-assembling clusters of membrane proteins}, volume = {122}, year = {2025}, }
• (2025). Comparative performance of viral landscape phylogeography approaches. PNAS, 122(26), e2506743122. (www)

  @article{ , abstract = {The rapid evolution of RNA viruses implies that their evolutionary and ecological processes occur on the same time scale. Genome sequences of these pathogens therefore can contain information about the processes that govern their transmission and dispersal. Landscape phylogeographic approaches use phylogeographic reconstructions to investigate the impact of environmental factors and variables on the spatial spread of viruses. Here, we extend and improve existing approaches and develop three novel landscape phylogeographic methods that can test the impact of continuous environmental factors on the diffusion velocity of viral lineages. In order to evaluate the different methods, we also implemented two simulation frameworks to test and compare their statistical performance. The results enable us to formulate clear guidelines for the use of three complementary landscape phylogeographic approaches that have sufficient statistical power and low rates of false positives. Our open-source methods are available to the cientific community and can be used to investigate the drivers of viral spread, with potential benefits for understanding virus epidemiology and designing tailored intervention strategies.}, archive = {J_PNAS}, author = {Dellicour, Simon and Gámbaro, Fabiana and Jacquot, Maude and Lequime, Sebastian and Baele, Guy and Gilbert, Marius and Pybus, Oliver G. and Suchard, Marc A. and Lemey, Philippe}, doi = {10.1073/pnas.2506743122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2506743122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Comparative performance of viral landscape phylogeography approaches}, volume = {122}, year = {2025}, }
• (2025). Crystal structure and catalytic mechanism of drimenol synthase, an unusual bifunctional terpene cyclase–phosphatase. PNAS, 122(26), e2506584122. (www)

  @article{ , abstract = {Drimenol synthase from Aquimarina spongiae (AsDMS) is a highly unusual chimera that integrates two distinct, sequential isoprenoid processing activities within a single polypeptide chain. AsDMS catalyzes the class II cyclization of farnesyl diphosphate (FPP) to form drimenyl diphosphate, which then undergoes enzyme-catalyzed hydrolysis to yield drimenol, a bioactive sesquiterpene alcohol with antifungal and anticancer properties. Here, we report the X-ray crystal structures of AsDMS and its complex with a sesquiterpene thiol. The AsDMS structure exhibits a didomain architecture consisting of a terpene cyclase β domain and a haloacid dehalogenase-like phosphatase domain, with two distinct active sites located on opposite sides of the protein. Mechanistic studies show that dephosphorylation of the drimenyl diphosphate intermediate proceeds through stepwise hydrolysis such that two equivalents of inorganic phosphate rather than inorganic pyrophosphate are coproducts of the reaction sequence. When the AsDMS reaction is performed in H 2 18 O, 18 O is not incorporated into drimenol, indicating that the hydroxyl oxygen of drimenol originates from the prenyl oxygen of FPP rather than a water molecule from bulk solution. These results correct a mechanistic proposal previously advanced by another group. Surprisingly, AsDMS exhibits substrate promiscuity, catalyzing the conversion of the slowly reactive substrate mimic farnesyl- S -thiolodiphosphate into cyclic and linear sesquiterpene products. Structural and mechanistic insights gained from AsDMS illustrate the functional diversity of terpene biosynthetic enzymes and provide a foundation for engineering “designer cyclase” assemblies capable of generating a wide variety of terpenoid products.}, archive = {J_PNAS}, author = {Osika, Kristin R. and Gaynes, Matthew N. and Christianson, David W.}, doi = {10.1073/pnas.2506584122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2506584122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Crystal structure and catalytic mechanism of drimenol synthase, an unusual bifunctional terpene cyclase–phosphatase}, volume = {122}, year = {2025}, }
• (2025). Institutions of public judgment established by social contract and taxation. PNAS, 122(26), e2506537122. (www)

  @article{ , abstract = {Indirect reciprocity is a compelling explanation for stable cooperation in a large society: Those who cooperate appropriately earn a good standing, so that others are more likely to cooperate with them. However, this mechanism requires a population to agree on who has good standing and who has bad standing. Consensus can be provided by a central institution that monitors and broadcasts reputations. But how might such an institution be maintained, and how can a population ensure that it is effective and incorruptible? Here, we explore a simple mechanism to sustain an institution for judging reputations: a tax collected from each member of the population. We analyze the possible tax rate that individuals will rationally pay to sustain an institution of judgment, which provides a public good in the form of information, and we derive necessary conditions for individuals to resist the temptation to evade their tax payment. We also consider the possibility that institution members may be corrupt and subject to bribery, and we analyze how strong the incentives against corruption need to be. Our analysis has implications for establishing robust public institutions that provide social information to support cooperation in large populations—and the potential negative consequences associated with wealth or income inequality.}, archive = {J_PNAS}, author = {Kessinger, Taylor A. and Plotkin, Joshua B.}, doi = {10.1073/pnas.2506537122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2506537122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Institutions of public judgment established by social contract and taxation}, volume = {122}, year = {2025}, }
• (2025). The RRM domain–containing protein rbp3 interacts with ribosomes and the 3’ ends of mRNAs encoding photosynthesis proteins. PNAS, 122(26), e2506275122. (www)

  @article{ , abstract = {RNA recognition motif (RRM) domain proteins are crucial RNA-binding proteins across all domains of life. In cyanobacteria, single RRM domain proteins are involved in mRNA targeting to the thylakoid membrane and acclimation to certain stress conditions, but many details of their physiological functions and molecular targets have remained unknown. The model cyanobacterium Synechocystis sp. PCC 6803 has a family of three genes encoding the RRM domain–containing proteins Rbp1, Rbp2, and Rbp3. Here, we verified the RNA-binding activity of Rbp3 in vivo and show that cells of a Δ rbp3 deletion strain had a lower photosystem (PS) I:PSII ratio and decreased pigment content and were significantly smaller than wild-type cells. To identify the set of interacting molecules, coimmunoprecipitation experiments were performed with a strain expressing a C-terminally FLAG-tagged Rbp3. Mass spectrometry of the elution fraction suggested physical proximity between Rbp3, ribosomes, and a very small number of other proteins. The most highly enriched transcript in the coeluting RNA fraction was the psaAB mRNA. This was corroborated by fluorescent in situ hybridization analyses showing decreased psaA mRNA signals in Δ rbp3 , and colocalization with Rbp3 fusions to the green fluorescent protein (GFP) in the wild type. Other mRNAs coenriched with Rbp3 encode thylakoid, plasma membrane, and carboxysome proteins. Binding assays using Bio-layer Interferometry validated the Rbp3- psaAB mRNA interaction, indicating a preference for folded RNA segments near or overlapping the respective stop codons.}, archive = {J_PNAS}, author = {Hemm, Luisa and Lichtenberg, Elisabeth and Tholen, Stefan and Reimann, Viktoria and Kakazu, Kenta and Machida, Sotaro and Mahbub, Moontaha and Schilling, Oliver and Wilde, Annegret and Watanabe, Satoru and Mullineaux, Conrad W. and Hess, Wolfgang R.}, doi = {10.1073/pnas.2506275122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2506275122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The RRM domain–containing protein rbp3 interacts with ribosomes and the 3’ ends of mRNAs encoding photosynthesis proteins}, volume = {122}, year = {2025}, }
• (2025). Women climate scientists are connected, productive, and successful but have shorter careers. PNAS, 122(26), e2506023122. (www)

  @article{ , abstract = {Scholars have long been concerned about gender representation in scientific research but there has been little work on gender differences in participation and performance in climate science, a field that engages with both male-majority disciplines (e.g., geosciences, engineering) and female-majority disciplines (e.g., life sciences, medical science). This has implications for both gender equity and viewpoint representation. Sampling over 400,000 publications and a similar number of authors, we examine gender differences in several scholarly outcomes including publication count, career survival, coauthor gender, journal status, and mean citation count. We find men and women are similarly productive, successful, and connected, though women have shorter research careers and thus fewer papers. We also find gender homophily effects in collaboration, but no evidence of gender bias in peer review.}, archive = {J_PNAS}, author = {Martin, Chris C. and Lockley, Andrew and Hendricks, Steve and Clark, Cory J. and Mundra, Ishita and Matzner, Nils}, doi = {10.1073/pnas.2506023122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2506023122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Women climate scientists are connected, productive, and successful but have shorter careers}, volume = {122}, year = {2025}, }
• (2025). The role of estrogen receptor β in maintaining basal cells and modulating the immune environment in the prostate. PNAS, 122(26), e2505797122. (www)

  @article{ , abstract = {Estrogen receptor β (ERβ) plays an important role in both the mouse and human prostate. The endogenous ligand for ERβ is the dihydrotestosterone metabolite, 5β-androstane-3β, 17β-diol (3β-Adiol). Thus, treatment with 5-α reductase inhibitor (5-ARI) should produce a phenotype similar to that seen in ERβ −/− mice. By comparing RNA-Seq of the ventral prostates (VP) of ERβ knockout mice (ERβ crispr−/− ) and wild-type (WT) mice, we confirmed that ERβ modulates androgen receptor (AR) signaling indirectly by suppressing AR coactivators. Compared to WT mice, basal cell genes from ERβ crispr−/− mouse VP were significantly upregulated. A population of abnormal basal cells coexpressing P63 and AR was identified in the ERβ crispr−/− mouse VP by immunohistochemistry. In men treated with 5-ARI for treatment of benign prostatic hyperplasia (BPH), there was induction of a P63-positive intermediate cell population characterized by down regulation of Krt14 without significant change in the expression of Krt15, upregulation of AR and NKX3.1, and increased proliferation. In both VP of aging ERβ crispr−/− mice and in human prostates after 5-ARI treatment, there was substantial immune infiltration. Testosterone treatment inhibited immune infiltration in the VP of ERβ crispr−/− mice. We conclude that ERβ is a gene critical in maintaining normal basal cells and modulating immune environment in the prostate. Its loss leads to histological changes suggesting prostatitis and increases the number of intermediate cells, which are considered to be the cells of origin of prostate cancers. We suggest that an ERβ agonist could protect against 5-ARI-induced inflammatory cell infiltration and defects in the basal cell layer in BPH.}, archive = {J_PNAS}, author = {Wu, Wan-fu and Song, Xiao-yu and Warner, Margaret and Imamov, Otabeck and Antonson, Per and Gustafsson, Jan-Ake}, doi = {10.1073/pnas.2505797122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2505797122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The role of estrogen receptor β in maintaining basal cells and modulating the immune environment in the prostate}, volume = {122}, year = {2025}, }
• (2025). Outdated reproductive norms, the naturalistic fallacy, and misunderstandings of welfare in recent call for zoo breed-and-feed programs. PNAS, 122(26), e2504225122. (www)

  @article{ , archive = {J_PNAS}, author = {Ferraro, Kristy M. and Ferraro, Anthony L. and Monk, Julia D. and Forbes, Elizabeth S.}, doi = {10.1073/pnas.2504225122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2504225122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Outdated reproductive norms, the naturalistic fallacy, and misunderstandings of welfare in recent call for zoo breed-and-feed programs}, volume = {122}, year = {2025}, }
• (2025). An ABA–ROP toggle switch orchestrates xylem differentiation and cell wall patterning. PNAS, 122(26), e2503363122. (www)

  @article{ , abstract = {The mutual antagonistic signaling of abscisic acid (ABA) and ROP GTPases highlights an intersection between stress responses and pattern formation. Previously, we have shown that signaling of ABA in the endodermis leads to protoxylem (PX) differentiation. In this study, we demonstrate that ROPs suppress PX differentiation in the roots of both Arabidopsis and tomato. Fourier transform and Shannon’s entropy show that endodermal ABA signaling controls the periodicity and overall order of PX secondary cell wall (SCW) coils in an ROP-dependent manner. Correspondingly, in the PX, GFP-ROP11 is initially dispersed and gradually becomes distributed in an oscillatory fashion with a periodicity corresponding to that of the SCW coils. Oryzalin treatments disrupt the frequency and increase the entropy of the GFP-ROP11 signal, suggesting that microtubules delimit ROP distribution. Signaling of ABA in the endodermis encourages the enlargement of metaxylem SCW pits, while ABA signaling in the stele limits this enlargement. Pit size and density are decreased in ROP mutants while ABA enhances ROP11 expression in the stele and broadens its distribution in the endodermis. Taken together, non-cell-autonomous and cell-autonomous interactions between ABA and ROPs regulate xylem differentiation and SCW patterning.}, archive = {J_PNAS}, author = {Alberti, Valentina Elettra and Bloch, Daria and Gengel, Erik and Puli, Mallikarjuna Rao and Poraty-Gavra, Limor and Yalovsky, Shaul}, doi = {10.1073/pnas.2503363122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2503363122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An ABA–ROP toggle switch orchestrates xylem differentiation and cell wall patterning}, volume = {122}, year = {2025}, }
• (2025). Roughness-dependent scaling of the contact area and separation gap with pressure for glassy polymers. PNAS, 122(26), e2503087122. (www)

  @article{ , abstract = {The contact between two rough surfaces has been a topic of significant interest since early studies on Coulombic friction and remains crucial for numerous technological applications. However, theoretical progress has outpaced experiments due to the challenges in measuring contact areas across scales ranging from subnanometers to macroscopic dimensions. Here, we demonstrate the use of commonly available infrared-based (IR) spectroscopy in combination with finite-difference time-domain (FDTD) optical simulations to measure separation gaps and contact areas for glassy polymers ranging in roughness over two orders in magnitude. With the combined IR and FDTD simulations, we can overcome the optical diffraction limits and take advantage of the chemical specificity of IR spectroscopy to overcome limitations due to scattering. The scaling of the contact area ratio as a function of pressure illustrated the limitations of using pure elastic or plastic deformation in explaining the results. At both low and high pressures, the contact area ratios scale linearly with pressure as expected for purely elastic deformations at low pressures or plastic deformations at high pressures. However, if analyzed over a broad range of pressure, the power laws we observe are much larger than 1, exemplifying the need to consider elastoplastic models in explaining results for softer polymer contacts compared to other brittle, glassy materials. In comparison, the separation gaps scale exponentially with pressure, as expected. These results have important implications for the interpretation of properties such as friction, adhesion, and conductivity for softer, glassy contact interfaces.}, archive = {J_PNAS}, author = {Patil, Utkarsh and Kumar, Shubhendu and Merriman, Stephen and Dhinojwala, Ali}, doi = {10.1073/pnas.2503087122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2503087122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Roughness-dependent scaling of the contact area and separation gap with pressure for glassy polymers}, volume = {122}, year = {2025}, }
• (2025). Synergistic deficits in parvalbumin interneurons and dopamine signaling drive ACC dysfunction in chronic pain. PNAS, 122(26), e2502558122. (www)

  @article{ , abstract = {Chronic pain arises from maladaptive changes in both peripheral and central nervous systems, including the anterior cingulate cortex (ACC), a key region implicated in descending pain modulation. Chronic pain increases the excitability of pyramidal neurons in the ACC. Although a reduction in inhibitory inputs onto pyramidal neurons has been observed in neuropathic conditions, the identity of the specific interneurons responsible remains unclear. We show that chronic pain selectively impairs parvalbumin (PV), but not somatostatin, interneurons in the rostral ACC. This is characterized by a decrease in the density of PV interneuron processes, a reduction in their surrounding perineuronal net, and a lower expression of PV. Functionally, PV interneurons display diminished inhibitory efficacy in vitro and reduced phasic activation in response to aversive stimuli in vivo. Dopamine (DA) fibers preferentially contact PV interneurons and excite them via D1 dopamine receptor activation, increasing their excitability and enhancing the frequency of inhibitory postsynaptic currents on pyramidal neurons in healthy, but not neuropathic, conditions. Furthermore, we show that this pathway is involved in hunger-induced analgesia: Food deprivation increases DA release in the ACC and consequently decreases pain thresholds in neuropathic mice. Conversely, when mice are not food deprived, neuropathic pain significantly reduces DA release in the ACC. We conclude that the loss of PV interneuron inhibitory efficacy, alongside convergent hypodopaminergic signaling, synergistically contributes to pathological ACC dysfunction and associated symptoms of chronic pain.}, archive = {J_PNAS}, author = {Lançon, Kevin and Tian, Jiakang and Bach, Haleigh and Drapeau, Pierre and Poulin, Jean-Francois and Séguéla, Philippe}, doi = {10.1073/pnas.2502558122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2502558122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synergistic deficits in parvalbumin interneurons and dopamine signaling drive ACC dysfunction in chronic pain}, volume = {122}, year = {2025}, }
• (2025). On the mechanism of photodriven hydrogenations of n2 and other substrates by hantzsch ester: Buffer is key to reactive H-atom donors. PNAS, 122(26), e2502484122. (www)

  @article{ , abstract = {The Hantzsch ester (HEH 2 ) has found considerable utility as a photoreductant in synthesis, with photodriven transfer hydrogenation reactions typically limited to activated substrates. We recently established that the addition of an organic buffer of collidinium triflate [(ColH)OTf] and collidine (Col) allows photodriven transfer hydrogenation from HEH 2 to N 2 forming NH 3 (nitrogen reduction; N 2 R) in the presence of a Mo catalyst. Given the requirements for Mo-catalyzed thermally driven N 2 R, this result suggested the generation of a significant driving force for proton-coupled electron transfer (PCET) when irradiating HEH 2 in the presence of Col-buffer. In this study, we probe how Col-buffer enables efficient photodriven proton-coupled reductions with HEH 2 . Wavelength-dependent NH 3 yields are consistent with HEH 2 photoexcitation, and the combination of HEH 2 with Col-buffer is privileged. Data are presented, suggesting that HEH 2 is statically quenched via ET to [ColH]OTf through an H-bonded association complex to release ColH • and [HEH 2 ] •+ . Transient absorbance data and EPR studies establish that the resulting [HEH 2 ] •+ intermediate is rapidly deprotonated by Col to yield HEH • , in net furnishing HEH • and ColH • as potent H-atom donors. Broader utility of this reagent combination is demonstrated in the photoreduction of a range of C=O and N=O π-bonds by HEH 2 , with a significant boost in rates and yield, and altered reactivity, observed on addition of Col-buffer. ColH • is posited as the most potent PCET donor generated (BDFE N−H of 28 kcal mol −1 ).}, archive = {J_PNAS}, author = {Johansen, Christian M. and Benazzi, Elisabetta and Peters, Jonas C.}, doi = {10.1073/pnas.2502484122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2502484122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {On the mechanism of photodriven hydrogenations of n2 and other substrates by hantzsch ester: Buffer is key to reactive H-atom donors}, volume = {122}, year = {2025}, }
• (2025). Spatial metabolomics informs the use of clinical imaging for improved detection of cribriform prostate cancer. PNAS, 122(26), e2502423122. (www)

  @article{ , abstract = {Cribriform prostate cancer (crPCa) is associated with poor clinical outcomes, yet its accurate detection remains challenging due to the poor sensitivity of standard-of-care diagnostic tools. Here, we use untargeted spatial metabolomics to identify fatty acid biosynthesis as a key metabolic pathway enriched in crPCa epithelium. We also show that imaging tumor lipid metabolism using [1- 11 C]acetate PET/CT and proton magnetic resonance spectroscopy differentiates cribriform from noncribriform intermediate-risk prostate cancers in two prospective patient cohorts. These findings support the feasibility of using clinical metabolic imaging techniques as adjunctive tools for improving crPCa detection in clinical practice, with prospective studies in larger cohorts warranted to obtain definitive results.}, archive = {J_PNAS}, author = {Sushentsev, Nikita and Hamm, Gregory and Manavaki, Roido and McLean, Mary A. and Birchall, Jonathan and Soloviev, Dmitry and Lewis, David Y. and Aloj, Luigi and Flint, Lucy and Zakirov, Aleksandr and Mills, Ian G. and Gnanapragasam, Vincent J. and Warren, Anne Y. and Barry, Simon T. and Goodwin, Richard J. A. and Gallagher, Ferdia A. and Barrett, Tristan}, doi = {10.1073/pnas.2502423122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2502423122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatial metabolomics informs the use of clinical imaging for improved detection of cribriform prostate cancer}, volume = {122}, year = {2025}, }
• (2025). In situ NMR reveals a pH sensor motif in an outer membrane protein that drives bacterial vesicle production. PNAS, 122(26), e2501638122. (www)

  @article{ , abstract = {The outer membrane vesicles (OMVs) produced by diderm bacteria have important roles in cell envelope homeostasis, secretion, interbacterial communication, and pathogenesis. The facultative intracellular pathogen Salmonella enterica Typhimurium (STm) activates OMV biogenesis inside the acidic vacuoles of host cells by upregulating the expression of the OM protein PagC, one of the most robustly activated genes in a host environment. Here, we used solid-state nuclear magnetic resonance (NMR) and electron microscopy (EM), with native bacterial OMVs, to demonstrate that three histidines, essential for the OMV biogenic function of PagC, constitute a key pH-sensing motif. The NMR spectra of PagC in OMVs show that they become protonated around pH 6, and His protonation is associated with specific perturbations of select regions of PagC. The use of bacterial OMVs is a key aspect of this work enabling NMR structural studies in the context of the physiological environment. PagC expression upregulates OMV production in Escherichia coli , replicating its function in STm. Moreover, the presence of PagC drives a striking aggregation of OMVs and increases bacterial cell pellicle formation at acidic pH, pointing to a potential role as an adhesin active in biofilm formation. The data provide experimental evidence for a pH-dependent mechanism of OMV biogenesis and aggregation driven by an OM protein.}, archive = {J_PNAS}, author = {Wood, Nicholas A. and Kraft, Alyssa and Shin, Kyungsoo and Gopinath, Tata and Marassi, Francesca M.}, doi = {10.1073/pnas.2501638122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2501638122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In situ NMR reveals a pH sensor motif in an outer membrane protein that drives bacterial vesicle production}, volume = {122}, year = {2025}, }
• (2025). Methane-powered sea spiders: Diverse, epibiotic methanotrophs serve as a source of nutrition for deep-sea methane seep sericosura. PNAS, 122(26), e2501422122. (www)

  @article{ , abstract = {Methane seeps harbor uncharacterized animal–microbe symbioses with unique nutritional strategies. Three undescribed sea spider species (family Ammotheidae; genus Sericosura ) endemic to methane seeps were found along the eastern Pacific margin, from California to Alaska, hosting diverse methane- and methanol-oxidizing bacteria on their exoskeleton. δ 13 C tissue isotope values of in situ specimens corroborated methane assimilation (−45‰, on average). Live animal incubations with 13 C-labeled methane and methanol, followed by nanoscale secondary ion mass spectrometry, confirmed that carbon derived from both compounds was actively incorporated into the tissues within five days. Methano- and methylotrophs of the bacterial families Methylomonadaceae, Methylophagaceae and Methylophilaceae were abundant, based on environmental metagenomics and 16S rRNA sequencing, and fluorescence and electron microscopy confirmed dense epibiont aggregations on the sea spider exoskeleton. Egg sacs carried by the males hosted identical microbes suggesting vertical transmission. We propose that these sea spiders farm and feed on methanotrophic and methylotrophic bacteria, expanding the realm of animals known to harness C1 compounds as a carbon source. These findings advance our understanding of the biology of an understudied animal lineage, unlocking some of the unique nutritional links between the microbial and faunal food webs in the oceans.}, archive = {J_PNAS}, author = {Dal Bó, Bianca and Guo, Yongzhao and Mayr, Magdalena J. and Pereira, Olivia S. and Levin, Lisa A. and Orphan, Victoria J. and Goffredi, Shana K.}, doi = {10.1073/pnas.2501422122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2501422122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Methane-powered sea spiders: Diverse, epibiotic methanotrophs serve as a source of nutrition for deep-sea methane seep sericosura}, volume = {122}, year = {2025}, }
• (2025). Structural mechanism for the recognition of E2F1 by the ubiquitin ligase adaptor cyclin f. PNAS, 122(26), e2501057122. (www)

  @article{ , abstract = {Cyclin F, a noncanonical member of the cyclin protein family, plays a critical role in regulating transitions in the cell division cycle. Unlike canonical cyclins, which bind and activate cyclin-dependent kinases (CDKs), Cyclin F functions as a substrate receptor protein within the Skp1–Cullin-F-box E3 ubiquitin ligase complex, enabling the ubiquitylation of target proteins. The structural features that distinguish Cyclin F as a ligase adaptor and the mechanisms underlying its selective substrate recruitment over Cyclin A, which functions in complex with CDK2 at a similar time in the cell cycle, remain largely unexplored. We utilized single-particle cryoelectron microscopy to elucidate the structure of a Cyclin F–Skp1 complex bound to an E2F1 peptide. The structure and biochemical analysis reveal important differences in the substrate-binding site of Cyclin F compared to Cyclin A. Our findings expand on the canonical cyclin-binding motif (Cy or RxL) and highlight the importance of electrostatics at the E2F1 binding interface, which varies between Cyclin F and Cyclin A. These results advance our understanding of E2F1 regulation and may inform strategies for selectively targeting Cyclin F in cancer or neurodegeneration.}, archive = {J_PNAS}, author = {Ngoi, Peter and Wang, Xianxi and Putta, Sivasankar and Da Luz, Ricardo F. and Serrão, Vitor Hugo B. and Emanuele, Michael J. and Rubin, Seth M.}, doi = {10.1073/pnas.2501057122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2501057122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural mechanism for the recognition of E2F1 by the ubiquitin ligase adaptor cyclin f}, volume = {122}, year = {2025}, }
• (2025). Light controls gene functions through alternative splicing in fungi. PNAS, 122(26), e2500966122. (www)

  @article{ , abstract = {Light controls important biological processes in fungi by regulating transcriptional gene activation. Here, we found that beyond the regulation of mRNA transcript abundance, light regulates alternative splicing (AS) in the filamentous fungi Aspergillus nidulans , Trichoderma guizhouense, and Neurospora crassa . Blue light-regulated AS was involved in ergothioneine biosynthesis and conidiation in T. guizhouense , which required the blue light receptor BLR1. Blue light activated the MAPK HOG (Sak) pathway which then transmitted the signal via the serine/threonine kinase SRK1 to the AS key regulator SRP1. SRK1 and SRP1 are important for light-induced conidiation. The light-activated HOG pathway led to an increase of the SRK1 protein level and its phosphorylation status. Phosphorylated SRK1 translocated from the cytoplasm to the nucleus to interact with SRP1, thereby regulating AS efficiency. This study unravels another level of complexity of fungal environmental sensing and responses and also first describes the entire cascade from an environmental signal to the splicing machinery.}, archive = {J_PNAS}, author = {Li, Yifan and Lu, Huanhong and Guo, Degang and Li, Xiaoyan and Qi, Fei and Zhang, Jian and Fischer, Reinhard and Shen, Qirong and Yu, Zhenzhong}, doi = {10.1073/pnas.2500966122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2500966122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Light controls gene functions through alternative splicing in fungi}, volume = {122}, year = {2025}, }
• (2025). PLAA/UFD-3 regulates P-bodies through its intrinsic disordered domain. PNAS, 122(26), e2427250122. (www)

  @article{ , abstract = {Regulation of proteome homeostasis is crucial for the survival and adaptation to changing environments for all species. In eukaryotes, this process is finely tuned through regulation at the level of transcription, translation, protein modification, and protein degradation. The phospholipase A2 activating protein (PLAA) is present in all eukaryotes and believed to be a key player in ubiquitin-dependent protein sorting and degradation via its interactions with ubiquitin and/or the AAA+ ATPase, valosin-containing protein (VCP/p97). PLAA’s molecular targets and interaction network remain unclear. We used Caenorhabditis elegans and unbiased proteome-scale approaches to investigate neuronal specific interactors of the C. elegans PLAA ortholog UFD-3 (ubiquitin fusion degradation 3), its effect on ubiquitinated proteins, and global protein expression changes in an ufd-3 mutant. We found that PLAA may play a unique role in cytoplasmic messenger ribonucleic acid (mRNA) processing bodies (P-bodies). Using biochemical analysis in vitro and fluorescence imaging in C. elegans , we show that UFD-3 directly interacts with the mRNA decapping complex regulatory subunit DCAP-1. UFD-3's intrinsic disordered region (IDR), which contains conserved amino acid motifs, is important for the recruitment of DCAP-1 to P-bodies. Finally, we show that loss of the IDR does not affect UFD-3's role in sorting ubiquitinated proteins through the multivesicular body pathway. Collectively, our results suggest that UFD-3's role in P-bodies is distinct from its role in the ubiquitin-dependent protein degradation pathway and the IDR is only critical for UFD-3-regulated P-bodies pathways. Thus, PLAA/UFD-3 might regulate the proteome via two distinct pathways: ubiquitinated protein turnover, as well as mRNA regulation through P-bodies.}, archive = {J_PNAS}, author = {Das, Alakananda and Qiu, Yanping and Wolf, Trevor J. and Brissett, Ella and Cho, Jaehyoung and Park, Heenam and Chen, Eugene C. and Chou, Tsui-Fen and Sternberg, Paul W.}, doi = {10.1073/pnas.2427250122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2427250122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PLAA/UFD-3 regulates P-bodies through its intrinsic disordered domain}, volume = {122}, year = {2025}, }
• (2025). The adaptive state determines the impact of mutations on evolving populations. PNAS, 122(26), e2427070122. (www)

  @article{ , abstract = {Darwinian evolution results from an interplay between stochastic diversification of heritable phenotypes, impacting the chance of survival and reproduction, and fitness-based selection. The ability of populations to evolve and adapt to environmental changes depends on rates of mutational diversification and the distribution of fitness effects of random mutations. In turn, the distribution of fitness effects of stochastic mutations can be expected to depend on the adaptive state of a population. To systematically study the impact of the interplay between the adaptive state of a population on the ability of asexual populations to adapt, we used a spatial agent-based model of a neoplastic population adapting to a selection pressure of continuous exposure to targeted therapy. We found favorable mutations were overrepresented at the extinction bottleneck but depleted at the adaptive peak. The model-based predictions were tested using an experimental cancer model of an evolution of resistance to a targeted therapy. Consistent with the model’s prediction, we found that enhancement of the mutation rate was highly beneficial under therapy but moderately detrimental under the baseline conditions. Our results highlight the importance of considering population fitness in evaluating the fitness distribution of random mutations and support the potential therapeutic utility of restricting mutational variability.}, archive = {J_PNAS}, author = {Tyczynska Weh, Malgorzata and Kumar, Pragya and Marusyk, Viktoriya and Marusyk, Andriy and Basanta, David}, doi = {10.1073/pnas.2427070122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2427070122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The adaptive state determines the impact of mutations on evolving populations}, volume = {122}, year = {2025}, }
• (2025). Contribution of glutamatergic projections to neurons in the nonhuman primate substantia nigra pars reticulata for reactive inhibition. PNAS, 122(26), e2427032122. (www)

  @article{ , abstract = {The basal ganglia play a crucial role in action selection by facilitating desired movements and suppressing unwanted ones. The substantia nigra pars reticulata (SNr), a key output nucleus, facilitates movement through disinhibition of the superior colliculus (SC). However, its role in action suppression, particularly in primates, remains less clear. We investigated whether individual SNr neurons in three male macaque monkeys bidirectionally modulate their activity to both facilitate and suppress actions and examined the role of glutamatergic inputs in suppression. Monkeys performed a sequential choice task, selecting or rejecting visually presented targets. Electrophysiological recordings showed that SNr neurons decreased firing rates during target selection and increased firing rates during rejection, demonstrating bidirectional modulation. Pharmacological blockade of glutamatergic inputs to the lateral SNr disrupted saccadic control and impaired suppression of reflexive saccades, providing causal evidence for the role of excitatory input in behavioral inhibition. These findings suggest that glutamatergic projections, potentially originating from sources including the subthalamic nucleus, contribute to the increased SNr activity during action suppression. Our results highlight conserved basal ganglia mechanisms across species and offer insights into the neural substrates of action selection and suppression in primates, with implications for understanding disorders such as Parkinson’s disease.}, archive = {J_PNAS}, author = {Yoshida, Atsushi and Hikosaka, Okihide}, doi = {10.1073/pnas.2427032122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2427032122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Contribution of glutamatergic projections to neurons in the nonhuman primate substantia nigra pars reticulata for reactive inhibition}, volume = {122}, year = {2025}, }
• (2025). Retinoic acid receptor assembly dynamics governs dual functions in cochlear organogenesis. PNAS, 122(26), e2426739122. (www)

  @article{ , abstract = {Retinoic acid (RA) is a morphogen that contributes to inner ear development. Gain and loss of function experiments have indicated retinoic acid’s critical role in cochlear hair cell development. However, the underlying molecular mechanisms are unclear. Here, we hypothesized that RA receptor alpha (RARA) has a dual role in cochlear organogenesis: First, during embryonic development, in the presence of RA, RARA functions as a transcriptional activator that induces prosensory gene expression in progenitor cells and supports differentiation of the organ of Corti; later during postnatal development, when RA is absent, the function of RARA switches, thereby repressing prosensory genes in postnatal hair cells and hindering trans-differentiation into supporting cells. This hypothesis was supported by demonstration that RARA forms a complex with either the coactivator NCOA1 or the corepressor NCOR1 depending on the developmental stage. In addition, modulation of RA levels was found to govern recruitment of the coactivator and corepressor to the RARA complex, and the expression of prosensory genes was validated to depend on RARA complex composition. Together, our results provide insights supporting the potential of harnessing RA signaling to induce prosensory progenitors in stem cell–based strategies for hearing loss.}, archive = {J_PNAS}, author = {Chakraborty, Saikat and Wang, Shuze and Ruhala, Jack and Mehling, Brett and Liu, Jie and Waldhaus, Joerg}, doi = {10.1073/pnas.2426739122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2426739122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Retinoic acid receptor assembly dynamics governs dual functions in cochlear organogenesis}, volume = {122}, year = {2025}, }
• (2025). De novo design of D-peptide ligands: Application to influenza virus hemagglutinin. PNAS, 122(26), e2426554122. (www)

  @article{ , abstract = {D-peptides hold great promise as therapeutics by alleviating the challenges of metabolic stability and immunogenicity in L-peptides. However, current D-peptide discovery methods are severely limited by specific size, structure, and the chemical synthesizability of their protein targets. Here, we describe a computational method for de novo design of D-peptides that bind to an epitope of interest on the target protein using Rosetta’s hotspot-centric approach. The approach comprises identifying hotspot sidechains in a functional protein–protein interaction and grafting these side chains onto much smaller structured peptide scaffolds of opposite chirality. The approach enables more facile design of D-peptides and its applicability is demonstrated by design of D-peptidic binders of influenza A virus hemagglutinin, resulting in identification of multiple D-peptide lead series. The X-ray structure of one of the leads at 2.38 Å resolution verifies the validity of the approach. This method should be generally applicable to targets with detailed structural information, independent of molecular size, and accelerate development of stable, peptide-based therapeutics.}, archive = {J_PNAS}, author = {Juraszek, Jarek and Kadam, Rameshwar U. and Branduardi, Davide and van Ameijde, Jeroen and Garg, Divita and Dailly, Nicolas and Jongeneelen, Mandy and Vermond, Jan and Brakenhoff, Just P. J. and Brandenburg, Boerries and van Dongen, Maria J. P. and Vogels, Ronald and Friesen, Robert H. E. and Wilson, Ian A.}, doi = {10.1073/pnas.2426554122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2426554122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {De novo design of D-peptide ligands: Application to influenza virus hemagglutinin}, volume = {122}, year = {2025}, }
• (2025). Sensory population activity reveals downstream confidence computations in the primate visual system. PNAS, 122(26), e2426441122. (www)

  @article{ , abstract = {Perception is fallible. Humans know this, and so do some nonhuman animals like macaque monkeys. When monkeys report more confidence in a perceptual decision, that decision is more likely to be correct. It is not known how neural circuits in the primate brain assess the quality of perceptual decisions. Here, we test two hypotheses. First, that decision confidence is related to the structure of population activity in the sensory cortex. And second, that this relation differs from the one between sensory activity and decision content. We trained macaque monkeys to judge the orientation of ambiguous stimuli and additionally report their confidence in these judgments. We recorded population activity in the primary visual cortex and used decoders to expose the relationship between this activity and the choice-confidence reports. Our analysis validated both hypotheses and suggests that perceptual decisions arise from a neural computation downstream of visual cortex that estimates the most likely interpretation of a sensory response, while decision confidence instead reflects a computation that evaluates whether this sensory response will produce a reliable decision. Our work establishes a direct link between neural population activity in the sensory cortex and the metacognitive ability to introspect about the quality of perceptual decisions.}, archive = {J_PNAS}, author = {Boundy-Singer, Zoe M. and Ziemba, Corey M. and Goris, Robbe L. T.}, doi = {10.1073/pnas.2426441122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2426441122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sensory population activity reveals downstream confidence computations in the primate visual system}, volume = {122}, year = {2025}, }
• (2025). SARS-CoV-2 nucleocapsid protein directly prevents cGAS–DNA recognition through competitive binding. PNAS, 122(26), e2426204122. (www)

  @article{ , abstract = {A hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the delayed interferon response. Interferons are typically produced upon host recognition of pathogen- or damage-associated molecular patterns, such as nucleic acids. While the mechanisms by which SARS-CoV-2 evades host recognition of its RNA are well studied, how it evades immune responses to cytosolic DNA—leaked from mitochondria or nuclei during infection—remains poorly understood. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein directly suppresses DNA sensing by cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS). Although primarily known for packaging the viral RNA genome, we uncover that the SARS-CoV-2 nucleocapsid protein also binds DNA with high affinity and competitively blocks cGAS activation. Using cell-free biochemical and biophysical approaches, including single-molecule optical tweezers, we show that the nucleocapsid protein binds to DNA at nanomolar concentrations and cocondenses with DNA at micromolar concentrations, thereby impeding stable cGAS-DNA interactions required for signal propagation. Hyperphosphorylation of the nucleocapsid protein diminishes its competitive binding capacity. Our findings reveal an unexpected role of the SARS-CoV-2 nucleocapsid protein in directly suppressing the cGAS-STING pathway, strongly suggesting that this contributes to the delayed interferon response during infection. This study raises the possibility that nucleocapsid proteins of other RNA viruses may also exhibit moonlighting functions by antagonizing host nucleic acid–sensing pathways.}, archive = {J_PNAS}, author = {Gutmann, Theresia and Kuster, David and Hyman, Anthony A.}, doi = {10.1073/pnas.2426204122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2426204122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SARS-CoV-2 nucleocapsid protein directly prevents cGAS–DNA recognition through competitive binding}, volume = {122}, year = {2025}, }
• (2025). Fluid dynamics model of the cerebral ventricular system. PNAS, 122(26), e2426067122. (www)

  @article{ , abstract = {Hydrocephalus, a neurological condition characterized by an excessive buildup of cerebrospinal fluid (CSF) in the brain, affects millions worldwide and leads to severe consequences. Current treatments, such as ventriculoperitoneal shunts, divert excess CSF from the brain but often face complications, mainly due to shunt obstructions caused by biological matter accumulation. While previous shunt designs aimed to improve fluid flow and reduce occlusion, they often lacked the precision needed for real-world applications due to simplified simulation models that did not fully capture the dynamics of the cerebral ventricular system. Here, we introduce BrainFlow, a computational model that integrates detailed anatomical and physiological features to simulate CSF dynamics in the presence of shunt implants. BrainFlow incorporates patient-specific medical imaging data, pulsatile flow to mimic cardiac cycles, adjustable parameters for various hydrocephalus conditions, and a biomolecule tracking feature to evaluate the long-term risk of shunt occlusion due to flow-mediated biomolecular transport. This model provides a more nuanced understanding of the factors contributing to shunt obstruction, offering insights into optimal shunt placement, design, and materials choice. Through validation against four-dimensional MRI flow data, BrainFlow demonstrates robust accuracy across multiple flow metrics. Our work lays the groundwork for the development of next-generation shunts tailored to individual patient anatomy and pathology, ultimately aiming to improve hydrocephalus treatment through informed, patient-specific design strategies.}, archive = {J_PNAS}, author = {Patel, Haritosh and Huang, Yu Xuan and Dengiz, Duygu and Pravdivtseva, Mariya and Jansen, Olav and Quandt, Eckhard and Aizenberg, Joanna}, doi = {10.1073/pnas.2426067122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2426067122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fluid dynamics model of the cerebral ventricular system}, volume = {122}, year = {2025}, }
• (2025). Cenozoic geoclimatic changes drove the evolutionary dynamics of floristic endemism on the Qinghai–Tibet plateau. PNAS, 122(26), e2426017122. (www)

  @article{ , abstract = {The Qinghai–Tibet Plateau (QTP) harbors extraordinarily high levels of biodiversity and endemism. The region is warming at a rate twice the global average, yet the evolutionary dynamics of its unique biota are poorly understood. Here, we used the endemic land plant genera of the QTP to investigate how its floristic endemism was shaped over time by Cenozoic geoclimatic changes. We first clarified that the QTP hosts 82 endemic land plant genera; we found that the origins of these endemic genera were most likely driven by ecological niche and elevation differentiation, caused by the uplift of the QTP and associated climate change. By sampling 37 land plant clades that together encompass 1,740 species, covering all 82 endemic genera, we show that QTP floristic endemism had emerged by the Early Eocene. Furthermore, the unique biodiversity of the QTP comprises a mix of indigenous elements and immigrants. Among the three subregions of the QTP (Plateau Platform, Himalaya, and the Hengduan Mountains), the processes associated with floristic endemism are asynchronous, reflecting different geoclimatic events with the Miocene as a particularly critical period. The relative contributions of in situ speciation and immigration to the unique biodiversity of the three subregions are also markedly different; in situ speciation dominated in the Hengduan Mountains, which hosts the oldest endemic components of the flora and has served as an important “pump” and “sink” of unique biodiversity. These findings provide insights into how past geoclimatic events may have shaped floristic endemism on the QTP and also have important conservation implications.}, archive = {J_PNAS}, author = {Cao, Guan-Long and Li, Xiao-Qian and Zhang, Jun and Peng, Huan-Wen and Li, Hong-Lei and Erst, Andrey S. and Jabbour, Florian and Ortiz, Rosa del C. and Soltis, Pamela S. and Soltis, Douglas E. and Wang, Wei}, doi = {10.1073/pnas.2426017122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2426017122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cenozoic geoclimatic changes drove the evolutionary dynamics of floristic endemism on the Qinghai–Tibet plateau}, volume = {122}, year = {2025}, }
• (2025). Widespread thiamine deficiency in california salmon linked to an anchovy-dominated marine prey base. PNAS, 122(26), e2426011122. (www)

  @article{ , abstract = {Thiamine (vitamin B 1 ) deficiency in marine systems is a globally significant threat to marine life. In 2020, newly hatched Chinook salmon ( Oncorhynchus tshawytscha ) fry in California’s Central Valley (CCV) hatcheries swam in corkscrew patterns and died at unusually high rates due to a lack of this essential vitamin. We subsequently investigated the impacts and causes of thiamine deficiency in California’s anadromous salmonids. Our laboratory studies defined the relationship between thiamine concentrations in Chinook salmon eggs and early life-stage survival in offspring; we used these data to develop a model that estimated 26 to 48% thiamine-dependent fry mortality across consecutive years (2020–2021) for winter-run Chinook salmon. We established an egg surveillance effort that found widespread thiamine deficiency in CCV Chinook salmon in 2020 and 2021, and emerging thiamine deficiency in Klamath River and Trinity River coho salmon ( Oncorhynchus kisutch ) in 2021. We determined that thiamine injections into adults raised egg thiamine concentrations above levels found to impact early life-stage survival and swimming behavior. Ocean surveys, prey nutrition, salmon gut contents, and stable isotope data link thiamine deficiency to an ocean diet dominated by a booming population of northern anchovy ( Engraulis mordax ). This forage fish had low thiamine, high lipid, and high thiaminase activity levels consistent with both a thiaminase and oxidative stress hypothesis for causing thiamine deficiency in California salmon. Our research suggests California’s already stressed anadromous salmonids will continue to be impacted by thiamine deficiency as long as their ocean forage base and diet are dominated by northern anchovy.}, archive = {J_PNAS}, author = {Mantua, Nathan J. and Bell, Heather and Todgham, Anne E. and Daniels, Miles E. and Rinchard, Jacques and Ludwig, Jarrod M. and Field, John C. and Lindley, Steven T. and Rowland, Freya E. and Richter, Catherine A. and Walters, David and Finney, Bruce and Distajo, Haskell Anne R. and Tillitt, Donald and Honeyfield, Dale C. and Lipscomb, Taylor and Kwak, Kevin and Kindopp, Jason and Cocherell, Dennis and Ward, Abigail and Williams, Thomas H. and Harding, Jeff and Fangue, Nann A. and Jeffres, Carson and Ruiz-Cooley, Rocio I. and Litvin, Steven Y. and Foott, Scott and Adkison, Mark and Kormos, Brett and Harte, Peggy and Colwell, Frederick and Suffridge, Christopher P. and Shannon, Kelly C. and Cranford, Amanda and Ambrose, Charlotte and Reed, Aimee and Johnson, Rachel C.}, doi = {10.1073/pnas.2426011122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2426011122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Widespread thiamine deficiency in california salmon linked to an anchovy-dominated marine prey base}, volume = {122}, year = {2025}, }
• (2025). Population structure limits the use of genomic data for predicting phenotypes and managing genetic resources in forest trees. PNAS, 122(26), e2425691122. (www)

  @article{ , abstract = {There is overwhelming evidence that forest trees are locally adapted to climate. Thus, genecological models based on population phenotypes have been used to measure local adaptation, infer genetic maladaptation to climate, and guide assisted migration. However, instead of phenotypes, there is increasing interest in using genomic data for gene resource management. We used whole-genome resequencing and common-garden experiments to understand the genetic architecture of adaptive traits in black cottonwood. We studied the potential of using genome-wide association studies (GWAS) and genomic prediction to detect causal loci, identify climate-adapted phenotypes, and inform gene resource management. We analyzed population structure by partitioning phenotypic and genomic (single-nucleotide polymorphism) variation among 840 genotypes collected from 91 stands along 16 rivers. Most phenotypic variation (60 to 81%) occurred among populations and was strongly associated with climate. Population phenotypes were predicted well using genomic data (e.g., predictive ability r > 0.9) but almost as well using climate or geography ( r > 0.8). In contrast, genomic prediction within populations was poor ( r < 0.2). We identified many GWAS associations among populations, but most appeared to be spurious based on pooled within-population analyses. Hierarchical partitioning of linkage disequilibrium and haplotype sharing suggested that within-population genomic prediction and GWAS were poor because allele frequencies of causal loci and linked markers differed among populations. Given the urgent need to conserve natural populations and ecosystems, our results suggest that climate variables alone can be used to predict population phenotypes, delineate seed zones and deployment zones, and guide assisted migration.}, archive = {J_PNAS}, author = {Slavov, Gancho T. and Macaya-Sanz, David and DiFazio, Stephen P. and Howe, Glenn T.}, doi = {10.1073/pnas.2425691122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2425691122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Population structure limits the use of genomic data for predicting phenotypes and managing genetic resources in forest trees}, volume = {122}, year = {2025}, }
• (2025). Multiomics integration prioritizes potential drug targets for multiple sclerosis. PNAS, 122(26), e2425537122. (www)

  @article{ , abstract = {Multiple sclerosis (MS) is an immune-mediated disease with no current cure. Drug discovery and repurposing are essential to enhance treatment efficacy and safety. We utilized summary statistics for protein quantitative trait loci (pQTL) of 2,004 plasma and 1,443 brain proteins, a genome-wide association study of MS susceptibility with 14,802 cases and 26,703 controls, both bulk and cell-type specific transcriptome data, and external pQTL data in blood and brain. Our integrative analysis included a proteome-wide association study to identify MS-associated proteins, followed by summary-data-based Mendelian randomization to determine potential causal associations. We used the HEIDI test and Bayesian colocalization analysis to distinguish pleiotropy from linkage. Proteins passing all analyses were prioritized as potential drug targets. We further conducted pathway annotations and protein–protein interaction network analysis (PPI) and verified our findings at mRNA and protein levels. We tested hundreds of MS-associated proteins and confirmed 18 potential causal proteins (nine in plasma and nine in brain). Among these, we found 78 annotated pathways and 16 existing non-MS drugs targeting six proteins. We also identified intricateAQ PPIs among seven potential drug targets and 19 existing MS drug targets, as well as PPIs of four targets across plasma and brain. We identified two targets using bulk mRNA expression data and four targets expressed in MS-related cell types. We finally verified 10 targets using external pQTL data. We prioritized 18 potential drug targets in plasma and brain, elucidating the underlying pathology and providing evidence for potential drug discovery and repurposing in MS.}, archive = {J_PNAS}, author = {Jiang, Yuan and Liu, Qianwen and Stridh, Pernilla and Kockum, Ingrid and Olsson, Tomas and Alfredsson, Lars and Diaz-Gallo, Lina-Marcela and Jiang, Xia}, doi = {10.1073/pnas.2425537122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2425537122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multiomics integration prioritizes potential drug targets for multiple sclerosis}, volume = {122}, year = {2025}, }
• (2025). Early warning signs of salt marsh drowning indicated by widespread vulnerability from declining belowground plant biomass. PNAS, 122(26), e2425501122. (www)

  @article{ , abstract = {Salt marshes provide valuable ecosystem services but are vulnerable to drowning with accelerated sea-level rise (SLR). Marsh belowground biomass (BGB) production helps avoid drowning by building marsh surface elevation. Reductions in BGB can serve as an early warning sign of marsh deterioration, as they often precede decreases in aboveground biomass (AGB). However, landscape-scale BGB assessments to predict broad trends in marsh deterioration have not been previously available. We applied the Belowground Ecosystem Resiliency Model (BERM) to assess standing stocks and trends in both BGB and AGB over the past decade (2014–2023) across US Georgia coast Spartina alterniflora marshes (691 km 2 ). Over this time period, BGB and AGB averaged 841 ± 323 and 221 ± 14 g m −2 , respectively, but showed opposite trends. BGB decreased on average by 0.94% per year and over most of the marsh area (72%), while AGB increased on average by 0.66% per year and showed a net increase across most of the marsh area (88%). This disconnect suggests that AGB is not a good indicator of marsh resilience, and we highlight two areas with similar AGB but different BGB. Inundation intensity, an important predictor of BGB, rose through time and was negatively related to BGB. SLR trends suggest continuing increases in inundation, which will result in further declines in BGB followed by widespread marsh drowning. Landscape BGB assessments are a valuable tool to identify ecosystem vulnerability and proactively manage salt marshes and the services they provide under rising sea levels.}, archive = {J_PNAS}, author = {Runion, Kyle D. and Alber, Merryl and Mishra, Deepak R. and Lever, Mark A. and Hladik, Christine M. and O’Connell, Jessica L.}, doi = {10.1073/pnas.2425501122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2425501122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Early warning signs of salt marsh drowning indicated by widespread vulnerability from declining belowground plant biomass}, volume = {122}, year = {2025}, }
• (2025). Genome-scale knockout simulation and clustering analysis of drug-resistant breast cancer cells reveal drug sensitization targets. PNAS, 122(26), e2425384122. (www)

  @article{ , abstract = {Anticancer chemotherapy is an essential part of cancer treatment, but the emergence of resistance remains a major hurdle. Metabolic reprogramming is a notable phenotype associated with the acquisition of drug resistance. Here, we develop a computational framework that predicts metabolic gene targets capable of reverting the metabolic state of drug-resistant cells to that of drug-sensitive parental cells, thereby sensitizing the resistant cells. The computational framework performs single-gene knockout simulation of genome-scale metabolic models that predicts genome-wide metabolic flux distribution in drug-resistant cells, and clusters the resulting knockout flux data using uniform manifold approximation and projection, followed by k -means clustering. From the clustering analysis, knockout genes that lead to the flux data near that of drug-sensitive cells are considered drug sensitization targets. This computational approach is demonstrated using doxorubicin- and paclitaxel-resistant MCF7 breast cancer cells. Drug sensitization targets are further refined based on proteome and metabolome data, which generate GOT1 for doxorubicin-resistant MCF7, GPI for paclitaxel-resistant MCF7, and SLC1A5 as a common target. These targets are experimentally validated where treating drug-resistant cancer cells with small-molecule inhibitors results in increased sensitivity of drug-resistant cells to doxorubicin or paclitaxel. The applicability of the developed framework is further demonstrated using drug-resistant triple-negative breast cancer cells. Taken together, the computational framework predicts drug sensitization targets in an intuitive and cost-efficient manner and can be applied to overcome drug-resistant cells associated with various cancers and other metabolic diseases.}, archive = {J_PNAS}, author = {Lim, JinA and Jung, Hae Deok and Park, Soo Young and Jeon, Moonhyeon and Kim, Da Sol and Cho, Ryeongeun and Han, Dohyun and Ryu, Han Suk and Kim, Yoosik and Kim, Hyun Uk}, doi = {10.1073/pnas.2425384122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2425384122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genome-scale knockout simulation and clustering analysis of drug-resistant breast cancer cells reveal drug sensitization targets}, volume = {122}, year = {2025}, }
• (2025). Enhanced chloroplast FtsZ-ring constriction by the ARC6–ARC3 module in arabidopsis. PNAS, 122(26), e2425129122. (www)

  @article{ , abstract = {Chloroplast division, a process tightly linked to the energy demands of plants, is initiated by the formation of the stromal filamenting temperature-sensitive Z (FtsZ) ring. The Z ring is highly dynamic, and its constriction provides the essential force for chloroplast division. However, the regulatory mechanisms governing Z-ring dynamics and constriction remain poorly understood. Here, we report that the chloroplast inner envelope membrane (IEM) protein ACCUMULATION AND REPLICATION OF CHLOROPLASTS6 (ARC6) interacts with the chloroplast stromal protein ARC3, and this interaction is negatively regulated by the conserved J-like domain of ARC6. ARC3 is found both distributed throughout the stroma and localized to a ring-like structure at the chloroplast division site. We demonstrate that ARC6 recruits ARC3 to the division site to form a ring-like structure, likely through direct interaction. This ARC6–ARC3 interaction enables ARC3 to bind FtsZs. Furthermore, we show that the ARC6–ARC3 complex significantly promotes the dynamics of chloroplast Z rings reconstituted in a heterologous system. Finally, the constriction of these reconstituted Z rings is markedly enhanced by ARC6–ARC3. Our findings reveal a regulatory mechanism that governs Z-ring dynamics and constriction, shedding light on the molecular mechanisms underlying chloroplast division.}, archive = {J_PNAS}, author = {Du, Wenbin and Cao, Lingyan and Zhou, Yuelong and Jackson, Shanelle and Naeem, Maryam and Chen, Zhaoyu and Yang, Yue and Glynn, Jonathan M. and Porter, Katie J. and Zhang, Runlong and He, Qian and Liu, Moyang and Xu, Jie and Liang, Wanqi and Feng, Peiqiang and Osteryoung, Katherine W. and Chen, Cheng}, doi = {10.1073/pnas.2425129122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2425129122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Enhanced chloroplast FtsZ-ring constriction by the ARC6–ARC3 module in arabidopsis}, volume = {122}, year = {2025}, }
• (2025). PIK3CA gain-of-function mutation in schwann cells leads to severe neuropathy and aerobic glycolysis through a non-cell autonomous effect. PNAS, 122(26), e2424867122. (www)

  @article{ , abstract = {PIK3CA -related disorders are rare genetic disorders due to somatic gain-of-function mutations in PIK3CA during embryonic development, a pathway involved in cell growth, proliferation, and metabolism. Accumulating evidence from patients with PIK3CA -related disorders indicates that peripheral nerves are frequently affected, leading to severe neurological symptoms. However, the exact underlying mechanism of these disorders remains unclear. To address this, we developed a mouse model with a PIK3CA gain-of-function mutation specifically in Schwann cells, which successfully mirrored the clinical features observed in patients. In this model, we observed that PIK3CA -mutated cells communicate with neighboring healthy cells, such as adipocytes and hair follicles, through a unique crosstalk mechanism that triggers their growth, proliferation, and anagen phase expansion. Additionally, we demonstrated that PIK3CA mutation in peripheral nerves leads to a metabolic shift through glycolytic activation. We investigated the effects of alpelisib, an approved pharmacological inhibitor of PIK3CA, in the model. Early administration of alpelisib significantly improved the signs and symptoms in the mice. However, when treatment was delayed, its efficacy was diminished due to the drug’s inability to penetrate the myelin sheath effectively. In summary, our study offers a valuable mouse model for studying PIK3CA -related neuropathy, uncovers a unique communication between healthy and affected tissues, and highlights the potential benefits of early pharmacological intervention using alpelisib.}, archive = {J_PNAS}, author = {Venot, Quitterie and Firpion, Marina and Ladraa, Sophia and Bayard, Charles and Magassa, Sato and Di Guardo, Roberta and Fraissenon, Antoine and Hoguin, Clément and Protic, Sanela and Morin, Gabriel and Mayeux, Franck and Gourdon, Genevieve and Fraitag, Sylvie and Balducci, Estelle and Kaltenbach, Sophie and Villarese, Patrick and Asnafi, Vahid and Viel, Thomas and Autret, Gwennhael and Tavitian, Bertrand and Goudin, Nicolas and Guibaud, Laurent and Bolino, Alessandra and Canaud, Guillaume}, doi = {10.1073/pnas.2424867122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2424867122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PIK3CA gain-of-function mutation in schwann cells leads to severe neuropathy and aerobic glycolysis through a non-cell autonomous effect}, volume = {122}, year = {2025}, }
• (2025). Diploidization in a wild rice allopolyploid is both episodic and gradual. PNAS, 122(26), e2424854122. (www)

  @article{ , abstract = {Polyploid organisms evolve from their initial doubled genomic condition through a number of processes collectively termed diploidization, whose tempo and mode remain poorly understood mainly due to the difficulty of discriminating de novo evolution subsequent to polyploidy from variation inherited from progenitors. Here, we generated chromosome-scale genome assemblies for the wild rice allopolyploid Oryza minuta and its two diploid progenitors, Oryza punctata and Oryza officinalis , and employed a population genomic approach to investigate the diploidization process in O. minuta at the sequence and transcriptomic level. We show that this wild rice allopolyploid originated around 0.7 Mya, and during subsequent diploidization, its two subgenomes have retained highly conserved synteny with the genomes of its extant diploid progenitors. This populational approach allowed us to distinguish parental legacy of inherited variation from postpolyploidy evolution, and our analyses revealed that whereas gene fractionation occurred in an early burst, accumulation of transposable elements (TEs) and homoeologous exchanges has been gradual. Patterns of homoeolog expression bias are highly variable across tissues, with no consistent subgenome expression bias. Our assessments of the impact of DNA methylation, TE distribution, and parental legacy on expression patterns provide some support for the TE load theory (the theory that the TE densities in flanking regions surrounding genes strongly influence expression levels), while also illustrating the complexity of transcription regulation.}, archive = {J_PNAS}, author = {Wang, Xin and Li, Ning and Wang, Qian and Lei, Tian-Yu and Zhou, Ju and Zhang, Fu-Min and Liao, Xue-Zhu and Qiang, Cheng-Gen and Yu, Wen-Hao and Han, Jing-Dan and Ye, Ya-Rong and Jing, Chun-Yan and Wang, Mei-Xia and Gao, Qiang and Chen, Jin-Feng and Jiao, Yuan-Nian and Wu, Zhi-Qiang and Guo, Ya-Long and Wing, Rod A. and Doyle, Jeff J. and Ge, Song and Zou, Xin-Hui}, doi = {10.1073/pnas.2424854122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2424854122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Diploidization in a wild rice allopolyploid is both episodic and gradual}, volume = {122}, year = {2025}, }
• (2025). Pressure-driven electronegativity inversion in alkali liquids. PNAS, 122(26), e2424701122. (www)

  @article{ , abstract = {Liquid–liquid phase transitions (LLPTs) are typically characterized as two-state systems, where transitions occur between two distinct liquid phases driven by local structural rearrangements. In this study, we observed a continuous LLPT with an inversion of electronegativity in a K–Rb binary alloy. This uniquely exhibits a three-state system behavior. The transition, induced by pressure-driven reordering of electronic orbital energies, progresses through a sequence from s -metal to electride to d -metal, accompanied by a valence reversal: Potassium transitions from a negative to a positive valence, while rubidium undergoes the opposite shift. This process is marked by two successive anomalies in the alloy’s optical, thermodynamic, and dynamic properties over a broad pressure range. The observation of similar LLPT phenomena in other alkali and alkaline earth metal liquids suggests that this three-state system mechanism may provide broader insights into the nature of continuous phase transitions.}, archive = {J_PNAS}, author = {Han, Chenxu and Zong, Hongxiang and Ding, Xiangdong and Sun, Jun and Ackland, Graeme J.}, doi = {10.1073/pnas.2424701122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2424701122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pressure-driven electronegativity inversion in alkali liquids}, volume = {122}, year = {2025}, }
• (2025). Setdb1 ablation in macrophages attenuates fibrosis in heart allografts. PNAS, 122(26), e2424534122. (www)

  @article{ , abstract = {Tissue fibrosis is commonly associated with organ malfunction and is strongly associated with the development of chronic rejection, cardiovascular diseases, and other chronic diseases. Fibrosis also contributes to immune exclusion in tumor tissues. Targeting fibrosis might be a strategy for prolonging allograft survival while suppressing cancer development. Here, single-cell transcriptomes of human and mouse heart allografts showed that macrophages accumulated in grafts with fibrosis were reprogrammed via histone methylation regulated by Setdb1, an H3K9 methyltransferase. Myeloid-specific deletion of Setdb1 prolonged heart allograft survival but reversed immune exclusion in tumor tissues. Interestingly, myeloid-specific Setdb1-knockout led to lower fibrosis in heart allografts and tumor tissues in mice. Our single-cell sequencing data showed that Setdb1 ablation impaired Fn1 + and SPP1 + profibrogenic macrophage reprogramming. Mechanistically, Fn1, which was induced by the CCR2-Creb/Setdb1 axis, upregulated the expression of genes related to fibrosis in fibroblasts and macrophages via ITGA5 and PIRA receptors. Blocking the interaction between FN1 and these receptors inhibited fibrosis in allograft and tumor tissues. Our results reveal a target, histone methylation in macrophages, for the treatment of fibrosis-related disease.}, archive = {J_PNAS}, author = {Ma, Zhibo and Zhou, Xi and Jia, Wenlong and Tan, Xiaosheng and Huang, Xia and Wang, Jingzeng and Sun, Lingjuan and Li, Qingwen and Zhao, Xiangli and Yuan, Naonao and Liu, Ping and Liu, Jing and Chen, Zhishui and Lan, Peixiang}, doi = {10.1073/pnas.2424534122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2424534122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Setdb1 ablation in macrophages attenuates fibrosis in heart allografts}, volume = {122}, year = {2025}, }
• (2025). Overcoming toxicity: How nonantagonistic microbes manage to thrive in boom-and-bust environments. PNAS, 122(26), e2424372122. (www)

  @article{ , abstract = {Antagonistic interactions are critical determinants of microbial community stability and composition, offering host benefits such as pathogen protection and providing avenues for antimicrobial control. While the ability to eliminate competitors confers an advantage to antagonistic microbes, it often incurs a fitness cost. Consequently, many microbes only produce toxins or engage in antagonistic behavior in response to specific cues like quorum sensing molecules or environmental stress. In laboratory settings, antagonistic microbes typically dominate over sensitive ones, raising the question of why both antagonistic and nonantagonistic microbes are found in natural environments and host microbiomes. Here, using both theoretical models and experiments with killer strains of Saccharomyces cerevisiae , we show that “boom-and-bust” dynamics—periods of rapid growth punctuated by episodic mortality events—caused by temporal environmental fluctuations can favor nonantagonistic microbes that do not incur the growth rate cost of toxin production. Additionally, using control theory, we derive bounds on the competitive performance and identify optimal regulatory toxin-production strategies in various boom-and-bust environments where population dilutions occur either deterministically or stochastically over time. Our mathematical investigation reveals that optimal toxin regulation is much more beneficial to killers in stochastic, rather than deterministic, boom-and-bust environments. Overall, our findings show how both antagonistic and nonantagonistic microbes can thrive under varying environmental conditions.}, archive = {J_PNAS}, author = {Wang, MingYi and Vladimirsky, Alexander and Giometto, Andrea}, doi = {10.1073/pnas.2424372122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2424372122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Overcoming toxicity: How nonantagonistic microbes manage to thrive in boom-and-bust environments}, volume = {122}, year = {2025}, }
• (2025). Observation of the electric Breit–Rabi effect. PNAS, 122(26), e2423902122. (www)

  @article{ , abstract = {The response of an atom to external electric and magnetic fields can reveal fundamental atomic properties. It has long been verified that, in a static magnetic field, those atomic energy levels with hyperfine interactions shift according to the Breit–Rabi formula, which introduces nonlinear dependence on the magnetic field. On the other hand, the corresponding Breit–Rabi dependence on a static electric field has not been observed before due to a combination of experimental challenges. Here, we precisely measure the Stark shift of the 6 s 2 1 S 0 ↔ 6 s 6 p 1 P 1 transition of 171 Yb ( I = 1/2) with cold atoms held by an optical dipole trap in a static electric field up to 120 kV/cm. We observe the electric Breit–Rabi effect displaying high-order ( E 4 and E 6 ) DC Stark shifts. These effects arise from the influence of the strong electric field on hyperfine interactions.}, archive = {J_PNAS}, author = {Wang, Shao-Zheng and Wang, Shou-Bo and Tao, Zhi-Jin and Xia, Tian and Lu, Zheng-Tian}, doi = {10.1073/pnas.2423902122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2423902122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Observation of the electric Breit–Rabi effect}, volume = {122}, year = {2025}, }
• (2025). Ena/VASP-EVH1 inhibition prevents chemotaxis and metastasis by blocking the EVH1–WAVE2 interaction. PNAS, 122(26), e2423512122. (www)

  @article{ , abstract = {Cancer therapy would benefit from suppressing cancer cell motility in the process of metastasis. Such directed cell migration relies on the propulsive force established by the filamentous actin network within lamellipodia. Proteins of the Ena/VASP family and the WAVE regulatory complex orchestrate lamellar protrusions and therefore provide promising targets for pharmacological interventions. Here, we report a cross-talk between Ena/VASP proteins and WAVE2 that is important for cancer cell extravasation. Mutating the EVH1 domain recognition motif in WAVE2 abrogates chemotaxis of triple-negative MDA-MB-231 breast cancer cells and reduces their extravasation in a zebrafish model. In pilot experiments, orthotopic implantation of these cells into mice led to a reduction in macrometastasis, resulting in prolonged survival. Similarly, intervention by an Ena/VASP-EVH1 inhibitor also reduced metastasis in vivo. Our results suggest that pharmacological interference with the Ena/VASP–WAVE2 interaction may thus reduce metastasis.}, archive = {J_PNAS}, author = {Müller, Matthias and Barone, Matthias and Dinther, Maarten van and Motzny, Kathrin and Ren, Jiang and Eichhorst, Jenny and Albat, Dominik and Chiha, Slim and Lehmann, Martin and Volkmer, Rudolf and Oschkinat, Hartmut and Schmalz, Hans-Günther and ten Dijke, Peter and Kühne, Ronald}, doi = {10.1073/pnas.2423512122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2423512122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ena/VASP-EVH1 inhibition prevents chemotaxis and metastasis by blocking the EVH1–WAVE2 interaction}, volume = {122}, year = {2025}, }
• (2025). The effects of social media criticism against public health institutions on trust, emotions, and social media engagement. PNAS, 122(26), e2422890122. (www)

  @article{ , abstract = {In recent years, trust in US public health and science institutions has faced unprecedented declines, particularly among Republicans/conservatives. To what extent might institutional criticism on social media be responsible for such politically polarized declines in institutional trust? Two online survey experiments (total N = 6,800), using samples roughly reflective of the US adult population, examined the effects of key types of criticism against the Agency for Healthcare Research and Quality (AHRQ) and the Centers for Disease Control and Prevention (CDC). The results suggest that just a single exposure to any of the key types of criticism was sufficient to undermine institutional trust. While an institutional rebuttal was partially able to reverse these effects, residual declines in trust were substantial enough to cause decreased intentions to adhere to the AHRQ/CDC health recommendation featured in the experiments. While institutions should, therefore, be concerned about all types of social media criticism, those featuring morally charged trust-undermining narratives attacking the integrity of the AHRQ/CDC generated dramatically more anger (i.e., moral outrage), which in turn attracted social media engagement preferences likely to promote viral spread and exacerbate preexisting institutional politicization and issue polarization. These results suggest that efforts to bolster institutional trust should pay special attention to criticisms featuring integrity-based trust-undermining narratives.}, archive = {J_PNAS}, author = {Lee, Jonathan Y.}, doi = {10.1073/pnas.2422890122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2422890122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The effects of social media criticism against public health institutions on trust, emotions, and social media engagement}, volume = {122}, year = {2025}, }
• (2025). The importance of small-island populations for the long-term survival of endangered large-bodied insular mammals. PNAS, 122(26), e2422690122. (www)

  @article{ , abstract = {Island populations of large vertebrates have experienced higher extinction rates than mainland populations over long timescales due to demographic stochasticity, genetic drift, and inbreeding. While being more susceptible to extinction and as such potentially targeted for conservation interventions such as genetic rescue, small-island populations can experience relatively less anthropogenic habitat degradation than those on larger islands. Here, we determine the consequences and conservation implications of long-term isolation and recent human activities on genetic diversity of island populations of two forest-dependent mammals endemic to the Wallacea archipelago: the anoa ( Bubalus spp.) and babirusa ( Babyrousa spp.). Using genomic analyses and habitat suitability models, we show that, compared to closely related species, populations on mainland Sulawesi exhibit low heterozygosity, high inbreeding, a high proportion of deleterious alleles, and experience a high rate of anthropogenic disturbance. In contrast, populations on smaller islands occupy higher-quality habitats, possess fewer deleterious mutations despite exhibiting lower heterozygosity and higher inbreeding. Site frequency spectra indicate that these patterns reflect stronger, long-term purging in smaller-island populations. Our results thus suggest that conservation efforts should focus on protecting small-island high-quality habitats and avoiding translocations from mainland populations. This study highlights the crucial role of small offshore islands for the long-term survival of Wallacea’s iconic and indigenous mammals in the face of development on the mainland.}, archive = {J_PNAS}, author = {Aninta, Sabhrina Gita and Drinkwater, Rosie and Carmagnini, Alberto and Deere, Nicolas J. and Priyono, Dwi Sendi and Andayani, Noviar and Winarni, Nurul L. and Supriatna, Jatna and Fumagalli, Matteo and Larson, Greger and Galbusera, Peter H. A. and Macdonald, Alastair and Greer, Deborah and Mohamad, Kusdiantoro and Prasetyaningtyas, Wahono Esthi and Mustari, Abdul Haris and Williams, John Lewis and Barnett, Ross and Shaw, Darren and Semiadi, Gono and Burton, James and Seaman, David J. I. and Voigt, Maria and Struebig, Matthew J. and Brace, Selina and Rossiter, Stephen J. and Frantz, Laurent}, doi = {10.1073/pnas.2422690122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2422690122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The importance of small-island populations for the long-term survival of endangered large-bodied insular mammals}, volume = {122}, year = {2025}, }
• (2025). Generative AI without guardrails can harm learning: Evidence from high school mathematics. PNAS, 122(26), e2422633122. (www)

  @article{ , abstract = {Generative AI is poised to revolutionize how humans work, and has already demonstrated promise in significantly improving human productivity. A key question is how generative AI affects learning—namely, how humans acquire new skills as they perform tasks. Learning is critical to long-term productivity, especially since generative AI is fallible and users must check its outputs. We study this question via a field experiment where we provide nearly a thousand high school math students with access to generative AI tutors. To understand the differential impact of tool design on learning, we deploy two generative AI tutors: one that mimics a standard ChatGPT interface (“GPT Base”) and one with prompts designed to safeguard learning (“GPT Tutor”). Consistent with prior work, our results show that having GPT-4 access while solving problems significantly improves performance (48% improvement in grades for GPT Base and 127% for GPT Tutor). However, we additionally find that when access is subsequently taken away, students actually perform worse than those who never had access (17% reduction in grades for GPT Base)—i.e., unfettered access to GPT-4 can harm educational outcomes. These negative learning effects are largely mitigated by the safeguards in GPT Tutor. Without guardrails, students attempt to use GPT-4 as a “crutch” during practice problem sessions, and subsequently perform worse on their own. Thus, decision-makers must be cautious about design choices underlying generative AI deployments to preserve skill learning and long-term productivity.}, archive = {J_PNAS}, author = {Bastani, Hamsa and Bastani, Osbert and Sungu, Alp and Ge, Haosen and Kabakcı, Özge and Mariman, Rei}, doi = {10.1073/pnas.2422633122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2422633122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Generative AI without guardrails can harm learning: Evidence from high school mathematics}, volume = {122}, year = {2025}, }
• (2025). Global kinetic model of lipid-induced α-synuclein aggregation and its inhibition by small molecules. PNAS, 122(26), e2422427122. (www)

  @article{ , abstract = {The aggregation of α -synuclein into amyloid fibrils is a hallmark of Parkinson’s disease. This process has been shown to directly involve interactions between proteins and lipid surfaces when the latter are present. Despite this importance, the molecular mechanisms of lipid-induced amyloid aggregation have remained largely elusive. Here, we present a global kinetic model to describe lipid-induced amyloid aggregation of α -synuclein. Using this framework, we find that α -synuclein fibrils form via a two-step primary nucleation mechanism and that lipid molecules are directly involved in both the nucleation and fibril elongation steps, giving rise to lipid–protein coaggregates. To illustrate the applicability of this kinetic approach to drug discovery, we identify the mechanism of action of squalamine, a known inhibitor of lipid-induced α -synuclein aggregation, revealing that this small molecule reduces the rate of lipid-dependent primary nucleation. Our work will likely guide the rational design of α -synuclein aggregation inhibitors.}, archive = {J_PNAS}, author = {Stevenson, Alisdair and Staats, Roxine and Dear, Alexander J. and Voderholzer, David and Dreier, Jesper E. and Meisl, Georg and Guido, Raphael and Knowles, Tuomas P. J. and Galvagnion, Céline and Buell, Alexander K. and Vendruscolo, Michele and Michaels, Thomas C. T.}, doi = {10.1073/pnas.2422427122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2422427122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global kinetic model of lipid-induced α-synuclein aggregation and its inhibition by small molecules}, volume = {122}, year = {2025}, }
• (2025). Fine structural design of 3βHSD1 inhibitors for prostate cancer therapy. PNAS, 122(26), e2422267122. (www)

  @article{ , abstract = {Prostate cancer is a global health challenge, particularly for patients resistant to the second-generation anti-androgen receptor pathway inhibitors. The steroidogenic enzyme 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) has emerged as a promising therapeutic target and the corresponding inhibitors, biochanin-A (BCA) and its derivatives, suppress tumor growth in preclinical models and patients. However, the poor oral bioavailability of BCA hinders its clinical application. Here, we employed a sophisticated computational approach to refine the structural design of 3βHSD1 inhibitors. AlphaFold2 was utilized to construct detailed models of 3βHSD1 binding to various substrates. These models, in conjunction with the elucidated enzymatic mechanism of 3βHSD1, guided the optimization of a series of BCA-related compounds. Our structure–activity relationship studies identified HEAL-116 as a potent 3βHSD1 inhibitor. HEAL-116 exhibited enhanced binding specificity to the substrate-binding pocket of 3βHSD1 and effectively neutralized the local charge environment. The incorporation of hydrophilic groups in its structure also markedly enhanced its oral bioavailability. HEAL-116 robustly inhibited 3βHSD1 activity and exerted pronounced antitumor effect in biochemical, cellular, and mouse models. Our findings lay the foundation for the clinical translation of 3βHSD1 inhibitors, offering a promising therapeutic strategy for the management of prostate cancer and potentially other diseases.}, archive = {J_PNAS}, author = {He, Dongyin and Zhang, Luyao and Yu, Leiye and Zhang, Yuhang and Chen, Jingjing and Wang, Leibo and Hu, Haoran and Liu, Hongyu and Zheng, Hong and Xia, Jixin and Chen, Jiahui and Li, Chenhui and Li, Xin and Tang, Huiru and Liu, Jia and Ren, Ruobing and Hu, Youhong and Li, Zhenfei}, doi = {10.1073/pnas.2422267122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2422267122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fine structural design of 3βHSD1 inhibitors for prostate cancer therapy}, volume = {122}, year = {2025}, }
• (2025). JunB–HBZ nuclear translocation by TGF-β is a key driver in HTLV-1-mediated leukemogenesis. PNAS, 122(26), e2420756122. (www)

  @article{ , abstract = {The HTLV-1 bZIP factor ( HBZ ) gene, which is the only viral gene conserved and consistently expressed in all adult T-cell leukemia–lymphoma (ATL) cases, is critical for ATL oncogenesis. Although HBZ protein is found in both the nucleus and the cytoplasm, the dynamics of HBZ protein localization and its contribution to oncogenesis have not been fully elucidated. In this study, we analyzed the subcellular expression pattern of HBZ in primary HTLV-1–infected T cells from asymptomatic carriers and leukemic cells of ATL patients using the Proximity Ligation Assay. Nuclear localization of HBZ protein was significantly higher in fresh ATL cells than in HTLV-1–infected cells from carriers. Importantly, translocation of HBZ protein from the cytoplasm to the nucleus after TGF-β activation was observed in ATL patients, but not in HTLV-1 carriers. In ATL cells, the cellular transcription factors JunB and pSmad3 interact with HBZ and facilitate its nuclear translocation upon TGF-β stimulation. JUNB knockdown inhibits cell proliferation in vitro and in vivo and promotes apoptosis in ATL cells but not in HTLV-1–infected nonleukemic cells, indicating that JunB has important roles in maintaining ATL cells. In conclusion, TGF-β-induced nuclear translocation of HBZ–JunB complexes is associated with ATL oncogenesis.}, archive = {J_PNAS}, author = {Zhang, Wenyi and Shichijo, Takafumi and Chen, Xueda and Watanabe, Miho and Nosaka, Kisato and Matsuoka, Masao and Yasunaga, Jun-ichirou}, doi = {10.1073/pnas.2420756122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2420756122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {JunB–HBZ nuclear translocation by TGF-β is a key driver in HTLV-1-mediated leukemogenesis}, volume = {122}, year = {2025}, }
• (2025). Repeated occurrences of marine anoxia under high atmospheric o2 and icehouse conditions. PNAS, 122(26), e2420505122. (www)

  @article{ , abstract = {The Late Paleozoic Ice Age (~340 to 260 Ma) occurred under peak atmospheric O 2 (1.2 to 1.7 PIAL, pre-industrial atmospheric levels) for Earth history and CO 2 concentrations comparable to those of the preindustrial to that anticipated for our near future. The evolution of the marine redox landscape under these conditions remains largely unexplored, reflecting that oceanic anoxia has long been considered characteristic of carbon cycle perturbation during greenhouse times. Despite elevated O 2 , a 10 5 -y period of CO 2 -forced oceanic anoxia was recently identified, but whether this short-term interval of widespread oceanic anoxia was anomalous during this paleo-ice age is unexplored. Here, we investigate these issues by building a high-resolution record of carbonate uranium isotopes (δ 238 U carb ) from an open-marine succession in South China that permits us to reconstruct the global marine redox evolution through the deep glacial interval (310 to 290 Ma) of near peak O 2 . Our data reveal repeated, short-term decreases in δ 238 U carb coincident with negative C isotopic excursions and rises in paleo-CO 2 , all superimposed on a longer-term rise in δ 238 U carb . A carbon–phosphorus–uranium biogeochemical model coupled with Bayesian inversion is employed to quantitatively explore the interplay between marine anoxia, carbon cycling, and climate evolution during this paleo-glacial period. Although our results indicate that protracted, enhanced organic carbon burial can account for the long-term O 2 increase, seafloor oxygenation, and overall low CO 2 , episodic pulses of C emissions had the potential to drive recurring short-term periods of marine anoxia (with 4 to 12% of seafloor anoxia) despite up to 1.7 times higher atmospheric O 2 than present day.}, archive = {J_PNAS}, author = {Chen, Jitao and Li, Shihan and Zhang, Shuang and Isson, Terry and Dahl, Tais W. and Planavsky, Noah J. and Zhang, Feifei and Wang, Xiang-dong and Shen, Shu-zhong and Montañez, Isabel P.}, doi = {10.1073/pnas.2420505122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2420505122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Repeated occurrences of marine anoxia under high atmospheric o2 and icehouse conditions}, volume = {122}, year = {2025}, }
• (2025). High tree diversity exposed to unprecedented macroclimatic conditions even under minimal anthropogenic climate change. PNAS, 122(26), e2420059122. (www)

  @article{ , abstract = {Tree species worldwide face increasing exposure to unprecedented macroclimatic conditions due to anthropogenic climate change, which may trigger biome shifts and ecosystem disruptions. We quantified climate change exposure–shifts to species’ currently unoccupied climate zones–for 32,089 tree species globally by 2100, assessing both species-level and local tree diversity risks. On average, 69% of species are predicted to experience macroclimatic shifts in at least 10% of their range, while 14% face exposure in over 50% of their range under a high-emission (4 °C warming) future scenario. This suggests that most species retain substantial climate refugia within their current range. However, local tree diversity exposure is predicted to be severe in vast regions, including Eurasia, the northwestern United States and Canada, northern Chile, and the Amazon Delta. Under a moderate (2 °C warming) scenario, high tree diversity exposure is mostly restricted to taiga regions in the Northern Hemisphere. These findings provide conservative estimates of climate-driven biodiversity risk, as our approach focuses solely on macroclimate and does not account for additional stressors such as land-use change or species interactions. Identifying tree species and areas of high macroclimatic shift exposure allows for targeted conservation strategies, including species stability monitoring, assisted migration, and the protection of climate refugia. Our results offer a foundation for prioritizing conservation actions in a rapidly changing climate, ensuring long-term ecosystem resilience.}, archive = {J_PNAS}, author = {Boonman, Coline C. F. and Hoeks, Selwyn and Serra-Diaz, Josep M. and Guo, Wen-Yong and Enquist, Brian J. and Maitner, Brian and Merow, Cory and Svenning, Jens-Christian}, doi = {10.1073/pnas.2420059122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2420059122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High tree diversity exposed to unprecedented macroclimatic conditions even under minimal anthropogenic climate change}, volume = {122}, year = {2025}, }
• (2025). Testicular somatic and germ cell maturation during rhesus macaque development. PNAS, 122(26), e2419995122. (www)

  @article{ , abstract = {The formation of bilateral testes in animals is critical for puberty, reproductive capacity, and testosterone production across the life course. In humans, testis development begins in embryonic life in the first trimester, with considerable effort focused on the cell and developmental events associated with testis cell specification, leaving limited knowledge on testicular organogenesis during the second and third trimesters. To fill this knowledge gap, we evaluated testicular cell maturation at weeks 5 (W5), W6, W8, W15, and W19 postconception using a rhesus macaque model. Our data identify a major transcriptional change in the somatic cells of the testis (Sertoli cells, interstitial cells and fetal Leydig cells) between W8 and W15, and this is associated with the maturation of seminiferous cords and maturation of PGCs into fetal spermatogonia. Through this work, we identified cellular changes and differential protein expression between W5 and W19 that can be used to holistically define testis development across the time course of embryonic and fetal life. This study provides important insights necessary to recreate the testicular niche from stem cells for biomedical research.}, archive = {J_PNAS}, author = {Sosa, Enrique and Wamaitha, Sissy E. and Hsu, Fei-man and Lara, Mary Jasmine D. and Oyama, Kiana and Custer, Maggie and Murphy, Melinda and Hennebold, Jon D. and Hwang, Young Sun and Clark, Amander T.}, doi = {10.1073/pnas.2419995122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2419995122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Testicular somatic and germ cell maturation during rhesus macaque development}, volume = {122}, year = {2025}, }
• (2025). Winters restrict a climate change–driven butterfly range expansion despite rapid evolution of seasonal timing traits. PNAS, 122(26), e2418392122. (www)

  @article{ , abstract = {Climate change pushes species toward higher latitudes and altitudes, but the proximate drivers of range expansions vary, and it is unclear whether evolution facilitates climate change–induced range changes. In a temporally replicated field experiment, we translocated wall brown butterflies ( Lasiommata megera ) descending from range interior and range margin populations to sites at 1) the range interior, 2) the range margin, and 3) beyond the current northern range edge. Thereby, we tested for local adaptation in seasonal timing and winter survival and evaluated to what extent local adaptation influences the ongoing, climate-driven range expansion. Almost all individuals from all populations entered diapause at an appropriate time, despite previously identified among-population variation in diapause induction thresholds. Caterpillars of northern descent, however, grew faster than those from southern populations at all field sites. This may be a countergradient adaptation to compensate for the short, northern growing seasons, but we found no evidence for prewinter body mass affecting winter survival. In fact, winter survival was low overall—extremely so at the beyond range site—regardless of population origin, indicating that the primary constraint to range expansion is an inability to adapt to winter conditions. Hence, although range-expanding wall browns show clear local evolution of two traits related to seasonal timing, these putative local adaptations likely do not contribute to range expansion, which is instead limited by winter survival. To predict future range changes, it will be important to distinguish between the traits that evolve during range expansion and those that set the range limit.}, archive = {J_PNAS}, author = {Ittonen, Mats and Nielsen, Matthew E. and Siemers, Isabelle and Friberg, Magne and Gotthard, Karl}, doi = {10.1073/pnas.2418392122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2418392122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Winters restrict a climate change–driven butterfly range expansion despite rapid evolution of seasonal timing traits}, volume = {122}, year = {2025}, }
• (2025). S-adenosylmethionine metabolism buffering is regulated by a decrease in glycine N-methyltransferase via the nuclear ubiquitin–proteasome system. PNAS, 122(26), e2417821122. (www)

  @article{ , abstract = {Metabolic homeostasis is essential for survival; however, many studies have focused on the fluctuations of these factors. Furthermore, while metabolic homeostasis depends on the balance between the production and consumption of metabolites, there have been limited investigations into the mechanisms regulating their consumption. S-adenosylmethionine (SAM) metabolism has diverse functions, including methylation, polyamine biosynthesis, and transsulfuration, making its regulation and control crucial. Recent studies have revealed the feedback regulation of SAM production; however, the mechanisms governing its consumption are still poorly understood. In this study, we focused on the stability of SAM levels in the fat body (FB) of Drosophila , which serves as a functional equivalent of the mammalian liver and adipose tissue, under conditions of SAM shortage, including nutrient deprivation. We found that glycine N-methyltransferase (Gnmt), a major SAM-consuming methyltransferase in the FB, decreased via the nuclear ubiquitin–proteasome system (UPS), along with the inhibition of SAM synthesis and starvation. The inhibition of Gnmt level reduction by suppression of the nuclear UPS causes starvation tolerance. Thus, the regulation of Gnmt levels through nuclear UPS-mediated reduction helps maintain SAM levels under SAM shortage conditions.}, archive = {J_PNAS}, author = {Kashio, Soshiro and Miura, Masayuki}, doi = {10.1073/pnas.2417821122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2417821122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {S-adenosylmethionine metabolism buffering is regulated by a decrease in glycine N-methyltransferase via the nuclear ubiquitin–proteasome system}, volume = {122}, year = {2025}, }
• (2025). Genetic contributions to brain criticality and its relationship with human cognitive functions. PNAS, 122(26), e2417010122. (www)

  @article{ , abstract = {Recently, extensive evidence has demonstrated that the brain operates close to a critical state, characterized by dynamic patterns known as neuronal avalanches. The critical state, reflecting the delicate balance between neural excitation and inhibition, offers numerous advantages in information processing. However, the role of genetics in shaping brain criticality is not fully understood. Whether there is any shared genetic factor influencing the critical state and cognitive functions remains elusive. Here, we aimed to address these questions by examining the heritability of brain criticality and its relation to cognitive function by analyzing resting-state functional magnetic resonance imaging (rs-fMRI) in 250 monozygotic twins, 142 dizygotic twins, and 437 Not-twin subjects. We found that genetic factors substantially influenced brain criticality across various scales, encompassing brain regions, functional networks, and the whole brain. These genetic influences exhibited heterogeneity, with the criticality of the primary sensory cortex being more strongly influenced by genetic factors compared to that of the association cortex. Furthermore, we combined rs-fMRI data with transcriptional microarray data from the Allen Brain Atlas: Human Brain (ABHB) dataset and found that the organization of regional critical dynamics was highly explained by a specific gene expression profile. Finally, our results showed that the critical state was correlated with total cognition and had a genetic link with it. These findings provide empirical evidence that brain criticality is a biological phenotype and suggest a shared genetic foundation underlying brain criticality and cognitive functions. Our results pave the way toward revealing specific biological mechanisms contributing to critical dynamics and their associations with brain function and dysfunction.}, archive = {J_PNAS}, author = {Xin, Yumeng and Cui, Yue and Yu, Shan and Liu, Ning}, doi = {10.1073/pnas.2417010122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2417010122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genetic contributions to brain criticality and its relationship with human cognitive functions}, volume = {122}, year = {2025}, }
• (2025). EIAV encodes an accessory protein that antagonizes the host restriction factor equine tetherin. PNAS, 122(26), e2413703122. (www)

  @article{ , abstract = {Equine infectious anemia virus (EIAV) is an important model for the study of pathogenesis in lentiviruses. Studies of viral genome organization and replication mechanisms are fundamental to the understanding of virus pathogenicity. In this study, we identified an unique transcript from EIAV in vivo and in vitro by Sanger sequencing and Northern blotting. The transcript contains a complete open reading frame and has length 369 nt. We named the protein encoded by this transcript S4 and demonstrated its expression in EIAV-infected cells. An S4-deficient EIAV infectious clone displayed obviously impaired virion release and attenuated virus replication in vitro, demonstrating that S4 plays a role in the release step of EIAV. The host restriction factor tetherin has broad-spectrum antiviral activity and prevents the release of a wide range of enveloped viruses, including lentiviruses. Here, we demonstrated that S4 enhances the release of the EIAV-like particle by counteracting the equine tetherin (eqTHN). S4 interacts with the eqTHN and sequesters it within intracellular membrane compartments, attenuating eqTHN expression on the cell surface and thereby disrupting its antiviral activity. Further investigation revealed that S4 retains eqTHN in the endoplasmic reticulum and trans-Golgi network through impacting its anterograde transport to the cell surface and may interfere with the posttranslational modification of this membrane protein. Collectively, our findings uncover an accessory protein, S4, of EIAV and reveal its ability to promote virion release by antagonizing the antiviral activity of the host restriction factor tetherin.}, archive = {J_PNAS}, author = {Bai, Bowen and Zhang, Xiangmin and Zhang, Mengmeng and Ma, Weiwei and Li, Jiwei and Zhang, Haili and Na, Lei and Guo, Xing and Lin, Yuezhi and Wang, Xue-Feng and Wang, Xiaojun}, doi = {10.1073/pnas.2413703122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2413703122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {EIAV encodes an accessory protein that antagonizes the host restriction factor equine tetherin}, volume = {122}, year = {2025}, }
• (2025). Immune cell profiling reveals diverse niches of immune residents of the enteric nervous system and potential neuroimmune interactions. PNAS, 122(26), e2413692122. (www)

  @article{ , abstract = {Gastrointestinal (GI) neuroimmune interactions are crucial sensors and regulators of tissue homeostasis. Most enteric neurons reside within the myenteric plexus of the enteric nervous system in the muscular region, forming a structure called the muscularis externa . Despite established interactions between muscularis macrophages and neurons, the presence and function of other immune cell types remains poorly characterized. Here, we mapped the muscularis immune cell landscape, revealing that diverse cell types are present within distinct locations of the GI tract, and they lie in proximity to neuronal cell bodies and their axons. Using a hypothesis-free computational approach, we identify putative ligand–receptor interactions from publicly available single-cell RNA datasets and further validate one of these (App-CD74). This study provides a valuable reference to encourage new avenues of research underpinning enteric neuroimmune interactions as key contributors to GI homeostasis and diseases.}, archive = {J_PNAS}, author = {Wang, Haozhe and Zaini, Aidil and Cardwell, Bailey and Rowe, Matthew C. and Butler, Alana and Wong, Connie H. Y. and Poole, Daniel P. and Marsland, Benjamin and Bornstein, Joel C. and Harris, Nicola L.}, doi = {10.1073/pnas.2413692122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2413692122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Immune cell profiling reveals diverse niches of immune residents of the enteric nervous system and potential neuroimmune interactions}, volume = {122}, year = {2025}, }
• (2025). Global overlooked multidimensional water scarcity. PNAS, 122(26), e2413541122. (www)

  @article{ , abstract = {Freshwater resources are fundamental to supporting humanity, and measures of water scarcity have been critical for identifying where water requirements and water availability are imbalanced. Existing water scarcity metrics typically account for blue water withdrawals (i.e., from surface-/groundwater), while the contribution of green water (i.e., soil moisture) and water quality—dimensions with important implications for multiple societal sectors—to water scarcity remains unclear. Here, we introduce the concept of multidimensional water scarcity that explicitly assesses all three of these dimensions of water scarcity and evaluates their individual and combined effects. We find that 22 to 26% of the global land area and 58 to 64% of the global population are exposed to some form of water scarcity annually, with multidimensional (i.e., blue, green, and quality) water scarcity particularly high in India, China, and Pakistan. Examining seasonal water scarcity, we estimate that 5.9 billion people (or 80% of the world’s population in 2015) were exposed to at least one dimension of water scarcity for at least 1 mo per year and that 1-in-10 people (10%) were exposed to multidimensional water scarcity at least 1 mo per year. Our findings demonstrate that the challenges of water scarcity are far more widespread than previously understood. As such, our assessment provides a more holistic view of global water scarcity issues and points to overlooked scarcity where action needs to bring human pressure on freshwater resources into balance with water quantity and quality.}, archive = {J_PNAS}, author = {Liu, Wenfeng and Fu, Zhonghao and van Vliet, Michelle T. H. and Davis, Kyle Frankel and Ciais, Philippe and Bao, Yuzhuang and Bai, Yawei and Du, Taisheng and Kang, Shaozhong and Yin, Zun and Fang, Yu and Wada, Yoshihide}, doi = {10.1073/pnas.2413541122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2413541122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global overlooked multidimensional water scarcity}, volume = {122}, year = {2025}, }
• (2025). Bone morphogenetic protein-9 controls pulmonary vascular growth and remodeling. PNAS, 122(26), e2410229122. (www)

  @article{ , abstract = {Pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT) are two distinct vascular diseases linked to impaired signaling through bone morphogenetic protein (BMP) receptor complexes in endothelial cells. Although BMP-9 plays a central role in activating this pathway by binding to ALK1 and BMPR-II, its precise function in the pulmonary microvasculature has remained unclear. In this study, we demonstrate a role for BMP-9 in regulating pulmonary vascular architecture and homeostasis. Our findings reveal that BMP-9 signaling intersects with VEGF pathways and contributes to the delicate balance between vascular growth and remodeling in the lungs. We also show that disruption of this pathway can shift vascular responses toward an HHT-like state, potentially altering disease susceptibility. These insights offer a unique perspective on how BMP-9 and ALK1 shape pulmonary vascular biology and suggest that targeting this axis could inform future strategies for treating complex vascular diseases such as PAH.}, archive = {J_PNAS}, author = {Berrebeh, Nihel and Mbouamboua, Yvon and Thuillet, Raphaël and Ottaviani, Mina and Robert, Fabien and Kamel Chelgham, Mustapha and Magnone, Virginie and Desroches-Castan, Agnès and Ricard, Nicolas and Anegon, Ignacio and Remy, Séverine and Schermuly, Ralph Theo and Lebrigand, Kevin and Kojonazarov, Baktybek and Savale, Laurent and Humbert, Marc and Bailly, Sabine and Barbry, Pascal and Tu, Ly and Guignabert, Christophe}, doi = {10.1073/pnas.2410229122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2410229122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bone morphogenetic protein-9 controls pulmonary vascular growth and remodeling}, volume = {122}, year = {2025}, }
• (2025). Make forensic case reports required legal and scientific documents. PNAS, 122(26), e2406456122. (www)

  @article{ , archive = {J_PNAS}, author = {Higley, Leon and Carter, David O. and Elowsky, Christian and Haskell, Christine and Haskell, Neal and Obanfunwa, John and Reinhard, Karl and Roe, Amanda and Schoenly, Ken and Simmons, Tal and Wells, Jeffrey}, doi = {10.1073/pnas.2406456122}, journal = {Proceedings of the National Academy of Sciences}, month = {7}, number = {26}, pages = {e2406456122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Make forensic case reports required legal and scientific documents}, volume = {122}, year = {2025}, }
• (2025). QnAs with anne k. churchland. PNAS, 122(25), e2513027122. (www)

  @article{ , archive = {J_PNAS}, author = {Hardcastle, Matthew}, doi = {10.1073/pnas.2513027122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2513027122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {QnAs with anne k. churchland}, volume = {122}, year = {2025}, }
• (2025). Correction for yang et al., synonymous edits in the escherichia coli genome have substantial and condition-dependent effects on fitness. PNAS, 122(25), e2512904122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2512904122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2512904122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for yang et al., synonymous edits in the escherichia coli genome have substantial and condition-dependent effects on fitness}, volume = {122}, year = {2025}, }
• (2025). Correction for luo and yu, NBS1 facilitates preribosomal RNA biogenesis. PNAS, 122(25), e2512482122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2512482122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2512482122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for luo and yu, NBS1 facilitates preribosomal RNA biogenesis}, volume = {122}, year = {2025}, }
• (2025). Correction for borovska and de haas, individual gaze shapes diverging neural representations. PNAS, 122(25), e2512475122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2512475122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2512475122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for borovska and de haas, individual gaze shapes diverging neural representations}, volume = {122}, year = {2025}, }
• (2025). Correction for manthey et al., rapid growth and the evolution of complete metamorphosis in insects. PNAS, 122(25), e2512324122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2512324122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2512324122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for manthey et al., rapid growth and the evolution of complete metamorphosis in insects}, volume = {122}, year = {2025}, }
• (2025). Correction for jiang et al., structural basis of the cysteinyl leukotriene receptor type 2 activation by LTD4. PNAS, 122(25), e2512181122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2512181122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2512181122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for jiang et al., structural basis of the cysteinyl leukotriene receptor type 2 activation by LTD4}, volume = {122}, year = {2025}, }
• (2025). Correction for liu et al., transparency by chinese cities reduces pollution violations and improves air quality. PNAS, 122(25), e2511617122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2511617122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2511617122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for liu et al., transparency by chinese cities reduces pollution violations and improves air quality}, volume = {122}, year = {2025}, }
• (2025). Reply to uveges et al.: The assumption of a time-constant emission factor leads to biased estimates of fossil fuel methane emissions. PNAS, 122(25), e2508781122. (www)

  @article{ , archive = {J_PNAS}, author = {Michel, Sylvia Englund and Lan, Xin and Miller, John and Tans, Pieter and Clark, Justin Reid and Schaefer, Hinrich and Sperlich, Peter and Brailsford, Gordon and Morimoto, Shinji and Moossen, Heiko and Li, Jianghanyang}, doi = {10.1073/pnas.2508781122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2508781122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to uveges et al.: The assumption of a time-constant emission factor leads to biased estimates of fossil fuel methane emissions}, volume = {122}, year = {2025}, }
• (2025). Fossil fuel methane emissions likely underestimated in a model based on atmospheric δ13C trends. PNAS, 122(25), e2507837122. (www)

  @article{ , archive = {J_PNAS}, author = {Uveges, Benjamin T. and Howarth, Robert W. and Sparks, Jed P.}, doi = {10.1073/pnas.2507837122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2507837122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fossil fuel methane emissions likely underestimated in a model based on atmospheric δ13C trends}, volume = {122}, year = {2025}, }
• (2025). Reply to musculus et al.: A case of offside in scientific discourse?. PNAS, 122(25), e2507207122. (www)

  @article{ , archive = {J_PNAS}, author = {Bonetti, Leonardo and Vestberg, Torbjörn and Jafari, Reza and Seghezzi, Debora and Ingvar, Martin and Kringelbach, Morten L. and Filgueiras, Alberto and Petrovic, Predrag}, doi = {10.1073/pnas.2507207122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2507207122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to musculus et al.: A case of offside in scientific discourse?}, volume = {122}, year = {2025}, }
• (2025). Deep origins, distinct adaptations, and species-level status indicated for a glacial relict seal. PNAS, 122(25), e2503368122. (www)

  @article{ , abstract = {Isolated populations of postglacial relicts are known from many regions and are typically found on mountains for terrestrial species and in lakes for aquatic species. Among the few aquatic mammalian relicts, the Saimaa ringed seal ( Pusa hispida saimensis ) has been landlocked in Lake Saimaa, Finland, for the last 10,000 y. Saimaa ringed seals show genetic, behavioral, and morphological differences from the other ringed seal subspecies, but the extent these differences stem from the end of the last glacial period remains unclear. Here, we demonstrate with comprehensive sampling and state-of-the-art genomic methods that the Saimaa ringed seals are much older than the lake they inhabit, having formed a separate evolutionary branch for at least 60,000 y. This deep evolutionary origin of the Saimaa ringed seals is further underscored by anatomical differences, including our ecomorphological analyses revealing adaptively distinct features in their dentition and tongue. Overall, glacial relicts may harbor a richer selection of evolutionary history than might be expected from their recent isolation history alone.}, archive = {J_PNAS}, author = {Löytynoja, Ari and Pohjoismäki, Jaakko and Valtonen, Mia and Laakkonen, Juha and Morita, Wataru and Kunnasranta, Mervi and Väinölä, Risto and Olsen, Morten Tange and Auvinen, Petri and Jernvall, Jukka}, doi = {10.1073/pnas.2503368122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2503368122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deep origins, distinct adaptations, and species-level status indicated for a glacial relict seal}, volume = {122}, year = {2025}, }
• (2025). Why “decoding the elite soccer player’s psychological profile” fails to score. PNAS, 122(25), e2502322122. (www)

  @article{ , archive = {J_PNAS}, author = {Musculus, Lisa and Araújo, Duarte and Bisagno, Elisa and Gustafsson, Henrik and Kalén, Anton and Lindwall, Magnus and Pérez-Ferreirós, Alexandra and Raab, Markus and Williams, A. Mark and Stenling, Andreas}, doi = {10.1073/pnas.2502322122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {25}, pages = {e2502322122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Why “decoding the elite soccer player’s psychological profile” fails to score}, volume = {122}, year = {2025}, }
• (2025). Editorial expression of concern for poon et al., targeting the muscarinic m1 receptor with a selective, brain-penetrant antagonist to promote remyelination in multiple sclerosis. PNAS, 122(24), e2512750122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2512750122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2512750122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Editorial expression of concern for poon et al., targeting the muscarinic m1 receptor with a selective, brain-penetrant antagonist to promote remyelination in multiple sclerosis}, volume = {122}, year = {2025}, }
• (2025). QnAs with david b. lobell. PNAS, 122(24), e2512213122. (www)

  @article{ , archive = {J_PNAS}, author = {Williams, Sarah C. P.}, doi = {10.1073/pnas.2512213122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2512213122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {QnAs with david b. lobell}, volume = {122}, year = {2025}, }
• (2025). Correction for rufin et al., to enhance sustainable development goal research, open up commercial satellite image archives. PNAS, 122(24), e2512054122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2512054122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2512054122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for rufin et al., to enhance sustainable development goal research, open up commercial satellite image archives}, volume = {122}, year = {2025}, }
• (2025). Correction for feng et al., phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue y722 by src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis. PNAS, 122(24), e2511499122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2511499122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2511499122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for feng et al., phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue y722 by src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis}, volume = {122}, year = {2025}, }
• (2025). Correction for izdebski et al., unbalanced social–ecological acceleration led to state formation failure in early medieval poland. PNAS, 122(24), e2511461122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2511461122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2511461122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for izdebski et al., unbalanced social–ecological acceleration led to state formation failure in early medieval poland}, volume = {122}, year = {2025}, }
• (2025). Correction for yuan et al., molecular mechanism and functional significance of wapl interaction with the cohesin complex. PNAS, 122(24), e2511393122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2511393122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2511393122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for yuan et al., molecular mechanism and functional significance of wapl interaction with the cohesin complex}, volume = {122}, year = {2025}, }
• (2025). Psychoactive plants and secret rituals in ancient peru. PNAS, 122(24), e2509867122. (www)

  @article{ , archive = {J_PNAS}, author = {Nesbitt, Jason}, doi = {10.1073/pnas.2509867122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2509867122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Psychoactive plants and secret rituals in ancient peru}, volume = {122}, year = {2025}, }
• (2025). Transgenerational epigenetic effect of kings’ aging on offspring’s caste fate mediated by sperm DNA methylation in termites. PNAS, 122(24), e2509506122. (www)

  @article{ , abstract = {The discovery of transgenerational epigenetic inheritance and the unraveling of its molecular mechanisms are currently solving previously puzzling challenges that Mendelian genetics based solely on DNA could not explain, leading to significant paradigm shifts across various fields of biology. There has been a long-standing controversy over the factors determining the caste fate of individuals in social insects. Increasing evidence supports heritable influences on division of labor. Here, we provide evidence that transgenerational epigenetic inheritance influences caste determination in a termite. We demonstrate that the age of the king influences the caste fate of offspring, with young kings’ progeny showing a higher tendency for reproductive differentiation compared to offspring from older kings (under controlled conditions). Then, we conducted a high-quality chromosome-level genome assembly for the Japanese subterranean termite Reticulitermes speratus . Genome-wide methylome analysis of kings’ sperm reveals a drastic change in DNA methylation patterns with aging. Among 39,399,411 CpG sites, 21,611 sites showed significant age differences in methylation levels. We identified 13 genes whose methylation levels are significantly different between young and old kings and suggestively correlated with the offspring’s differentiation into the reproductive pathway. Our results suggest that sperm DNA methylation, which changes with the age of kings, is a potential transgenerational epigenetic factor involved in offspring caste differentiation in a termite. These findings may have broad applicability to caste differentiation in social insects and to phenotypic plasticity more generally.}, archive = {J_PNAS}, author = {Takata, Mamoru and Takahashi, Michihiko and Ishibashi, Tomoki and Tasaki, Eisuke and Rueppell, Olav and Vargo, Edward L. and Matsuura, Kenji}, doi = {10.1073/pnas.2509506122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2509506122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transgenerational epigenetic effect of kings’ aging on offspring’s caste fate mediated by sperm DNA methylation in termites}, volume = {122}, year = {2025}, }
• (2025). No mass extinction for south american mammals at the Eocene–Oligocene transition. PNAS, 122(24), e2509023122. (www)

  @article{ , archive = {J_PNAS}, author = {Godfrey, Laurie R. and Samonds, Karen E.}, doi = {10.1073/pnas.2509023122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2509023122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {No mass extinction for south american mammals at the Eocene–Oligocene transition}, volume = {122}, year = {2025}, }
• (2025). A specific negatively charged sequence confers intramolecular regulation on munc13-1 function in synaptic exocytosis. PNAS, 122(24), e2508915122. (www)

  @article{ , abstract = {Munc13 family proteins are crucial for the secretion of neurotransmitters and hormones necessary for cell communication. They share a conserved C-terminal region that includes C 2 and the MUN domains, which facilitate membrane interactions and the assembly of soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) complexes. Neuronal isoforms of Munc13 possess a variable N-terminal region that is essential for neurotransmitter release and short-term plasticity, although the precise functions of this region remain not fully understood. Here, we identified a negatively charged sequence within the N terminus of Munc13-1, termed polyE, which is specific to Munc13-1 among all Munc13 isoforms and potentially derived from a common ancestor of homeotherms. We found that polyE binds significantly to the MUN domain through charge–charge interactions, inhibiting MUN activity in promoting SNARE complex assembly. Disrupting the polyE–MUN interaction by introducing pseudophosphorylated mutations in the MUN domain alleviates this inhibition, thereby enhancing neurotransmitter release. Strikingly, Ca 2+ ions exhibit significant binding to polyE. We found that 40 μM of Ca 2+ adequately competes with the polyE–MUN interaction to reduce polyE inhibition. This concentration is comparable to presynaptic local [Ca 2+ ] i triggered by a single action potential. Taken together, these results indicate an autoinhibition conformation of Munc13-1 mediated by the polyE–MUN interaction. In addition, the relief of this autoinhibition conformation of Munc13-1 by presynaptic Ca 2+ influx and/or posttranslational modifications in the MUN domain may underlie Munc13-1 function in neurotransmitter release and short-term plasticity.}, archive = {J_PNAS}, author = {Zhao, Kexu and Zhang, Li and Lei, Mengshi and Jin, Ziqi and Du, Tianxin and Zhang, Hong and Sheng, Yin and Hu, Zhitao and Wang, Shen and Ma, Cong}, doi = {10.1073/pnas.2508915122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2508915122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A specific negatively charged sequence confers intramolecular regulation on munc13-1 function in synaptic exocytosis}, volume = {122}, year = {2025}, }
• (2025). Homology-arm length of donor DNA affects the impact of msh2 loss on homologous recombination–mediated gene targeting. PNAS, 122(24), e2508507122. (www)

  @article{ , abstract = {Efficient targeted integration (TI) of homologous donor DNA is crucial for precise genome editing. Although mismatch repair (MMR) is known to suppress TI as well as homologous recombination (HR) when sequence divergence is present, it remains controversial as to whether MMR affects TI of isogenic donor DNA. In this study, we investigated whether and how the MMR protein Msh2 affects TI of isogenic donor DNA. We found that HR-dependent TI is suppressed by Msh2 only when a homology arm of donor DNA is as short as 1.7 kb. In contrast, single-strand annealing–mediated TI, which is cell cycle–independent and becomes prominent when HR or non-homologous end joining is inactivated, is weakly but constantly affected by Msh2 irrespective of the size of homology arms. Our results reveal a previously unrecognized type of HR suppression by Msh2 and provide implications for precise genome editing using short-arm donor DNA vectors.}, archive = {J_PNAS}, author = {Saito, Shinta and Suzuki, Tetsuya and Nohmi, Takehiko and Adachi, Noritaka}, doi = {10.1073/pnas.2508507122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2508507122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Homology-arm length of donor DNA affects the impact of msh2 loss on homologous recombination–mediated gene targeting}, volume = {122}, year = {2025}, }
• (2025). N6-methyladenosine modification of HCMV IE1 transcript promotes the repressive state of viral genome to achieve latent infection. PNAS, 122(24), e2508475122. (www)

  @article{ , abstract = {Human cytomegalovirus (HCMV) is a prevalent pathogen that chronically infects the majority of human population. Among the many features that allow such widespread HCMV infection, one is its ability to maintain a transcriptionally dormant immune-evasive state called latency by suppressing its own major immediate early promoter (MIEP) via epigenetic alterations. In this study, we show a mechanism of MIEP regulation in which the major immediate early (MIE) gene product, immediate early 1 (IE1) transcript, downregulates its own promoter activity in an m 6 A modification-dependent manner. We found that the loss of the m 6 A writer, METTL3, in host cells impedes latency establishment in these cells. Through transcriptome-wide m 6 A profiling of latently infected monocytes, we identified that the major immediate early gene product IE1 transcript is m 6 A-modified during latent infection. Using IE1-specific m 6 A-abolished mutants, we found that m 6 A modification of the IE1 transcript was necessary for the efficient repression of MIEP, and these mutant viruses exhibited a significant defect in establishing latency and progressed toward lytic-like infection in the human monocytic cell line (THP-1) and primary CD14+ monocytes. Our findings demonstrate that HCMV exploits the host m 6 A machinery to suppress its own lytic program to establish latency and uncover an unexpected role of immediate early gene messenger RNA (mRNA) in regulating its own expression.}, archive = {J_PNAS}, author = {Jeong, Heena and Yeo, Nagyeong and Hwang, Hyeonseo and Park, Junhyun and Baek, Daehyun and Ahn, Kwangseog}, doi = {10.1073/pnas.2508475122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2508475122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {N6-methyladenosine modification of HCMV IE1 transcript promotes the repressive state of viral genome to achieve latent infection}, volume = {122}, year = {2025}, }
• (2025). Mycobacteriophage-mediated gene transfer enables in vitro drug screening and in vivo tracking of mycobacterium leprae. PNAS, 122(24), e2508271122. (www)

  @article{ , abstract = {Mycobacterium leprae , the causative agent of leprosy, has never been cultured in vitro, posing significant challenges for genetic manipulation and drug discovery. Current antileprosy drug screening methods relying on microscopic count, radiorespirometry, and qPCR are time consuming and require the use of radioactive elements. We demonstrate mycobacteriophage-mediated introduction of foreign DNA using the broad-host range mycobacteriophage TM4 and the application of the luciferase reporter mycobacteriophage (LRM) for drug screening. Mycobacteriophage infection of M. leprae was shown using TM4 expressing the highly sensitive BRET-nanoluciferase-based reporter, GeNL (TM4 ::GeNL ), which enables luminescence measurement for over 72 h. When M. leprae was exposed to rifampicin, dapsone, and Q203 for 24 and 48 h, followed by TM4 ::GeNL infection, the luminescence output decreased in a dose-dependent manner, establishing an in vitro two-day screening assay for drugs. We have also electroporated M. leprae with a ColE1 -integration proficient plasmid expressing GeNL and shown that the transformed leprosy bacilli could be propagated in mice footpads and detected using an in vivo imaging system (IVIS). These findings introduce powerful genetic tools for M. leprae research enabling in vivo tracking and in vitro viability testing.}, archive = {J_PNAS}, author = {Das, Lahari and Chen, Bing and Rajagopalan, Saranathan and Vilcheze, Catherine and Mullholland, Claire V. and Berney, Michael and Andrews, Patrick K. and Edwards, Ashley and Lahiri, Ramanuj and Jacobs, William R.}, doi = {10.1073/pnas.2508271122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2508271122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mycobacteriophage-mediated gene transfer enables in vitro drug screening and in vivo tracking of mycobacterium leprae}, volume = {122}, year = {2025}, }
• (2025). Dismantling EPA’s research office jeopardizes environmental safety, public health, and US competitiveness. PNAS, 122(24), e2508060122. (www)

  @article{ , archive = {J_PNAS}, author = {Glaberman, Scott and Frey, H. Christopher and Tal, Tamara}, doi = {10.1073/pnas.2508060122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2508060122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dismantling EPA’s research office jeopardizes environmental safety, public health, and US competitiveness}, volume = {122}, year = {2025}, }
• (2025). Built-in redundant killing by bt Cry1Ab toxin delays insect resistance. PNAS, 122(24), e2507583122. (www)

  @article{ , archive = {J_PNAS}, author = {Heckel, David G.}, doi = {10.1073/pnas.2507583122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2507583122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Built-in redundant killing by bt Cry1Ab toxin delays insect resistance}, volume = {122}, year = {2025}, }
• (2025). Reply to larsen and riisgård: Fluid dynamics of choanocyte chambers. PNAS, 122(24), e2507566122. (www)

  @article{ , archive = {J_PNAS}, author = {Ogawa, Takumi and Koyama, Shuji and Omori, Toshihiro and Kikuchi, Kenji and de Maleprade, Hélène and Goldstein, Raymond E. and Ishikawa, Takuji}, doi = {10.1073/pnas.2507566122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2507566122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to larsen and riisgård: Fluid dynamics of choanocyte chambers}, volume = {122}, year = {2025}, }
• (2025). The pumping function of sponge choanocyte chambers. PNAS, 122(24), e2507215122. (www)

  @article{ , archive = {J_PNAS}, author = {Larsen, Poul S. and Riisgård, Hans Ulrik}, doi = {10.1073/pnas.2507215122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2507215122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The pumping function of sponge choanocyte chambers}, volume = {122}, year = {2025}, }
• (2025). Early evidence for pig domestication (8,000 cal. BP) in the lower yangtze, south china. PNAS, 122(24), e2507123122. (www)

  @article{ , abstract = {The domestication of pigs ( Sus scrofa ) has had profound socioeconomic and ecological consequences. Although pigs are believed to have been independently domesticated in South China, the timing and initial mechanisms of this process remain debated. This study presents a microfossil analysis of pig dental calculus from two early Neolithic sites in the Lower Yangtze River region: Jingtoushan (8,300 to 7,800 cal. BP) and Kuahuqiao (8,200 to 7,000 cal. BP). Analyses of starch, phytolith, and parasite remains indicate that pigs consumed human-associated foods and waste, including cooked starchy plants and human whipworm ( Trichuris trichiura ) eggs, likely derived from food preparation and fecally contaminated materials. Identified plant taxa include acorns (Fagaceae), rice ( Oryza sp.), underground storage organs such as yam ( Dioscorea sp.), and wild grasses (Triticeae and Panicoideae), all present in the local botanical assemblages. Coefficients of variation in dental metrics further indicate the coexistence of both domestic and wild populations. Together, these lines of evidence point to multiple modes of human–pig interaction, including early domestic pigs under human management, pigs scavenging near settlements, and free-ranging individuals foraging beyond human influence. Pig domestication in the Lower Yangtze had begun by 8,000 y ago, likely following both commensal and prey pathways, in parallel with the development of rice cultivation and sedentary lifeways. This study also demonstrates the value of dental calculus analysis for revealing early human–animal relationships before the appearance of clear morphological markers of domestication in the archaeological record.}, archive = {J_PNAS}, author = {Wang, Jiajing and Tang, Yiyi and Zheng, Yunfei and Jiang, Leping and Ma, Xiaolin and Hou, Yanfeng and Sun, Guoping}, doi = {10.1073/pnas.2507123122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2507123122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Early evidence for pig domestication (8,000 cal. BP) in the lower yangtze, south china}, volume = {122}, year = {2025}, }
• (2025). Ligand-specific regulation of a binary enhancer code dictating cellular senescence. PNAS, 122(24), e2506321122. (www)

  @article{ , abstract = {Cellular senescence, a major contributor to aging and age-related pathologies, is characterized by irreversible proliferative arrest and a disease-linked, proinflammatory profile known as the Senescence Associated Secretory Phenotype (SASP). A critical unanswered question is whether these properties are regulated by specific enhancer subsets, potentially licensing strategies that selectively block deleterious SASP components. Here, we identify two functionally distinct and independently regulated enhancer programs underlying senescence that are controlled by different TGF-β family ligands. Whereas Activin A stimulates recruitment of nuclear factor IA/C (NFIA/C) and SMAD2/3 transcription factors to an enhancer network that induces proliferation arrest, TGF-β2 promotes SMAD2/3-mediated suppression of a p65-dependent enhancer cohort driving the SASP. We have also uncovered reciprocal SMAD2/3-super-enhancer-regulated feedback loops that govern expression of the TGF-β2 ( TGFB2) and Activin A ( INHBA ) transcription units, both of which are significantly up-regulated in replicative senescence. The characteristic enhancer usage and transcriptional landscape of high-passage senescent cells are sensitive to rapamycin treatment, discontinuation of which results in robust but selective senescent enhancer activation and exacerbation of the SASP. Collectively, this study uncovers separable enhancer programs and their key constituent transcription factors that contribute to the canonical features of cellular senescence, potentially informing the development of SASP-targeted therapies.}, archive = {J_PNAS}, author = {Suter, Thomas and Friedman, Meyer J. and Tazearslan, Cagdas and Merkurjev, Daria and Ohgi, Kenny and Meluzzi, Dario and Rosenfeld, Michael G. and Suh, Yousin}, doi = {10.1073/pnas.2506321122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2506321122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ligand-specific regulation of a binary enhancer code dictating cellular senescence}, volume = {122}, year = {2025}, }
• (2025). Solution mapping of MHC-I:TCR interactions using a minimalistic protein system. PNAS, 122(24), e2506016122. (www)

  @article{ , abstract = {Recognition of epitopic peptide antigens presented on class I major histocompatibility complex (MHC-I) proteins by T cell receptors (TCRs) forms the cornerstone of immune surveillance, leading to a plethora of adaptive immune responses. Characterization of TCR:peptide/MHC-I interactions is critical for understanding immune recognition, and developing immunotherapies, but the large variation in docking orientations of TCRs on their peptide/MHC-I targets challenges structural modeling. NMR spectroscopy could potentially resolve this ambiguity, but the large size of the TCR:peptide/MHC-I complex limits data quality. Here, we demonstrate that a designed MHC-I protein, SMART A*02:01, enables facile solution mapping of MHC-I:TCR interactions at scale. Our approach can be combined with computational modeling and structure-guided engineering to aid the development of TCR-based therapeutics.}, archive = {J_PNAS}, author = {Woodward, Claire H. and Chaudhuri, Apala and Chen, Xiaojing Tina and White, William L. and Garcia, K. Christopher and Baker, David and Sgourakis, Nikolaos G.}, doi = {10.1073/pnas.2506016122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2506016122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Solution mapping of MHC-I:TCR interactions using a minimalistic protein system}, volume = {122}, year = {2025}, }
• (2025). Reply to kleinsasser et al.: Superimposed acclimatization and adaptation to low and high altitudes in highlanders compared to lowlanders. PNAS, 122(24), e2505709122. (www)

  @article{ , archive = {J_PNAS}, author = {Day, Trevor A. and Bigham, Abigail W. and Brutsaert, Tom D.}, doi = {10.1073/pnas.2505709122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2505709122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to kleinsasser et al.: Superimposed acclimatization and adaptation to low and high altitudes in highlanders compared to lowlanders}, volume = {122}, year = {2025}, }
• (2025). A synthetic jasmonate receptor agonist uncouples the growth–defense trade-off in rice. PNAS, 122(24), e2505675122. (www)

  @article{ , abstract = {Herbivore attack elicits jasmonate (JA) signaling which in turn elicits both anti-herbivore plant defenses and growth inhibitions. The resulting growth–defense trade-offs constrain the utility of JA-based plant defense inducers to enhance endogenous pest resistance. Here, we designed and screened selective JA receptor agonists by synthesizing 6-substituted 1-oxoindanoyl isoleucine (In-Ile) conjugates and their free-acid forms, structural mimics of the bioactive hormone (+)-7-iso-jasmonoyl-L-Ile. These compounds differentially activate JA responses through selective binding of specific COI-JAZ coreceptor complexes. Notably, In-Ile treatments enhanced rice resistance to brown planthopper attack, a destructive rice pest, under both laboratory and field conditions, without compromising rice’s growth or yield. Mechanistically, this agonist activates the OsMYB55-mediated lignin biosynthesis defense receptor module [OsCOI1a/2-OsJAZs (3,4,6,7,12)] without activating the growth-suppression receptor module (OsCOI1b-OsJAZs). These findings demonstrate that synthetic JA agonists can provide nuanced manipulations of endogenous plant defenses without yield penalties—a promising biorational strategy for pest control in rice.}, archive = {J_PNAS}, author = {Xiao, Junli and Nakamura, Yoko and Wu, Zhixin and Fu, Wenjie and Chen, Yumeng and Lou, Yonggen and Baldwin, Ian T. and Boland, Wilhelm and Li, Ran}, doi = {10.1073/pnas.2505675122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2505675122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A synthetic jasmonate receptor agonist uncouples the growth–defense trade-off in rice}, volume = {122}, year = {2025}, }
• (2025). LDL receptor–mediated endocytosis of escherichia coli α-hemolysin mediates renal epithelial toxicity. PNAS, 122(24), e2505482122. (www)

  @article{ , abstract = {The α-hemolysin (HlyA) of uropathogenic Escherichia coli (UPEC) is a pore-forming toxin (PFT) that is thought to function by disrupting the host cell plasma membrane. Although CD18 (LFA-1) has been implicated as a receptor on myeloid cells, the mechanisms underlying HlyA cytotoxicity to epithelial cells are poorly defined. Here, we show that HlyA secretion by UPEC markedly intensifies renal tubular epithelial injury in a murine model of ascending pyelonephritis. A CRISPR-Cas9 loss-of-function screen in renal collecting duct cells revealed an unexpected requirement for clathrin-mediated endocytosis in HlyA-induced cytotoxicity. Following internalization, HlyA triggered lysosomal permeabilization, resulting in protease leakage, cytoplasmic acidification, and mitochondrial impairment, culminating in rapid epithelial cell death—a pathway distinct from canonical membrane-disrupting mechanisms of other PFTs. Moreover, we identify the low-density lipoprotein receptor (LDLR) as a critical epithelial receptor for HlyA; genetic ablation or competitive inhibition of the HlyA–LDLR interaction fully abrogated cytotoxicity. Our findings detail a paradigm for HlyA function in which epithelial toxicity relies on LDLR-mediated endocytic uptake rather than plasma membrane poration. These mechanistic insights illuminate potential therapeutic strategies to attenuate HlyA-mediated tissue damage during UPEC infections.}, archive = {J_PNAS}, author = {Kuhn, Hunter W. and Smither, Madeleine R. and Jin, Rachel J. and Collins, Christina A. and Ma, Hongming and Sina, Jason and Gaut, Joseph P. and Diamond, Michael S. and Hunstad, David A.}, doi = {10.1073/pnas.2505482122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2505482122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {LDL receptor–mediated endocytosis of escherichia coli α-hemolysin mediates renal epithelial toxicity}, volume = {122}, year = {2025}, }
• (2025). Development of an in situ CAR-T cell protocol through optical and PSMA-targeted PET imaging. PNAS, 122(24), e2504950122. (www)

  @article{ , abstract = {In situ T cell transfection methods overcome the complexity and high costs associated with conventional chimeric antigen receptor (CAR)-T therapy. However, the in situ CAR-T cell approach operates within the patient’s complex immune environment and bypasses preinfusion ex vivo cellular quality controls, necessitating advanced imaging techniques to track immune cell migration and function. Positron emission tomography (PET) can detect biochemical processes in patients and, when combined with a radiotracer specific for the engineered cells, can monitor CAR-T cell trafficking. Herein, we develop an approach for in situ T cell generation, tracking, and functional assessment using anti-CD5-conjugated lipid nanoparticles for codelivering CD19 CAR mRNA (mCAR19) and a prostate-specific membrane antigen mRNA (mPSMA) tag. With interleukin-7 (IL-7) preconditioning and repeated administration, this approach achieves tumor-free survival in 75% of B cell lymphoma-bearing mice (similar efficacy to ex vivo approaches), and through PET imaging of 68 Ga-PSMA-617, the generation and tumor infiltration of in situ-engineered PSMA-tagged CD19 CAR-T cells is validated.}, archive = {J_PNAS}, author = {Zhang, Nisi and Seo, Jai Woong and Robinson, Elise and Rivera-Rodriguez, Angelie and Wang, James and Guo, Yutong and Czerwinski, Debra K. and Kim, Ha Rin and Tumbale, Spencer K. and Raie, Marina N. and Jan, Basit L. and Engudar, Gokce and Sallets, Adrienne and Minn, Il and Pomper, Martin G. and Levy, Ronald and Ferrara, Katherine W.}, doi = {10.1073/pnas.2504950122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2504950122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Development of an in situ CAR-T cell protocol through optical and PSMA-targeted PET imaging}, volume = {122}, year = {2025}, }
• (2025). Macroevolutionary analysis of polysynthesis shows that language complexity is more likely to evolve in small, isolated populations. PNAS, 122(24), e2504483122. (www)

  @article{ , abstract = {Evolution of complexity in human languages has been vigorously debated, including the proposal that complexity can build in small, isolated populations but is often lost in situations of language contact. If it is generally true that small, isolated languages can build morphological complexity over time, but complexity tends to be lost in situations of language contact, then we should find that forms of language complexity that have evolved multiple times will tend to be associated with population size, isolation, and language age. We test this hypothesis by focusing on one particular form of morphological complexity, polysynthesis, where words built from many parts embody complex phrases. By assembling a global database of polysynthetic languages and conducting phylospatial analyses, we show that languages with highly complex word morphology are more likely to have small population sizes, less likely to occur with many other languages in direct contact, and have a greater tendency to be on long phylogenetically isolated lineages. These findings are consistent with the hypothesis that languages that evolve in isolation for long periods may be more likely to accrue morphological complexity. Polysynthetic languages also tend to have higher levels of endangerment. Our results provide phylogenetically informed evidence that one particular form of complex language morphology is more likely to occur in small, isolated languages and is prone to loss in contact.}, archive = {J_PNAS}, author = {Bromham, Lindell and Yaxley, Keaghan and Wilson, Oscar and Hua, Xia}, doi = {10.1073/pnas.2504483122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2504483122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Macroevolutionary analysis of polysynthesis shows that language complexity is more likely to evolve in small, isolated populations}, volume = {122}, year = {2025}, }
• (2025). Enzymatic carbon–fluorine bond cleavage by human gut microbes. PNAS, 122(24), e2504122122. (www)

  @article{ , abstract = {Fluorinated compounds are used for agrochemical, pharmaceutical, and numerous industrial applications, resulting in global contamination. In many molecules, fluorine is incorporated to enhance the half-life and improve bioavailability. Fluorinated compounds enter the human body through food, water, and xenobiotics including pharmaceuticals, exposing gut microbes to these substances. The human gut microbiota is known for its xenobiotic biotransformation capabilities, but it was not previously known whether gut microbial enzymes could break carbon–fluorine bonds, potentially altering the toxicity of these compounds. Here, through the development of a rapid, miniaturized fluoride detection assay for whole-cell screening, we identified active gut microbial defluorinases. We biochemically characterized enzymes from diverse human gut microbial classes including Clostridia, Bacilli, and Coriobacteriia, with the capacity to hydrolyze (di)fluorinated organic acids and a fluorinated amino acid. Whole-protein alanine scanning, molecular dynamics simulations, and chimeric protein design enabled the identification of a disordered C-terminal protein segment involved in defluorination activity. Domain swapping exclusively of the C-terminus conferred defluorination activity to a nondefluorinating dehalogenase. To advance our understanding of the structural and sequence differences between defluorinating and nondefluorinating dehalogenases, we trained machine learning models which identified protein termini as important features. Models trained on 41-amino acid segments from protein C termini alone predicted defluorination activity with 83% accuracy (compared to 95% accuracy based on full-length protein features). This work is relevant for therapeutic interventions and environmental and human health by uncovering specificity-determining signatures of fluorine biochemistry from the gut microbiome.}, archive = {J_PNAS}, author = {Probst, Silke I. and Felder, Florian D. and Poltorak, Victoria and Mewalal, Ritesh and Blaby, Ian K. and Robinson, Serina L.}, doi = {10.1073/pnas.2504122122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2504122122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Enzymatic carbon–fluorine bond cleavage by human gut microbes}, volume = {122}, year = {2025}, }
• (2025). Sensitivity of mass-independent sn isotope fractionation to UV radiation and magnetic fields. PNAS, 122(24), e2504065122. (www)

  @article{ , abstract = {Mass-independent isotope fractionation (MIF) enables powerful geochemical tracers for various geological and planetary problems, yet the mechanisms driving MIF for tin (Sn) remain ambiguous. Here, we demonstrate that distinct Sn isotope fractionation signatures were produced during photolysis of organic Sn species (i.e., methyltin) under laboratory UV irradiation and natural sunlight. UV irradiation of methyltin induced pronounced Sn-MIF in all odd Sn isotopes (Δ 115 Sn up to 21.82‰, Δ 117 Sn up to 23.16‰, Δ 119 Sn up to 24.01‰), with their ratios (Δ 117 Sn/Δ 115 Sn = 1.069; Δ 119 Sn/Δ 115 Sn = 1.099; Δ 119 Sn/Δ 117 Sn = 1.028) strongly correlating with nuclear magnetic moments. This unambiguously identifies the magnetic isotope effect (MIE) as the driving mechanism, ruling out other causes such as the nuclear volume effect (NVE). Methyl radicals (•CH 3 ) were detectable during the methyltin photolysis experiments, and the magnitude of MIF for Sn was suppressed by the presence of electron spin trapping agent (DMPO) for radicals, supporting that the pronounced Sn-MIF originated from radical-mediated singlet-triplet state transitions of Sn species. Furthermore, the magnitude of Sn-MIF depended nonmonotonically on external magnetic fields (peak suppression at 100 to 180 G), implying competition between hyperfine coupling and Zeeman interactions. Notably, Sn-MIF was absent during photolysis of methyltin by natural sunlight despite significant mass-dependent Sn isotope fractionation (e.g., >3‰ in δ 122/116 Sn), attributed to atmospheric ozone shielding of short-wavelength UV (<290 nm) required for radical generation. Our results register Sn-MIF as a sensitive tracer of UV-driven photochemistry in low-oxygen environments, underlining the potential of Sn isotopes in studies of early Earth’s atmosphere and planetary environments.}, archive = {J_PNAS}, author = {She, Jia-Xin and Li, Weiqiang and Zhang, Shujuan and Gu, Cheng and Chen, Xiru and Zheng, Hongcen and Xu, Cheng and Liu, Wei}, doi = {10.1073/pnas.2504065122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2504065122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sensitivity of mass-independent sn isotope fractionation to UV radiation and magnetic fields}, volume = {122}, year = {2025}, }
• (2025). Predicting high-fitness viral protein variants with bayesian active learning and biophysics. PNAS, 122(24), e2503742122. (www)

  @article{ , abstract = {The early detection of high-fitness viral variants is critical for pandemic response, yet limited experimental resources at the onset of variant emergence hinder effective identification. To address this, we introduce an active learning framework, VIRAL (Viral Identification via Rapid Active Learning), that integrates protein language model, Gaussian process with uncertainty estimation, and a biophysical model to predict the fitness of novel variants in a few-shot learning setting. By benchmarking on past SARS-CoV-2 data, we demonstrate that our method accelerates the identification of high-fitness variants by up to fivefold compared to random sampling while requiring experimental characterization of fewer than 1% of possible variants. We also demonstrate that our framework effectively identifies sites that are frequently mutated during natural viral evolution with a predictive advantage of up to two years compared to baseline strategies, particularly those enabling antibody escape while preserving ACE2 binding. Through systematic analysis of different acquisition strategies, we show that incorporating uncertainty in variant selection enables broader exploration of the sequence landscape, leading to the identification of evolutionarily distant but potentially dangerous variants. Our results suggest that VIRAL could serve as an effective early warning system for identifying concerning SARS-CoV-2 variants and potentially emerging viruses with pandemic potential before they achieve widespread circulation.}, archive = {J_PNAS}, author = {Huot, Marian and Wang, Dianzhuo and Liu, Jiacheng and Shakhnovich, Eugene I.}, doi = {10.1073/pnas.2503742122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2503742122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Predicting high-fitness viral protein variants with bayesian active learning and biophysics}, volume = {122}, year = {2025}, }
• (2025). SlPLT6 controls ripening initiation and quality traits through modulation of histone acetylation and methylation in tomato. PNAS, 122(24), e2503732122. (www)

  @article{ , abstract = {Improving fruit growth and quality without compromising yield is a highly sought-after goal in crop breeding. Here, we report that an EAR motif-containing transcription factor SlPLT6 controls the onset of fruit ripening and quality traits in tomato. SlPLT6 knockout caused precocious ripening initiation and enhanced fruit qualities without penalizing yield in two tomato cultivars. SlPLT6 represses genes involved in ripening initiation and major quality traits by directly binding to their promoters. Moreover, SlPLT6 connects two repressive mechanisms by recruiting Histone Deacetylase 1 via its C-terminal EAR motif and LIKE HETEROCHROMATIN PROTEIN 1b through the first AP2 domain. Furthermore, Sly-miR159 acts upstream of SlPLT6 to release its repression. Taken together, our data provide insights into the operating mode of SlPLT6 in modulating fruit ripening and quality traits and define a unique gene for targeted crop improvement aimed at upgrading fruit quality without yield penalty.}, archive = {J_PNAS}, author = {He, Xiaoqing and Wu, Yi and Shu, Peng and Yin, Yanpeng and Deng, Heng and Ying, Shiyu and Wu, Mengbo and Zhao, Panpan and Huang, Tengbo and Pirrello, Julien and Zhang, Yang and Grierson, Don and Zhong, Zhenhui and Hong, Yiguo and Bouzayen, Mondher and Liu, Mingchun}, doi = {10.1073/pnas.2503732122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2503732122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SlPLT6 controls ripening initiation and quality traits through modulation of histone acetylation and methylation in tomato}, volume = {122}, year = {2025}, }
• (2025). Dual-laser “808 and 1,064 nm” strategy that circumvents the achilles’ heel of photothermal therapy. PNAS, 122(24), e2503574122. (www)

  @article{ , abstract = {Breast cancer has now overtaken lung cancer as the “world’s leading cancer,” yet detecting and implementing effective therapies remains a significant challenge. Substantial advances have been made in photothermal therapy (PTT), where photosensitizers use photonic energy to induce localized hyperthermia for cancer eradication. This pioneering approach is gaining traction in clinical settings. However, traditional PTT faces inherent limitations, including the risk of damage to neighboring healthy tissues and potential inflammatory responses due to overheating. Drawing inspiration from the distinct characteristics of aggregation-induced emission the small molecule, PM331, was chosen for study. This donor–acceptor–donor system displays good photothermal conversion efficiencies (40% and 66%) upon excitation at 808 nm and 1,064 nm, respectively. It is also characterized by attractive optical features in the second near-infrared (NIR-II) window. Using nanoparticles containing PM331, PM331@F127 , we have developed a PTT strategy, termed dual-laser PTT (DLPTT), that involves successive excitation using 808 nm and 1,064 nm lasers guided by both NIR-II fluorescence and photoacoustic imaging. The DLPTT strategy involves two steps. First, it initiates DNA damage and downregulates heat shock protein expression as the result of an initial brief irradiation with an 808 nm laser. This is then followed by irradiation with a 1,064 nm laser to ablate tumor cells while minimizing inflammation and harm to surrounding healthy tissues. Based on the findings reported here, we suggest that DLPTT could represent an attractive approach to precision medicine and one that could make PTT more amenable to clinical implementation.}, archive = {J_PNAS}, author = {Ding, Qihang and Liu, Jiqiang and Wang, Yue and Kim, Jungryun and Huang, Zhihui and Lee, Yubin and Zhou, Hui and Zhang, Pengfei and Sessler, Jonathan L. and Kim, Jong Seung}, doi = {10.1073/pnas.2503574122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2503574122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dual-laser “808 and 1,064 nm” strategy that circumvents the achilles’ heel of photothermal therapy}, volume = {122}, year = {2025}, }
• (2025). The dependence of the amino acid backbone conformation on the translated synonymous codon is not statistically significant. PNAS, 122(24), e2503264122. (www)

  @article{ , abstract = {The correlation between synonymous codon usage and secondary structure in translated proteins has been widely demonstrated. This usage plays a capital role in tuning translational rates and protein folding kinetics, indirectly influencing multiple biological processes. A recent report [A. A. Rosenberg, A. Marx, A. M. Bronstein, Nat. Commun. 13 , 2815 (2022).] suggests that the translated synonymous codon influences the ( ϕ , ψ ) dihedral angles within secondary structure elements. If true, this conclusion would have strong consequences in several scientific fields, including structural biology and protein design, where results would depend on DNA sequence rather than protein sequence. Here, we show that the original statistical methodology used in the referred study was formally incorrect. Furthermore, when using a correct approach, we demonstrate that the influence of the codon on the distribution of the dihedral angles is not statistically significant for any type of secondary structure.}, archive = {J_PNAS}, author = {González-Delgado, Javier and Mier, Pablo and Bernadó, Pau and Neuvial, Pierre and Cortés, Juan}, doi = {10.1073/pnas.2503264122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2503264122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The dependence of the amino acid backbone conformation on the translated synonymous codon is not statistically significant}, volume = {122}, year = {2025}, }
• (2025). Equilibrium-gated pattern formation: How molecular dissociation thermodynamics drive emergent behavior in dissipative polymeric systems. PNAS, 122(24), e2503176122. (www)

  @article{ , abstract = {Emergent patterns in biological systems arise through dissipative processes that balance reaction and transport phenomena, producing highly functional properties from self-regulating mechanisms. Synthetic fabrication, by contrast, often relies on user-controlled, multistep methods that lack the self-organizing capabilities of natural systems. Inspired by nature, we sought chemical systems that integrate strongly coupled reaction and transport phenomena, identifying frontal ring-opening metathesis polymerization (FROMP) as a method capable of creating diverse forms and functions through reactive processing. By employing discrete molecular initiators, FROMP allows precise control of key reaction steps—inhibition, initiation, and propagation. Using an integrated computational and experimental framework, we uncover how near-equilibrium inhibition dynamics, coupled with far-from-equilibrium reaction kinetics, drive pattern formation in frontally polymerized synthetic materials. We propose the concept of equilibrium-gated pattern formation, demonstrating how initiator chemistry can be tuned to achieve programmable macroscale properties. Our study reveals a surprising insight: Emergent behavior in FROMP systems arises from the inhibition-dominated regime of resin composition, expanding prior observations that such behavior is confined to a narrow compositional space near the boundary between front quenching and uniform front propagation. We identify a broader compositional window, far from the quenching regime, where emergent behavior reliably manifests. This expanded design space significantly enhances the operational flexibility of reactive systems and their capacity for self-organization. These insights provide a roadmap for designing bioinspired materials with self-organizing capabilities, unlocking possibilities in synthetic manufacturing.}, archive = {J_PNAS}, author = {Bistri, Donald and Cramblitt, Anna and Arretche, Ignacio and Zhang, Conan and Cope, Reid B. and Zakoworotny, Michael and Mills, Mya G. and Rodriguez Koett, Luis E. and Chua, Lauren and Gómez-Bombarelli, Rafael and Tawfick, Sameh H. and Sottos, Nancy R. and Moore, Jeffrey S. and Geubelle, Philippe H.}, doi = {10.1073/pnas.2503176122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2503176122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Equilibrium-gated pattern formation: How molecular dissociation thermodynamics drive emergent behavior in dissipative polymeric systems}, volume = {122}, year = {2025}, }
• (2025). Local and distal changes in dynamics are caused by an L205R cushing’s syndrome mutant in PRKACA. PNAS, 122(24), e2502898122. (www)

  @article{ , abstract = {Cushing’s syndrome (CS) is an abnormal condition characterized by elevated cortisol levels, often resulting from genetic alterations in the PRKACA gene, which encodes the catalytic subunit of cAMP-dependent protein kinase A (PKA-C). The most common CS mutation, L205R, lies at the P + 1 loop. Understanding how this mutation alters the internal allosteric network within PKA-C and changes nucleotide and substrate cooperativity is a major goal. Using molecular dynamics (MD) simulations and protein residue networks based on local spatial pattern (LSP) method, we compare crystal structures of wild-type PKA-C and L205R. Our findings indicate that L205R not only locally disrupts the P + 1 hydrophobic pocket, leading to the displacement of the P + 1-residue and altered substrate specificity, but also has long-range effects in the linker connecting the A helix to β strand 1. The MD simulations and LSP analyses also reveal critical changes at the phosphoryl transfer site. Some of these changes are captured in the L205R crystal structure while others are not. With this strategy, we also show how the dynamics of local and distal allosteric networks are differentially influenced by backbone and side-chain dynamics.}, archive = {J_PNAS}, author = {Kalle, Anagha and Wu, Jian and Tawfeeq, Caesar and Kornev, Alexandr P. and Veglia, Gianluigi and Maillard, Rodrigo and Taylor, Susan S. and Jonniya, Nisha Amarnath}, doi = {10.1073/pnas.2502898122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2502898122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Local and distal changes in dynamics are caused by an L205R cushing’s syndrome mutant in PRKACA}, volume = {122}, year = {2025}, }
• (2025). A physical model links structure and function in the plant immune system. PNAS, 122(24), e2502872122. (www)

  @article{ , abstract = {Effector-Triggered Immunity (ETI) is an important part of the plant immune system, allowing plants to sense and respond to harmful pathogen proteins known as “effectors.” Effectors can be sensed directly or indirectly by NLR (Nucleotide-binding Leucine-rich Repeat) proteins, many of which “guard” the plant proteins targeted by effectors. Although a few effector–target–NLR interactions have been characterized, a general understanding of how these molecular interactions give rise to a functioning immune system is lacking. Here, we present a physics-based model of ETI based on protein–protein interactions. We show that the simplest physical model consistent with the biology gives rise to a robust immune sensor and explains the empirical phenomenon of effector interference as a generic consequence of molecules competing for binding partners. Using the evolutionarily conserved ZAR1 defense gene as a model, we explain how more complex interaction networks integrate multiple pathogen signals into a single response. We then examine alternatives to a guarding architecture, including direct sensing, decoys, and blended “integrated decoy” strategies, and reveal that these sensing architectures obey functional trade-offs between their sensitivity, target protection, and proteomic cost. This allows a quantitative analysis of the trade-offs between different forms of ETI. We discuss these findings in the context of the evolutionary forces shaping the plant immune system.}, archive = {J_PNAS}, author = {Weiner, Benjamin G. and Märkle, Hanna and Laderman, Eric and Demirjian, Choghag and Bergelson, Joy}, doi = {10.1073/pnas.2502872122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2502872122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A physical model links structure and function in the plant immune system}, volume = {122}, year = {2025}, }
• (2025). Evolution of gene order in prokaryotes is driven primarily by gene gain and loss. PNAS, 122(24), e2502752122. (www)

  @article{ , abstract = {Evolution of bacterial and archaeal genomes is highly dynamic, including extensive gene gain via horizontal gene transfer (HGT) and gene loss as well as different types of genome rearrangements, such as inversions and translocations, so that gene order is not highly conserved even among closely related organisms. We sought to quantify the contributions of different genome dynamics processes to the evolution of the gene order in prokaryote genomes, relying on the recently developed, simple, stochastic model of genome rearrangement through single gene translocations (“jump” model). The jump model was completely solved analytically in our previous work and provides the exact distribution of syntenic gene block lengths (SBL) in compared genomes based on gene translocations alone. Comparing the SBL distribution predicted by the jump model with the distributions empirically observed for multiple groups of closely related bacterial and archaeal genomes, we obtained robust estimates of the genome rearrangement to gene flux (gain and loss) ratio. In most groups of bacteria and archaea, this ratio was found to be on the order of 0.1 indicating that the loss of synteny in the evolution of bacteria and archaea is driven primarily by gene gain and loss rather than by gene translocation.}, archive = {J_PNAS}, author = {Brezner, Shelly and Garushyants, Sofya K. and Wolf, Yuri I. and Koonin, Eugene V. and Snir, Sagi}, doi = {10.1073/pnas.2502752122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2502752122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolution of gene order in prokaryotes is driven primarily by gene gain and loss}, volume = {122}, year = {2025}, }
• (2025). Preacclimatization and base excess rather than deficit?. PNAS, 122(24), e2502740122. (www)

  @article{ , archive = {J_PNAS}, author = {Kleinsasser, Axel and Burtscher, Martin}, doi = {10.1073/pnas.2502740122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2502740122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Preacclimatization and base excess rather than deficit?}, volume = {122}, year = {2025}, }
• (2025). Cryptic isoprene emission of soybeans. PNAS, 122(24), e2502360122. (www)

  @article{ , abstract = {Isoprene is the most abundant nonmethane biogenic hydrocarbon emitted by some plants, mostly trees. It plays critical roles in atmospheric chemistry by contributing to ozone and aerosol formation. Isoprene also benefits plants, particularly under stress, through its signaling roles. Legume crops like soybean were thought to have evolutionarily lost isoprene synthase (ISPS) and are typically considered nonemitters. Here, we report that damage to soybean leaves by wounding or burning triggered a burst of isoprene emission from the undamaged part of the leaves. In silico analysis identified intact ISPS genes in the soybean genome, with features similar to known ISPSs. Protein made from these gene sequences catalyzed isoprene production in the presence of dimethylallyl diphosphate. Isoprene emission in soybeans was linked to reduced photosynthesis rates and stomatal conductance. Metabolomic analysis showed that leaf damage caused a surge in glyceraldehyde 3-phosphate and pyruvate levels, leading to an increase of most of the methylerythritol 4-phosphate pathway metabolites.}, archive = {J_PNAS}, author = {Mostofa, Mohammad Golam and Sahu, Abira and Xu, Yuan and Basrai, Insiya and Doron, Lior and Lefrancois, Violet and Sharkey, Thomas D.}, doi = {10.1073/pnas.2502360122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2502360122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryptic isoprene emission of soybeans}, volume = {122}, year = {2025}, }
• (2025). Unraveling the role of rat and flea population dynamics on the seasonality of plague epidemics in madagascar. PNAS, 122(24), e2502161122. (www)

  @article{ , abstract = {Plague continues to pose a public health problem in multiple regions of the world, including Madagascar, where it is characterized by a pronounced seasonal pattern. The drivers of plague seasonality remain poorly understood. Using a deterministic compartmental model, calibrated to rat and flea capture data, serological data collected in active rural foci, and human plague surveillance data, we analyzed the effects of seasonal rat and flea population dynamics on plague transmission. The models that incorporated seasonal fluctuations in rat and flea populations provided better predictive performances than those that did not. We found that a simpler mass-action model also performed well. Driven by these seasonal changes, the effective reproduction number (R e ) between rats peaks at 1.45 [95% credible interval (CI): 1.41, 1.48] in October and falls to 0.6 (95% CI: 0.57, 0.63) in March. We estimated that 0.5% (95% CI: 0.2%, 0.9%) of rats are infected annually, indicating that plague is not the main driver of rat population changes. Using our model, we evaluated intervention strategies and found that targeting both rats and their fleas at the start of the epidemic season (July–September) was the most effective approach for reducing human plague cases. Such an approach contrasts with the reactive strategy currently employed in Madagascar. Our findings highlight the role of flea and rat populations in plague seasonality and identify strategies that could be deployed in Madagascar to better control plague epidemics.}, archive = {J_PNAS}, author = {Rasoamalala, Fanohinjanaharinirina and Ramasindrazana, Beza and Parany, Mamionah J. and Rahajandraibe, Soloandry and Randriantseheno, Lovasoa and Rahelinirina, Soanandrasana and Gorgé, Olivier and Valade, Eric and Harimalala, Mireille and Rajerison, Minoarisoa and Cauchemez, Simon and Brault, Antoine}, doi = {10.1073/pnas.2502161122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2502161122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unraveling the role of rat and flea population dynamics on the seasonality of plague epidemics in madagascar}, volume = {122}, year = {2025}, }
• (2025). Synergistic hydrogen embrittlement in high-strength steels. PNAS, 122(24), e2501850122. (www)

  @article{ , abstract = {Hydrogen embrittlement (HE) remains a critical scientific challenge in building reliable infrastructure for a carbon-free hydrogen economy. Predictive models for hydrogen-induced material failure are still lacking, largely due to an incomplete understanding of hydrogen’s effects on deformation behavior, especially in multiphase alloys with complex compositions and microstructures. Here, we demonstrate a synergistic hydrogen embrittlement (SHE) phenomenon in high-strength martensitic steels, where hydrogen interacts with carbon in solution to activate hydrogen-enhanced localized plasticity (HELP). Microcantilever bending tests revealed greater hydrogen susceptibility with higher carbon content, evidenced by a significant reduction in work-hardening capacity, promoting slip localization and reduced ductility. First-principles calculations and theoretical modeling revealed that carbon intensifies hydrogen–dislocation interactions and amplifies hydrogen redistribution around screw dislocations, inhibiting cross-slip. This work integrates experimental and modeling approaches to elucidate the synergistic interactions between hydrogen and solute elements, providing critical insights for designing high-strength, hydrogen-tolerant structural materials.}, archive = {J_PNAS}, author = {Li, Zhi and Lu, Yiran and Gao, Huajian and Kumar, Sharvan}, doi = {10.1073/pnas.2501850122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2501850122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synergistic hydrogen embrittlement in high-strength steels}, volume = {122}, year = {2025}, }
• (2025). Take caution in using LLMs as human surrogates. PNAS, 122(24), e2501660122. (www)

  @article{ , abstract = {Recent studies suggest large language models (LLMs) can generate human-like responses, aligning with human behavior in economic experiments, surveys, and political discourse. This has led many to propose that LLMs can be used as surrogates or simulations for humans in social science research. However, LLMs differ fundamentally from humans, relying on probabilistic patterns, absent the embodied experiences or survival objectives that shape human cognition. We assess the reasoning depth of LLMs using the 11-20 money request game. Nearly all advanced approaches fail to replicate human behavior distributions across many models. The causes of failure are diverse and unpredictable, relating to input language, roles, safeguarding, and more. These results warrant caution in using LLMs as surrogates or for simulating human behavior in research.}, archive = {J_PNAS}, author = {Gao, Yuan and Lee, Dokyun and Burtch, Gordon and Fazelpour, Sina}, doi = {10.1073/pnas.2501660122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2501660122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Take caution in using LLMs as human surrogates}, volume = {122}, year = {2025}, }
• (2025). Reflection and refraction of directrons at the interface. PNAS, 122(24), e2501488122. (www)

  @article{ , abstract = {Reflection and refraction are ubiquitous phenomena with extensive applications, yet minimizing energy loss and information distortion during these processes remains a significant challenge. This study examines the behavior of structurally stable solitons, known as directrons, in nematic liquid crystals interacting with an interface where the director field orientation changes, despite identical physical properties, external potentials, and boundary anchoring in the two regions. During reflection and refraction, the directrons maintain nearly constant structure and velocity, ensuring energy conservation and information integrity. Microscopic analyses of the director field and macroscopic evaluations of effective potential are employed to elucidate the dependence of reflection and refraction probabilities on the directron’s incident angle and the orientation difference across the interface. The findings provide valuable insights into the dynamics of solitary waves in structured liquid crystal systems, offering significant implications for the development of tunable photonic devices, reconfigurable optical systems, and nanoscale material engineering.}, archive = {J_PNAS}, author = {Tang, Xing-Zhou and Li, Chao-Yi and Huang, Zhi-Jun and Zhao, Jia-Hui and Chen, Yu-Xi and Abbott, Nicholas L. and de Pablo, Juan J. and Lu, Yan-Qing and Li, Bing-Xiang}, doi = {10.1073/pnas.2501488122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2501488122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reflection and refraction of directrons at the interface}, volume = {122}, year = {2025}, }
• (2025). Metallicity and anomalous hall effect in epitaxially strained, atomically thin RuO2 films. PNAS, 122(24), e2500831122. (www)

  @article{ , abstract = {The anomalous Hall effect (AHE), a hallmark of time-reversal symmetry breaking, has been reported in rutile RuO 2 , a debated metallic altermagnetic candidate. Previously, AHE in RuO 2 was observed only in strain-relaxed thick films under extremely high magnetic fields (~50 T). Yet, in ultrathin strained films with distinctive anisotropic electronic structures, there are no reports, likely due to disorder and defects suppressing metallicity thus hindering its detection. Here, we demonstrate that ultrathin, fully strained 2 nm TiO 2 / t nm RuO 2 /TiO 2 (110) heterostructures, grown by hybrid molecular beam epitaxy, retain metallicity and exhibit a sizeable AHE at a significantly lower magnetic field (< 9 T). Density functional theory calculations reveal that epitaxial strain stabilizes a noncompensated magnetic ground state and reconfigures magnetic ordering in RuO 2 (110) thin films. These findings establish ultrathin RuO 2 as a platform for strain-engineered magnetism and underscore the transformative potential of epitaxial design in advancing spintronic technologies.}, archive = {J_PNAS}, author = {Jeong, Seung Gyo and Lee, Seungjun and Lin, Bonnie and Yang, Zhifei and Choi, In Hyeok and Oh, Jin Young and Song, Sehwan and Lee, Seung wook and Nair, Sreejith and Choudhary, Rashmi and Parikh, Juhi and Park, Sungkyun and Choi, Woo Seok and Lee, Jong Seok and LeBeau, James M. and Low, Tony and Jalan, Bharat}, doi = {10.1073/pnas.2500831122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2500831122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Metallicity and anomalous hall effect in epitaxially strained, atomically thin RuO2 films}, volume = {122}, year = {2025}, }
• (2025). Structural insights into the activation and inhibition of the ADAM17–iRhom2 complex. PNAS, 122(24), e2500732122. (www)

  @article{ , abstract = {The endopeptidase activity of ADAM (a disintegrin and metalloproteinase)-17, the primary processor of several EGFR ligands and tumor necrosis factor-alpha (TNF-α), is essential for proper embryonic development and immune regulation. Dysregulated ADAM17 activity is prevalent in a wide array of human diseases, including cancer, chronic inflammation, and SARS-CoV-2 viral progression. Initially translated as an inactive zymogen, ADAM17 maturation and enzymatic function are tightly regulated by its obligate binding partners, the inactive rhomboid proteins (iRhom) -1 and -2. Here, we present the cryo-EM structure of the ADAM17 zymogen bound to iRhom2. Our findings elucidate the interactions within the ADAM17–iRhom2 complex, the inhibitory mechanisms of the therapeutic MEDI3622 antibody and ADAM17 prodomain, and the previously unknown role of a membrane-proximal cytoplasmic reentry loop of iRhom2 involved in the mechanism of activation. Importantly, we perform cellular assays to validate our structural findings and provide further insights into the functional implications of these interactions, paving the way for developing therapeutic strategies targeting this biomedically critical enzyme complex.}, archive = {J_PNAS}, author = {Maciag, Joseph J. and Slone, Conner E. and Alnajjar, Hala F. and Rich, Maria F. and Guion, Bryce and Ifergan, Igal and Blobel, Carl P. and Seegar, Tom C. M.}, doi = {10.1073/pnas.2500732122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2500732122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural insights into the activation and inhibition of the ADAM17–iRhom2 complex}, volume = {122}, year = {2025}, }
• (2025). Bruch’s membrane heparan sulfate retains lipoproteins in the early stages of age-related macular degeneration. PNAS, 122(24), e2500727122. (www)

  @article{ , abstract = {Lipoprotein retention in Bruch’s membrane is a key event in the pathobiology of early and intermediate age-related macular degeneration (AMD). However, the mechanism of lipoprotein retention in BrM is unknown. Given the established role of glycosaminoglycans (GAG) in binding lipoproteins, our laboratory sought to determine the role of GAGs in AMD BrM. In this study, BrM GAG content in AMD pathobiology was analyzed in human postmortem tissue. Strikingly, increased levels of highly sulfated heparan sulfate were present in AMD Bruch’s membrane as compared to non-AMD samples. In addition, using scanning electron microscopy of postmortem AMD tissue, we show aggregates of lipoprotein-like particles on the retinal pigmented epithelium side of Bruch’s membrane adjacent to heparan sulfate. We also show that heparin displaces lipoproteins rich in apolipoprotein A1 from human BrM, suggesting their identity as high-density lipoproteins. Using human BrM immobilized to quartz crystal microbalance biosensor (QCM) chips, we show that heparan sulfate is required for lipoprotein binding to BrM and soluble heparan sulfate can remove lipoproteins bound to BrM. Thus, our data establish that heparan sulfate regulates lipoprotein deposition in AMD BrM. These findings provide a foundation for targeted therapies capable of either preventing lipoprotein accumulation or removing drusen in the early and intermediate stages of AMD prior to vision loss.}, archive = {J_PNAS}, author = {Toomey, Christopher B. and Pflugmacher, Savanna and Park, Kamalu and Pihl, Jessica and Weiser Novak, Sammy and Rodriguez, Jessica and Jalali, Maryam and Jung, Jaesoo and Mozafari, Madeline and Omran, Sima P. and Pormir, Cameron K. and Hauer, Jill and Painter, Chelsea and Walker, Evan and Huang, Alex S. and Boassa, Daniela and Handa, James T. and Aastrup, Teodor and Gordts, Philip L. S. M. and Esko, Jeffrey D.}, doi = {10.1073/pnas.2500727122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2500727122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bruch’s membrane heparan sulfate retains lipoproteins in the early stages of age-related macular degeneration}, volume = {122}, year = {2025}, }
• (2025). The CARD14sh–BCL10–MALT1 complex regulates MAVS-mediated antiviral response in keratinocytes. PNAS, 122(24), e2500711122. (www)

  @article{ , abstract = {The Mitochondrial Antiviral Signaling Protein (MAVS) is a key adaptor in antiviral immunity, mediating type I interferon responses downstream of RIG1 and TLR3. While MAVS regulation is essential for antiviral defense, its modulation in keratinocytes is poorly understood. Here, we examine the role of the CARD14–BCL10–MALT1 (CBM) complex, a skin-specific signaling module, in controlling MAVS-dependent antiviral responses. We identify CARD14 short as a dual regulator that activates NF-κB while inhibiting IRF3 signaling. Psoriasis-associated CARD14 mutations are less efficient in restricting IRF3 activation and cytokine production upon Poly (I:C) stimulation, highlighting a potential mechanism in psoriasis pathogenesis. BCL10 is essential for MAVS-induced IRF3 activation, while MALT1 limits IRF3 signaling by promoting MAVS cleavage, K48-linked ubiquitination, and proteasomal degradation. Genetic and chemical inhibition of MALT1 enhances IRF3 activation and type I IFN expression. These findings reveal a MAVS-CBM regulatory network linking innate immunity to epithelial homeostasis.}, archive = {J_PNAS}, author = {Zerillo, Lucrezia and Zotti, Tiziana and Tutela, Angelapia and Madera, Jessica Raffaella and Grasso, Gabriella and Vito, Pasquale and Stilo, Romania}, doi = {10.1073/pnas.2500711122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2500711122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The CARD14sh–BCL10–MALT1 complex regulates MAVS-mediated antiviral response in keratinocytes}, volume = {122}, year = {2025}, }
• (2025). Why grain growth is not curvature flow. PNAS, 122(24), e2500707122. (www)

  @article{ , abstract = {Grain growth in polycrystals is traditionally considered a capillarity-driven process, where grain boundaries (GBs) migrate toward their centers of curvature (i.e., mean curvature flow) with a velocity proportional to the local curvature (including extensions to account for anisotropic GB energy and mobility). Experimental and simulation evidence shows that this simplistic view is untrue. We demonstrate that the failure of the classical mean curvature flow description of grain growth mainly originates from the shear deformation naturally coupled with GB motion (i.e., shear coupling). Our findings are built on large-scale microstructure evolution simulations incorporating the fundamental (crystallography-respecting) microscopic mechanism of GB migration. The nature of the deviations from curvature flow revealed in our simulations is consistent with observations in recent experimental studies on different materials. This work also demonstrates how to incorporate the mechanical effects that are essential to the accurate prediction of microstructure evolution.}, archive = {J_PNAS}, author = {Qiu, Caihao and Srolovitz, David J. and Rohrer, Gregory S. and Han, Jian and Salvalaglio, Marco}, doi = {10.1073/pnas.2500707122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2500707122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Why grain growth is not curvature flow}, volume = {122}, year = {2025}, }
• (2025). Neuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer. PNAS, 122(24), e2500632122. (www)

  @article{ , abstract = {Tumor-infiltrating nerves play a critical role in cancer progression and treatment resistance. Our recent work identified ALKAL2, a ligand for the Anaplastic Lymphoma Kinase (ALK) receptor, as a key mediator of inflammatory pain, with its expression significantly elevated in TRPV1+ sensory neurons during inflammation. Here, we explored the regulation of neuronal ALKAL2 in a colitis-associated colorectal cancer (CAC) model. We found that neuronal ALKAL2 is upregulated at early stages of CAC, which in turn activates ALK signaling in the colonic mucosa. Notably, treating mouse colonic organoids with exogenous ALKAL2 triggered ALK activation. In vivo, mice treated with the ALK inhibitor lorlatinib at the onset of colitis exhibited a remarkable 90% reduction in tumor burden without significantly affecting overall inflammation. Moreover, activating TRPV1+ neurons using DREADD technology exacerbated tumor growth, whereas silencing these neurons significantly reduced it. These findings reveal that TRPV1+ nociceptors drive CAC progression via the ALKAL2/ALK pathway.}, archive = {J_PNAS}, author = {Delanne-Cuménal, Mélissa and Defaye, Manon and Delanne-Cuménal, Améline and Ahmed, Mansoor and Ho, Valerie and Abdullah, Nasser S. and Alhassoun, Mohamad and Svendsen, Kristofer and Mager, Lukas and Schlessinger, Joseph and Hirota, Simon and Altier, Christophe}, doi = {10.1073/pnas.2500632122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2500632122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer}, volume = {122}, year = {2025}, }
• (2025). Acquired resistance to immunotherapy by physical barriers with cancer cell–expressing collagens in non–small cell lung cancer. PNAS, 122(24), e2500019122. (www)

  @article{ , abstract = {Immunotherapy has become the standard treatment for many types of cancers, but an increasing number of patients who initially respond to these treatments develop acquired immunotherapy resistance (AIR). Here, we recapitulated the entire process of immunotherapy from response to AIR in mice with non–small cell lung cancer (NSCLC). With implanted tumor organoids derived from these models and serial transplants, we demonstrated that tumor cell–intrinsic mechanisms contributed significantly to AIR. Single-cell RNA sequencing and electron microscope assays revealed that resistant tumor cell–expressing collagens, including Col3a1 and Col6a1 , formed multiple physical barriers surrounding tumor cells. Disruption of these barriers by collagenase or knockout of both Col3a1 and Col6a1 in tumor cells could sensitize the tumors of AIR. Mechanistically, the TGFβ pathway was upregulated upon immunotherapy, and treatment with TGFβ significantly increased the expression levels of both Col3a1 and Col6a1 in tumor cells. COL3A1 formed a castle-like barrier for a cluster of tumor cells and prevented T cell infiltration, while COL6A1 formed an armor-like barrier surrounding individual tumor cells to protect them against direct T cell attack. Our data reveal a tumor cell–intrinsic mechanism of AIR, mediated by collagen-containing physical barriers, which immediately suggests a clinical treatment option.}, archive = {J_PNAS}, author = {Wang, Manli and Wang, Yiyun and Pan, Xiangyu and Wang, Bo and Wang, Yuying and Luo, Xiangmeng and Deng, Xiaofeng and Liu, Li and Chen, Xuelan and Zhai, Xiaoqian and Wu, Baohong and Zhang, Qi and Ren, Yifeng and Li, Jia and Li, Xiaoyu and Cao, Fujun and Yang, Yang and Deng, Xintong and Li, Runhong and Lu, Zhenghao and Tan, Ping and Chen, Jingyao and Li, Yan and Liu, Yanyang and Liu, Jiewei and Wang, Yuan and Deng, Hongxin and Su, Zhaoming and Wang, Weiya and Wang, Yongsheng and Yang, Shengyong and Zhao, Chengjian and Xue, Jianxin and Wei, Yuquan and Zhang, Kang and Na, Feifei and Liu, Yu and Chen, Chong}, doi = {10.1073/pnas.2500019122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2500019122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Acquired resistance to immunotherapy by physical barriers with cancer cell–expressing collagens in non–small cell lung cancer}, volume = {122}, year = {2025}, }
• (2025). Hamiltonella symbionts benefit whitefly fertilization by regulating the maternal protein tudor–mediated piRNA pathway. PNAS, 122(24), e2427053122. (www)

  @article{ , abstract = {Although it is widely recognized that nutritional symbionts can manipulate host reproduction, the underlying molecular and cellular mechanisms are largely unclear. The facultative symbiont Hamiltonella in bacteriocyte induces female-biased sex ratio of whiteflies. Here, we demonstrate that a maternal gene tudor ( tud ) and its encoded protein have lower expression levels in ovaries of Hamiltonella- cured whiteflies. Tud family proteins can interlink the various stages of biosynthesis of PIWI-interacting RNA (piRNA), a class of small noncoding RNAs. We find that Hamiltonella affects the abundance of a piRNA through the maternal gene tud , thereby regulating the expression of the vacuolar ( H+ ) -ATPase H subunit ( VATPH ), which is the switch of activity of the vacuolar (H+)-ATPase that plays a crucial role in maintaining the homeostasis of intracellular energy and supporting mitochondrial respiration. This regulation adjusts the ATP level in ovaries of whiteflies. The ATP level shapes the F-actin pattern in ovaries and eggs of whiteflies, ultimately manipulating whitefly fertilization. Silencing tud inhibited whitefly fertilization by impairing ATP levels and F-actin patterns in ovaries and eggs. This study reveals that symbiont and maternal protein associations can regulate host fertilization by piRNA biosynthesis.}, archive = {J_PNAS}, author = {Sun, Xiang and Li, Huan and Chen, Zhan-Bo and Liu, Bing-Qi and Li, Chu-Qiao and Zhao, Zheng-Yang and Li, Xing-Ye and Luan, Jun-Bo}, doi = {10.1073/pnas.2427053122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2427053122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hamiltonella symbionts benefit whitefly fertilization by regulating the maternal protein tudor–mediated piRNA pathway}, volume = {122}, year = {2025}, }
• (2025). Defining CDK12 as a tumor suppressor and therapeutic target in mouse models of tubo-ovarian high-grade serous carcinoma. PNAS, 122(24), e2426909122. (www)

  @article{ , abstract = {Ovarian cancer is the sixth leading cause of cancer death among American women, with most fatalities attributable to tubo-ovarian high-grade serous carcinoma (HGSC). This malignancy usually develops resistance to conventional chemotherapy, underscoring the need for robust preclinical models to guide the development of novel therapies. Here, we introduce an HGSC mouse model generated via Ovgp1 -driven Cre recombinase effecting CRISPR/Cas9-mediated deletion of Trp53, Rb1 , and Nf1 tumor suppressors in mouse oviductal epithelium ( m-sgPRN model). Cyclin-dependent kinase 12 (CDK12) inactivation—frequently observed in human HGSC—is associated with poorer outcomes, DNA damage accumulation (including tandem duplications), and increased tumor immunogenicity. In our system, coablation of Cdk12 ( m-sgPRN;Cdk12KO ) recapitulated hallmark features of HGSC, while accelerating tumor progression and reducing survival. In a conventional (Cre-lox-mediated) Trp53/Nf1/Rb1 triple knockout model with concurrent Cdk12 ablation ( PRN ; Cdk12KO mice), we observed T cell–rich immune infiltrates mirroring those seen clinically. We established both models as subcutaneous or intraperitoneal syngeneic allografts of CDK12 -inactivated HGSC that exhibited sensitivity to immune checkpoint blockade. Furthermore, a CRISPR/Cas9 synthetic lethality screen in PRN;Cdk12KO -derived cell lines identified CDK13—an essential paralog of CDK12—as the most depleted candidate, confirming a previously reported synthetic lethal interaction. Pharmacologic CDK13/12 degradation (employing YJ1206) demonstrated enhanced efficacy in cell lines derived from both m-sgPRN;Cdk12KO and PRN ; Cdk12KO models. Our results define CDK12 as a key tumor suppressor in tubo-ovarian HGSC and highlight CDK13 targeting as a promising therapeutic approach in CDK12 -inactive disease. Additionally, we have established valuable in vivo resources to facilitate further investigation and drug development in this challenging malignancy.}, archive = {J_PNAS}, author = {Tien, Jean Ching-Yi and Zhai, Yali and Wu, Rong and Zhang, Yuping and Chang, Yu and Cheng, Yunhui and Todd, Abigail J. and Wheeler, Christina E. and Li, Shuqin and Mannan, Rahul and Cheng, Caleb and Magnuson, Brian and Cruz, Gabriel and Cao, Yizhi and Mahapatra, Somnath and Stolfi, Carmine and Cao, Xuhong and Su, Fengyun and Wang, Rui and Yang, Jianzhang and Zhou, Licheng and Qiao, Yuanyuan and Xiao, Lanbo and Cieslik, Marcin and Wang, Xiaoju and Wang, Zhen and Chou, Jonathan and Fearon, Eric R. and Ding, Ke and Cho, Kathleen R. and Chinnaiyan, Arul M.}, doi = {10.1073/pnas.2426909122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2426909122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Defining CDK12 as a tumor suppressor and therapeutic target in mouse models of tubo-ovarian high-grade serous carcinoma}, volume = {122}, year = {2025}, }
• (2025). Parental mixed-gender preferences revealed by IVF twin births. PNAS, 122(24), e2426838122. (www)

  @article{ , abstract = {In vitro fertilization (IVF) affects human fertility by 1) increasing the probability of multiple births through the transfer of multiple embryos, 2) raising the proportion of dizygotic twins, which leads to a higher occurrence of one-boy-one-girl twins, and 3) enabling gender selection through preimplantation genetic screening (PGS) when parents have specific gender preferences. While the above-mentioned increase in multiple births is well documented, the impact on the twins’ gender composition remains under-explored, partly because 2) and 3) are intertwined. This study uses millions of administrative observations from Taiwan to disentangle the effects of IVF on twin birth rates, gender composition, and parental preferences. Families are grouped by maternal age and family wealth across different periods, enabling a comparative analysis of socioeconomic and temporal factors. By examining the gender composition of first-born twins within these age-wealth-time groups, we can identify and test whether parents have gender preferences for one-boy-one-girl twins. Our empirical evidence reveals a significant increase in IVF adoption, particularly among older and wealthier mothers. The proportion of one-boy-one-girl twins among first-birth twins has risen from 20.42 to 41.86% over the past 30 y, and this proportion increases with wealth ranking, significantly exceeding expected ratios in the absence of gender preference. Parental gender preference contributed to approximately 10.95% of one-boy-one-girl twins among the wealthiest group, revealing a significant impact of parental preference on twin gender composition. These trends raise ethical and social concerns regarding reproductive technologies.}, archive = {J_PNAS}, author = {Chu, C. Y. Cyrus and Lin, Chang-Ching and Lu, Shih-Ting and Kao, Ching-Yuan}, doi = {10.1073/pnas.2426838122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2426838122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Parental mixed-gender preferences revealed by IVF twin births}, volume = {122}, year = {2025}, }
• (2025). PARP12-mediated mono-ADP-ribosylation as a checkpoint for necroptosis and apoptosis. PNAS, 122(24), e2426660122. (www)

  @article{ , abstract = {Necroptosis and apoptosis are two alternatively regulated cell death pathways. Activation of RIPK1 upon engagement of TNFR1 by TNFα may promote necroptosis by interacting with RIPK3 or apoptosis by activating caspases. RIPK1 is extensively regulated by a variety of dynamic posttranslational modifications which control its kinase activity and formation of downstream complexes to mediate necroptosis and apoptosis. Here, we investigate the functional significance and mechanism by which PARP12, a mono-ADP-ribosyltransferase, interacts with RIPK1 and RIPK3 in cells stimulated by IFNγ and TNFα. We show that PARP12 catalyzes the mono-ADP-ribosylation (MARylation) of RIPK1 in both the intermediate domain and the kinase domain, as well as the MARylation of RIPK3. PARP12 deficiency reduces necroptosis by inhibiting the activation of RIPK1 kinase and its interaction with RIPK3, as well as sensitizes to apoptosis by promoting the binding of RIPK1 with caspase-8. Thus, upon induction by IFNs, PARP12 may function as a cellular checkpoint that controls RIPK1 to promote necroptosis and inhibit apoptosis. Importantly, while PARP12 is a known interferon-stimulated gene (ISG), PARP12 deficiency promotes the expression of a subset of ISGs and confers protection against influenza A virus-induced mortality in mice. Our study demonstrates that PARP12 is an important modulator of cellular antiviral response.}, archive = {J_PNAS}, author = {Huang, Xin and Li, Fangxia and Liu, Lin and Li, Yanxia and Zhang, Mengmeng and Ma, Guoming and Gao, Ying and Shan, Bing and Liang, Xiaozhen and Yuan, Junying and Pan, Heling}, doi = {10.1073/pnas.2426660122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2426660122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PARP12-mediated mono-ADP-ribosylation as a checkpoint for necroptosis and apoptosis}, volume = {122}, year = {2025}, }
• (2025). SARS-CoV-2 nsp15 enhances viral virulence by subverting host antiviral defenses. PNAS, 122(24), e2426528122. (www)

  @article{ , abstract = {SARS-CoV-2 encodes numerous virulence factors, yet their precise mechanisms of action remain unknown. We provide evidence that the SARS-CoV-2 nonstructural protein 15 (nsp15) enhances viral virulence by suppressing the production of viral double-stranded (dsRNA), a potent inducer of antiviral signaling. The viral variants lacking nsp15 endoribonuclease activity elicited higher innate immune responses and exhibited reduced replication in human stem cell–derived lung alveolar type II epithelial cells, as well as in the lungs of infected hamsters. Consistently, these variants caused significantly less weight loss and mortality compared to wild-type (WT) virus in K18-hACE2 mice. Mechanistically, the cells infected with nsp15 mutants accumulated more viral dsRNA, causing enhanced stimulation of the interferon pathway. Chemical inhibition of interferon signaling dampened immune responses to nsp15 mutants and restored their replication to levels similar to the WT virus. These findings indicate that the endoribonuclease activity of nsp15 contributes to viral virulence by limiting the accumulation of viral dsRNA, thereby allowing robust replication with reduced activation of the host innate immune response.}, archive = {J_PNAS}, author = {Caobi, Allen and Su, Chia-Ming and Beusch, Christian M. and Kenney, Devin and Darling, Tamarand L. and Feng, Shuchen and Semaan, Marc and Wacquiez, Alan and Sanders, Nathan L. and Tully, Ena S. and Chen, Da-Yuan and Evdokimova, Monika and Ding, Zhen and Jones, Dakota and Alysandratos, Konstantinos-Dionysios and Mizgerd, Joseph P. and Kirchdoerfer, Robert N. and Kotton, Darrell N. and Douam, Florian and Crossland, Nicholas A. and Boon, Adrianus C. M. and Gordon, David E. and Baker, Susan C. and Saeed, Mohsan}, doi = {10.1073/pnas.2426528122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2426528122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SARS-CoV-2 nsp15 enhances viral virulence by subverting host antiviral defenses}, volume = {122}, year = {2025}, }
• (2025). The great phage escape: Activating and escaping lactococcal antiphage systems. PNAS, 122(24), e2426508122. (www)

  @article{ , abstract = {In recent years, the number of newly discovered systems that bacteria use to combat bacteriophages is increasing at an impressive rate. To obtain mechanistic insights into several antiphage systems identified in previous studies, we isolated 66 phage escape mutants which had become insensitive to 13 distinct, plasmid-encoded lactococcal phage resistance systems (i.e. Rhea, Kamadhenu, Rugutis, Audmula, PARIS, type II CBASS, Septu, AbiA, AbiB, AbiD/F, AbiG, AbiJ, AbiP). Genome analysis of these phage escape mutants identified a total of 15 mutated genes. Six of the encoded proteins appear to activate specific antiphage systems. Furthermore, AbiA escape mutants were found to be insensitive to AbiJ, while distinct antiphage systems (AbiG and AbiP) were observed to be activated by a major phage tail protein, indicating mechanistic commonalities. PARIS homologues encoded by members of different bacterial genera appear to share similar sensing mechanisms, whereas our data indicate mechanistic differences between Septu homologues from different genera. Based on our escape mutant sequence analysis, previously predicted domains, and experimental data using the purified endolysin of phage c2, we propose that Audmula modifies the cell wall of the host bacterium, delaying cell lysis and release of progeny phages, protecting the host cell by a heretofore unknown mode of action. The obtained advances in our understanding of lactococcal antiphage mechanisms provide fundamental insights into phage–host interactions, which undoubtedly benefits the dairy industry but may also be useful for biotechnological or biomedical applications.}, archive = {J_PNAS}, author = {Mosterd, Cas and Grafakou, Andriana and Ortiz Charneco, Guillermo and de Waal, Paul P. and van Rijswijck, Irma M. H. and van Peij, Noël N. M. E. and Péchoux, Christine and Kulakauskas, Saulius and Cambillau, Christian and Mahony, Jennifer and van Sinderen, Douwe}, doi = {10.1073/pnas.2426508122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2426508122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The great phage escape: Activating and escaping lactococcal antiphage systems}, volume = {122}, year = {2025}, }
• (2025). Human–AI collectives most accurately diagnose clinical vignettes. PNAS, 122(24), e2426153122. (www)

  @article{ , abstract = {AI systems, particularly large language models (LLMs), are increasingly being employed in high-stakes decisions that impact both individuals and society at large, often without adequate safeguards to ensure safety, quality, and equity. Yet LLMs hallucinate, lack common sense, and are biased—shortcomings that may reflect LLMs’ inherent limitations and thus may not be remedied by more sophisticated architectures, more data, or more human feedback. Relying solely on LLMs for complex, high-stakes decisions is therefore problematic. Here, we present a hybrid collective intelligence system that mitigates these risks by leveraging the complementary strengths of human experience and the vast information processed by LLMs. We apply our method to open-ended medical diagnostics, combining 40,762 differential diagnoses made by physicians with the diagnoses of five state-of-the art LLMs across 2,133 text-based medical case vignettes. We show that hybrid collectives of physicians and LLMs outperform both single physicians and physician collectives, as well as single LLMs and LLM ensembles. This result holds across a range of medical specialties and professional experience and can be attributed to humans’ and LLMs’ complementary contributions that lead to different kinds of errors. Our approach highlights the potential for collective human and machine intelligence to improve accuracy in complex, open-ended domains like medical diagnostics.}, archive = {J_PNAS}, author = {Zöller, Nikolas and Berger, Julian and Lin, Irving and Fu, Nathan and Komarneni, Jayanth and Barabucci, Gioele and Laskowski, Kyle and Shia, Victor and Harack, Benjamin and Chu, Eugene A. and Trianni, Vito and Kurvers, Ralf H. J. M. and Herzog, Stefan M.}, doi = {10.1073/pnas.2426153122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2426153122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Human–AI collectives most accurately diagnose clinical vignettes}, volume = {122}, year = {2025}, }
• (2025). A plant lysin motif receptor-like kinase plays an ancestral function in mycorrhiza. PNAS, 122(24), e2426063122. (www)

  @article{ , abstract = {Arbuscular mycorrhiza (AM) with soilborne Glomeromycota fungi was pivotal in the conquest of land by plants almost half a billion years ago. In flowering plants, it is hypothesized that AM is initiated by the perception of AM fungi-derived chito- and lipochito-oligosaccharides (COs/LCOs) in the host via Lysin Motif Receptor-Like Kinases (LysM-RLKs). However, it remains uncertain whether plant perception of these molecules is a prerequisite for AM establishment and for its origin. Here, we made use of the reduced LysM-RLK complement present in the liverwort Marchantia paleacea to assess the conservation of the role played by this class of receptors during AM and in CO/LCO perception. Our reverse genetic approach demonstrates the critical function of a single LysM-RLK, MpaLYKa, in AM formation, thereby supporting an ancestral function for this receptor in symbiosis. Binding studies, cytosolic calcium variation recordings and genome-wide transcriptomics indicate that another LysM-RLK of M. paleacea , MpaLYR, is also required for triggering a response to COs and tested LCOs, despite being dispensable for AM formation. Collectively, our results demonstrate that the perception of symbionts by LysM-RLK is an ancestral feature in land plants, and suggest the existence of yet-uncharacterized AM fungi signals.}, archive = {J_PNAS}, author = {Teyssier, Eve and Grat, Sabine and Landry, David and Ouradou, Mathilde and Rich, Mélanie K. and Fort, Sébastien and Keller, Jean and Lefebvre, Benoit and Delaux, Pierre-Marc and Mbengue, Malick}, doi = {10.1073/pnas.2426063122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2426063122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A plant lysin motif receptor-like kinase plays an ancestral function in mycorrhiza}, volume = {122}, year = {2025}, }
• (2025). Observation-based estimate of earth’s effective radiative forcing. PNAS, 122(24), e2425445122. (www)

  @article{ , abstract = {Human emissions continue to influence Earth’s climate. Effective radiative forcing quantifies the effect of such anthropogenic emissions together with natural factors on Earth’s energy balance. Evaluating the exact rate of effective radiative forcing is challenging, because it can not be directly observed. Therefore, estimating the effective forcing usually relies on climate models. Here, we present an estimate of effective radiative forcing that makes optimal use of observations. We use machine learning to learn the relationship between surface temperature and radiation caused by internal variability in a multimodel ensemble. Combining this with observations of surface temperature and the Earth’s net radiative imbalance, we predict an effective forcing trend of 0.71 ± 0.21 Wm − 2 per decade for 2001–2024. This is an independent assessment of the observed effective radiative forcing since 1985, that can be updated simultaneously with available observations and aligns with our physical understanding of radiative feedbacks. We make advances to close the Earth’s energy budget on annual timescales, by separating the influence of forcing versus the radiative response to surface temperature variations. Effective radiative forcing has substantially increased since 2021 and has not been countered by a strongly negative radiative response until 2024, consistent with exceptional warmth in 2023 and 2024.}, archive = {J_PNAS}, author = {Van Loon, Senne and Rugenstein, Maria and Barnes, Elizabeth A.}, doi = {10.1073/pnas.2425445122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2425445122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Observation-based estimate of earth’s effective radiative forcing}, volume = {122}, year = {2025}, }
• (2025). Intermediate light adaptation induces oscillatory phototaxis switching and pattern formation in chlamydomonas. PNAS, 122(24), e2425369122. (www)

  @article{ , abstract = {Biological microswimmers exhibit intricate taxis behaviors in response to environmental stimuli and swim in complex trajectories to navigate their environment. How microswimmers respond to stimulus instantaneously, and how adaptation to stimulus influences their long-term behavioral changes, remains largely unclear. Here, we report an oscillatory phototaxis observed in Chlamydomonas reinhardtii at intermediate light intensities, where cells swim back-and-forth under a constant, unidirectional light stimulus due to alternation between positive and negative phototaxis. The phototaxis switching can be captured by the change in phase relationship between eyespot and helical swimming. Oscillatory phototaxis of individual cells leads to a global pattern of millimeter-scale propagating density bands that persists for ∼ 30 min. High-speed imaging and long-time tracking experiments at single-cell level verify a unified phototaxis mechanism that couples light detection, light adaptation, flagella responses, and behavioral switching. By experimentally tracking steady swimming and transient turning states, we verify that phototaxis transition is achieved via the modulation of flagella waveforms and flagella phase difference, which can be captured by a hydrodynamic model accounting for photoresponses. Adaptation acts effectively as an oscillator damper to mediate multipurpose tasking across multiple system levels (subcellular flagella beats, oscillatory phototaxis, colonial pattern formation) and timescales (from milliseconds to over 30 min). This adaptive phototaxis mechanism provides a comprehensive understanding of how microswimmers achieve complex behavioral changes across multiple temporal scales with a single sensor–actuator circuit featuring relatively simple adaptive feedback responses.}, archive = {J_PNAS}, author = {Wang, Zhao and Tsang, Alan C. H.}, doi = {10.1073/pnas.2425369122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2425369122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intermediate light adaptation induces oscillatory phototaxis switching and pattern formation in chlamydomonas}, volume = {122}, year = {2025}, }
• (2025). A unifying principle for multispecies coexistence under resource fluctuations. PNAS, 122(24), e2424996122. (www)

  @article{ , abstract = {Resource fluctuations are ubiquitous in nature and yet are generally assumed to play a limited role in the maintenance of biodiversity. We challenge this assumption by analyzing resource competition dynamics under conditions where prevailing theory does not hold. We show that multispecies coexistence can be sustained when species are able to specialize on different temporal patterns of resource variability, including the asymmetries and periodic extremes commonly observed in natural systems. We further show how this partitioning of the statistical moments of the resource distribution provides a unified framework for explaining coexistence in variable resource environments. The multiplicity of niches we find in a single fluctuating resource highlights the potential for anthropogenic changes in resource regimes to drive cascading biodiversity losses.}, archive = {J_PNAS}, author = {Richardson, James A. and Engelstädter, Jan and Letten, Andrew D.}, doi = {10.1073/pnas.2424996122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2424996122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A unifying principle for multispecies coexistence under resource fluctuations}, volume = {122}, year = {2025}, }
• (2025). CRISPR screens and quantitative proteomics reveal remodeling of the aryl hydrocarbon receptor–driven proteome through PARP7 activity. PNAS, 122(24), e2424985122. (www)

  @article{ , abstract = {PARP7 is an enzyme that uses donor substrate NAD + to attach a single ADP-ribose moiety onto proteins related to immunity, transcription, and cell growth and motility. Despite the importance of PARP7 in these processes, PARP7 signaling networks remain underresearched. Here, we used genome-wide CRISPR screens and multiplex quantitative proteomics in distinct lung cancer cell lines treated with a PARP7 inhibitor to better understand PARP7 molecular functions. We find that manipulating the aryl hydrocarbon receptor (AHR) transcriptional activity mediates PARP7 inhibitor sensitivity and triggers robust changes to the AHR-controlled proteome (AHR-ome). One of the striking features of such AHR-ome remodeling was the downregulation of filamins A and B concurrent with the induction of the corresponding E3 ubiquitin ligase ASB2. We also show that suppressor of cytokine signaling 3 (SOCS3) crosstalks to AHR. Inhibition of PARP7 in SOCS3 knockout cells leads to reduced viability compared to wild-type cells treated with a PARP7 inhibitor. Our results reveal signaling interplay between PARP7, AHR, and SOCS3 and establish an invaluable resource to study the role of PARP7 in the regulation of AHR signaling and innate immunity through its ADP-ribosyl transferase activity.}, archive = {J_PNAS}, author = {Gorelik, Andrii and Paulo, Joao A. and Schroeter, Christina B. and Lad, Melanie and Shurr, Abigail and Mastrokalou, Chara and Siddiqi, Samrah and Suyari, Osamu and Brognard, John and Walter, David and Matthews, Jason and Palmer, Timothy M. and Gygi, Steven P. and Ahel, Ivan}, doi = {10.1073/pnas.2424985122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2424985122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CRISPR screens and quantitative proteomics reveal remodeling of the aryl hydrocarbon receptor–driven proteome through PARP7 activity}, volume = {122}, year = {2025}, }
• (2025). Induction of a neurotoxin in diatoms by iron limitation via cysteine synthase. PNAS, 122(24), e2424843122. (www)

  @article{ , abstract = {The β- N -methylamino- L -alanine (BMAA) is an emerging neurotoxin associated with human neurodegenerative diseases such as Alzheimer’s disease. Here, we report the prevalence of BMAA synthesis in protein forms by marine diatoms and reconstruct its tentative biosynthesis pathway. Remarkably, the BMAA production is strongly induced by iron limitation. Transcriptomic analyses suggest that cysteine synthase (CysK) is involved in BMAA synthesis. This is verified as CRISPR/Cas9-based CysK knockout abolished BMAA production and addition of the recombinant CysK to the mutant restored BMAA synthesis. As diatoms are the most abundant primary producers in ocean, the prevalence of BMAA in diatoms has significant public health implications. The biosynthesis pathway provides biomarkers for further investigation of BMAA production in marine diatoms and insights for understanding the pathological mechanism for human neurodegenerative diseases.}, archive = {J_PNAS}, author = {Zheng, Xianyao and Wu, Shuaishuai and Qiu, Jiangbing and Li, Aifeng and Li, Ling and Yan, Guowang and Li, Min and Meng, Fanping and Zhang, Kaidian and Lin, Senjie}, doi = {10.1073/pnas.2424843122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2424843122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Induction of a neurotoxin in diatoms by iron limitation via cysteine synthase}, volume = {122}, year = {2025}, }
• (2025). Whole-genome duplication leads to significant but inconsistent changes in climatic niche. PNAS, 122(24), e2424785122. (www)

  @article{ , abstract = {Polyploidization (whole-genome duplication, WGD) is a widespread large-effect macromutation with far-reaching genomic, phenotypic, and evolutionary consequences. Yet, we do not know whether the consistent phenotypic changes that are associated with polyploidization translate into predictable changes in ecological preferences. Niche modeling studies in mixed-ploidy species provide an opportunity to compare recently originated polyploids with their lower-ploidy ancestors. However, the available isolated studies provide contrasting results and the diverse methodologies used limit generalization. Based on 25,857 georeferenced ploidy-verified occurrence data for 129 mixed-ploidy flowering plant species, we tested in a unified statistical framework whether WGD is associated with consistent changes in climatic niche and in past, current, and predicted future range size. We found that 74% of species exhibited significant niche shifts associated with ploidy transition. However, there was no consistent environmental parameter underlying ploidy differentiation across species, nor was there consistent support for polyploid range or niche expansion in a subset of 75 densely sampled species with sufficient data for modeling. Our results demonstrate that polyploidization is an important factor affecting niche evolution of a species, but the environmental parameters underlying the ploidy-related niche shifts vary from species to species, demonstrating limited predictability of the outcomes of WGD in ecological space.}, archive = {J_PNAS}, author = {Meirmans, Patrick G. and Kolář, Filip}, doi = {10.1073/pnas.2424785122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2424785122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Whole-genome duplication leads to significant but inconsistent changes in climatic niche}, volume = {122}, year = {2025}, }
• (2025). Conformation-specific synthetic intrabodies modulate mTOR signaling with subcellular spatial resolution. PNAS, 122(24), e2424679122. (www)

  @article{ , abstract = {Subcellular compartmentalization is integral to the spatial regulation of mechanistic target of rapamycin (mTOR) signaling. However, the biological outputs associated with location-specific mTOR signaling events are poorly understood and challenging to decouple. Here, we engineered synthetic intracellular antibodies (intrabodies) that are capable of modulating mTOR signaling with genetically programmable spatial resolution. Epitope-directed phage display was exploited to generate high affinity synthetic antibody fragments (Fabs) against the FKBP12–Rapamycin binding site of mTOR (mTOR FRB ). We determined high-resolution crystal structures of two unique Fabs that discriminate distinct conformational states of mTOR FRB through recognition of its substrate recruitment interface. By leveraging these conformation-specific binders as intracellular probes, we uncovered the structural basis for an allosteric mechanism governing mTOR complex 1 (mTORC1) stability mediated by subtle structural adjustments within mTOR FRB . Furthermore, our results demonstrated that synthetic binders emulate natural substrates by employing divergent yet complementary hydrophobic residues at defined positions, underscoring the broad molecular recognition capability of mTOR FRB . Intracellular signaling studies showed differential time-dependent inhibition of S6 kinase 1 and Akt phosphorylation by genetically encoded intrabodies, thus supporting a mechanism of inhibition analogous to the natural product rapamycin. Finally, we implemented a feasible approach to selectively modulate mTOR signaling in the nucleus through spatially programmed intrabody expression. These findings establish intrabodies as versatile tools for dissecting the conformational regulation of mTORC1 and should be useful to explore how location-specific mTOR signaling influences disease progression.}, archive = {J_PNAS}, author = {O’Leary, Kelly M. and Slezak, Tomasz and Kossiakoff, Anthony A.}, doi = {10.1073/pnas.2424679122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2424679122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Conformation-specific synthetic intrabodies modulate mTOR signaling with subcellular spatial resolution}, volume = {122}, year = {2025}, }
• (2025). Antlers on does: An unexpected role of macrophages in deer biology. PNAS, 122(24), e2424448122. (www)

  @article{ , abstract = {Antlers, a male deer secondary sex characteristic, are unique mammalian appendages that fully regenerate annually, under androgen regulation. Stem cells located in the antlerogenic periosteum (AP), a tissue overlaying the frontal crest of both male and female deer, play a crucial role in antlerogenesis. Nonetheless, the underlying molecular mechanisms as to how antlerogenesis is regulated by androgens remain largely unexplored. Here, we show that androgens regulate antler growth via macrophages. Bulk RNA sequencing revealed a significant enrichment of immune-related factors in the androgen-activated antlerogenic periosteum (AAP), and single-cell RNA sequencing identified a cluster of AAP cells overexpressing macrophage chemokine CCL2. Additionally, the presence of a substantial number of monocytes/macrophages was detected in the skin overlying the AAP. Histological examination confirmed macrophage accumulation in the AAP. Removal of macrophages with clodronate effectively inhibited antler generation in male sika deer as well as in nude mice engrafted with the AP. Furthermore, testosterone up-regulated CCL2 expression in the AP cells (APCs), thus enhancing their chemotactic effect on recruitment of macrophages. Remarkably, female sika deer developed antlers following local injection of CCL2, autologous macrophages, or even immune response inducer lipopolysaccharide (LPS). Therefore, macrophages play an essential role in deer antler generation.}, archive = {J_PNAS}, author = {Wang, Datao and Ba, Hengxing and Li, Xunsheng and Landete-Castillejos, Tomas and Shi, Wanwan and Wang, Zhen and Ren, Jing and Sun, Hongmei and Chonco, Louis and Ma, Chao and Zhang, Guokun and Melino, Gerry and Shi, Yufang and Li, Chunyi}, doi = {10.1073/pnas.2424448122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2424448122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Antlers on does: An unexpected role of macrophages in deer biology}, volume = {122}, year = {2025}, }
• (2025). Organellar genome divergence and environmental stress induce transcriptional cytonuclear responses in wheat alloplasmic hybrids. PNAS, 122(24), e2424424122. (www)

  @article{ , abstract = {The union of two or more different nuclear genomes with maternally inherited organellar genomes may lead to cytonuclear incompatibilities in plant allopolyploids. These incompatibilities may be reconciled by coevolutionary responses at the genomic and transcriptional levels. To date, the relationship between extent of divergence among parental organellar genomes and cytonuclear coevolutionary responses remains largely unexplored. Here, we studied transcriptional cytonuclear expression in synthetic alloplasmic allohexaploid wheat lines having the same nuclear subgenomic composition (the nuclear genome of Chinese Spring) but with varying cytoplasmic organelles (plasmon donors from B- and D- lineage Triticum/Aegilops species). A positive association between the extent of plastid organellar divergence from naturally occurring organelles in euplasmic Chinese Spring and transcriptional cytonuclear responses was observed. This response was enhanced under stress (highlight) treatment and was determined to be related to differential subgenomic methylation levels. These data comprise a transcriptional dimension of cytonuclear responses to polyploidy and point to a potentially responsible epigenomic regulatory mechanism.}, archive = {J_PNAS}, author = {Zhao, Yue and Zhang, Keren and Li, Guo and Wang, Yuming and Ding, Xiaoyang and Wang, Shuo and Pang, Xi and Zhao, Xueru and Yu, Yue and Liu, Jiaqi and Yu, Tingting and Bao, Guixian and Wang, Tianya and Ni, Zhongfu and Xin, Mingming and Liu, Bao and Wendel, Jonathan F. and Zhang, Zhibin and Gong, Lei}, doi = {10.1073/pnas.2424424122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2424424122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Organellar genome divergence and environmental stress induce transcriptional cytonuclear responses in wheat alloplasmic hybrids}, volume = {122}, year = {2025}, }
• (2025). CDADC1 is a vertebrate-specific dCTP deaminase that metabolizes gemcitabine and decitabine to prevent cellular toxicity. PNAS, 122(24), e2424409122. (www)

  @article{ , abstract = {Cancer therapy is limited by resistance to standard-of-care chemotherapeutic and/or by treatment-associated toxicity. Identifying molecular mechanisms that modulate cellular toxicity is crucial for enhancing treatment efficacy. We characterize CDADC1, a vertebrate-specific orphan enzyme, as an unprecedented eukaryotic dCTP deaminase. CDADC1 catalyzes the conversion of dCTP into dUTP. While bacteria use this activity to sustain proliferation, CDADC1 evolved independently and is not required for mammalian cell proliferation, as demonstrated in cell lines and by the normal growth and standard lifespan of Cdadc1-deficient mice. However, we uncover a role of CDADC1 in metabolizing nucleotide analogs gemcitabine and decitabine. Gain- and loss-of-function assays in cancer cell lines, along with ectopic mouse models of pancreatic cancer, show that CDADC1 reduces these drugs’ efficacy. By the same token, Cdadc1 −/− mice are hypersensitive to gemcitabine. Mechanistically, CDADC1 deaminates the active triphosphate form of gemcitabine and decitabine, rendering them susceptible to inactivation by deoxyuridine triphosphatase. In contrast, the dCMP deaminase DCTD contributes to cell proliferation and promotes gemcitabine and decitabine toxicity. Thus, CDADC1 underpins a previously unrecognized mechanism of intrinsic chemoresistance in cancer cells and has a nonredundant role in protecting from gemcitabine toxicity. CDADC1 reveals a clinically relevant metabolic pathway that might be exploited to enhance the efficacy of deoxycytidine analogs but calls for assessing CDADC1 status to avoid lethal toxicities.}, archive = {J_PNAS}, author = {Rodriguez, Marcelo M. and Chatterjee, Debashree and Guerry, Johanna and Patenaude, Anne-Marie and Cohen, Charles C. H. and Bois, Therence and Larouche, Ariane and Ferreira, Silvana R. and Bertomeu, Thierry and Chatr-aryamontri, Andrew and Zhang, Li and Mader, Sylvie and Nislow, Corey and St-Jean, Guillaume and Guindon, Yvan and Zahn, Astrid and Di Noia, Javier M.}, doi = {10.1073/pnas.2424409122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2424409122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CDADC1 is a vertebrate-specific dCTP deaminase that metabolizes gemcitabine and decitabine to prevent cellular toxicity}, volume = {122}, year = {2025}, }
• (2025). Disruption of constitutive CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms. PNAS, 122(24), e2424186122. (www)

  @article{ , abstract = {The chemokine receptor CXCR4 is overexpressed in many cancers and contributes to pathogenesis, disease progression, and resistance to therapies. CXCR4 is known to form oligomers, but the potential functional relevance in malignancies remains elusive. Using a nanobody-based BRET method, we demonstrate that oligomerization of endogenous CXCR4 on lymphoid cancer cell lines correlates with enhanced expression levels. Specific disruption of CXCR4 oligomers reduced basal cell migration and prosurvival signaling via changes in the phosphoproteome, indicating the existence of constitutive CXCR4 oligomer-mediated signaling. Oligomer disruption also inhibited growth of primary CLL 3D spheroids and sensitized primary malignant cells to clinically used Bcl-2 inhibitor venetoclax. Given its limited efficacy in some patients and the ability to develop resistance, sensitizing malignant B cells to venetoclax is of clinical relevance. Taken together, we established a noncanonical and critical role for CXCR4 oligomers in lymphoid neoplasms and demonstrated that their selective targeting has clinical potential.}, archive = {J_PNAS}, author = {Mobach, Simon and Bergkamp, Nick D. and Ma, Ziliang and Haselager, Marco V. and Anbuhl, Stephanie M. and Jurriens, Daphne and van den Bor, Jelle and Wang, Ziming and Crudden, Caitrin and Roos, Jamie L. and Perez Almeria, Claudia V. and Boergonje, Rick A. and Lohse, Martin J. and Bosma, Reggie and Eldering, Eric and Siderius, Marco and Wu, Wei and Spaargaren, Marcel and Tonino, Sanne H. and Kater, Arnon P. and Smit, Martine J. and Heukers, Raimond}, doi = {10.1073/pnas.2424186122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2424186122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Disruption of constitutive CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms}, volume = {122}, year = {2025}, }
• (2025). Sleep deficiency exacerbates periodontal inflammation via trigeminal TRPV1 neurons. PNAS, 122(24), e2424169122. (www)

  @article{ , abstract = {Periodontitis, a prevalent chronic inflammatory disease, profoundly impacts both quality of life and overall health. Clinical studies have suggested a correlation between periodontitis and sleep deficiency, but the underlying mechanisms involved remain elusive. Here, we observed an elevated risk of periodontitis in individuals with sleep deficiency, as demonstrated in both clinical subjects and mouse models. Retrograde tracing from the periodontium revealed a neural connection from trigeminal TRPV1 neurons, which may mediate the aggravating effects of sleep deficiency on periodontitis. The ablation of TRPV1 neurons effectively mitigated the aggravating effects of sleep deficiency on periodontitis. Under periodontitis, sleep restriction increased the secretion of substance P from trigeminal neurons in the periodontium, enhancing vasodilation and vascular permeability, which in turn promoted the infiltration of proinflammatory immune cells. Blocking substance P signaling via a Neurokinin-1 receptor antagonist or knocking down Tacr1 in vascular endothelial cells alleviated these detrimental effects. Our findings unveil a critical neuron-vessel-immune axis that exacerbates periodontitis during sleep deficiency and suggest potential therapeutic strategies targeting this axis for managing periodontitis in individuals suffering from sleep deficiency.}, archive = {J_PNAS}, author = {Li, Junhui and Cui, Zhicheng and Gong, Hongyu and Zhang, Yan and Yuan, Zhenlin and Zhang, Zihao and Ma, Zengyi and Zhou, Nan and Huang, Chuanxin and Zhao, Yao and Li, Xia and Zhang, Zhi and Sun, Yao}, doi = {10.1073/pnas.2424169122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2424169122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sleep deficiency exacerbates periodontal inflammation via trigeminal TRPV1 neurons}, volume = {122}, year = {2025}, }
• (2025). Eradication efforts catalyze rapid evolution in an invasive predatory fish. PNAS, 122(24), e2424067122. (www)

  @article{ , abstract = {Species invasions spur costly and labor-intensive control efforts, yet even local eradication is seldom achieved. When control measures are initially effective, they may drive evolutionary adaptation that prevents full eradication, as has been documented for some chemical and biocontrol approaches. Although the intensity, directionality, and persistence of selection required to increase the frequency of resistant genotypes in complex natural ecosystems remains an open question, theory predicts that high mortality can cause life-history evolution even in the absence of a strong selective agent. Here, we use annually collected ecological and genetic data to show that rapid evolution of introduced smallmouth bass has undermined a 20-y manual suppression effort in a mid-sized lake. Despite nearly doubling annual mortality, our intensive control program produced a larger bass population dominated by young and early-maturing fish. These shifts were accompanied by large allele frequency changes in three genomic regions associated with earlier maturation and increased somatic growth. Our findings bear out the theoretical prediction that high mortality can drive evolutionary adaptation in target species. Controlling species invasions are worldwide practices that typically remove a substantial proportion of a population during each of many successive generations, hence life history adaptation may be commonplace. Such evolutionary responses could be salient in explaining the widespread failure of invasion control efforts. Genetic and phenotypic monitoring to detect cryptic adaptation and preemptive design of invader eradication programs to deliberately disrupt directional selection for resistance could improve invasion control outcomes.}, archive = {J_PNAS}, author = {Zarri, Liam J. and Kraft, Clifford E. and McIntyre, Peter B. and Baetscher, Diana S. and Jirka, Kurt J. and Randall, Eileen A. and Marcy-Quay, Benjamin and St. John, Carl A. and Sethi, Suresh A. and Airey, Montana E. and Detmer, Thomas M. and Flecker, Alexander S. and Therkildsen, Nina O.}, doi = {10.1073/pnas.2424067122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2424067122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Eradication efforts catalyze rapid evolution in an invasive predatory fish}, volume = {122}, year = {2025}, }
• (2025). Protein kinase a signaling regulates immune evasion by shaving and concealing fungal β-1,3-glucan. PNAS, 122(24), e2423864122. (www)

  @article{ , abstract = {Fungal pathogens infect billions and kill millions of people each year. Many of these pathogens have evolved strategies to evade our antifungal immune defenses. Candida albicans, for example, masks the proinflammatory pathogen-associated molecular pattern (PAMP) β-1,3-glucan, in response to specific host signals such as lactate. In C. albicans , most β-1,3-glucan lies in the inner cell wall shielded, by the outer mannan layer, from recognition by certain immune cells such as macrophages. β-1,3-glucan that becomes exposed at the cell surface can be shaved off by secreted enzymes. By integrating mathematical modeling with experimentation, we show that the dynamics of this shaving, together with the dynamics of β-1,3-glucan exposure during growth, can account for a range of β-1,3-glucan masking phenotypes. The mathematical model accurately simulates the dynamics of β-1,3-glucan exposure during growth and predicts levels of β-1,3-glucan shaving under a variety of conditions, revealing how subtle differences in growth contribute to observed variabilities in lactate-induced β-1,3-glucan masking. For example, clinical isolates previously thought to display minimal lactate-induced masking are shown to mask robustly. Using a range of C. albicans mutants, we confirm the importance of Gpr1/Gpa2-protein kinase A signaling for lactate-induced β-1,3-glucan shaving and define the contributions of the Xog1 and Eng1 glucanases to this shaving. Furthermore, examination of a shielding-defective C. albicans mnn2 x6 mutant confirms that both β-1,3-glucan shaving and shielding contribute to the dynamism of β-1,3-glucan masking at the fungal cell surface. Dynamism in PAMP masking is likely to be relevant to other fungal pathogens of humans.}, archive = {J_PNAS}, author = {Pradhan, Arnab and Nev, Olga A. and Leaves, Ian and Nev, Oleg A. and Ma, Qinxi and Milne, Gillian and Patterson, Grace and Netea, Mihai G. and Erwig, Lars P. and Farrer, Rhys A. and Brown, Gordon D. and van den Berg, Hugo A. and Gow, Neil A. R. and Brown, Alistair J. P.}, doi = {10.1073/pnas.2423864122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2423864122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Protein kinase a signaling regulates immune evasion by shaving and concealing fungal β-1,3-glucan}, volume = {122}, year = {2025}, }
• (2025). Prospects for cereal self-sufficiency in sub-saharan africa. PNAS, 122(24), e2423669122. (www)

  @article{ , abstract = {Sub-Saharan Africa (SSA) has the world’s largest projected increase in demand for food. Increased dependence on imports makes SSA vulnerable to geopolitical and economic risks, while further expansion of agricultural land is environmentally harmful. Cereals, in particular, maize, millet, rice, sorghum, and wheat, take nearly 50% of the cropland and 43% of the calories and proteins consumed in the region. Demand is projected to double until 2050. Here, we assess recent developments in cereal self-sufficiency and provide outlooks until 2050 under different intensification, area expansion, and climate change scenarios. We use detailed data for ten countries. Cereal self-sufficiency increased between 2010 and 2020 from 84 to 92% despite the 29% population increase. The production increase was achieved by increased yields per hectare (44%), area expansion (34%), and a shift from millet to the higher yielding maize (22%). Outlooks for 2050 are less pessimistic than earlier assessments because of the larger 2020 baseline area, higher shares of maize and somewhat less steep projected population increase. Yet, to halt further area expansion, a drastic trend change in annual yield increase from the present 20 to 58 kg ha −1 y −1 is needed to achieve cereal self-sufficiency. While such yield increases have been achieved elsewhere and are feasible given the yield potentials in SSA, they require structural changes and substantial agronomic, socioeconomic, and political investments. We estimate that amounts of added nitrogen need to at least triple to achieve such yield improvements, but it is essential that this comes with improved context-specific agronomy.}, archive = {J_PNAS}, author = {Ittersum, Martin K. van and Alimagham, Seyyedmajid and Silva, João Vasco and Adjei-Nsiah, Samuel and Baijukya, Frederick P. and Bala, Abdullahi and Chikowo, Regis and Grassini, Patricio and de Groot, Hugo L.E. and Nshizirungu, Aphrodis and Mahamane Soulé, Abdelkader and Sulser, Timothy B. and Taulya, Godfrey and Amor Tenorio, Fatima and Tesfaye, Kindie and Yuan, Shen and van Loon, Marloes P.}, doi = {10.1073/pnas.2423669122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2423669122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prospects for cereal self-sufficiency in sub-saharan africa}, volume = {122}, year = {2025}, }
• (2025). Repurposing a drug to punish carbapenem-resistant acinetobacter baumannii. PNAS, 122(24), e2423650122. (www)

  @article{ , abstract = {The OXA β-lactamases in Acinetobacter baumannii represent a primary mechanism for resistance to the carbapenems, a class of antibiotics that represent a last line for treatment. In a screen of an U.S. Food and Drug Administration (FDA)-approved drug library, we identified fendiline, a calcium channel blocker, had significantly more antimicrobial activity against OXA-23 expressing cells. Genetic and proteomic studies revealed that fendiline inhibited the essential lipoprotein trafficking pathway (Lol) in both A. baumannii (LolFD) and Escherichia coli (LolCDE). We demonstrate that OXA-23 is an outer membrane lipoprotein and its overexpression resulted in increased lethality in lolFD- depleted A. baumannii . Our results indicate that overexpression of the OXA-23 β-lactamase in A. baumannii stresses normal lipoprotein trafficking, which makes these cells more susceptible to fendiline. Overall, our data reveal a link between carbapenem resistance and the Lol pathway, which can be leveraged for new drug development.}, archive = {J_PNAS}, author = {Colquhoun, Jennifer M. and Brzezinski, Carter U. and Ji, Andrew and Marotta, Julianna and Elsen, Franziska A. V. and Bonomo, Robert A. and May, Kerrie L. and Sieber, Stephan A. and Grabowicz, Marcin and Wuest, William M. and Rather, Philip N.}, doi = {10.1073/pnas.2423650122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2423650122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Repurposing a drug to punish carbapenem-resistant acinetobacter baumannii}, volume = {122}, year = {2025}, }
• (2025). Co-opted SUMO machinery promotes condensate formation associated with membranous replication organelles of a positive-strand RNA virus. PNAS, 122(24), e2423465122. (www)

  @article{ , abstract = {Positive-strand RNA viruses are important pathogens of humans and plants. These viruses built viral replication organelles (VROs) with the help of co-opted host proteins and intracellular membranes to support robust virus replication in infected cells. Tomato bushy stunt virus (TBSV), a model (+)RNA virus, assembles membranous VROs, which are associated with vir-condensate substructures driven by TBSV p33 replication-associated protein. In this work, we provide evidence that the peroxisome-associated TBSV and the mitochondria-associated carnation Italian ringspot virus hijack the host small ubiquitin-like modifier (SUMO) machinery in yeast model host and plants. Based on knockdown of components of the SUMO pathway, we show that SUMO machinery acts as a cellular proviral dependency factor during TBSV replication. The sumoylation machinery was found to be partially retargeted from the nucleus into vir-condensate associated with membranous VROs through direct interactions with TBSV p33. We developed a yeast-based sumoylation assay that demonstrated p33 sumoylation. Absence of sumoylation or mutations in SIM SUMO-interacting motif in p33 replication protein reduced the ability of p33 to form droplets in vitro via phase separation. We demonstrate that p33 sumoylation and its intrinsically disordered region play noncomplementary roles in droplet formation. Mutations in p33 sumoylation sites and p33-SIM sequence resulted in reduced-sized VROs, which showed diminished protection of TBSV p33 and the viral RNA from degradation and also reduced viral RNA recombination. Altogether, the co-opted host sumoylation machinery promotes viral replication and RNA recombination. This finding could provide opportunities for antiviral interventions via targeting protein posttranslational modifications.}, archive = {J_PNAS}, author = {Lin, Wenwu and Nagy, Peter D.}, doi = {10.1073/pnas.2423465122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2423465122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Co-opted SUMO machinery promotes condensate formation associated with membranous replication organelles of a positive-strand RNA virus}, volume = {122}, year = {2025}, }
• (2025). Carbon and oxygen isotope evidence for a protoplanetary disk origin of organic solids in meteorites. PNAS, 122(24), e2423345122. (www)

  @article{ , abstract = {Macromolecular organic solids found in primitive meteorites were the main source of carbon delivered to forming planets in the early Solar System. However, the conditions under which this material formed and its subsequent incorporation into growing planetesimals remains a subject of vigorous debate. Here, we show that C isotope variations among these organics in most carbonaceous chondrites are strongly correlated with mass-independent O isotope anomalies exhibited by their host meteorites. As the latter signature has been argued to track abundances of nebular water generated from photochemical processing of CO gas, the C isotope variability of refractory organic solids may relate to this same process. We propose a framework in which CO photolysis simultaneously produces H 2 O and generates a pool of C + ions that serve as precursors for C-rich organic solids, with their C isotope compositions suggesting formation over a relatively narrow and warm range of temperatures in the protoplanetary disk (~200 to 400 K). Two populations of organic precursors with different C isotope compositions became associated with distinct dust reservoirs prior to their delivery to the carbonaceous-chondrite-forming region, which likely resided at lower temperatures (<170 K). This finding places detailed constraints on the location and distribution of chemical reactions that generated both water and organic-rich reservoirs in the early Solar System.}, archive = {J_PNAS}, author = {Lawrence, William M. and Blake, Geoffrey A. and Eiler, John}, doi = {10.1073/pnas.2423345122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2423345122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Carbon and oxygen isotope evidence for a protoplanetary disk origin of organic solids in meteorites}, volume = {122}, year = {2025}, }
• (2025). Route of fire: Pregame rituals and emotional synchrony among brazilian football fans. PNAS, 122(24), e2422779122. (www)

  @article{ , abstract = {Sporting events are powerful social phenomena that extend beyond the game itself, offering a unique lens to study collective emotional dynamics. We examine emotional alignment among football fans during a high-stakes match in Brazil, focusing on both the game and the preceding Rua de Fogo, a pregame ritual marked by chants, flares, and collective anticipation. Using wearable electrocardiographic (ECG) sensors to monitor heart rate patterns, we apply multidimensional recurrence quantification analysis to track group synchrony over time. We find that the Rua de Fogo, driven by its sensory-rich and ritualized interactions, elicited the highest levels of emotional synchrony, surpassing even key moments of the game. This synchrony was sustained across participants, including the driver of the team delegation bus, who was not physically engaged in the ritual. Our results demonstrate the importance of pregame rituals in enhancing shared emotional experiences, underscoring the broader appeal of sports as a cultural phenomenon. By identifying the mechanisms underlying emotional alignment, this work contributes to understanding how collective gatherings promote unity and shared identities, with implications extending to other domains, such as religious ceremonies, political rallies, and public celebrations.}, archive = {J_PNAS}, author = {Xygalatas, Dimitris and Profeta, Vitor Leandro da Silva and Saraei, Mohammadamin and Baranowski-Pinto, Gabriela}, doi = {10.1073/pnas.2422779122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2422779122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Route of fire: Pregame rituals and emotional synchrony among brazilian football fans}, volume = {122}, year = {2025}, }
• (2025). Oscillatory redox behavior in oxides: Cyclic surface reconstruction and reactivity modulation via the mars–van krevelen mechanism. PNAS, 122(24), e2422711122. (www)

  @article{ , abstract = {The breaking of translational symmetry at oxide surfaces gives rise to coordinatively unsaturated cations/anions and surface restructuring—key factors that govern surface reactivity. Using direct in situ environmental transmission electron microscopy (TEM) observations along with atomistic modeling, we report oscillatory redox behavior in CuO under H 2 , where cyclic surface reconstruction and reactivity modulation occur via the Mars–van Krevelen (MvK) mechanism. We observe self-switching between oxygen-rich and oxygen-deficient surface reconstructions, alternately activating and deactivating the surface for H 2 O formation. During periods of chemical inactivity, the oxygen-deficient surface undergoes slow reoxidation via lattice oxygen diffusing from subsurface and bulk reservoirs, restoring the active oxygen-rich surface termination. The inherent disparity in chemical activity among undercoordinated surface ions, along with sluggish subsurface-to-surface oxygen replenishment, drives this oscillatory redox cycle, modulating H 2 -induced loss of lattice oxygen at the surface and its delayed replenishment from the subsurface. This creates spatiotemporally separated redox steps at the oxide surface. The phenomena and atomistic insights presented here have significant implications for manipulating the surface reactivity of oxides by tuning the separation of these redox steps.}, archive = {J_PNAS}, author = {Sun, Xianhu and Wu, Dongxiang and Wang, Jianyu and Patel, Shyam B. and Zhu, Wenhui and Yang, Ji and Yang, Timothy T. and Ye, Shuonan and Chen, Xiaobo and Zhu, Yaguang and Qiao, Linna and Li, Meng and House, Stephen D. and Su, Ji and Saidi, Wissam A. and Boscoboinik, Jorge Anibal and Yang, Judith C. and Sharma, Renu and Zhou, Guangwen}, doi = {10.1073/pnas.2422711122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2422711122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Oscillatory redox behavior in oxides: Cyclic surface reconstruction and reactivity modulation via the mars–van krevelen mechanism}, volume = {122}, year = {2025}, }
• (2025). Spatiotemporal regulation of target mRNA cleavage by 21-nt phasiRNAs in maize anthers. PNAS, 122(24), e2422647122. (www)

  @article{ , abstract = {21-nt phasiRNAs are abundantly expressed in anthers and play crucial roles in anther development and male reproduction in grasses. In maize, the target genes that 21-nt phasiRNAs regulate remain largely unknown. Here, we show that 21-nt phasiRNAs direct the cleavage of hundreds of target mRNAs in maize. Interestingly, while 21-nt phasiRNAs in anthers (somatic anther wall cells) do not have obvious preference for a particular nucleotide at the 5′ end and target genes implicated in stress response and cellular homeostasis, 21-nt phasiRNAs in male germ cells preferentially initiate with 5′ C and target genes related to meiotic processes in a ZmAGO5c-dependent manner. Our results indicate that mRNA cleavage is a conserved mechanism used by 21-nt phasiRNAs for gene regulation in grasses. However, the sequences of 21-nt phasiRNAs and their targets show little conservation in maize and rice, suggesting that 21PHAS loci and 21-nt phasiRNA targets have undergone fast divergence in grasses.}, archive = {J_PNAS}, author = {Lian, Bi and Huang, Tianxiao and Huang, Wei and Jiang, Pengfei and Jin, Weiwei and Qi, Yijun}, doi = {10.1073/pnas.2422647122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2422647122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatiotemporal regulation of target mRNA cleavage by 21-nt phasiRNAs in maize anthers}, volume = {122}, year = {2025}, }
• (2025). Order induces toughness in anisotropic colloidal crystal composites. PNAS, 122(24), e2422532122. (www)

  @article{ , abstract = {Spatial ordering of matter elicits exotic properties sometimes absent from a material’s constituents. A few highly mineralized natural materials achieve high toughness through delocalized damage, whereas synthetic particulate composites must trade toughness for mineral content. We test whether ordering the mineral phase in particulate composites through the formation of macroscopic colloidal crystals can trigger the same damage resistance found in natural materials. Our macroscopic silica rod-based anisotropic colloidal crystal composites are processed fully at room temperature and pressure, reach volume fractions of mineral higher than 80%, and aided by a ductile interface, unveil toughness up to two orders of magnitude higher than bulk silica through the collective movement of rods and damage delocalization over millimeter. These composites demonstrate key design rules to break free from conventionally accepted structural materials’ properties trade-off.}, archive = {J_PNAS}, author = {Vilchez, Victoria and Zhou, Shitong and Bouville, Florian}, doi = {10.1073/pnas.2422532122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2422532122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Order induces toughness in anisotropic colloidal crystal composites}, volume = {122}, year = {2025}, }
• (2025). Global health and climate benefits from walking and cycling infrastructure. PNAS, 122(24), e2422334122. (www)

  @article{ , abstract = {We use a globally consistent dataset—Google Environmental Insights Explorer—to quantify how urban form and transport infrastructure affect walking and cycling rates in 11,587 cities from 121 countries across six continents. At the city level, population density has the largest effect on walk mode share and has a positive impact on cycling too, as higher densities bring destinations within feasible walk and cycle distances. Density has the strongest effects in wealthier countries where travelers often have more travel choices, while in lower-income places, walking and cycling may be primarily driven by financial constraints. We also find positive effects of bicycle lanes (proxying for a wider array of street design practices) on both walking and cycling. In the median city, each new km of bicycle lanes is associated with ~13,400 additional km yr -1 of bicycle travel. If every city increased the extent of its bicycle network to the level of Copenhagen, Denmark, our simulations indicate reductions in private vehicle emissions of ~6% and health benefits of ~US$435 billion per year.}, archive = {J_PNAS}, author = {Millard-Ball, Adam and Reginald, Monisha and Yusuf, Yasmina and Bian, Christopher}, doi = {10.1073/pnas.2422334122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2422334122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global health and climate benefits from walking and cycling infrastructure}, volume = {122}, year = {2025}, }
• (2025). Targeting ryanodine receptors with allopurinol and xanthine derivatives for the treatment of cardiac and musculoskeletal weakness disorders. PNAS, 122(24), e2422082122. (www)

  @article{ , abstract = {Ryanodine receptors (RyRs) are intracellular Ca 2+ channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance activation of RyRs by increasing the sensitivity to Ca 2+ . We previously showed that xanthine, the only physiologically relevant xanthine derivative, also binds to and activates RyR2. Most xanthine derivatives and analogs are safe and widely prescribed, with the most popular being the xanthine oxidoreductase inhibitor allopurinol (~15M yearly prescriptions in USA). We propose that xanthine derivatives and analogs that enhance RyRs activity could be used for lead optimization and eventually for the treatment of the diseases that exhibit decreased muscle contraction and reduced RyRs activity, such as RyR1-related diseases, sarcopenia, and heart failure. Here, we show by cryo-EM that xanthine derivatives, analogs, and other related compounds bind to the xanthine/caffeine binding site and activate RyR1, and identify 4-oxopyrimidine as the minimal motif necessary for such interaction.}, archive = {J_PNAS}, author = {Miotto, Marco C. and Luna-Figueroa, Estefania and Tchagou, Carl and Bahlouli, Laith and Reiken, Steven and Dridi, Haikel and Liu, Yang and Weninger, Gunnar and Marks, Andrew R.}, doi = {10.1073/pnas.2422082122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2422082122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Targeting ryanodine receptors with allopurinol and xanthine derivatives for the treatment of cardiac and musculoskeletal weakness disorders}, volume = {122}, year = {2025}, }
• (2025). Comparative evaluation of behavioral epidemic models using COVID-19 data. PNAS, 122(24), e2421993122. (www)

  @article{ , abstract = {Characterizing the feedback linking human behavior and the transmission of infectious diseases (i.e., behavioral changes) remains a significant challenge in computational and mathematical epidemiology. Existing behavioral epidemic models often lack real-world data calibration and cross-model performance evaluation in both retrospective analysis and forecasting. In this study, we systematically compare the performance of three mechanistic behavioral epidemic models across nine geographies and two modeling tasks during the first wave of COVID-19, using various metrics. The first model, a Data-Driven Behavioral Feedback Model, incorporates behavioral changes by leveraging mobility data to capture variations in contact patterns. The second and third models are Analytical Behavioral Feedback Models, which simulate the feedback loop either through the explicit representation of different behavioral compartments within the population or by utilizing an effective nonlinear force of infection. Our results do not identify a single best model overall, as performance varies based on factors such as data availability, data quality, and the choice of performance metrics. While the Data-Driven Behavioral Feedback Model incorporates substantial real-time behavioral information, the Analytical Compartmental Behavioral Feedback Model often demonstrates superior or equivalent performance in both retrospective fitting and out-of-sample forecasts. Overall, our work offers guidance for future approaches and methodologies to better integrate behavioral changes into the modeling and projection of epidemic dynamics.}, archive = {J_PNAS}, author = {Gozzi, Nicolò and Perra, Nicola and Vespignani, Alessandro}, doi = {10.1073/pnas.2421993122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2421993122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Comparative evaluation of behavioral epidemic models using COVID-19 data}, volume = {122}, year = {2025}, }
• (2025). Biparental inheritance of germline-specific chromosomes in the sea lamprey and their roles in oocytes. PNAS, 122(24), e2421883122. (www)

  @article{ , abstract = {Many eukaryotic species undergo programmed elimination of specific chromosomes during embryogenesis, typically retaining these chromosomes only in their germ cells. In some species, programmatic elimination of GRCs, or sex chromosomes, also occurs in a sex-specific manner, with specific chromosomes being transmitted or eliminated by only one sex. As such, these chromosomes provide a unique perspective on the evolution of gene functions that are advantageous to the germline and genetic tradeoffs between somatic vs germline or oocyte vs sperm biology. While GRCs have been extensively characterized in male sea lampreys ( Petromyzon marinus ), the status of GRCs in females has not yet been resolved, though it has been hypothesized that male-specific expression/transmission of these chromosomes might provide a solution to resolving the long-standing mystery of lamprey sex determining mechanisms. To gain insight into the roles of GRCs in female lampreys, we performed several karyological, transcriptomic, and genomic analyses, which demonstrate that GRCs are present in the female lamprey germline, transmitted by oocytes and somatically eliminated in both sexes. These analyses also show that GRCs play important roles in the maintenance and development of female germline but provide no evidence for sex-specific variation in the elimination and transmission of lamprey GRCs. These findings underscore the diversity of germline functions that are carried out by GRCs in both male and female lampreys and highlight the fact that sex-specific transmission/retention of GRCs likely follows no universal rules across the diverse lineages that have independently evolved to undergo developmentally programmed DNA elimination.}, archive = {J_PNAS}, author = {Timoshevskiy, Vladimir A. and Timoshevskaya, Nataliya and Eşkut, Kaan I. and Rajandran, Kasturi and Smith, Jeramiah J.}, doi = {10.1073/pnas.2421883122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2421883122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biparental inheritance of germline-specific chromosomes in the sea lamprey and their roles in oocytes}, volume = {122}, year = {2025}, }
• (2025). Cross-species modeling of plant genomes at single-nucleotide resolution using a pretrained DNA language model. PNAS, 122(24), e2421738122. (www)

  @article{ , abstract = {Interpreting function and fitness effects in diverse plant genomes requires transferable models. Language models (LMs) pretrained on large-scale biological sequences can capture evolutionary conservation and offer cross-species prediction better than supervised models through fine-tuning limited labeled data. We introduce PlantCaduceus, a plant DNA LM that learns evolutionary conservation patterns in 16 angiosperm genomes by modeling both DNA strands simultaneously. When fine-tuned on a small set of labeled Arabidopsis data for tasks such as predicting translation initiation/termination sites and splice donor/acceptor sites, PlantCaduceus demonstrated remarkable transferability to maize, which diverged 160 Mya. The model outperformed the best existing DNA language model by 1.45-fold in maize splice donor prediction and 7.23-fold in maize translation initiation site prediction. In variant effect prediction, PlantCaduceus showed performance comparative to state-of-the-art protein LMs. Mutations predicted to be deleterious by PlantCaduceus showed threefold lower average minor allele frequencies compared to those identified by multiple sequence alignment-based methods. Additionally, PlantCaduceus successfully identifies well-known causal variants in both Arabidopsis and maize. Overall, PlantCaduceus is a versatile DNA LM that can accelerate plant genomics and crop breeding applications.}, archive = {J_PNAS}, author = {Zhai, Jingjing and Gokaslan, Aaron and Schiff, Yair and Berthel, Ana and Liu, Zong-Yan and Lai, Wei-Yun and Miller, Zachary R. and Scheben, Armin and Stitzer, Michelle C. and Romay, M. Cinta and Buckler, Edward S. and Kuleshov, Volodymyr}, doi = {10.1073/pnas.2421738122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2421738122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cross-species modeling of plant genomes at single-nucleotide resolution using a pretrained DNA language model}, volume = {122}, year = {2025}, }
• (2025). RACK1 promotes the development and function of alveolar macrophages through directly binding to and stabilizing PPARγ. PNAS, 122(24), e2421672122. (www)

  @article{ , abstract = {Alveolar macrophages (AMs) are indispensable to prevent pulmonary alveolar proteinosis and clear inhaled pathogens. Receptor for activated C kinase 1 (RACK1) is a versatile adaptor protein that regulates multiple signaling pathways. Whether RACK1 is implicated in AM alterations remains elusive. Alveolar type 2 cells-derived granulocyte-macrophage colony-stimulating factor and autocrine transforming growth factor-β1 drive the transcription of Pparg , the gene encoding AM signature transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). The regulation of PPARγ stability during AM development and maintenance remains unexplored. Here, we report that myeloid RACK1 deficiency results in the scarcity of mature AMs and pulmonary alveolar proteinosis. A mixed bone marrow chimera approach reveals a cell-intrinsic role of RACK1 in AM differentiation. Bulk RNA-sequencing indicates a considerable loss of AM identity, impaired PPAR signaling, but a largely unchanged Pparg messenger RNA (mRNA) level in the absence of RACK1. Indeed, myeloid deletion of Rack1 halts AM differentiation in vivo and blocks the ability of PPARγ agonist to induce AM-like cells in vitro. Mechanistically, RACK1 directly binds to and stabilizes PPARγ by preventing its ubiquitination and degradation. Moreover, myeloid RACK1 deficiency renders mice susceptible to Streptococcus pneumoniae infection.}, archive = {J_PNAS}, author = {Jiang, Hui and Yun, Hongfang and Wang, Xu and Shen, Zhuo and Liu, Genyu and Zou, Tao and Guo, Tingting and Wu, Mengyao and Lu, Yuchen and Deng, Lijiao and Miao, Ju and Deng, Hongbin and Yuan, Zengqiang and Zhang, Jiyan}, doi = {10.1073/pnas.2421672122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2421672122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RACK1 promotes the development and function of alveolar macrophages through directly binding to and stabilizing PPARγ}, volume = {122}, year = {2025}, }
• (2025). Pathogenic variants in the polycystin pore helix cause distinct forms of channel dysfunction. PNAS, 122(24), e2421362122. (www)

  @article{ , abstract = {PKD2 is a member of the polycystin subfamily of transient receptor potential (TRP) ion channel subunits which traffic and function in primary cilia organelle membranes. Millions of individuals carry pathogenic genetic variants in PKD2 that cause a life-threatening condition called autosomal dominant polycystic kidney disease (ADPKD). Although ADPKD is a common monogenetic disorder, there is no drug cure or available therapeutics which address the underlying channel dysregulation. Furthermore, the structural and mechanistic impacts of most disease-causing variants are uncharacterized. Using direct cilia electrophysiology, cryogenic electron microscopy (cryo-EM), and superresolution imaging, we have found mechanistic differences in channel dysregulation caused by three germline missense variants located in PKD2’s pore helix 1. Variant C632R reduces protein thermal stability, resulting in impaired channel assembly and abolishes primary cilia trafficking. In contrast, variants F629S and R638C retain native cilia trafficking but exhibit gating defects. Cryo-EM structures (2.7 to 2.8 Å resolution) indicate loss of critical pore helix interactions which precipitate allosteric collapse of the channels inner gate. Results demonstrate how ADPKD-causing mutations cause mechanistically divergent and ranging impacts on PKD2 function, despite their shared structural proximity. These unexpected findings highlight the need for structural and biophysical characterization of polycystin variants, which will guide rational drug development of ADPKD therapeutics.}, archive = {J_PNAS}, author = {Palomero, Orhi Esarte and Guadarrama, Eduardo and DeCaen, Paul G.}, doi = {10.1073/pnas.2421362122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2421362122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pathogenic variants in the polycystin pore helix cause distinct forms of channel dysfunction}, volume = {122}, year = {2025}, }
• (2025). Structural basis of the hepatitis b virus x protein in complex with DDB1. PNAS, 122(24), e2421325122. (www)

  @article{ , abstract = {A cure for chronic hepatitis B requires eliminating or permanently silencing covalently closed circular DNA (cccDNA). A pivotal target of this approach is the hepatitis B virus (HBV) X protein (HBx), which is a key factor that promotes transcription from cccDNA. However, the HBx structure remains unsolved. Here, we present the cryoelectron microscopy structure of HBx in complex with DDB1, which is an essential complex for cccDNA transcription. In this structure, hydrophobic interactions within HBx were identified, and mutational analysis highlighted their importance in the HBV life cycle. Our biochemical analysis revealed that the HBx–DDB1 complex directly interacts simultaneously with NSE3, which is a component of the SMC5/6 complex, and Spindlin1. Additionally, HBx–DDB1 complex dynamics were explored via high-speed atomic force microscopy. These findings provide comprehensive insights into the structure and function of HBx in HBV replication.}, archive = {J_PNAS}, author = {Tanaka, Hiroki and Diogo Dias, Joao and Jay, Basile and Kita, Shunsuke and Sasaki, Mina and Takeda, Hiroyuki and Kishimoto, Naoki and Sasaki, Shunsuke and Misumi, Shogo and Mizokami, Masashi and Neuveut, Christine and Sumikama, Takashi and Shibata, Mikihiro and Maenaka, Katsumi and Machida, Shinichi}, doi = {10.1073/pnas.2421325122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2421325122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis of the hepatitis b virus x protein in complex with DDB1}, volume = {122}, year = {2025}, }
• (2025). Subfossil bald cypress trees suggest localized, enduring effects of major climatic episodes on the southeast atlantic coast of the united states. PNAS, 122(24), e2421181122. (www)

  @article{ , abstract = {Bald cypress ( Taxodium distichum ) is the longest-lived tree species in Eastern North America, but coastal cypress forests are vulnerable to a range of environmental factors [D. W. Stahle et al ., Q. Sci. Rev. 34 , 1–15 (2012)]. Here, we present analyses of bald cypress trees from a subfossil deposit at the mouth of the Altamaha River on the Georgia Coast, United States. Shifts in tree lifespans and growth rates correspond temporally to the onset of the Vandal Minimum environmental downturn, c. 500 CE. Trees that sprouted after c. 500 CE had significantly shorter lifespans on average (<200 y) than those that sprouted before this point in time (>470 y). Trees sprouting after c. 500 CE also grew significantly faster than those that sprouted before this point. Bald cypress lifespans at the Altamaha River mouth never recovered to pre-Vandal Minimum levels and, in fact, continued to decrease significantly over time. The last long-lived trees retrieved from the deposit died at the beginning of the Little Ice Age, another major climatic shift. This study suggests the enduring, localized impacts of climatic downturns and indicates the vulnerability to climate change of coastal cypress forests of the Southeast. These conclusions pertain to this location and, perhaps, other near-coastal forests. In remaining pockets of old-growth forest with bald cypress in the Southeast, 800 to 2600-y-old trees are still proven to be alive [D. W. Stahle et al ., Q. Sci. Rev . 34 , 1–15 (2012); D. W. Stahle et al ., Environ. Res. Commun. 1 , 1002 (2019)].}, archive = {J_PNAS}, author = {Napora, Katharine G. and Lecher, Alanna L. and Cherkinsky, Alexander and Horan, Robert and Jacobs, Craig and Tyler, Blaine and Thompson, Victor D.}, doi = {10.1073/pnas.2421181122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2421181122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Subfossil bald cypress trees suggest localized, enduring effects of major climatic episodes on the southeast atlantic coast of the united states}, volume = {122}, year = {2025}, }
• (2025). The bunkbed conjecture is false. PNAS, 122(24), e2420725122. (www)

  @article{ , abstract = {We give an explicit counterexample to the bunkbed conjecture introduced by Kasteleyn in 1985. The counterexample is given by a planar graph on 7,222 vertices and is built on the recent work of Hollom (2024).}, archive = {J_PNAS}, author = {Gladkov, Nikita and Pak, Igor and Zimin, Aleksandr}, doi = {10.1073/pnas.2420725122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2420725122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The bunkbed conjecture is false}, volume = {122}, year = {2025}, }
• (2025). Reproductive state controls transcription in the murine liver, with implications for breast cancer liver metastasis. PNAS, 122(24), e2420174122. (www)

  @article{ , abstract = {Liver biology is functionally linked to lactation, as liver size and metabolic output increase during lactation to support synthesis of breast milk. Upon weaning, the rodent liver returns to baseline homeostasis via hepatocyte cell death, in a process considered liver involution. To explore liver biology changes across a lactation-wean cycle, we employed transcriptomic profiling. We identified elevated hepatocyte proliferation and anabolic metabolism gene signatures during lactation, consistent with the liver being a major producer of substrates needed for milk production. Rapid loss of these capacities upon weaning correlated with catabolic metabolism, lysosomal-mediated cell death, and an enrichment of immune-suppressive cells. Furthermore, we identified that the transcriptional profiles associated with liver involution share similarities with the gene expression patterns of liver premetastatic niches. This work identifies features of reproductive control of liver biology that set a foundation for better understanding the potential role of the liver in maternal health.}, archive = {J_PNAS}, author = {Ozaki, Michelle K. and Zhang, Yi and Bartlett, Alexandra Q. and de Wilde, Elise and Guan, Xiangnan and Yang, Alex and Xia, Zheng and Schedin, Pepper}, doi = {10.1073/pnas.2420174122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2420174122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reproductive state controls transcription in the murine liver, with implications for breast cancer liver metastasis}, volume = {122}, year = {2025}, }
• (2025). Transglutaminase 2–mediated glutamine deamidation enhances p21 stability during senescence. PNAS, 122(24), e2419762122. (www)

  @article{ , abstract = {The limited doubling capacity of human cells, known as replicative senescence or cellular senescence, is a major factor in cellular aging. This process is triggered by telomere erosion, which activates a p53-mediated DNA damage response (DDR) that halts cell proliferation. p53, a transcriptional regulator, responds to DNA damage by increasing the expression of the cyclin-dependent kinase inhibitor p21. p21 then arrests cells at specific stages of the cell cycle. Additionally, p53 upregulates serpinB2 (also known as plasminogen activator inhibitor-2, PAI-2), which stabilizes p21 in senescent cells. This study reveals that serpinB2 upregulation activates transglutaminase 2 (TGM2), which selectively deamidates multiple glutamine residues on p21, stabilizing the protein and halting cell proliferation in senescent cells. Moreover, inhibiting TGM2-mediated deamidation accelerates p21 degradation, delaying the onset of senescence. Notably, pharmacological inhibition of TGM2 improves aging phenotypes in an accelerated aging model of chronic kidney disease (CKD). These findings provide crucial insights into the role of TGM2-mediated enzymatic deamidation in senescence and its potential relevance to age-associated conditions.}, archive = {J_PNAS}, author = {Liao, Yi-Wen and Hsieh, Hsi-Hsien and Yeh, Jin-Wei and Wang, Hsin-Chiao and Huang, Shang-Yi and Wang, Pei-Yu and Lin, Jing-Jer}, doi = {10.1073/pnas.2419762122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2419762122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transglutaminase 2–mediated glutamine deamidation enhances p21 stability during senescence}, volume = {122}, year = {2025}, }
• (2025). Synthetic models of the nitrogenase FeMo cofactor. PNAS, 122(24), e2419655122. (www)

  @article{ , abstract = {The FeMo cofactor (FeMoco), the key active site in the Mo-based nitrogenase, is one of the most complicated metalloenzyme molecules. Synthesis of the FeMoco model cluster ([MoFe 7 S 9 C]) is essential to understanding its function in dinitrogen binding, activation, and conversion. However, the complex framework of the FeMoco cluster, which features a unique trigonal prismatic [Fe 6 C] moiety comprising a µ 6 -bridging carbide, has made the synthesis of the cluster a persistent challenge. In this work, two analogous mimics of FeMoco have been synthesized, using a cluster-coupling synthetic strategy facilitated by the fabrication of unsaturated ligand/metal coordination. The incorporation of a µ 6 -X (X = C 4− or N 3− ) to construct the characteristic triangular prismatic [Fe 6 ( µ 6 -X)] moiety, replicating that in FeMoco, has been achieved synthetically. The two mimics have similar key structural parameters to FeMoco in natural nitrogenase, but differ from the FeMoco structure in two major aspects: the µ 2 -bridging ligands and the metal atoms capping the [Fe 6 S 9 C] cores (Mo/Fe in FeMoco vs. Mo/Mo or W/W in the synthetic models). Quantum chemical studies indicate that the electronic ground states of these clusters resemble those observed for FeMoco, with maximized antiferromagnetic coupling among the iron centers. A future systematic study on the physical and chemical properties of a family of mimics with programmed variations of key structural elements can provide a valuable comparison and facilitate a better understanding of the structure and function of FeMoco.}, archive = {J_PNAS}, author = {Xu, Yun-Yu and Jiang, Xue-Lian and Chai, Jia-Lu and Qiu, Shu-Juan and He, Juan and Xu, Gan and Wei, Jia and Yu, Qiu-Xiang and Zhang, Hong-Ying and Li, Yue and Zhang, Xiao-Wen and Cao, Guo-Liang and Li, Yong and Cui, Yun-Shu and Xu, Cong-Qiao and Li, Jun and Chen, Xu-Dong}, doi = {10.1073/pnas.2419655122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2419655122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synthetic models of the nitrogenase FeMo cofactor}, volume = {122}, year = {2025}, }
• (2025). Abundant piRNA production mediated by the drosophila GTSF1 homolog tpp ensures aubergine localization and germ plasm assembly. PNAS, 122(24), e2419375122. (www)

  @article{ , abstract = {Germ cells transmit genetic information to offspring and maintain the genome of the species. In many animals including Drosophila , germ cell formation relies on maternal determinants in the germ plasm. Several proteins present in the germ plasm of oocytes also localize to the perinuclear nuage in nurse cells, where they contribute to the production of PIWI-interacting RNAs (piRNAs). These piRNAs guide the silencing of transposons, thereby protecting the germline genome from invading mobile elements. Aubergine (Aub) is a germ plasm/nuage protein and a piRNA-directed endonuclease that inactivates transposons. Aub is also essential for germ plasm assembly. The Aub-bound piRNAs in the germ plasm are inherited by the progeny germline and serve as templates for piRNA biogenesis in the next generation. Thus, piRNA production in the nurse cell nuage is thought to be coordinated with germ plasm assembly in the oocyte. However, the underlying mechanism remains unclear. Here, we report that a maternal factor, named tiny pole plasm ( tpp ), mediates this coordination. Tpp is a GTSF1 family PIWI cofactor. In tpp − ovaries, the production of piRNAs, particularly Aub-bound piRNAs, is defective, resulting in reduced Aub localization to the germ plasm and impaired germ cell formation. Notably, the levels of piRNA production required for proper Aub localization are much higher than those required for transposon silencing. We propose that producing abundant piRNAs beyond what is required for transposon silencing in the ovary promotes germ plasm assembly, thereby enabling the progeny germline to properly silence transposons for species survival.}, archive = {J_PNAS}, author = {Kina, Hirono and Izumi, Natsuko and Hanyu-Nakamura, Kazuko and Yoshitani, Takashi and Yamane, Mariko and Niwa, Hitoshi and Tomari, Yukihide and Nakamura, Akira}, doi = {10.1073/pnas.2419375122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2419375122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Abundant piRNA production mediated by the drosophila GTSF1 homolog tpp ensures aubergine localization and germ plasm assembly}, volume = {122}, year = {2025}, }
• (2025). Improving polygenic prediction from whole-genome sequencing data by leveraging predicted epigenomic features. PNAS, 122(24), e2419202122. (www)

  @article{ , abstract = {Polygenic risk scores (PRS) are essential tools for estimating individual susceptibility to complex diseases by aggregating the effects of many genetic variants. With the advent of whole-genome sequencing (WGS), rare and de novo variants can now be detected at scale, presenting new opportunities to enhance PRS performance. Additionally, regulatory mechanisms that govern gene expression play a critical role in disease manifestation, suggesting further potential for improvement. However, most existing PRS methods are not well-equipped to incorporate nonlinear variant effects, rare variant contributions, or regulatory context. To address these limitations, we developed Epi-PRS, a novel framework that leverages large language models (LLMs) to impute cell-type-specific epigenomic signals from personal diploid genotypes. These imputed signals act as informative intermediates between genotype and phenotype, allowing for more accurate modeling of variant impact. Our simulation studies demonstrate that Epi-PRS improves predictive accuracy by incorporating nonlinear relationships, rare variant effects, and regulatory information across large genomic regions. When applied to real data from the UK Biobank, Epi-PRS significantly outperforms existing PRS approaches in predicting risk for both breast cancer and type 2 diabetes. These results underscore the advantages of integrating WGS data, epigenomic context, and advanced LLMs framework to enhance both the predictive power and interpretability of PRS. Overall, Epi-PRS represents a promising step toward more precise and biologically informed disease risk prediction, with broad implications for advancing personalized medicine and understanding complex genetic architectures.}, archive = {J_PNAS}, author = {Zeng, Wanwen and Guo, Hanmin and Liu, Qiao and Wong, Wing Hung}, doi = {10.1073/pnas.2419202122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2419202122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Improving polygenic prediction from whole-genome sequencing data by leveraging predicted epigenomic features}, volume = {122}, year = {2025}, }
• (2025). Structural basis of the catalytic and allosteric mechanism of bacterial acetyltransferase PatZ. PNAS, 122(24), e2419096122. (www)

  @article{ , abstract = {GCN5-related N -acetyltransferases (GNATs) are essential for regulating bacterial metabolism by acetylating specific target proteins. Despite their importance in bacterial physiology, the mechanisms behind their enzymatic and regulatory functions remain poorly understood. In this study, we investigated the structures of Escherichia coli protein acetyltransferase Z (PatZ), a Type I GNAT, and examined its ligand interactions, catalytic mechanism, and allosteric regulation. PatZ functions as a homotetramer, with each subunit comprising a catalytic and a regulatory domain. Our results demonstrate that the regulatory domain is vital for acetyltransferase activity, as it triggers cooperative conformational changes in the catalytic domain and directly aids in the formation of substrate-binding pockets. Additionally, a protein structure-based evolutionary analysis of bacterial GNAT types revealed a distinct regulatory domain pattern across phyla, highlighting its crucial role in responding to cellular energy levels.}, archive = {J_PNAS}, author = {Park, Jun Bae and Lee, Gwanwoo and Han, Yu-Yeon and Kim, Dongwook and Heo, Kyoo and Kim, Jeesoo and Park, Juhee and Yun, Hyosuk and Lee, Chul Won and Cho, Hyun-Soo and Kim, Jong-Seo and Steinegger, Martin and Seok, Yeong-Jae and Roh, Soung-Hun}, doi = {10.1073/pnas.2419096122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2419096122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis of the catalytic and allosteric mechanism of bacterial acetyltransferase PatZ}, volume = {122}, year = {2025}, }
• (2025). Electrical spinal cord stimulation promotes focal sensorimotor activation that accelerates brain–computer interface skill learning. PNAS, 122(24), e2418920122. (www)

  @article{ , abstract = {Injuries affecting the central nervous system may disrupt neural pathways to muscles causing motor deficits. Yet the brain exhibits sensorimotor rhythms (SMRs) during movement intents, and brain–computer interfaces (BCIs) can decode SMRs to control assistive devices and promote functional recovery. However, noninvasive BCIs suffer from the instability of SMRs, requiring longitudinal training for users to learn proper SMR modulation. Here, we accelerate this skill learning process by applying cervical transcutaneous electrical spinal stimulation (TESS) to inhibit the motor cortex prior to longitudinal upper-limb BCI training. Results support a mechanistic role for cortical inhibition in significantly increasing focality and strength of SMRs leading to accelerated BCI control in healthy subjects and an individual with spinal cord injury. Improvements were observed following only two TESS sessions and were maintained for at least one week in users who could not otherwise achieve control. Our findings provide promising possibilities for advancing BCI-based motor rehabilitation.}, archive = {J_PNAS}, author = {Alawieh, Hussein and Liu, Deland and Madera, Jonathan and Kumar, Satyam and Racz, Frigyes Samuel and Fey, Ann Majewicz and del R. Millán, José}, doi = {10.1073/pnas.2418920122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2418920122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electrical spinal cord stimulation promotes focal sensorimotor activation that accelerates brain–computer interface skill learning}, volume = {122}, year = {2025}, }
• (2025). Systemic in utero gene editing as a treatment for cystic fibrosis. PNAS, 122(24), e2418731122. (www)

  @article{ , abstract = {In utero gene editing has the potential to modify disease-causing genes in multiple developing tissues before birth, possibly allowing for normal organ development, disease improvement, and conceivably, cure. In cystic fibrosis (CF), a disease that arises from mutations in the CF transmembrane conductance regulator ( CFTR ) gene, there are signs of multiorgan disease affecting the function of the respiratory, gastrointestinal, and reproductive systems already present at birth. Thus, treating CF patients early is crucial for preventing or delaying irreversible organ damage. Here, we demonstrate proof-of-concept of multiorgan mutation correction in CF using peptide nucleic acids encapsulated in polymeric nanoparticles and delivered systemically in utero. In utero editing was associated with sustained postnatal CFTR activity, at a level similar to that of wild-type mice, in both respiratory and gastrointestinal tissues, without detection of off-target mutations in partially homologous loci. This work suggests that systemic in utero gene editing represents a viable strategy for treating monogenic diseases before birth that impact multiple tissue types.}, archive = {J_PNAS}, author = {Ricciardi, Adele S. and Barone, Christina and Putman, Rachael and Quijano, Elias and Gupta, Anisha and Nguyen, Richard and Mandl, Hanna and Piotrowski-Daspit, Alexandra S. and Lopez-Giraldez, Francesc and Luks, Valerie and Freedman-Weiss, Mollie R. and Farrelly, James and Ahle, Samantha and Lynn, Anna Y. and Glazer, Peter M. and Saltzman, W. Mark and Stitelman, David H. and Egan, Marie E.}, doi = {10.1073/pnas.2418731122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2418731122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Systemic in utero gene editing as a treatment for cystic fibrosis}, volume = {122}, year = {2025}, }
• (2025). Impact of large-scale solar on property values in the united states: Diverse effects and causal mechanisms. PNAS, 122(24), e2418414122. (www)

  @article{ , abstract = {As the renewable energy transition continues into less receptive communities, local opposition is expected to intensify, potentially slowing the process. Since the local impacts are neither well quantified nor widely recognized, we lack policies and common practices to mitigate the potential associated welfare loss in affected communities. Based on a nationwide dataset combining property transactions and large-scale solar photovoltaic (LSSPV) sites, we analyze the heterogeneous effects of LSSPV on property prices and the associated causal pathways. Difference-in-differences estimates show that LSSPV significantly increases agricultural or vacant land value by about 19.4% within a 2-mile radius, while simultaneously reducing residential property values within 3 miles by about 4.8%. The estimated average negative impact on home values is primarily driven by site proximity and diminishes with both distance and time. Effect estimates are more robust to alternative specifications when proximity pairs with visibility rather than invisibility, but no evidence suggests visibility significantly amplifies the proximity effect. Heterogeneous effect estimates indicate that high solar lease potential, being in heavily Democratic-leaning counties, and brownfield redevelopment largely mitigate the negative residential value impact. The analysis reveals no significant heterogeneity across a few factors, including varying site visibility, directional orientation of properties relative to the LSSPV site, and different tracking systems. Evidence indicates that the negative impact on residential values might mainly stem from negative perceptions, but channels through physical conditions cannot be entirely dismissed. Our assessment provides benchmark information for local externality mitigation plans, potentially reducing community opposition and expediting the renewable energy transition.}, archive = {J_PNAS}, author = {Hu, Chenyang and Chen, Zhenshan and Liu, Pengfei and Zhang, Wei and He, Xi and Bosch, Darrell}, doi = {10.1073/pnas.2418414122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2418414122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Impact of large-scale solar on property values in the united states: Diverse effects and causal mechanisms}, volume = {122}, year = {2025}, }
• (2025). Nutrient storage links past thermal exposure to current performance in phytoplankton. PNAS, 122(24), e2418108122. (www)

  @article{ , abstract = {The growth of populations and organisms often depends on their previous history of environmental exposure: a phenomenon referred to as “phenotypic memory.” The field of ecology presently lacks a mechanistic theory describing phenotypic memory and, as such, evaluating the ecological consequences of this phenomenon is a major challenge. Here, we show that internal nutrient storage connects past thermal experience to current growth in phytoplankton. We develop a mechanistic model showing that delays in the response of nutrient stores to changing temperatures produces phenotypic memory. By testing this model against experimental data of phytoplankton growth rates following temperature perturbations, we find general patterns in the population consequences of phenotypic memory: Prior exposure to warm temperatures depletes nutrient stores, and, in doing so, slows growth during subsequent temperature exposure and restricts the breadth of the thermal niche (i.e., the range of acute temperature exposures yielding a positive growth rate). Our model reveals how phenotypic memory produces temporal variation in critical thermal minima and maxima and predicts that the thermal niche is constricted by long-term exposure to warm temperatures (e.g., during summer months), but that high frequency temperature fluctuations can expand a population’s thermal niche. This work provides a mechanistic framework for considering the ecological implications of phenotypic memory.}, archive = {J_PNAS}, author = {Anderson, David M. and Fey, Samuel B. and Meier, Hannah S. and Vasseur, David A. and Kremer, Colin T.}, doi = {10.1073/pnas.2418108122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2418108122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nutrient storage links past thermal exposure to current performance in phytoplankton}, volume = {122}, year = {2025}, }
• (2025). Continuous self-repair protects vimentin intermediate filaments from fragmentation. PNAS, 122(24), e2417660122. (www)

  @article{ , abstract = {Intermediate filaments are key regulators of cell mechanics. Vimentin, a type of intermediate filament expressed in mesenchymal cells and involved in migration, forms a dense network in the cytoplasm that is constantly remodeling through filament transport, elongation/shortening, and subunit exchange. While it is known that filament elongation involves end-to-end annealing, the reverse process of filament shortening by fragmentation remains unclear. Here, we use a combination of in vitro reconstitution, probed by fluorescence imaging and atomic force microscopy, with theoretical modeling to uncover the molecular mechanism involved in filament breakage. We first show that vimentin filaments are composed of two populations of subunits, half of which are exchangeable and half immobile. We also show that the exchangeable subunits are tetramers. Furthermore, we reveal a mechanism of continuous filament self-repair, where a soluble pool of vimentin tetramers in equilibrium with the filaments is essential to maintain filament integrity. Filaments break due to local fluctuations in the number of tetramers per cross-section, induced by the constant subunit exchange. We determine that a filament tends to break if approximately four tetramers are removed from the same filament cross-section. Finally, we analyze the dynamics of association/dissociation and fragmentation to estimate the binding energy of a tetramer to a complete versus a partially disassembled filament. Our results provide a comprehensive description of vimentin turnover and reveal the link between subunit exchange and fragmentation.}, archive = {J_PNAS}, author = {Tran, Quang D. and Lenz, Martin and Lamour, Guillaume and Paty, Lilian and Varela-Salgado, Maritzaida and Campillo, Clément and Wioland, Hugo and Jegou, Antoine and Romet-Lemonne, Guillaume and Leduc, Cécile}, doi = {10.1073/pnas.2417660122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2417660122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Continuous self-repair protects vimentin intermediate filaments from fragmentation}, volume = {122}, year = {2025}, }
• (2025). Motor-driven microtubule diffusion in a photobleached dynamical coordinate system. PNAS, 122(24), e2417020122. (www)

  @article{ , abstract = {A hallmark feature of active matter systems is the ability of individual elements to interact and organize over length scales exceeding that of the constituent molecular players. However, the nature of internal redistribution that occurs in the bulk of the collective is less clear. Using light-dimerizable kinesin motors to spatially control the formation and contraction of a microtubule network, we deliberately photobleach a grid pattern onto the filament network serving as a transient and dynamic coordinate system to observe the deformation and translation of the remaining fluorescent squares of microtubules. We find that the network contracts at a rate set by motor speed but is accompanied by a diffusive-like spread throughout the bulk of the contracting network with effective diffusion constant two orders of magnitude lower than that for freely diffusing microtubules. We further find that on micron scales, the diffusive timescale is only a factor of ≈3 slower than that of advection regardless of conditions, showing that the global contraction and long-time relaxation from this diffusive behavior are both motor-driven but exhibit local competition within the network bulk.}, archive = {J_PNAS}, author = {Hirokawa, Soichi and Lee, Heun Jin and Banks, Rachel A. and Duarte, Ana I. and Najma, Bibi and Thomson, Matt and Phillips, Rob}, doi = {10.1073/pnas.2417020122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2417020122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Motor-driven microtubule diffusion in a photobleached dynamical coordinate system}, volume = {122}, year = {2025}, }
• (2025). Bias-aware training and evaluation of link prediction algorithms in network biology. PNAS, 122(24), e2416646122. (www)

  @article{ , abstract = {For biomedical applications, new link prediction algorithms are continuously being developed. These algorithms are typically evaluated computationally, using test sets generated by sampling the edges uniformly at random. However, as we demonstrate, this evaluation approach introduces a bias toward “rich nodes,” i.e., those with higher degrees in the network. More concerningly, this bias persists even when different network snapshots are used for evaluation, as recommended in the machine learning community. This creates a cycle in research where newly developed algorithms generate more knowledge on well-studied biological entities while understudied entities are commonly overlooked. To overcome this issue, we propose a weighted validation setting specifically focusing on low-degree nodes and present AWARE strategies to facilitate bias-aware training and evaluation of link prediction algorithms. These strategies can help researchers gain better insights from computational evaluations and promote the development of new algorithms focusing on novel findings and understudied proteins.}, archive = {J_PNAS}, author = {Yılmaz, Serhan and Yorgancioglu, Kaan and Koyutürk, Mehmet}, doi = {10.1073/pnas.2416646122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2416646122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bias-aware training and evaluation of link prediction algorithms in network biology}, volume = {122}, year = {2025}, }
• (2025). Revealing unseen dynamical regimes of ecosystems from population time-series data. PNAS, 122(24), e2416637122. (www)

  @article{ , abstract = {Many dynamical systems can exist in alternative regimes for which small changes in an environmental driver can cause sudden jumps between regimes. In ecology, predicting the regime of population fluctuations under unobserved levels of an environmental driver has remained an unsolved challenge with important implications for conservation and management. Here, we show that integrating time-series data and information on a putative driver into a Gaussian Process regression model for the system’s dynamics allows us to predict dynamical regimes without the need to specify the equations of motion of the system. As a proof of concept, we demonstrate that we can accurately predict fixed-point, cyclic, or chaotic dynamics under unseen levels of a control parameter for a range of simulated population dynamics models. For a model with an abrupt population collapse, we show that our approach goes beyond an early warning signal by characterizing the regime that follows the tipping point. We then apply our approach to data from an experimental microbial food web and from a lake planktonic food web. We find that we can reconstruct transitions away from chaos in the microbial food web and anticipate the dynamics of the oligotrophic regime in the planktonic food web. These results lay the groundwork for making rational decisions about preventing, or preparing for, regime shifts in natural ecosystems and other dynamical systems.}, archive = {J_PNAS}, author = {Medeiros, Lucas P. and Sorenson, Darian K. and Johnson, Bethany J. and Palkovacs, Eric P. and Munch, Stephan B.}, doi = {10.1073/pnas.2416637122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2416637122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Revealing unseen dynamical regimes of ecosystems from population time-series data}, volume = {122}, year = {2025}, }
• (2025). Feedback regulation between histone lactylation and ALKBH3-mediated glycolysis regulates age-related macular degeneration pathology. PNAS, 122(24), e2416046122. (www)

  @article{ , abstract = {Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly. It is characterized by degeneration of the retinal pigment epithelium (RPE), which can develop into choroidal neovascularization (CNV) to cause severe and rapid vision loss. Preventing this progression might help save vision, but the exact mechanisms remain unclear. In this study, using clinical AMD samples and the gene knockout mice, we reported that the m 1 A eraser ALKBH3 reshaped retinal metabolism to promote this progression. In RPE, the dm 1 ACRISPR system demonstrated that ALKBH3 demethylated the rate-limiting glycolytic enzyme HK2 to activate glycolysis, resulting in excess lactate production. This lactate promoted histone lactylation at H3K18, which in turn bound to ALKBH3 to amplify its transcription, establishing a positive feedback loop. The ALKBH3 inhibitor HUHS015 disrupted this loop, effectively mitigating RPE degeneration. Furthermore, ALKBH3 directly targeted the proangiogenic factor VEGFA to modulate the metabolic cross-talk between RPE and choroidal capillaries, thus promoting CNV. HUHS015 inhibited CNV synergistically with the anti-VEGF drug Aflibercept. Overall, our study provides critical insights into the molecular mechanisms and metabolic events that facilitates the progression from RPE degeneration to CNV in AMD, laying the groundwork for new treatments of age-related retinal disorders.}, archive = {J_PNAS}, author = {Wang, Ying and Zhang, Yi-Chen and Ding, Zi-Qin and Xu, Shi-Yao and Zhang, Ye-Ran and Zhu, Hong-Jing and Huang, Chang and Wang, Jia-Nan and Zhu, Meidong and Ji, Jiang-Dong and Yan, Biao and Liu, Qing-Huai and Chen, Xue}, doi = {10.1073/pnas.2416046122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2416046122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Feedback regulation between histone lactylation and ALKBH3-mediated glycolysis regulates age-related macular degeneration pathology}, volume = {122}, year = {2025}, }
• (2025). Generative prediction of causal gene sets responsible for complex traits. PNAS, 122(24), e2415071122. (www)

  @article{ , abstract = {The relationship between genotype and phenotype remains an outstanding question for organism-level traits because these traits are generally complex . The challenge arises from complex traits being determined by a combination of multiple genes (or loci), which leads to an explosion of possible genotype–phenotype mappings. The primary techniques to resolve these mappings are genome/transcriptome-wide association studies, which are limited by their lack of causal inference and statistical power. Here, we develop an approach that combines transcriptional data endowed with causal information and a generative machine learning model designed to strengthen statistical power. Our implementation of the approach—dubbed transcriptome-wide conditional variational autoencoder (TWAVE)—includes a variational autoencoder trained on human transcriptional data, which is incorporated into an optimization framework. Given a trait phenotype, TWAVE generates expression profiles, which we dimensionally reduce by identifying independently varying generalized pathways (eigengenes). We then conduct constrained optimization to find causal gene sets that are the gene perturbations whose measured transcriptomic responses best explain trait phenotype differences. By considering several complex traits, we show that the approach identifies causal genes that cannot be detected by the primary existing techniques. Moreover, the approach identifies complex diseases caused by distinct sets of genes, meaning that the disease is polygenic and exhibits distinct subtypes driven by different genotype–phenotype mappings. We suggest that the approach will enable the design of tailored experiments to identify multigenic targets to address complex diseases.}, archive = {J_PNAS}, author = {Kuznets-Speck, Benjamin and Ogonor, Buduka K. and Wytock, Thomas P. and Motter, Adilson E.}, doi = {10.1073/pnas.2415071122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2415071122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Generative prediction of causal gene sets responsible for complex traits}, volume = {122}, year = {2025}, }
• (2025). Longitudinal trajectories of brain development from infancy to school age and their relationship with literacy development. PNAS, 122(24), e2414598122. (www)

  @article{ , abstract = {Reading is one of the most complex skills that we utilize daily, and it involves the early development and interaction of various lower-level subskills, including phonological processing and oral language. These subskills recruit brain structures, which begin to develop long before the skill manifests and exhibit rapid development during infancy. However, how longitudinal trajectories of early brain development in these structures support long-term acquisition of literacy subskills and subsequent reading is unclear. Children underwent structural and diffusion MRI scanning at multiple timepoints between infancy and second grade and were tested for literacy subskills in preschool and decoding and word reading in early elementary school. We developed and implemented a reproducible pipeline to generate longitudinal trajectories of early brain development. We then examined whether these trajectories were associated with literacy (sub)skills or influenced by familial risk of reading difficulty and children’s home literacy environments, two common literacy-related covariates. Results showed that individual differences in curve features (e.g., intercepts and slopes) for longitudinal trajectories of volumetric, surface-based, and white matter organization measures were linked directly to phonological processing and indirectly to early elementary school decoding and word reading skills via phonological processing. Altogether, these findings suggest that the brain bases of phonological processing, previously identified as one of the strongest behavioral predictors of decoding and word reading skills, may already begin to develop by birth but undergo further refinement between infancy and preschool. The present study underscores the importance of considering academic skill acquisition from the very beginning of life.}, archive = {J_PNAS}, author = {Turesky, Ted K. and Escalante, Elizabeth S. and Loh, Megan and Gaab, Nadine}, doi = {10.1073/pnas.2414598122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2414598122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Longitudinal trajectories of brain development from infancy to school age and their relationship with literacy development}, volume = {122}, year = {2025}, }
• (2025). A synchrotron-like pumped ring resonator for water waves. PNAS, 122(24), e2414587122. (www)

  @article{ , abstract = {The wave-like behavior of matter in quantum physics has spurred insightful analogies between the dynamics of particles and waves in classical systems. In this study, drawing inspiration from synchrotrons that resonate to accelerate ions along a closed path, we introduce a synchrowave: a waveguide designed to generate and sustain traveling water waves within an annular channel. In analogy to unavoidable energy losses in conventional particle accelerators due to electromagnetic radiation and inelastic collisions, the system displays undesired water-wave dampening, which we address through the synchronized action of underwater wavemakers. Our analogies extend the resonance mechanisms of synchrotrons to generate and sustain gravity waves in closed waveguides efficiently. A proof-of-concept experiment at a laboratory scale demonstrates the unique capability of this technique to build up anomalously large traveling waves displaying a flat response in the long-wave limit. Besides quantifying the performance of wave generation, our findings offer a framework for both industrial and computational applications, opening up unexplored possibilities in hydraulics, coastal science, and engineering. In a broader context, our experimental apparatus and methods highlight the versatility of a simple yet powerful concept: a closed-path continuous-energy-pumping scheme to effectively harvest prominent resonant responses within wave-supporting systems displaying weak dissipation.}, archive = {J_PNAS}, author = {Vivanco, Isis and Egli, Alexander and Cartwright, Bruce and Marín, Juan F. and Gordillo, Leonardo}, doi = {10.1073/pnas.2414587122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2414587122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A synchrotron-like pumped ring resonator for water waves}, volume = {122}, year = {2025}, }
• (2025). China’s SO2 emission reductions enhance atmospheric ozone–driven sulfate aerosol production in east asia. PNAS, 122(24), e2414064122. (www)

  @article{ , abstract = {Reduction of China’s SO 2 emissions has been found to nonlinearly decrease the atmospheric sulfate (SO 4 2− ) aerosol concentrations in East Asia. Compared to Europe and North America, the lower effectiveness of SO 4 2− reduction in East Asia suggested much effects of “acidity-sensitive” feedback mechanisms in this high anthropogenic emission region, which have not been yet examined. In this work, we investigated these feedback mechanisms in East Asia through long-term measurements of the mass-independent oxygen-17 anomaly (Δ 17 O) in sulfate aerosols, machine learning and Community Multiscale Air Quality (CMAQ) model. As China’s emissions reduced, the atmospheric acidity decreased, enhancing the ozone-driven oxidation of S(IV) and production efficiency of sulfate formation. This explained the weaker declining SO 4 2− concentrations than SO 2 emissions. By the evidence from observed Δ 17 O in non-sea-salt sulfate (Δ 17 O-nss-SO 4 2− ) and CMAQ simulations, the highly enhanced contributions of S(IV)+O 3 to sulfate driven by reduced SO 2 emissions explained the low effectiveness of SO 4 2− reduction in East Asia. Additionally, the decreases of acidity by substantial NH 3 emissions are projected to continue until 2050, limiting SO 4 2− reduction effectiveness. Thus, we highlighted that global control of both SO 2 and NH 3 emissions are needed to efficiently mitigate the sulfate-related climate and pollution, especially in high NH 3 emission region, such as East Asia.}, archive = {J_PNAS}, author = {Lin, Yu-Chi and Zhao, Yan and Zhang, Yan-Lin and Hong, Yihang and Hattori, Shohei and Itahashi, Syuichi and Fan, Mei-Yi and Xie, Feng and Zhao, Zhu-Yu and Yu, Mingyuan and Cao, Fang and Xu, Rongshuang and Li, Jianghanyang and Kawamura, Kimitaka and Thiemens, Mark H.}, doi = {10.1073/pnas.2414064122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2414064122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {China’s SO2 emission reductions enhance atmospheric ozone–driven sulfate aerosol production in east asia}, volume = {122}, year = {2025}, }
• (2025). Representation of locomotive action affordances in human behavior, brains, and deep neural networks. PNAS, 122(24), e2414005122. (www)

  @article{ , abstract = {To decide how to move around the world, we must determine which locomotive actions (e.g., walking, swimming, or climbing) are afforded by the immediate visual environment. The neural basis of our ability to recognize locomotive affordances is unknown. Here, we compare human behavioral annotations, functional MRI (fMRI) measurements, and deep neural network (DNN) activations to both indoor and outdoor real-world images to demonstrate that the human visual cortex represents locomotive action affordances in complex visual scenes. Hierarchical clustering of behavioral annotations of six possible locomotive actions show that humans group environments into distinct affordance clusters using at least three separate dimensions. Representational similarity analysis of multivoxel fMRI responses in the scene-selective visual cortex shows that perceived locomotive affordances are represented independently from other scene properties such as objects, surface materials, scene category, or global properties and independent of the task performed in the scanner. Visual feature activations from DNNs trained on object or scene classification as well as a range of other visual understanding tasks correlate comparatively lower with behavioral and neural representations of locomotive affordances than with object representations. Training DNNs directly on affordance labels or using affordance-centered language embeddings increases alignment with human behavior, but none of the tested models fully captures locomotive action affordance perception. These results uncover a type of representation in the human brain that reflects locomotive action affordances.}, archive = {J_PNAS}, author = {Bartnik, Clemens G. and Sartzetaki, Christina and Sanchez, Abel Puigseslloses and Molenkamp, Elijah and Bommer, Steven and Vukšić, Nikolina and Groen, Iris I. A.}, doi = {10.1073/pnas.2414005122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2414005122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Representation of locomotive action affordances in human behavior, brains, and deep neural networks}, volume = {122}, year = {2025}, }
• (2025). An N-terminal domain specifies developmental control by the SMAX1-LIKE family of transcriptional regulators in arabidopsis thaliana. PNAS, 122(24), e2412793122. (www)

  @article{ , abstract = {SMAX1-LIKE (SMXL) proteins in plants are cellular signaling hubs, many of which are posttranslationally regulated by karrikins from smoke, the plant hormones strigolactones (SLs), and/or cues such as light and nutrients. SMXL proteins control diverse aspects of growth, development, and environmental adaptation in plants through transcriptional corepression and interactions with transcriptional regulator proteins. In flowering plants, the SMXL family comprises four phylogenetic clades with different roles. Functions of the aSMAX1 clade include control of germination and seedling development, while the SMXL78 clade controls shoot architecture. We investigated how SMXL roles are specified in Arabidopsis thaliana. Through promoter-swapping experiments, we found that SMXL7 can partially replicate SMAX1 function, but SMAX1 cannot replace SMXL7 . This implies that the distinct roles of these genes are primarily due to differences in protein sequences rather than expression patterns. To determine which part of SMXL proteins specifies downstream control, we tested a series of protein chimeras and domain deletions of SMAX1 and SMXL7. We found an N-terminal region that is necessary and sufficient to specify control of germination, seedling growth, or axillary branching. We screened 158 transcription factors (TFs) for interactions with SMAX1 and SMXL7 in yeast two-hybrid assays. The N-terminal domain was necessary and/or sufficient for most of the 33 potential protein–protein interactions that were identified for SMAX1. This finding unlocks different ways to engineer plant growth control through cross-wiring SMXL regulatory “input” and developmental “output” domains from different clades and lays a foundation for understanding how functional differences evolved in the SMXL family.}, archive = {J_PNAS}, author = {Chang, Sun Hyun and George, Wesley J. and Nelson, David C.}, doi = {10.1073/pnas.2412793122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2412793122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An N-terminal domain specifies developmental control by the SMAX1-LIKE family of transcriptional regulators in arabidopsis thaliana}, volume = {122}, year = {2025}, }
• (2025). Keratinocyte–TRPV1 sensory neuron interactions in a genetically controllable mouse model of chronic neuropathic itch. PNAS, 122(24), e2411724122. (www)

  @article{ , abstract = {Our understanding of neural circuits that respond to skin dysfunction, triggering itch, and pathophysiological scratching remains incomplete. Here, we describe a profound chronic itch phenotype in transgenic mice expressing the tetracycline transactivator (tTA) gene within the Phox2a lineage. Phox2a; tTA mice exhibit intense, localized scratching and regional skin lesions, controllable by the tTA inhibitor, doxycycline. As gabapentin and the kappa opioid receptor agonist, nalfurafine, but not morphine, significantly reduce scratching, this phenotype has a pharmacological profile of neuropathic pruritus. Importantly, the Phox2a; tTA expression occurs in a spatially restricted population of skin keratinocytes that overlaps precisely with the skin area that is scratched. Localized G i -DREADD-mediated inactivation of these Phox2a-keratinocytes completely reverses the skin lesions, while inducible tTA activation of keratinocytes initiates the condition. Notably, ablation of TRPV1-expressing primary afferent neurons also reduces scratching and skin lesions, but this occurs slowly, over a course of two months. In contrast denervation induced loss of all cutaneous input rapidly blocks scratching. These findings identify the cellular, molecular, and topographic basis of a robust and chronic sensory neuron–dependent and gabapentin-responsive neuropathic itch that is initiated by genetic factors within keratinocytes.}, archive = {J_PNAS}, author = {Crowther, Andrew J. and Kashem, Sakeen W. and Jewell, Madison E. and Le Chang, Henry and Midavaine, Élora and Rosa Casillas, Mariela and Danchine, Veronika and Rodriguez, Sian and Kania, Artur and Chen, Ritchie and Braz, Joao M. and Basbaum, Allan I.}, doi = {10.1073/pnas.2411724122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2411724122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Keratinocyte–TRPV1 sensory neuron interactions in a genetically controllable mouse model of chronic neuropathic itch}, volume = {122}, year = {2025}, }
• (2025). Measuring historical pollution: Natural history collections as tools for public health and environmental justice research. PNAS, 122(24), e2403781122. (www)

  @article{ , abstract = {Through the industrial era, pollutants have been unevenly distributed in the environment, disproportionately impacting disenfranchised communities. Redressing the unequal distribution of environmental pollution is thus a question of environmental justice and public health that requires policy solutions. However, data on pollutants for many locations and time periods are limited because environmental monitoring is largely reactive—i.e., pollutants are monitored only after they are recognized as harmful and are circulating in the environment at elevated levels. Without comprehensive historical pollution data, it is difficult to understand the full, intergenerational consequences of pollutants on environmental and human health. We assert that biological specimens in natural history collections are an underutilized source of quantitative pollution data for tracking environmental pollutants over two centuries to inform justice-centered policy solutions. Specifically, we: 1) discuss the need for quantitative pollution data in environmental research and its implications for public health and policy, 2) examine the capacity of biological specimens as tools for tracking environmental pollutants through space and time, 3) present a framework for integrating pollution datasets from specimens with spatially and temporally matched human health datasets to inform and evaluate policy, and 4) identify challenges and research directions associated with the use of quantitative pollution datasets. Biological specimens present a unique opportunity to fill critical gaps that address environmental challenges relevant to public health and policy. This work demands interdisciplinary partnerships and inclusive practices to connect data generated from specimens with urgent questions about environmental health and justice.}, archive = {J_PNAS}, author = {DuBay, Shane and Weeks, Brian C. and Davis-Kean, Pamela E. and Fuldner, Carl and Harris, Nyeema C. and Hughes, Sara and O’Brien, Bruce and Perkins, Marie and Weyant, Cheryl}, doi = {10.1073/pnas.2403781122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2403781122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Measuring historical pollution: Natural history collections as tools for public health and environmental justice research}, volume = {122}, year = {2025}, }
• (2025). Measuring premature and cumulative family member bereavement: Racial disparities and later mortality risk. PNAS, 122(24), e2313600122. (www)

  @article{ , abstract = {Though racial disparities in shortened life expectancy have been well established, racial disparities in the burden of bereavement after such premature deaths are severely understudied. This is, in part, due to a lack of measurement tools for characterizing lifetime exposure to loss. We propose three indices that simultaneously quantify premature and cumulative lifetime loss—two typically unmeasured dimensions of loss. Using a longitudinal US sample of 27,985 participants from the Health and Retirement Study (1992 to 2020) who experienced at least one lifetime loss, hierarchical linear models accounting for participants nested within households showed that Black participants and Native American participants had higher premature and cumulative burden of family member loss over the lifetime than all other racial groups across all three indices. These effects remained for Black participants after controlling for covariates such as parental education, household size, and years in the study. Second, we found that loss burden at study enrollment prospectively related to all-cause mortality. Depending on prematurity, each additional loss related to higher odds of dying during the study period after controlling for covariates such as chronic health conditions. Together, our work leverages prospective, longitudinal methodologies to identify racial disparities in exposure to earlier and repeated death and its impact on mortality among the bereaved. The proposed measurement approach has future applications for understanding how loss exposure—both “too soon” and “too much”—predicts poor health and earlier mortality.}, archive = {J_PNAS}, author = {Chang, Michelle and Robles, Theodore F.}, doi = {10.1073/pnas.2313600122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {24}, pages = {e2313600122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Measuring premature and cumulative family member bereavement: Racial disparities and later mortality risk}, volume = {122}, year = {2025}, }
• (2025). Correction for yin et al., tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling. PNAS, 122(23), e2511044122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2511044122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2511044122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for yin et al., tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling}, volume = {122}, year = {2025}, }
• (2025). Correction for bizup et al., cochlear zinc signaling dysregulation is associated with noise-induced hearing loss, and zinc chelation enhances cochlear recovery. PNAS, 122(23), e2510900122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2510900122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2510900122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for bizup et al., cochlear zinc signaling dysregulation is associated with noise-induced hearing loss, and zinc chelation enhances cochlear recovery}, volume = {122}, year = {2025}, }
• (2025). Correction for arseni et al., TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin. PNAS, 122(23), e2510823122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2510823122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2510823122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for arseni et al., TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin}, volume = {122}, year = {2025}, }
• (2025). Correction for guo et al., targeting amyloid-β in glaucoma treatment. PNAS, 122(23), e2510179122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2510179122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2510179122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for guo et al., targeting amyloid-β in glaucoma treatment}, volume = {122}, year = {2025}, }
• (2025). Location, location, location: Cholesterol in lipid droplets as a driver of MASH progression. PNAS, 122(23), e2509899122. (www)

  @article{ , archive = {J_PNAS}, author = {Wang, Xiaobo and Tabas, Ira}, doi = {10.1073/pnas.2509899122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2509899122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Location, location, location: Cholesterol in lipid droplets as a driver of MASH progression}, volume = {122}, year = {2025}, }
• (2025). Reply to apanovich and weeks: Exceptions exist, as recognized in the paper, but are too rare to challenge the original findings. PNAS, 122(23), e2509168122. (www)

  @article{ , archive = {J_PNAS}, author = {Eshel, Gidon and Flamholz, Avi I. and Shepon, Alon and Milo, Ron}, doi = {10.1073/pnas.2509168122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2509168122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to apanovich and weeks: Exceptions exist, as recognized in the paper, but are too rare to challenge the original findings}, volume = {122}, year = {2025}, }
• (2025). Early dynamics of chromatin decompaction drive nuclear stiffening. PNAS, 122(23), e2508415122. (www)

  @article{ , archive = {J_PNAS}, author = {Ivanovska, Irena L.}, doi = {10.1073/pnas.2508415122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2508415122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Early dynamics of chromatin decompaction drive nuclear stiffening}, volume = {122}, year = {2025}, }
• (2025). Direct sensing of host ferric iron by an archetype histidine kinase mediates virulence of an enteric pathogen. PNAS, 122(23), e2507874122. (www)

  @article{ , abstract = {Two-component system (TCS) histidine kinases enable bacterial pathogens to sense environmental signals and regulate adaptive responses during infection. The EnvZ/OmpR TCS, known for its role in osmolarity/pH-dependent regulation of outer membrane porins across bacterial species, is also a central virulence regulator. However, the environmental cues that activate EnvZ/OmpR to trigger pathogenicity have remained unclear, limiting our understanding of host–pathogen interactions. Here, we demonstrate that in Vibrio parahaemolyticus , a major etiological agent of seafood-associated gastroenteritis, EnvZ functions as a direct ferric iron (Fe 3+ ) sensor governing virulence programs. Fe 3+ -EnvZ interaction triggers kinase phosphorylation and activation, enabling transcriptional control of biofilm formation, swarming motility, and type 3/6 secretion systems. An iron-binding-deficient EnvZ mutant (EnvZ Q103A ) abrogated Fe 3+ responsiveness and downstream signaling pathways. In an infant rabbit infection model, Fe 3+ enhanced V. parahaemolyticus intestinal colonization and virulence through EnvZ/OmpR signaling. This study identifies Fe 3+ as the physiological ligand activating the EnvZ/OmpR virulence regulon and provides insight into how enteric pathogens exploit host-derived iron cues to promote infection.}, archive = {J_PNAS}, author = {Zhang, Yibei and Xiao, Gang and Ding, Haoyuan and Zou, Qian and Gu, Dan and Wen, Jiachen and Pei, Yonggang and Guo, Rongxian and Wang, Qiyao and Zhou, Xiaohui}, doi = {10.1073/pnas.2507874122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2507874122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Direct sensing of host ferric iron by an archetype histidine kinase mediates virulence of an enteric pathogen}, volume = {122}, year = {2025}, }
• (2025). Updated fossil analyses reveal critical insights into the origins of monotreme lifestyles. PNAS, 122(23), e2507579122. (www)

  @article{ , archive = {J_PNAS}, author = {Whitney, Megan R.}, doi = {10.1073/pnas.2507579122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2507579122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Updated fossil analyses reveal critical insights into the origins of monotreme lifestyles}, volume = {122}, year = {2025}, }
• (2025). Why excluding regenerative grazing skews beef’s carbon profile. PNAS, 122(23), e2506941122. (www)

  @article{ , archive = {J_PNAS}, author = {Apanovich, Nataliya and Weeks, Deseret}, doi = {10.1073/pnas.2506941122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2506941122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Why excluding regenerative grazing skews beef’s carbon profile}, volume = {122}, year = {2025}, }
• (2025). Summer solstice optimizes the thermal growing season. PNAS, 122(23), e2506796122. (www)

  @article{ , abstract = {Multiple studies have recently proposed the summer solstice as a universal cue for major plant physiological processes. While this would have strong implications for fundamental plant biology and climate change forecasting, we currently have no clear mechanisms to explain the emergence and importance of solstice as a cue. Here, we analyze temperature accumulation patterns in relation to the summer solstice across Europe and North America—in past, historical, and projected future climates. We show that, on average, the summer solstice coincides with a thermal optimum during the growing season. However, we also find significant local variation in the timing of this optimum across different climates—suggesting the potential of alternative cues.}, archive = {J_PNAS}, author = {Van der Meersch, Victor and Wolkovich, E. M.}, doi = {10.1073/pnas.2506796122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2506796122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Summer solstice optimizes the thermal growing season}, volume = {122}, year = {2025}, }
• (2025). MyD88 knockdown by RNAi prevents bacterial stimulation of tubeworm metamorphosis. PNAS, 122(23), e2505805122. (www)

  @article{ , abstract = {Diverse animals across the tree of life undergo the life-history transition of metamorphosis in response to bacteria. Although immunity has been implicated in this metamorphosis in response to bacteria, no functional connection has yet been demonstrated between immunity and metamorphosis. We investigated a host–microbe interaction involving a marine tubeworm, Hydroides elegans , that undergoes metamorphosis in response to Pseudoalteromonas luteoviolacea , a metamorphosis-inducing marine bacterium. By creating a marine bacteria–mediated RNA interference approach, we show that myeloid differentiation factor 88 (MyD88), a critical immune adaptor for Toll-like receptor and interleukin pathways, is necessary for the stimulation of metamorphosis in response to bacteria. In addition to a developmental role, we show that MyD88 is necessary for survival during exposure to the bacterial pathogen Pseudomonas aeruginosa , showing that Hydroides utilizes MyD88 during both development and an immune response. These results provide a functional characterization of the innate immune system involved in an animal's metamorphosis.}, archive = {J_PNAS}, author = {Darin, Emily and Farrell, Morgan V. and Ali, Tatyana N. and Rivera Alfaro, Josefa and Malter, Kyle E. and Shikuma, Nicholas J.}, doi = {10.1073/pnas.2505805122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2505805122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MyD88 knockdown by RNAi prevents bacterial stimulation of tubeworm metamorphosis}, volume = {122}, year = {2025}, }
• (2025). Reply to ogutu et al.: Cattle–wild herbivore interaction studies warrant new lenses from community ecology and environmental justice. PNAS, 122(23), e2505717122. (www)

  @article{ , archive = {J_PNAS}, author = {Butt, Bilal and Xu, Wenjing}, doi = {10.1073/pnas.2505717122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2505717122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to ogutu et al.: Cattle–wild herbivore interaction studies warrant new lenses from community ecology and environmental justice}, volume = {122}, year = {2025}, }
• (2025). Increased excitatory synapse size in hippocampal place cells compared to silent cells. PNAS, 122(23), e2505322122. (www)

  @article{ , abstract = {Neuronal activity in the hippocampus creates a cognitive map of space that is essential for navigation. In any given environment, a fraction of hippocampal pyramidal cells (PCs) is active at specific locations (place cells), others are sparsely active without spatial tuning, and a significant proportion of the PCs is entirely silent. The mechanisms underlying the vastly different activities of PCs in the rodent hippocampal CA1 area are unknown. Here, we measured the in vivo activity of CA1 PCs using two-photon [Ca 2+ ] imaging in head-restrained mice during navigation in a virtual corridor and then performed in vitro patch-clamp recording to probe their intrinsic electrical properties and anatomical investigation to characterize their input synapses. The active and passive electrical properties of PCs were similar between PCs with different prior in vivo activities. Perisomatic inhibitory synapse density was also comparable among PCs. The average dendritic spine density and spine head area did not correlate with the mean in vivo activity of PCs, but the size of the spines of place cells was significantly larger compared to that of silent cells. Our results are consistent with excitatory synaptic plasticity as a major mechanism underlying spatially tuned activity of place cells in hippocampal networks.}, archive = {J_PNAS}, author = {Heredi, Judit and Olah, Gaspar and Sumegi, Mate and Paul Lukacs, Istvan and Aldahabi, Mohammad and Újfalussy, Balázs B. and Makara, Judit K. and Nusser, Zoltan}, doi = {10.1073/pnas.2505322122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2505322122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Increased excitatory synapse size in hippocampal place cells compared to silent cells}, volume = {122}, year = {2025}, }
• (2025). Parallel sensory compensation following independent subterranean colonization by groundwater salamanders (Eurycea). PNAS, 122(23), e2504850122. (www)

  @article{ , abstract = {Lineages that have invaded subterranean environments have repeatedly evolved remarkable adaptations to life in darkness. However, observational and experimental studies in additional natural systems are needed to further our understanding of repeated evolution and convergence. In Texas, a radiation of groundwater salamanders (genus Eurycea ), with independent invasions of subterranean karstic environments, offers an opportunity to investigate phenotypic convergence, parallel evolution, and the enhancement and regression of sensory systems. Adaptations to a troglobitic life in this clade include morphological, behavioral, and physiological changes within and among species. Intraspecific and interspecific variation in morphology in response to the selective pressures of life underground allows for detailed examination of physical, behavioral, and physiological changes associated with subterranean adaptation within a comparative phylogenetic framework. We find a correlated change between two sensory systems repeated across multiple subterranean Eurycea lineages: the degeneration of the eye and the expansion of the mechanosensory lateral line. The increase in anterior neuromast organs in subterranean lineages was positively correlated with the expression of pax6 (Paired-box 6), a conserved transcription factor important for vertebrate neurogenesis. Our results show a decreasing trend of PAX6 labeling in the neuromasts of adult surface salamanders ( Eurycea nana ) relative to the maintained labeling in subterranean species ( Eurycea rathbuni ). These lateral line enhancements are correlated with reductions in the development of optic systems in subterranean salamander lineages. Altogether, our findings provide a starting point for future evolutionary developmental investigations examining the genetic underpinnings of adaptive, repeated evolution in a novel system.}, archive = {J_PNAS}, author = {Tovar, Ruben U. and Dobbins, Brittany A. and Hartman, Nicholas R. and Leelani, Sheena and Devitt, Thomas J. and García, Dana M. and Gignac, Paul M. and Cannatella, David C. and Hillis, David M.}, doi = {10.1073/pnas.2504850122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2504850122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Parallel sensory compensation following independent subterranean colonization by groundwater salamanders (Eurycea)}, volume = {122}, year = {2025}, }
• (2025). Assembly and activation of the death-inducing signaling complex. PNAS, 122(23), e2504819122. (www)

  @article{ , abstract = {The death-inducing signaling complex (DISC), comprising Fas, Fas-associated death domain (FADD), and caspase-8, initiates extrinsic apoptosis. Using cryogenic electron microscopy (cryo-EM), we show that Fas and FADD death domains (DDs) form an asymmetric 7:5 oligomer, which promotes FADD death effector domain (DED) filament formation. Structural analysis reveals that FADD DED filaments closely resemble caspase-8 tandem DED filaments, suggesting that FADD DED serves as a nucleation scaffold for caspase-8 assembly. These findings provide a mechanistic framework for how DISC assembly initiates apoptosis and amplifies signaling via higher-order oligomerization.}, archive = {J_PNAS}, author = {Fosuah, Elizabeth and Shen, Zhangfei and Xie, Jiale and Wang, Chen and Lin, Qingpeng and Fu, Tian-Min}, doi = {10.1073/pnas.2504819122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2504819122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Assembly and activation of the death-inducing signaling complex}, volume = {122}, year = {2025}, }
• (2025). Evolutionarily conserved BON1 regulates the basal cytosolic ca2+ level by calmodulin-independent activation of ca2+ pumps in arabidopsis. PNAS, 122(23), e2504457122. (www)

  @article{ , abstract = {Plasma membrane-localized autoinhibited Ca 2+ pumps are essential for maintaining basal cytosolic Ca 2+ levels for regulating growth processes and environmental responses. These pumps are known to be activated by calmodulins to maintain Ca 2+ homeostasis in plants and animals. Here, we demonstrate that the evolutionarily conserved copine protein BON1 is critical for maintaining low cytosolic Ca 2+ concentrations by directly regulating two plasma membrane-localized Ca 2+ pumps ACA8 and ACA10 in Arabidopsis . BON1 interacts with a region within the N-terminal domain of ACA8 and ACA10, preceding the calmodulin binding sites, and stimulates ACA8 activity. This activation can occur without calmodulin binding, indicating that BON1 and calmodulin independently regulate the Ca 2+ pump. Loss of BON1 function results in elevated basal cytosolic Ca 2+ concentrations, which can be partially rescued by overexpressing hyperactive ACA8 or ACA10. Furthermore, we show that BON1 has one high-affinity Ca 2+ binding site in the VWA domain that is critical for activation of ACA8 as well as for BON1 function, suggesting a feedback mechanism for Ca 2+ homeostasis at resting concentrations. Our findings suggest that this Ca 2+ responsive regulatory mechanism extends beyond Arabidopsis , as we show interactions between ACA and BON proteins from algae to flowering plants, pointing to an ancient regulatory mechanism for maintaining low basal cytosolic Ca 2+ . Notably, a human plasma membrane-localized autoinhibited Ca 2+ pump can also be activated by a human BON protein in a yeast functional assay system, suggesting evolutionary conservation in Ca 2+ regulation across species.}, archive = {J_PNAS}, author = {Li, Zhan and Kim, Hyo Jung and Luoni, Laura and Conter, Carolina and Masè, Nicola and Resentini, Francesca and Xie, Peiqiao and Astegno, Alessandra and Bonza, Maria Cristina and Hua, Jian}, doi = {10.1073/pnas.2504457122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2504457122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolutionarily conserved BON1 regulates the basal cytosolic ca2+ level by calmodulin-independent activation of ca2+ pumps in arabidopsis}, volume = {122}, year = {2025}, }
• (2025). Multiple cortical systems influence a single vibrissa muscle. PNAS, 122(23), e2503325122. (www)

  @article{ , abstract = {What is the neural substrate that enables the cerebral cortex to control a single mystacial vibrissa and orchestrate its movement? To answer this question, we injected rabies virus into the intrinsic muscle that protracts the rat C3 vibrissa and used retrograde transneuronal transport to identify the cortical neurons that influence the muscle. A surprisingly diverse set of cortical areas is the origin of disynaptic control over the motoneurons that influence the C3 protractor. More than two thirds of these layer 5 pyramidal neurons (L5PNs) are dispersed in frontal and parietal areas outside the primary motor cortex (vM1). This observation emphasizes the importance of descending motor commands from non-primary motor areas. More than a third of the L5PNs originate from somatosensory areas, such as the barrel field (vS1). The barrel field has been long considered a prototypic model system for studying sensory processing at the level of the cerebral cortex. Even so, we find that the number of L5PNs in vS1, and even their peak density, rivals the number and peak density of L5PNs in vM1. Thus, our results emphasize the importance of the barrel field in processing motor output. The distribution of L5PNs in vM1 and vS1 leads us to propose a model of vibrissa protraction in which vM1 output results in protraction, and vS1 output results in reciprocal inhibition (suppression) of protraction. This paired initiation and suppression of complementary movements may be a general feature of the descending output from the rodent M1 and S1.}, archive = {J_PNAS}, author = {Maharjan, Aman and Guest, Jason M. and Rathelot, Jean-Alban and Gomez Osorio, Fiorella M. and Strick, Peter L. and Oberlaender, Marcel}, doi = {10.1073/pnas.2503325122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2503325122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multiple cortical systems influence a single vibrissa muscle}, volume = {122}, year = {2025}, }
• (2025). Programmable seconds-to-days-long delayed snapping in jumping metashells. PNAS, 122(23), e2503313122. (www)

  @article{ , abstract = {Shape-shifting structures can transform and recover their shapes in response to external stimuli, but they often lack programmable, clock-like control over spatiotemporal deformation and motion, especially after stimuli are removed. Achieving autonomous, time-regulated spatiotemporal motion remains a grand challenge. Here, we present an autonomous delayed-jumping metashell that integrates viscoelastic materials with monostable architected structures to address this limitation. The metashell with tunable prestored elastic energy features an internal time clock enabling programmable autonomous delayed snapping and jumping after actuation removal. The delay spans from seconds to 2.4 d, with jumping heights decreasing from over 9 to 0.5 body heights. We demonstrate its utility in autonomous explosive seed dispersal devices, achieving wide-area omnidirectional distribution with high survival rates. This strategy paves the way for creating autonomous spatiotemporal shape-shifting structures with broad applications in robotics, morphing matter, ecology, and intelligent systems.}, archive = {J_PNAS}, author = {Qing, Haitao and Zhou, Caizhi and Qi, Fangjie and Yin, Jie}, doi = {10.1073/pnas.2503313122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2503313122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Programmable seconds-to-days-long delayed snapping in jumping metashells}, volume = {122}, year = {2025}, }
• (2025). Endogenous competition and the underrealized reproduction of infectious diseases. PNAS, 122(23), e2502676122. (www)

  @article{ , abstract = {Scientific inquiry about the transmissibility of infectious diseases is largely based on the basic reproduction number ( R 0 ) and its derivations. This paper describes a mechanism overlooked in most conventional analyses, in which a disease can endogenously “compete” with itself when multiple infectious individuals race to infect the same susceptible individual, thereby reducing the effective reproductive rate. Utilizing an empirically calibrated network epidemiological model of wild-type COVID-19 diffusion in its early pandemic, we show that the mechanism would be expected to reduce its reproductive rate by an average of 39%. Simulation experiments further identify different types of endogenous competition mechanisms and their relative effect sizes. We highlight the incorporation of endogenous competition mechanism as a necessary step in realistically modeling the reproduction process of infectious diseases.}, archive = {J_PNAS}, author = {Huang, Peng and Almquist, Zack W. and Butts, Carter T.}, doi = {10.1073/pnas.2502676122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2502676122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Endogenous competition and the underrealized reproduction of infectious diseases}, volume = {122}, year = {2025}, }
• (2025). A green dichromophoric protein enabling foliage mimicry in arthropods. PNAS, 122(23), e2502567122. (www)

  @article{ , abstract = {Molecular mechanisms underlying the green insect camouflage have puzzled researchers for over a century. Here, we isolated and identified a green water-soluble protein from the integument of bush-cricket Tettigonia cantans . De novo sequencing and cloning revealed a severely fragmented form of vitellogenins, ubiquitous and multifunctional, but still largely enigmatic glycolipoproteins essential for embryonic development and lacking structural characterization. The distinctive color of the identified chromoprotein results from binding of a remarkable combination of farnesylated bilins (recently identified, tentative heme A catabolites) and xanthophylls, which commensurably absorb light in the 600 to 700 nm and 400 to 550 nm spectral regions and thereby produce a hue that perfectly mimics foliage. The high-resolution crystal structure of this unique ~80 kDa dichromophoric protein, which we named “dibilinoxanthinin” (DBXN), revealed two DBXN protomers, each consisting of three polypeptides, with a novel fold enclosing a large hydrophobic cavity that accommodates two bilins, two luteins, and four phosphatidylcholines, all anchored by hydrogen bonds and giving DBXN unique biochemical and optical properties. Among the green insects tested, some contained yellow and blue chromophores in separate fractions, while others had green proteins similar to DBXN, although not necessarily of the same size. Surprisingly, we isolated and identified a larger vitellogenin proteoform with DBXN-like absorption, from the green huntsman spider Micrommata virescens . These data illustrate striking variations in the DBXN-related pigmentation mechanism among different green arthropods and suggest that vitellogenins may have undergone neofunctionalization, reflecting their potential for functional diversification.}, archive = {J_PNAS}, author = {Egorkin, Nikita A. and Aleksin, Anatoly M. and Sedlov, Ilya A. and Zhiganov, Nikita I. and Bodunova, Daria V. and Varfolomeeva, Larisa A. and Slonimskiy, Yury B. and Ziganshin, Rustam H. and Popov, Vladimir O. and Boyko, Konstantin M. and Vassilevski, Alexander A. and Maksimov, Eugene G. and Sluchanko, Nikolai N.}, doi = {10.1073/pnas.2502567122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2502567122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A green dichromophoric protein enabling foliage mimicry in arthropods}, volume = {122}, year = {2025}, }
• (2025). Short-term study fails to capture negative impacts of livestock intensification on wildlife. PNAS, 122(23), e2502418122. (www)

  @article{ , archive = {J_PNAS}, author = {Ogutu, Joseph O. and Stabach, Jared A. and Hopcraft, J. Grant C. and Boone, Randall B. and Dublin, Holly T. and Dutton, Christopher L. and Gichira, Andrew and Guthmann, Abby and Herrik, Ask L. and Holekamp, Kay E. and Karimi, Rebekah R. and Kifugo, Shem C. and Leimgruber, Peter and Mogensen, Niels and Moiko, Stephen S. and Mukeka, Joseph M. and Nabaala, Harrison and Ndambuki, Stephen and Njino, Lucy M. and Ojwang, Gordon O. and Olff, Han and Packer, Craig and Parmuntoro, Lemein and Reid, Robin S. and Rioba, Rehema B. and Said, Mohammed Y. and Senteu, Jully S. and Subalusky, Amanda L. and Svenning, Jens-Christian and Thompson, Stewart and Uzal, Antonio and Veldhuis, Michiel P. and Buitenwerf, Robert}, doi = {10.1073/pnas.2502418122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2502418122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Short-term study fails to capture negative impacts of livestock intensification on wildlife}, volume = {122}, year = {2025}, }
• (2025). The highly conserved intron of tyrosine tRNA is critical for m1A58 modification and controls the integrated stress response. PNAS, 122(23), e2502364122. (www)

  @article{ , abstract = {tRNA introns are a universally conserved feature of eukaryotic genomes, but the reason for their conservation has remained obscure. We have previously shown that a defect in the essential tRNA splicing endonuclease of yeast results in transcriptome remodeling, resembling that of the integrated stress response (ISR). In this study, we show that ISR activation in this mutant requires the canonical ISR components, including the collided ribosome sensor Gcn1. We further show that splicing of tyrosine tRNA, but not splicing of any of the other intron-containing tRNAs, controls the ISR. Using nanopore direct RNA sequencing, we show that the intron of tyrosine tRNA affects m1 A58 modification in the T arm loop of the mature tRNA. In support of these results, we show that deletion of either subunit of the enzyme that adds the m1 A58 modification also controls the ISR. Unlike the few intron-dependent modifications previously described, the intron-dependent m1 A58 modification site is distal from the intron and has a clear physiological impact. Finally, we survey the occurrence of tRNA introns in eukaryotic genomes and show that the tyrosine tRNA intron is more prevalent than any other tRNA intron. These data suggest that tRNA splicing is conserved in eukaryotes because hypomodified tyrosine tRNAs lead to collided ribosomes, resulting in stress to cell physiology.}, archive = {J_PNAS}, author = {Stuart, Catherine J. and Hurtig, Jennifer E. and Tzadikario, Talia and Thomas, Niki K. and Jain, Miten and van Hoof, Ambro}, doi = {10.1073/pnas.2502364122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2502364122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The highly conserved intron of tyrosine tRNA is critical for m1A58 modification and controls the integrated stress response}, volume = {122}, year = {2025}, }
• (2025). Control of seed-to-seedling transition by an upstream open reading frame in ABSCISIC ACID DEFICIENT2. PNAS, 122(23), e2502155122. (www)

  @article{ , abstract = {The start of seed germination is a major decision point in plant life cycle, which relies on seed stored mRNA. However, the underlying translational mechanism remains less illustrated. Here, we demonstrate that inhibiting translation using translation inhibitors and ribosome-defective mutants delays germination in Arabidopsis . Through comprehensive transcriptome deep sequencing (RNA-seq) and polysome profiling analyses, we elucidated the dynamic interplay of regulation at the transcriptional and translational levels during germination. We show that delayed germination in some ribosome-defective mutants is partially regulated by the gene ABSCISIC ACID DEFICIENT2 ( ABA2 ), with an upstream open reading frame (uORF) in the 5′ untranslated region that represses translation of the downstream ORF encoding ABA2. In addition, disrupting rice OsABA2 uORF inhibited preharvest sprouting (PHS). Furthermore, we found two main haplotypes for the uORF among rice cultivars that result in different OsABA2 expression levels, thus contributing to diverse PHS phenotypes. This work highlights the critical role of translational control and genetic variation in seed dormancy and germination, with implications for crop improvement.}, archive = {J_PNAS}, author = {Wang, Zhen and Zhang, Xiaofan and Zhou, Can and Cao, Xiaofeng}, doi = {10.1073/pnas.2502155122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2502155122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Control of seed-to-seedling transition by an upstream open reading frame in ABSCISIC ACID DEFICIENT2}, volume = {122}, year = {2025}, }
• (2025). Projecting neurons from the lateral entorhinal cortex to the basolateral amygdala mediate the encoding of incidental odor–taste associations. PNAS, 122(23), e2502127122. (www)

  @article{ , abstract = {Since our first steps in life, we are forming incidental associations between diverse stimuli across various sensory modalities that influence our future choices and facilitate adaptation to environmental fluctuations. Daily behavior is usually governed by indirect incidental associations among sensory cues that have never been explicitly paired with a reinforcer. This phenomenon, known as higher-order conditioning, can be systematically investigated in laboratory animals through specific behavioral paradigms such as sensory preconditioning protocols. In this study, using “Targeted Recombination in Active Populations” (TRAP2) transgenic mice, we have interrogated which are the brain areas orchestrating the encoding of associations between olfactory and gustatory stimuli and the expression of an aversive odor–taste sensory preconditioning paradigm. We identified neuronal ensembles within the basolateral amygdala specifically activated during odor–taste associations. To demonstrate the causal involvement of this brain region in our sensory preconditioning task, we inhibited it during the preconditioning phase (i.e., incidental associations) using a chemogenetic approach, which caused a clear impairment of the mediated responses. In addition, using retrograde tracers in the basolateral amygdala of TRAP2 mice, we observed that the projections from the lateral entorhinal cortex to the basolateral amygdala are particularly activated during odor–taste associations. Notably, the chemogenetic inhibition of this brain circuit impaired the mediated aversion performance in our sensory preconditioning task. Overall, these findings highlight the amygdala as a pivotal modulator of incidental associations during an aversive sensory preconditioning task and point toward a brain circuit crucially involved in these complex cognitive processes.}, archive = {J_PNAS}, author = {González-Parra, Jose Antonio and Acciai, Vittoria and Vidal-Palencia, Laura and Canela-Grimau, Marc and Busquets-Garcia, Arnau}, doi = {10.1073/pnas.2502127122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2502127122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Projecting neurons from the lateral entorhinal cortex to the basolateral amygdala mediate the encoding of incidental odor–taste associations}, volume = {122}, year = {2025}, }
• (2025). Climate warming increases global oceanic dimethyl sulfide emissions. PNAS, 122(23), e2502077122. (www)

  @article{ , abstract = {Oceanic dimethyl sulfide (DMS) is the largest natural source of atmospheric sulfur. DMS is biologically produced in seawater and emitted into the atmosphere, where its oxidation products contribute to aerosol formation with consequences for cloud albedo and the Earth’s radiative budget and climate. Climate model projections of how DMS emissions change with global warming are largely uncertain, even contradictory. Here, we use machine-learning models trained with biome-resolved global observations to simulate seawater DMS concentrations (1850 to 2100) using physico-chemical and biological predictors from eight CMIP6 models. The scatter in current projections is largely reduced, and globally averaged seawater DMS concentrations are predicted to decrease in the coming decades. However, global DMS emissions will increase due to rising surface wind speeds and sea surface temperatures which contradicts the current AR6 assessment that the DMS flux will reduce in the future. Concurrence of increasing DMS emissions and declining anthropogenic sulfur dioxide emissions suggests an increase in the relative importance of DMS to sulfate aerosol formation and its climate cooling impact.}, archive = {J_PNAS}, author = {Joge, Sankirna D. and Mansour, Karam and Simó, Rafel and Galí, Martí and Steiner, Nadja and Saiz-Lopez, Alfonso and Mahajan, Anoop S.}, doi = {10.1073/pnas.2502077122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2502077122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Climate warming increases global oceanic dimethyl sulfide emissions}, volume = {122}, year = {2025}, }
• (2025). Creb5 controls its own expression and directly induces the joint interzone regulatory program. PNAS, 122(23), e2501830122. (www)

  @article{ , abstract = {Prior studies have indicated that the transcription factor Creb5 is expressed in the joint interzone, which contains the progenitors for all synovial joint tissues in both mouse and human embryos. In the absence of Creb5 function, most synovial joint interzones fail to form and the cartilage templates in the long bones remain fused. This earlier work did not clarify whether Creb5 initiates a cascade of signaling molecules, such as growth and differentiation factor 5 (Gdf5) and Wnt-family members, that in turn induce the formation of the joint interzone, or instead directly activates the expression of joint interzone markers. In the present study, an integrative analysis of the transcriptome, chromatin accessibility, and Creb5-occupancy in joint progenitors revealed that Creb5 directly binds to both its own two promoters and to the regulatory regions of Gdf5 and Sfrp2 , each of whose expression in the joint interzone is Creb5-dependent. Functional enhancer analysis indicated that Creb5 binding sites in either the two Creb5 promoters, or in Gdf5 and Sfrp2 regulatory elements are necessary for these sequences to drive transgene expression in the developing synovial joints. While Creb5 directly drives Gdf5 and Sfrp2 expression in the inner joint interzone, Creb5 activates Barx1 expression specifically in the outer joint interzone. Our findings indicate that Creb5 initiates a regulatory network that both promotes the formation of synovial joints, and subsequently activates distinct transcriptional targets in the inner versus the outer regions of the joint interzone, thus regionalizing gene expression in the developing joint.}, archive = {J_PNAS}, author = {Zhang, Cheng-Hai and Shahini, Aref and Cook, Laura E. and Mistry, Meeta and Kim, Jongkil and Wick, Heather and Pennacchio, Len A. and Lassar, Andrew B.}, doi = {10.1073/pnas.2501830122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2501830122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Creb5 controls its own expression and directly induces the joint interzone regulatory program}, volume = {122}, year = {2025}, }
• (2025). Dynamic relocation of PKA regulatory subunits during sperm capacitation: Linking PKA to the CatSper signaling complex. PNAS, 122(23), e2501741122. (www)

  @article{ , abstract = {To fertilize an oocyte, mammalian spermatozoa must undergo a maturation step known as capacitation that takes place after ejaculation. Protein kinase A (PKA) plays a fundamental role in capacitation in all mammalian species. Before capacitation, PKA is maintained in an inactive state where the catalytic subunits are bound to a dimer of inhibitory regulatory subunits. A key element in the regulation of PKA lies in its intracellular compartmentalization achieved by docking at A-kinase anchoring proteins (AKAP). Despite the crucial role of the modulation of local PKA activity in fertilization, its localization and mechanism of compartmentalization are not well understood. Here, we approach this problem using quantitative laser scanning microscopy and superresolution imaging to dissect the interactions and relocalization of PKA subunits during capacitation. We find that in the resting state, both catalytic and regulatory subunits colocalize close to the axoneme. Upon capacitation, the PKA regulatory subunits, but not the catalytic subunits, relocate to a quadrilateral structure along the flagellum principal piece, in the vicinity of AKAP4 and the CatSper channel signaling complex. Furthermore, this quadrilateral localization of PKA regulatory subunits disappears in sperm from CatSper1 knockout mice. The sharp difference between the localization of PKA regulatory subunits in capacitated vs. noncapacitated sperm cells demonstrates its suitability as a biomarker for identifying capacitation, an enduring problem in the study of sperm physiology.}, archive = {J_PNAS}, author = {Novero, Analia G. and Matamoros-Volante, Arturo and Gomez-Olivieri, Lucila R. and Stival, Cintia and Luque, Guillermina M. and Szalai, Alan M. and Ambrosio, Andrea L. and Stefani, Fernando D. and Buffone, Mariano G. and Krapf, Dario and Krapf, Diego}, doi = {10.1073/pnas.2501741122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2501741122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic relocation of PKA regulatory subunits during sperm capacitation: Linking PKA to the CatSper signaling complex}, volume = {122}, year = {2025}, }
• (2025). Declining coral calcification to enhance twenty-first-century ocean carbon uptake by gigatonnes. PNAS, 122(23), e2501562122. (www)

  @article{ , abstract = {The sensitivity of coral reefs to climate change is well established. As the oceans warm and acidify, the calcification of coral reefs declines with net calcium carbonate dissolution projected under even moderate emissions trajectories. The impact of this on the global carbon cycle is however yet to be accounted for. Here, we use a synthesis of the sensitivity of coral reef calcification to climate change, alongside reef distribution products to estimate alkalinity and dissolved inorganic carbon fluxes resulting from reductions in reef calcification. Using a global ocean biogeochemical model, we simulate the impact on ocean carbon uptake under different emissions scenarios, accounting for uncertainty in present-day calcification rates. Reductions in net coral reef carbonate production can enhance the ocean carbon sink by up to 1.25 GtCO 2 y −1 by midcentury (0.48 GtCO 2 y −1 median estimate) with cumulative ocean carbon uptake up to 13% greater by 2300 (7% median estimate). Our findings indicate that accounting for the coral reef feedback in projections will increase estimates of the remaining carbon budget associated with global warming thresholds, as well as the likelihood that net zero emissions can be achieved without negative emissions.}, archive = {J_PNAS}, author = {Kwiatkowski, Lester and Planchat, Alban and Pyolle, Marc and Torres, Olivier and Bouttes, Nathaelle and Comte, Adrien and Bopp, Laurent}, doi = {10.1073/pnas.2501562122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2501562122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Declining coral calcification to enhance twenty-first-century ocean carbon uptake by gigatonnes}, volume = {122}, year = {2025}, }
• (2025). In-plane ferroelectricity with high curie temperatures in nonequilibrium SnSe1-xSx van der waals semiconductors. PNAS, 122(23), e2501509122. (www)

  @article{ , abstract = {While symmetry breaking in 2D ferroelectrics is obviously linked to the single-layer structure, layered (van der Waals) ferroelectrics can have a multitude of underlying mechanisms, making their identification nontrivial and often controversial. This complexity is exemplified by tin chalcogenides whose equilibrium structure, the orthorhombic α-phase with space group Pnma , includes an inversion center and which therefore should not be ferroelectric. Yet, recent work demonstrated polarization switching and ferroelectric domains in few-layer SnS and SnSe. Here, we use in situ electron microscopy and diffraction to determine the mechanism and characteristics of ferroelectricity across the SnSe 1-x S x system. We identify two distinct phases of synthetic SnSe 1-x S x : nonpolar (centrosymmetric) equilibrium (α-phase) crystals and metastable crystals adopting a distorted monoclinic structure, which are in-plane ferroelectrics with Curie temperatures of 320 to 420 °C. A surprising structural plasticity of the ferroelectric crystals during heating/cooling indicates a shallow energy landscape. This in turn suggests absence of a pronounced driving force for conversion to the α-phase that can explain the formation of the nonequilibrium crystals and their stability even after transfer to other supports. Our results highlight opportunities for the discovery of novel ferroelectrics among nonequilibrium van der Waals crystals.}, archive = {J_PNAS}, author = {Sutter, Eli and Sutter, Peter}, doi = {10.1073/pnas.2501509122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2501509122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In-plane ferroelectricity with high curie temperatures in nonequilibrium SnSe1-xSx van der waals semiconductors}, volume = {122}, year = {2025}, }
• (2025). Single-cell resolution uncovers neighboring cell subtypes that share steroidogenic capacity during fetal testis development. PNAS, 122(23), e2501392122. (www)

  @article{ , abstract = {Historically, endocrine cells were perceived to coordinate their output in a uniform manner. Recently however, single-cell technologies have uncovered heterogeneity within these populations, indicating that individual cells may operate as independently regulated units. Using high-resolution tools such as single-molecule fluorescent in situ hybridization (sm-FISH) and single-cell RNA sequencing (scRNA-seq), we investigated the contributions of individual and the collective of fetal Leydig cells to androgen production over time during mouse testis development. Temporal profiles of intratesticular androgens alongside the expression of steroidogenic pathway genes ( Star, Cyp11a1, Cyp17a1, and Hsd3b1 ) from prenatal to perinatal testes demonstrated that the peak in gene expression preceded the peak in androgen production. Spatially, steroidogenic cells were initially observed to be concentrated toward the anterior–posterior poles along the center of the dorsal–ventral axis of the fetal testis at embryonic day (E) 13 and then expanded to a uniform distribution by E16. Next, sm-FISH using probes for individual steroidogenic pathway genes exposed the following findings: gene transcription and processing of individual and combinations of steroidogenic pathway genes are not synchronized among fetal Leydig cells; and some fetal Leydig cells express incomplete sets of genes. Further, sm-FISH and scRNA-seq data corroborated the presence of fetal Leydig and other interstitial cell types harboring incomplete sets of steroidogenic pathway genes throughout developmental stages. Taken together, these findings highlight that fetal steroidogenic gene expression is tightly regulated and that transcript presence among interstitial cell types promotes the possibility that optimal androgen biosynthesis results from a cooperative effort among neighboring steroidogenic cells.}, archive = {J_PNAS}, author = {Jiang, Keer and Fu, Zirui and Tsourkas, Philippos and Kothandapani, Anbarasi and Kearse, Tyler and McIlwain, Sean J. and Mayère, Chloé and Nef, Serge and Jorgensen, Joan S.}, doi = {10.1073/pnas.2501392122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2501392122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Single-cell resolution uncovers neighboring cell subtypes that share steroidogenic capacity during fetal testis development}, volume = {122}, year = {2025}, }
• (2025). Assembly of a functional neuronal circuit in embryos of an ancestral metazoan is influenced by temperature and the microbiome. PNAS, 122(23), e2501225122. (www)

  @article{ , abstract = {Understanding how neural populations emerge to give rise to behavior is a major goal in neuroscience. Here, we explore the self-assembly of neural circuits in Hydra , an organism with a simple nervous system but no centralized information processing, to enhance the understanding of nervous system evolution. We define self-assembly as spontaneous organization of neurons into functional circuits without requiring a prespecified structural template. In this context, the N4 neuronal circuit, which we have previously found to be particularly important in the feeding of the animal, develops in embryos through activity-driven self-assembly, a process in which intrinsic calcium activity drives connectivity and synchronization among spatially distributed neurons over time. Gap junctions and vesicle-mediated communication between neuronal and non-neuronal cells drive rapid assembly, with the embryo’s prospective oral region exhibiting the highest neuronal density. An artificial electrical circuit–based model as a biophysically inspired simulation demonstrates dynamic increases in synchronization over time, along with predictions for selective dynamic adaptions of connections. Environmental factors, like temperature and an absent microbiome, modify neural architecture, suggesting the existence of a certain adaptability during neural development. We propose that these fundamental features originated in the last common bilaterian ancestor, supporting the hypothesis that the basic architecture of the nervous system is universal. Since in the natural habitat of Hydra both temperature fluctuations and changes in the microbiome can occur, our work not only illuminates a fundamental developmental process but also may guide environmental and evolutionary studies by explaining how organisms adapt to environmental variations.}, archive = {J_PNAS}, author = {Noack, Christopher and Jenderny, Sebastian and Giez, Christoph and Merza, Ornina and Hofacker, Lisa-Marie and Wittlieb, Jörg and Repnik, Urska and Bramkamp, Marc and Ochs, Karlheinz and Bosch, Thomas C. G.}, doi = {10.1073/pnas.2501225122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2501225122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Assembly of a functional neuronal circuit in embryos of an ancestral metazoan is influenced by temperature and the microbiome}, volume = {122}, year = {2025}, }
• (2025). A skin-interfaced wireless wearable device and data analytics approach for sleep-stage and disorder detection. PNAS, 122(23), e2501220122. (www)

  @article{ , abstract = {Accurate identification of sleep stages and disorders is crucial for maintaining health, preventing chronic conditions, and improving diagnosis and treatment. Direct respiratory measurements, as key biomarkers, are missing in traditional wrist- or finger-worn wearables, which thus limit their precision in detection of sleep stages and sleep disorders. By contrast, this work introduces a simple, multimodal, skin-integrated, energy-efficient mechanoacoustic sensor capable of synchronized cardiac and respiratory measurements. The mechanical design enhances sensitivity and durability, enabling continuous, wireless monitoring of essential vital signs (respiration rate, heart rate and corresponding variability, temperature) and various physical activities. Systematic physiology-based analytics involving explainable machine learning allows both precise sleep characterization and transparent tracking of each factor’s contribution, demonstrating the dominance of respiration, as validated through a diverse range of human subjects, both healthy and with sleep disorders. This methodology enables cost-effective, clinical-quality sleep tracking with minimal user effort, suitable for home and clinical use.}, archive = {J_PNAS}, author = {Du, Yayun and Gu, Jianyu and Duan, Shiyuan and Trueb, Jacob and Tzavelis, Andreas and Shin, Hee-Sup and Arafa, Hany and Li, Xiuyuan and Huang, Yonggang and Carr, Andrew N. and Davies, Charles R. and Rogers, John A.}, doi = {10.1073/pnas.2501220122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2501220122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A skin-interfaced wireless wearable device and data analytics approach for sleep-stage and disorder detection}, volume = {122}, year = {2025}, }
• (2025). Broadband measurement of feibelman’s quantum surface response functions. PNAS, 122(23), e2501121122. (www)

  @article{ , abstract = {Feibelman d -parameter, a mesoscopic complement to the local bulk permittivity, describes quantum optical surface responses for interfaces, including nonlocality, spill-in and -out, and surface-enabled Landau damping. It has been incorporated into the macroscopic Maxwellian framework for convenient modeling and understanding of nanoscale electromagnetic phenomena, calling for the compilation of a d -parameter database for interfaces of interest in nano-optics. However, accurate first-principles calculations of d -parameters face computational challenges, whereas existing measurements of d -parameters are scarce and restricted to narrow spectral windows. We demonstrate a general broadband ellipsometric approach to measure d -parameters at a gold–air interface across the visible–ultraviolet regimes. Gold is found to spill-in and spill-out at different frequencies. We also observe gold’s Bennett mode, a surface-dipole resonance associated with a pole of the d -parameter, around 2.5 eV. Our measurements give rise to and are further validated by the passivity and Kramers–Kronig causality analysis of d -parameters. Our work advances the understanding of quantum surface response and may enable applications like enhanced electron field emission.}, archive = {J_PNAS}, author = {Chen, Zeling and Yang, Shu and Xie, Zetao and Hu, Jinbing and Zhang, Xudong and Xia, Yipu and Shen, Yonggen and Su, Huirong and Xie, Maohai and Christensen, Thomas and Yang, Yi}, doi = {10.1073/pnas.2501121122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2501121122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Broadband measurement of feibelman’s quantum surface response functions}, volume = {122}, year = {2025}, }
• (2025). Epithelial regnase-1 inhibits colorectal tumor growth by regulating IL-17 signaling via degradation of NFKBIZ mRNA. PNAS, 122(23), e2500820122. (www)

  @article{ , abstract = {Regnase-1 is a ribonuclease that regulates inflammation in immune cells by degrading cytokine mRNA. Regnase-1 was identified as one of the frequently mutated genes in the inflamed colorectal epithelium of patients with ulcerative colitis; however, its significance in intestinal epithelial cells during the tumorigenic process remains unknown. Therefore, we developed an Apc Min/+ mouse model lacking Regnase-1 in intestinal epithelia. Regnase-1 deletion significantly enhanced colon tumor growth accompanied by elevated levels of extracellular signal-regulated kinase (ERK) phosphorylation in tumor tissues. Transcriptome analysis of the tumor tissues revealed that Nfkbiz , a mediator of the interleukin (IL)-17 signaling pathway, was the primary degradative target of Regnase-1 in enterocytes and that Regnase-1 deficiency enhanced IL-17 signaling. The treatment with antibiotics or IL-17-neutralizing antibody canceled the proliferative effect of colon tumors due to Regnase-1 deletion, suggesting the protective role of Regnase-1 against colon tumor growth was dependent on IL-17 signaling triggered by gut microbes. Analysis of the Nfkbiz knockout mouse model demonstrated that the tumor-suppressive effect of Regnase-1 depended on Nfkbiz expression. Remarkably, oral treatment of dimethyl fumarate, a potential inhibitor of Regnase-1 protein inactivation, suppressed tumor growth, downregulated Nfkbiz , and suppressed ERK activation. Furthermore, TCGA data analysis revealed that low Regnase-1 expression in colorectal cancer tissue was related to poor prognosis. Therefore, Regnase-1 represses colon tumor growth by regulating IL-17 signaling via Nfkbiz mRNA degradation. Regnase-1 could be a potential therapeutic target in colon tumors.}, archive = {J_PNAS}, author = {Iguchi, Eriko and Takai, Atsushi and Oe, Natsumi and Fujii, Yosuke and Omatsu, Mayuki and Takeda, Haruhiko and Shimizu, Takahiro and Maruno, Takahisa and Nakanishi, Yuki and Yoshinaga, Masanori and Maruyama, Takashi and Marusawa, Hiroyuki and Obama, Kazutaka and Takeuchi, Osamu and Seno, Hiroshi}, doi = {10.1073/pnas.2500820122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2500820122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Epithelial regnase-1 inhibits colorectal tumor growth by regulating IL-17 signaling via degradation of NFKBIZ mRNA}, volume = {122}, year = {2025}, }
• (2025). Spatially resolved DNP-assisted NMR illuminates the conformational ensemble of α-synuclein in intact viable cells. PNAS, 122(23), e2500367122. (www)

  @article{ , abstract = {The protein α-syn adopts a wide variety of conformations including an intrinsically disordered monomeric form and an α-helical-rich membrane-associated form that is thought to play an important role in cellular membrane processes. However, despite the high affinity of α-syn for membranes, evidence that the α-helical form is adopted inside cells has been indirect. DNP-assisted solid-state NMR on frozen cellular samples can report directly on the entire conformational ensemble. By controlling the distribution of the DNP agent throughout the cellular biomass, such experiments can provide quantitative information upon the entire structural ensemble or provide information about spatially resolved subpopulations. When the polarization agent is dispersed homogeneously throughout the cell, a minority of the α-syn inside HEK293 cells adopts a highly α-helical-rich conformation. When the polarization agent is peripherally localized, the α-helical-rich conformation predominates, indicating that it is preferentially adopted near the cellular periphery. This demonstrates how selectively altering the spatial distribution of the DNP agent can be a powerful tool to observe spatially distinct structural ensembles. This approach paves the way for more nuanced investigations into the conformations that proteins adopt in different areas of the cell.}, archive = {J_PNAS}, author = {Kragelj, Jaka and Ghosh, Rupam and Xiao, Yiling and Dumarieh, Rania and Lagasca, Dominique and Krishna, Sakshi and Frederick, Kendra K.}, doi = {10.1073/pnas.2500367122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2500367122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatially resolved DNP-assisted NMR illuminates the conformational ensemble of α-synuclein in intact viable cells}, volume = {122}, year = {2025}, }
• (2025). A mouse model of jansen’s metaphyseal chondrodysplasia for investigating disease mechanisms and candidate therapeutics. PNAS, 122(23), e2500176122. (www)

  @article{ , abstract = {Jansen’s metaphyseal chondrodysplasia (JMC) is a rare disorder caused by activating mutations in the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTH1R). Patients exhibit short stature, dysmorphic bones, and severe growth plate abnormalities, as well as hypercalcemia, hypercalciuria, hypophosphatemia, and reduced plasma PTH levels. Humanized PTH1R (hPTH1R) mice expressing the H223R-hPTH1R JMC mutation die early without breeding. We therefore generated and characterized a stable mouse line expressing the T410R-hPTH1R allele, which confers a milder disease phenotype in patients. Mutant mice show near-normal longevity and reproductive capacity yet exhibit a profound skeletal phenotype characteristic of the disease. The long bones of T410R mice are markedly misshapen and have expanded metaphyses with disarrayed chondrocyte zones in growth plates and reduced primary spongiosa. PET/CT scanning revealed diminished uptake of [ 18 F]-sodium fluoride in the growth plate area, consistent with reduced mineralization and vascularization. Genetic ablation of Hdac4 rescued the growth plate abnormalities in T410R mice, thereby establishing the PTH1R-Gαs-cAMP-PKA-SIK3-HDAC4/5 pathway as the main mediator of growth plate abnormalities in JMC. Serum calcium was elevated and endogenous PTH was suppressed in T410R mice, and both parameters could be normalized by acute injection of an optimized PTH inverse agonist peptide. The T410R mouse thus represents a stable animal model of JMC that recapitulates the abnormalities in skeletal development and mineral ion homeostasis which characterize this disease. The mice should help efforts to further define the cellular and molecular mechanisms underlying the JMC phenotype and to develop a potential mode of therapy.}, archive = {J_PNAS}, author = {Höppner, Jakob and Firat, Damla and Parvez-Khan, Mohd and Reyes, Monica and Hanna, Patrick and Yadav, Prem Swaroop and Dean, Thomas and Ramos-Torres, Karla M. and Brugarolas, Pedro and Collins, Michael T. and Wein, Marc N. and Liu, Shi and Gellman, Samuel H. and Schipani, Ernestina and Kronenberg, Henry M. and Gardella, Thomas J. and Jüppner, Harald}, doi = {10.1073/pnas.2500176122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2500176122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A mouse model of jansen’s metaphyseal chondrodysplasia for investigating disease mechanisms and candidate therapeutics}, volume = {122}, year = {2025}, }
• (2025). Convergent expansions of keystone gene families drive metabolic innovation in saccharomycotina yeasts. PNAS, 122(23), e2500165122. (www)

  @article{ , abstract = {Many remarkable phenotypes have repeatedly occurred across vast evolutionary distances. When convergent traits emerge on the tree of life, they are sometimes driven by the same underlying gene families, while other times, many different gene families are involved. Conversely, a gene family may be repeatedly recruited for a single trait or many different traits. To understand the general rules governing convergence at both genomic and phenotypic levels, we systematically tested associations between 56 binary metabolic traits and gene count in 14,785 gene families from 993 Saccharomycotina yeasts. Using a recently developed phylogenetic approach that reduces spurious correlations, we found that gene family expansion and contraction were significantly linked to trait gain and loss in 45/56 (80%) traits. While 595/739 (81%) significant gene families were associated with only one trait, we also identified several “keystone” gene families that were significantly associated with up to 13/56 (23%) of all traits. Strikingly, most of these families are known to encode metabolic enzymes and transporters, including all members of the industrially relevant MAL tose fermentation loci in the baker’s yeast Saccharomyces cerevisiae . These results indicate that convergent evolution on the gene family level may be more widespread across deeper timescales than previously believed.}, archive = {J_PNAS}, author = {David, Kyle T. and Schraiber, Joshua G. and Crandall, Johnathan G. and Labella, Abigail L. and Opulente, Dana A. and Harrison, Marie-Claire and Wolters, John F. and Zhou, Xiaofan and Shen, Xing-Xing and Groenewald, Marizeth and Hittinger, Chris Todd and Pennell, Matt and Rokas, Antonis}, doi = {10.1073/pnas.2500165122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2500165122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Convergent expansions of keystone gene families drive metabolic innovation in saccharomycotina yeasts}, volume = {122}, year = {2025}, }
• (2025). Water-rich incipient melt of the deep upper mantle indicates locally preserved low-velocity zones above the 410 km discontinuity. PNAS, 122(23), e2500017122. (www)

  @article{ , abstract = {Seismic low-velocity layers (LVLs), frequently attributed to hydrous-silicate melts, are detected globally but exhibit lateral discontinuities. Geophysical and laboratory studies of water content in the mantle transition zone (MTZ) and upper mantle solubility limits suggest these layers likely form through global dehydration melting near the 410 km discontinuity (D410). A key hypothesis posits that melts form globally but are preserved only where melt stability permits retention. However, challenges in quenching melts into glass or fine-grained crystals at mantle pressures have precluded precise determination of melt composition, fueling debates over the mechanisms governing LVLs’ sporadic distribution. Here, we developed a fast-quenching high-pressure cell assembly to synthesize hydrous glasses or fine-grained quench crystals at pressures >10 GPa, enabling high-precision analysis of incipient melt composition. Experiments at 13 GPa reveal that the 410 melt contains 43 mol% H 2 O, 9.2 mol% CaO, 30.5 mol% (Mg, Fe)O, 0.2 mol% Al 2 O 3 , and 17 mol% SiO 2 . The melt’s high water content necessitates Fe enrichment to achieve neutral buoyancy, which can only be sourced from Fe-rich heterogeneities (Fe # = 100Fe/(Mg+Fe) in mole; Fe # >18) within the MTZ. In contrast, melts derived from normal MTZ material (Fe # <18) remain buoyant and migrate upward, precluding stable layer formation. We conclude that global dehydration melting generates hydrous melts, but only Fe-rich heterogeneities enable melt retention, reconciling the coexistence of widespread LVL detections and their lateral discontinuities.}, archive = {J_PNAS}, author = {Xie, Longjian and Katsura, Tomoo and Miyajima, Nobuyoshi and Qu, Tongzhang and Mao, Ho-Kwang}, doi = {10.1073/pnas.2500017122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2500017122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Water-rich incipient melt of the deep upper mantle indicates locally preserved low-velocity zones above the 410 km discontinuity}, volume = {122}, year = {2025}, }
• (2025). Sensitivity of simulations of Plio–Pleistocene climate with the CLIMBER-2 earth system model to details of the global carbon cycle. PNAS, 122(23), e2427236122. (www)

  @article{ , abstract = {The Earth system model CLIMBER-2 has been used in past work to successfully reproduce the glacial/interglacial cycles of the Plio–Pleistocene and the Mid-Pleistocene Transition (MPT) from predominantly 40 to 100 ky timescale oscillatory behavior as a function of declining volcanic outgassing and regolith removal. In this study, we further examine the sensitivity of this previous work to varying prescribed levels of volcanic outgassing and regolith extent and the long-term dynamics of the global carbon cycle, affecting the exchange and partitioning of carbon between different Earth system reservoirs and therefore global atmospheric CO 2 concentrations. As volcanic outgassing decreases, CO 2 and land carbon storage decrease, while ocean carbon storage, including CaCO 3 sediment, increases. At volcanic outgassing levels below a threshold value of roughly 5.7 Tmol C yr −1 , sea level decreases due to land ice formation, leading to increased carbon accumulation in the ocean and decreased carbon in the CaCO 3 sediment reservoir. Our previous finding of strong hysteresis and path dependence in the glacial/interglacial alternation history [J. Carrillo et al. , Proc. Natl. Acad. Sci. 121, e2322926121 (2024)] appears to be a tenuous climate feature, dependent on the precise representation of carbon cycle processes and, specifically, the numerical precision used in the calculation of certain key state variables in the model’s carbon cycle.}, archive = {J_PNAS}, author = {Carrillo, Judit and Mann, Michael E. and Marinov, Irina and Christiansen, Shannon A. and Willeit, Matteo and Ganopolski, Andrey}, doi = {10.1073/pnas.2427236122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2427236122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sensitivity of simulations of Plio–Pleistocene climate with the CLIMBER-2 earth system model to details of the global carbon cycle}, volume = {122}, year = {2025}, }
• (2025). Template-free 3D programmable magnetization of soft millirobots induced by interlayer stress. PNAS, 122(23), e2426846122. (www)

  @article{ , abstract = {Soft magnetic miniature devices are crucial for applications in minimally invasive medicine, soft electronics, and robotics. While substantial progress has been made, current magnetic programming techniques are inherently tied to template-based and sequential fabrication processes. These processes limit scalability, precision, and programmability. Here, we present a template-free, integrative strategy that leverages interlayer stress-induced 3D shape morphing in xerogel-PDMS bilayer materials triggered by temperature variations. This process induces preprogrammed deformation and fixes the 3D structure via interlayer stress and solid–liquid phase transition. It is akin to an insect encased in amber, resulting in a soft machine with precisely tailored magnetic domains upon saturated magnetization. The approach eliminates the need for predesigned molds, which offers scalable, template-free programmable magnetization, reducing time and labor costs. The versatility of this method is demonstrated through reconfigurable mechanical behavior in kirigami metamaterial structures, information encryption, and multilegged millirobots. Moreover, by incorporating a nonmagnetic PDMS layer, laser-based engraving and ablation allow simultaneous control of interlayer stress and material properties. This facilitates precise regulation of stress-induced deformation and magnetically responsive regions with 20 μm resolution and over 1.8 T magnetization strength. This template-free 3D magnetization strategy significantly enhances design flexibility, machining precision, and mass production. It paves the way for advanced multiscale and programmable soft magnetic devices.}, archive = {J_PNAS}, author = {Han, Jie and Wang, Shuideng and Zheng, Zhiqiang and Chen, Donglei and Zhang, Wenqi and Qu, Zhi and Cheng, Mingxing and Yao, Yiqing and Sitti, Metin and Dong, Lixin}, doi = {10.1073/pnas.2426846122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2426846122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Template-free 3D programmable magnetization of soft millirobots induced by interlayer stress}, volume = {122}, year = {2025}, }
• (2025). BRCA2 reversion mutation–independent resistance to PARP inhibition through impaired DNA prereplication complex function. PNAS, 122(23), e2426743122. (www)

  @article{ , abstract = {Recent approvals of polymeric adenosine diphosphate ribose (poly(ADP-ribose) polymerase inhibitors (PARPi) for BRCA-mutant metastatic castration resistant prostate cancer necessitate an understanding of the factors that shape sensitivity and resistance. Reversion mutations that restore homologous recombination (HR) repair are detected in ~50 to 80% of BRCA-mutant patients who respond but subsequently relapse, but there is currently little insight into why only ~50% of BRCA-mutant patients display upfront resistance. To address this question, we performed a genome-wide CRISPR screen to identify genomic determinants of PARPi resistance in murine Brca2 Δ/Δ prostate organoids genetically engineered in a manner that precludes the development of reversion mutations. Remarkably, we recovered multiple independent single guide RNAs (sgRNAs) targeting three different members ( Cdt1, Cdc6, and Dbf4 ) of the DNA prereplication complex (pre-RC), each of which independently conferred resistance to olaparib and the next-generation PARP-1 selective inhibitor AZD5305. Moreover, sensitivity to PARP inhibition was restored in Brca2 Δ/Δ , Cdc6-depleted prostate cells by knockdown of geminin, a negative regulator of Cdt1, further implicating the critical role of a functional pre-RC complex in PARPi sensitivity. Furthermore, ~50% of CRPC tumors have copy number loss of pre-RC complex genes, particularly CDT1 . Mechanistically, prostate cells with impaired pre-RC activity displayed rapid resolution of olaparib-induced DNA damage as well as protection from replication fork degradation caused by Brca2 loss, providing insight into how Brca2-mutant cancer cells can escape cell death from replication stress induced by PARP inhibition in the absence of HR repair. Of note, a pharmacologic inhibitor that targets the CDT1/geminin complex (AF615) restored sensitivity to AZD5305, providing a potential translational avenue to enhance sensitivity to PARP inhibition.}, archive = {J_PNAS}, author = {Pappas, Kyrie and Ferrari, Matteo and Smith, Perianne and Nandakumar, Subhiksha and Khan, Zahra and Young, Serina B. and LaClair, Justin and Russo, Marco Vincenzo and Huang-Hobbs, Emmet and Schultz, Nikolaus and Abida, Wassim and Karthaus, Wouter and Jasin, Maria and L. Sawyers, Charles}, doi = {10.1073/pnas.2426743122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2426743122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {BRCA2 reversion mutation–independent resistance to PARP inhibition through impaired DNA prereplication complex function}, volume = {122}, year = {2025}, }
• (2025). Jund orchestrates cis-regulatory element dynamics to facilitate endothelial-to-hematopoietic transition. PNAS, 122(23), e2426714122. (www)

  @article{ , abstract = {The tightly controlled spatiotemporal expression of developmental genes depends on the concerted action of cis -regulatory elements (CREs) and transcription factors (TFs) to ensure cell fate decisions. Endothelial-to-hematopoietic transition (EHT) is a cell fate transition process by which endothelial cells acquire hematopoietic identity and become hemogenic endothelial cells (HECs) and then hematopoietic stem and progenitor cells, but the underlying CRE network dynamics and its regulation by TFs remain unclear. In this study, we characterized the dynamics of CRE activation and TF occupancy during zebrafish EHT, and found that the enhancer–promoter collaboration forms the basis for EHT. Moreover, a ubiquitously expressed TF AP-1 collaborates with diverse lineage-specific TFs to remodel enhancer landscape. Deletion of AP-1 family member Jund impaired hematopoietic specification, resulting from the enhanced endothelial identity in the HEC. Mechanistically, Jund and hematopoietic TF Hoxa9a collectively repress the activity of an endothelial-related dll4 enhancer through tight control of the active histone modification H3K27ac. Our study provides insights into the cooperative function among ubiquitous TFs and cell type–specific TFs in orchestrating cell fate transition.}, archive = {J_PNAS}, author = {Guo, Jiani and Liu, Mengyao and Liu, Feng and Wang, Lu}, doi = {10.1073/pnas.2426714122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2426714122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Jund orchestrates cis-regulatory element dynamics to facilitate endothelial-to-hematopoietic transition}, volume = {122}, year = {2025}, }
• (2025). The tumor suppressor RASSF8: A WAVE interaction partner controlling migration and cohesion of invasive border cells in drosophila. PNAS, 122(23), e2426702122. (www)

  @article{ , abstract = {Collective cell migration is a key driver of tissue morphogenesis and cancer invasion. Here, we identified the tumor suppressor Ras association domain-containing protein 8 (RASSF8) as a WAVE interactor required for border cell migration. RASSF8 colocalizes with F-actin and cell adhesion molecules at border cell– border cell contacts. Loss of RASSF8 function results in border cell cohesion defects, a phenotype associated with changes in the localization of the Echinoid (Ed) and Coracle (Cora). Cell-type-specific RNA interference (RNAi) experiments suggest that cohesion defects are caused by changes in localization of Ed rather than E-cadherin. Gain-of-function experiments further revealed reciprocal functional interactions between RASSF8 and WAVE controlling collective border cell movement. Thus, we propose a dual function of RASSF8 in coordinating border cell cluster behavior. RASSF8 is thought to regulate the collective movement of border cells by restricting WAVE function, while it controls the epithelial cluster integrity by regulating cell–cell adhesion and septate junction molecules such as Ed and Cora.}, archive = {J_PNAS}, author = {Höhne, Mila Y. and Milani, Wiebke and Ramlow, Kirsten and Bogdan, Sven}, doi = {10.1073/pnas.2426702122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2426702122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The tumor suppressor RASSF8: A WAVE interaction partner controlling migration and cohesion of invasive border cells in drosophila}, volume = {122}, year = {2025}, }
• (2025). High-throughput metabolic engineering of yarrowia lipolytica through gene expression tuning. PNAS, 122(23), e2426686122. (www)

  @article{ , abstract = {The challenge of accurately predicting which genetic alternations lead to the desired phenotype necessitates high-throughput metabolic engineering approaches where numerous hypotheses can be tested simultaneously. We describe the CRISPR-Cas9-based method TUNE YALI that enables high-throughput tuning of gene expression in the common industrial yeast Yarrowia lipolytica . The method is based on replacing the promoters of the target genes with native Y. lipolytica promoters of varying strengths or removing the promoters entirely. To demonstrate the method’s capabilities, we created a plasmid library that targets 56 transcription factors (TFs) and changes the expression of each TF to seven different levels. We transformed this library into reference and betanin-producing strains of Y. lipolytica and screened the resulting clones for changes in morphology, thermotolerance, or improved betanin production. The genetic markup of the yeast clones with the desired phenotypic changes was determined by sequencing the inserted plasmids. We identified multiple TFs whose regulatory changes increased thermotolerance, two TFs that eliminated pseudohyphal growth, and several TFs that increased betanin production. Analogous libraries can be designed to target any chosen group of genes and even all the genes. The libraries can be shared and reused, accelerating applied strain development projects and fundamental functional genomics research (TUNE YALI -TF kit and TUNE YALI -TF library are available via AddGene under catalog numbers #1000000255 and #217744).}, archive = {J_PNAS}, author = {Jiang, Wei and Wang, Shengbao and Ahlheit, Daniel and Fumagalli, Tommaso and Yang, Zhijie and Ramanathan, Shreemaya and Jiang, Xinglin and Weber, Tilmann and Dahlin, Jonathan and Borodina, Irina}, doi = {10.1073/pnas.2426686122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2426686122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High-throughput metabolic engineering of yarrowia lipolytica through gene expression tuning}, volume = {122}, year = {2025}, }
• (2025). Polaron catastrophe within quantum acoustics. PNAS, 122(23), e2426518122. (www)

  @article{ , abstract = {The quantum acoustic framework has recently emerged as a nonperturbative, coherent approach to electron–lattice interactions, uncovering rich physics often obscured by perturbative methods with incoherent scattering events. Here, we model the strongly coupled dynamics of electrons and acoustic lattice vibrations within this framework, representing lattice vibrations as coherent states and electrons as quantum wave packets, in a manner distinctively different from tight-binding or discrete hopping-based approaches. We derive and numerically implement electron backaction on the lattice, providing both visual and quantitative insights into electron wave packet evolution and the formation of acoustic polarons. We investigate polaron binding energies across varying material parameters and compute key observables—including mean square displacement, kinetic energy, potential energy, and vibrational energy—over time. Our findings reveal the conditions that favor polaron formation, which is enhanced by low temperatures, high deformation potential constants, slow sound velocities, and high effective masses. Additionally, we explore the impact of external electric and magnetic fields, showing that while polaron formation remains robust under moderate fields, it is weakly suppressed at higher field strengths. These results deepen our understanding of polaron dynamics and pave the way for future studies into nontrivial transport behavior in quantum materials.}, archive = {J_PNAS}, author = {Aydin, Alhun and Keski-Rahkonen, Joonas and Graf, Anton M. and Yuan, Shaobing and Ouyang, Xiao-Yu and Müstecaplıoğlu, Özgür E. and Heller, Eric J.}, doi = {10.1073/pnas.2426518122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2426518122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Polaron catastrophe within quantum acoustics}, volume = {122}, year = {2025}, }
• (2025). Suborbital- and millennial-scale monsoon variability during pleistocene interglacials. PNAS, 122(23), e2426353122. (www)

  @article{ , abstract = {Observational and modeling results show that the frequency and amplitude of extreme climatic events have increased significantly in the context of global warming. However, whether abrupt climate changes intensified during past warm periods remains poorly constrained due to the lack of high-resolution geological records. Here, we report a 512-m predominantly lacustrine sedimentary record from the Weihe Basin (North China), revealing that lake levels fluctuated significantly on suborbital (half- and quarter-precession) and millennial timescales over the last 2 Ma. Grain-size results reveal that magnitudes of rapid lake level fluctuations increased dramatically during Pleistocene interglacials, differing from glacial amplification of abrupt climate events recorded in North Atlantic marine sediments. Model results indicate that summer insolation maxima in low-latitude region of both hemispheres can lead to intensified monsoon precipitation in East Asia. Our proxy-model comparison highlights the importance of low-latitude bihemispheric insolation maxima in driving millennial-scale hydroclimatic variability in a warming future.}, archive = {J_PNAS}, author = {Sun, Youbin and Wang, Ting and Yin, Qiuzhen and Clemens, Steven C. and Liu, Xingxing and Ai, Li and Wu, Zhipeng and Qiang, Xiaoke and Wang, Xulong and Chang, Hong and Song, Yougui and Vogel, Hendrik and Dodson, John and Berger, Andre and An, Zhisheng}, doi = {10.1073/pnas.2426353122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2426353122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Suborbital- and millennial-scale monsoon variability during pleistocene interglacials}, volume = {122}, year = {2025}, }
• (2025). Deciphering decomposition pathways of high explosives with cryogenic X-ray raman spectroscopy. PNAS, 122(23), e2426320122. (www)

  @article{ , abstract = {We employed cryogenic X-ray Raman spectroscopy to investigate the early-stage decomposition of the high explosive molecule hexanitrohexaazaisowurtzitane (CL-20). By systematically varying the radiation dose under cryogenic conditions, we induced the decomposition of the molecule using ionizing radiation and observed the evolution of spectral features at the carbon, nitrogen, and oxygen K edges. Through extensive first-principles calculations, we identified key intermediates in the early stages of the decomposition process, resulting from C–C and C–N bond cleavage which leads to the opening of the internal cage structure. A detailed analysis of spectral trends and fingerprints provided evidence supporting N–NO 2 homolytic cleavage as the primary initial decomposition pathway. The combination of advanced core-level spectroscopy methods and state-of-the-art theoretical calculations enabled a comprehensive characterization of the molecular changes induced by controlled radiation dose exposures. Our findings establish a benchmark for understanding the decomposition chemistry of high-explosive materials, offering important insights into their stability and reactivity under extreme conditions.}, archive = {J_PNAS}, author = {Paredes Mellone, Oscar A. and Nielsen, Michael H. and Babicz, Jeffrey Thomas and Vinson, John and Willey, Trevor M. and Sokaras, Dimosthenis}, doi = {10.1073/pnas.2426320122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2426320122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deciphering decomposition pathways of high explosives with cryogenic X-ray raman spectroscopy}, volume = {122}, year = {2025}, }
• (2025). Complexity myths and the misappropriation of evolutionary theory. PNAS, 122(23), e2425772122. (www)

  @article{ , abstract = {Recent papers by physicists, chemists, and geologists lay claim to the discovery of new principles of evolution that have somehow eluded over a century of work by evolutionary biologists, going so far as to elevate their ideas to the same stature as the fundamental laws of physics. These claims have been made in the apparent absence of any awareness of the theoretical framework of evolutionary biology that has existed for decades. The numerical indices being promoted suffer from numerous conceptual and quantitative problems, to the point of being devoid of meaning, with the authors even failing to recognize the distinction between mutation and selection. Moreover, the promulgators of these new laws base their arguments on the idea that natural selection is in relentless pursuit of increasing organismal complexity, despite the absence of any evidence in support of this and plenty pointing in the opposite direction. Evolutionary biology embraces interdisciplinary thinking, but there is no fundamental reason why the field of evolution should be subject to levels of unsubstantiated speculation that would be unacceptable in any other area of science.}, archive = {J_PNAS}, author = {Lynch, Michael}, doi = {10.1073/pnas.2425772122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2425772122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Complexity myths and the misappropriation of evolutionary theory}, volume = {122}, year = {2025}, }
• (2025). Establishment of cell size–dependent growth rate via differential scaling of metabolite uptake and release. PNAS, 122(23), e2425347122. (www)

  @article{ , abstract = {Metabolism fuels cell growth and functions. While it is well established that cellular growth rate scales with cell size, how cells alter their metabolism as they change size remains largely unexplored. Here, we conducted a systematic analysis of cell size–dependent metabolism across the NCI60 cancer cell line panel comprising a diverse range of cell sizes. We demonstrate that cellular metabolism and growth rate display 2/3 allometric scaling due to differential scaling of overall nutrient uptake and waste metabolite release with respect to cell size, with waste elimination decreasing less rapidly than nutrient uptake rate as cells grow larger. This results in cell size–dependent growth rate and predicts a maximum cell size where net nutrient uptake equals zero and cell enlargement ceases despite active metabolism. We experimentally confirm this prediction and identify that electron acceptor demand constrains cell enlargement as evidenced by depletion of intracellular aspartate and scaling of aspartate uptake, which is more than proportional to cell volume. Overall, these findings may have implications for understanding cell size homeostasis, developmental biology, and the design principles of living organisms.}, archive = {J_PNAS}, author = {Meliala, Ian and Chen, Jingyuan and Lyu, Jiahang and Björklund, Mikael}, doi = {10.1073/pnas.2425347122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2425347122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Establishment of cell size–dependent growth rate via differential scaling of metabolite uptake and release}, volume = {122}, year = {2025}, }
• (2025). Study design and the sampling of deleterious rare variants in biobank-scale datasets. PNAS, 122(23), e2425196122. (www)

  @article{ , abstract = {One key component of study design in population genetics is the “geographic breadth” of a sample (i.e., how broad a region across which individuals are sampled). How the geographic breadth of a sample impacts observations of rare, deleterious variants is unclear, even though such variants are of particular interest for biomedical and evolutionary applications. Here, in order to gain insight into the effects of sample design on ascertained genetic variants, we formulate a stochastic model of dispersal, genetic drift, selection, mutation, and geographically concentrated sampling. We use this model to understand the effects of the geographic breadth of sampling effort on the discovery of negatively selected variants. We find that samples which are more geographically broad will discover a greater number of variants as compared to geographically narrow samples (an effect we label “discovery”); though the variants will be detected at lower average frequency than in narrow samples (e.g., as singletons, an effect we label “dilution”). Importantly, these effects are amplified for larger sample sizes and fitness effects. We validate these results using both population genetic simulations and empirical analyses in the UK Biobank. Our results are particularly important in two contexts: the association of large-effect rare variants with particular phenotypes and the inference of negative selection from allele frequency data. Overall, our findings emphasize the importance of considering geographic breadth when designing and carrying out genetic studies, especially at biobank scale.}, archive = {J_PNAS}, author = {Steiner, Margaret C. and Rice, Daniel P. and Biddanda, Arjun and Ianni-Ravn, Mariadaria K. and Porras, Christian and Novembre, John}, doi = {10.1073/pnas.2425196122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2425196122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Study design and the sampling of deleterious rare variants in biobank-scale datasets}, volume = {122}, year = {2025}, }
• (2025). Multiphasic size-dependent growth dynamics of nanoparticle ensembles. PNAS, 122(23), e2424950122. (www)

  @article{ , abstract = {Colloidal nanoparticles are of great interest in modern science and industry. However, the thermodynamic mechanism and dynamics of nanoparticle growth have yet to be understood. Addressing these issues, we tracked hundreds of in-situ growth trajectories of a nanoparticle ensemble using liquid-phase TEM and found that the nanoparticle growth, including coalescence, exhibits nanoparticle size-dependent multiphasic dynamics, unexplainable by current theories. Motivated by this finding, we developed a model and theory for an ensemble of growing nanoparticles, providing a unified, quantitative understanding of the time-dependent mean and fluctuation of nanoparticle size and size-dependent growth rate profiles across various nanoparticle systems and experimental conditions. Our work reveals that the chemical potential in a small nanoparticle strongly deviates from the Gibbs–Thomson equation, shedding light on how it governs the size-dependent growth dynamics of nanoparticles.}, archive = {J_PNAS}, author = {Kim, Ji-Hyun and Kim, Joodeok and Kim, Byung Hyo and Song, Sanggeun and Kang, Jingyu and Rhee, Jinho and Kim, Donghee and Chun, Hoje and Choi, Hyesung and Cho, Hyungjin and Kim, Yongjoon and Jung, Jae Won and Son, Youngju and Jung, Junhyeok and Park, Kunwoo and Jeon, Sungho and Lee, Minho and Han, Byungchan and Lee, Won Chul and Kim, Dongjun and Hyeon, Taeghwan and Sung, Jaeyoung and Park, Jungwon}, doi = {10.1073/pnas.2424950122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2424950122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multiphasic size-dependent growth dynamics of nanoparticle ensembles}, volume = {122}, year = {2025}, }
• (2025). Detection of the knee point in lithium-ion battery degradation using a state-of-charge-dependent parameter. PNAS, 122(23), e2424838122. (www)

  @article{ , abstract = {The rapidly expanding lithium-ion battery (LIB) market has heightened the demand for efficient diagnostics for in-use cells and the reliable grading of used cells. Various purpose-built analysis tools and statistical algorithms have been developed, but often rely on redundant instrumentation and computationally intensive procedures. Here, we propose using the variance of the capacity difference between 0.2C and 1C, Var(Δ Q 0.2C-1C (V) ), based on the strong correlation between the interfacial state of the anode and mode of capacity degradation, as a measure of the health state of individual cells. A single-point “off-board” measurement of Var(Δ Q 0.2C-1C (V) ) indicates whether a particular cell is experiencing self-limiting or accelerating degradation and is thus near a knee point in its cycle life. This assessment additionally provides a quantitative criterion for differentiating used cells for reuse or recycling. Our findings suggest that utilizing state-of-charge-dependent key electrochemical properties enables the cell health to be accurately monitored, thereby promoting sustainability in the expanding battery market.}, archive = {J_PNAS}, author = {Kim, Hyunjae and Kim, Inwoo and Kim, Minsoo and An, Seongha and Ahn, Hyo Chul and Park, Dongmin and Lee, Jun Hee and Kang, Chun Yong and Choi, Jang Wook}, doi = {10.1073/pnas.2424838122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2424838122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Detection of the knee point in lithium-ion battery degradation using a state-of-charge-dependent parameter}, volume = {122}, year = {2025}, }
• (2025). Population sequencing for phylogenetic diversity and transmission analyses. PNAS, 122(23), e2424797122. (www)

  @article{ , abstract = {Genomic diversity in pathogen populations is foundational for evolution and adaptation. Understanding population-level diversity is also essential for tracking sources and revealing detailed pathways of transmission and spread. For bacteria, culturing, isolating, and sequencing the large number of individual colonies required to adequately sample diversity can be prohibitively time-consuming and expensive. While sequencing directly from a mixed population will show variants among reads, they cannot be linked to reveal allele combinations associated with phylogenetic inheritance patterns. Here, we describe the theory and method for using population sequencing directly from a mixed sample, along with a minimal number of individually sequenced colonies, to describe the phylogenetic diversity of a population without haplotype reconstruction. To demonstrate the utility of population sequencing in capturing phylogenetic diversity, we compared isogenic clones to population sequences of Burkholderia pseudomallei from sputum of a single patient. Our results point to the pathogen population being highly structured, suggesting that for some pathogens, sputum sampling may preserve structuring in the lungs and thus present a noninvasive alternative to understanding colonization, movement, and pathogen/host interactions. We also analyzed population sequences of Staphylococcus aureus derived from different people and different body sites to reveal directionality of transmission between hosts and across body sites, demonstrating the power and utility for characterizing the spread of disease and identification of reservoirs at the finest levels. We anticipate that population sequencing and analysis can be broadly applied to accelerate research in a wide range of fields reliant on a foundational understanding of population phylogenetic diversity.}, archive = {J_PNAS}, author = {Pearson, Talima and Furstenau, Tara and Wood, Colin and Rigas, Vanessa and Drake, Kylie and Sahl, Jason and Maltinsky, Sara and Currie, Bart J. and Mayo, Mark and Hall, Carina and Keim, Paul and Fofanov, Viacheslav}, doi = {10.1073/pnas.2424797122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2424797122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Population sequencing for phylogenetic diversity and transmission analyses}, volume = {122}, year = {2025}, }
• (2025). Structure and organization of full-length epidermal growth factor receptor in extracellular vesicles by cryo-electron tomography. PNAS, 122(23), e2424678122. (www)

  @article{ , abstract = {We report here transport of full-length epidermal growth factor receptor (EGFR), Insulin Receptor, 7-pass transmembrane receptor Smoothened, and 13-pass Sodium-iodide symporter to extracellular vesicles (EVs) for structural and functional studies. Mass spectrometry confirmed the transported proteins are the most abundant in EV membranes, and the presence of many receptor-interacting proteins in EVs demonstrates their utility for characterizing membrane protein interactomes. Cryo-electron tomography of EGFR-containing EVs reveals that EGFR forms clusters in both the presence and absence of EGF with a ~3 nm gap between the inner membrane and cytoplasmic density. EGFR extracellular region (ECR) dimers do not form regular arrays in these clusters. Subtomogram averaging of the 150 kDa EGF-bound EGFR ECR dimer yielded a 15 Å map into which the crystal structure of the ligand-bound EGFR ECR dimer fits well. These findings refine our understanding of EGFR activation, clustering, and signaling and establish EVs as a versatile platform for structural and functional characterization of human membrane proteins in cell-derived membranes.}, archive = {J_PNAS}, author = {Gonzalez-Magaldi, Monica and Gullapalli, Anuradha and Papoulas, Ophelia and Liu, Chang and Leung, Adelaide Y.-H. and Guo, Luqiang and Brilot, Axel F. and Marcotte, Edward M. and Ke, Zunlong and Leahy, Daniel J.}, doi = {10.1073/pnas.2424678122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2424678122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure and organization of full-length epidermal growth factor receptor in extracellular vesicles by cryo-electron tomography}, volume = {122}, year = {2025}, }
• (2025). Increasing boreal fires reduce future global warming and sea ice loss. PNAS, 122(23), e2424614122. (www)

  @article{ , abstract = {Biomass burning can affect climate via the emission of aerosols and their subsequent impact on radiation, cloud microphysics, and surface and atmospheric albedo. Biomass burning emissions (BBEs) over the boreal region have strongly increased during the last decade and are expected to continue increasing as the climate warms. Climate models simulate aerosol processes, yet historical and future Coupled Model Intercomparison Project (CMIP) simulations have no active fire component, and BBEs are prescribed as external forcings. Here, we show that CMIP6 used future boreal BBEs scenarios with unrealistic near-zero trends that have a large impact on climate trends. By running sensitivity experiments with ramped up boreal emissions based on observed trends, we find that increasing boreal BBEs reduces global warming by 12% and Arctic warming by 38%, reducing the loss of sea ice. Tropical precipitation shifts southward as a result of the hemispheric difference in boreal aerosol forcing and subsequent temperature response. These changes stem from the impact of aerosols on clouds, increasing cloud droplet number concentration, cloud optical depth, and low cloud cover, ultimately reducing surface shortwave flux over northern latitudes. Our results highlight the importance of realistic boreal BBEs in climate model simulations and the need for improved understanding of boreal emission trends and aerosol–climate interactions.}, archive = {J_PNAS}, author = {Blanchard-Wrigglesworth, Edward and DeRepentigny, Patricia and Frierson, Dargan M. W.}, doi = {10.1073/pnas.2424614122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2424614122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Increasing boreal fires reduce future global warming and sea ice loss}, volume = {122}, year = {2025}, }
• (2025). CACNA1D is a circadian gene and causes familial advanced sleep phase. PNAS, 122(23), e2424387122. (www)

  @article{ , abstract = {Familial advanced sleep phase (FASP) is a heritable human sleep trait characterized by early sleep onset and offset times. We have identified five variants in five different families in the human voltage-gated calcium channel subunit alpha1 D ( CACNA1D ) that cosegregate with FASP. The variants in CACNA1D lead to altered channel dynamics in vitro. A mouse model of the E427K variant has a normal circadian period under constant darkness but displays altered phase shifts in response to light in the subjective night at circadian time (CT) 16 and CT22. Overall, these experiments establish CACNA1D as an FASP gene with altered entrainment, highlighting the ability of human genetics to uncover novel aspects of human circadian regulation.}, archive = {J_PNAS}, author = {Webb, John M. and Abderemane-Ali, Fayal and Ashbrook, Liza and Ma, Mingyang and Nibber, Neha and Zou, Xianlin and Yamazaki, Maya and Wohler, Elizabeth and Sobreira, Nara and Minor, Daniel L. and Fu, Ying-Hui and Ptáček, Louis J.}, doi = {10.1073/pnas.2424387122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2424387122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CACNA1D is a circadian gene and causes familial advanced sleep phase}, volume = {122}, year = {2025}, }
• (2025). Material properties of biomolecular condensates emerge from nanoscale dynamics. PNAS, 122(23), e2424135122. (www)

  @article{ , abstract = {Biomolecular condensates form by phase separation of biological polymers and have important functions in the cell—functions that are inherently linked to their physical properties at different scales. A notable aspect of such membraneless organelles is that their viscoelastic properties can vary by orders of magnitude, but it has remained unclear how these pronounced differences are rooted in the nanoscale dynamics at the molecular level. Here, we investigate a series of condensates formed by complex coacervation of highly charged disordered proteins and polypeptides that span about two orders of magnitude in bulk viscosity. We find that their viscosity is highly correlated with protein translational diffusion and nano- to microsecond chain dynamics. Remarkably, analytical relations from polymer physics can predict condensate viscosity from diffusivity and chain dynamics, and vice versa, even for more hydrophobic disordered proteins and for synthetic polyelectrolytes, indicating a mechanistic link across several decades of length- and timescales. Atomistic simulations reveal that the observed differences in friction—a key quantity underlying these relations—reflect differences in interresidue contact lifetimes as a function of arginine content and salt concentration, leading to the vastly different dynamics among condensates. The rapid exchange of interresidue contacts we observe may be a general mechanism for preventing dynamic arrest in compartments densely packed with polyelectrolytes, such as the cell nucleus.}, archive = {J_PNAS}, author = {Galvanetto, Nicola and Ivanović, Miloš T. and Del Grosso, Simone A. and Chowdhury, Aritra and Sottini, Andrea and Nettels, Daniel and Best, Robert B. and Schuler, Benjamin}, doi = {10.1073/pnas.2424135122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2424135122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Material properties of biomolecular condensates emerge from nanoscale dynamics}, volume = {122}, year = {2025}, }
• (2025). Reciprocal projections between the globus pallidus externa and cortex span motor and nonmotor regions. PNAS, 122(23), e2423367122. (www)

  @article{ , abstract = {The globus pallidus externa (GPe) is a heterogeneous nucleus of the basal ganglia, with intricate connections to other basal ganglia nuclei, as well as direct connections to the cortex. The anatomic, molecular, and electrophysiologic properties of cortex-projecting pallidocortical neurons are not well characterized. Here, we show that pallidocortical neurons project to diverse motor and nonmotor cortical regions, are organized topographically in the GPe, and segregate into at least two distinct electrophysiological and molecular phenotypes. In addition, we find that the GPe receives direct synaptic input from deep layers of diverse motor and nonmotor cortical regions, some of which form reciprocal connections onto pallidocortical neurons. These results demonstrate the existence of a fast, bidirectional circuit between the GPe and the cortex that is ideally positioned to integrate information about behavioral goals, internal states, and environmental cues to rapidly modulate behavior.}, archive = {J_PNAS}, author = {Ferenczi, Emily A. and Wang, Wengang and Biswas, Anushka and Pottala, Trent and Dong, Yihuan and Chan, Alison K. and Albanese, Madeline A. and Sohur, Raina S. and Jia, Tingying and Mastro, Kevin J. and Sabatini, Bernardo L.}, doi = {10.1073/pnas.2423367122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2423367122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reciprocal projections between the globus pallidus externa and cortex span motor and nonmotor regions}, volume = {122}, year = {2025}, }
• (2025). Multiple sources of atmospheric CO2 activated by AMOC recovery at the onset of interglacial MIS 9. PNAS, 122(23), e2423057122. (www)

  @article{ , abstract = {Using high-precision ice core measurements of CO 2 , δ 13 C–CO 2 , CH 4 , and N 2 O, this study provides carbon isotope constraints on a sizeable, centennial-scale CO 2 jump at the onset of Marine Isotope Stage 9 (MIS 9). The very end of the Heinrich stadial (HS) characterizing Termination IV (T-IV, ca. 343 to 333 ka ago) shows a 250-y-long jump in greenhouse gas concentrations, followed by a 1.3 ka gradual decline back to the initial concentration. During this so-called overshoot, CO 2 and CH 4 reach their highest levels (about 303 ppm and 800 ppb, respectively) over the past 800 ka prior to industrialization. The jump in CO 2 is not accompanied by a change in δ 13 C–CO 2, suggesting that multiple mechanisms contributed to the exceptionally elevated CO 2 values. Following the jump, a slow 0.2‰ enrichment in δ 13 C–CO 2 occurs. We propose that during the jump, the sudden resumption of deepwater formation in the North Atlantic (NA) triggered an amplified release of CO 2 from the Southern Ocean (SO) by a northward shift of the Intertropical Convergence Zone (ITCZ) and the SO westerlies, potentially in combination with a rapid land carbon release. The latter is expected from temporally enhanced wildfire activity related to higher fuel load and regionally changing weather conditions in connection to the ITCZ shift. A combination of marine proxy records and box model simulation suggests that the δ 13 C–CO 2 decrease expected from these processes is compensated by a net temperature increase in global sea surface temperature (SST) at the time of the AMOC resumption.}, archive = {J_PNAS}, author = {Krauss, Florian and Baggenstos, Daniel and Schmitt, Jochen and Tuzson, Béla and Menking, James A. and Mächler, Lars and Silva, Lucas and Grimmer, Markus and Capron, Emilie and Stocker, Thomas F. and Bauska, Thomas K. and Fischer, Hubertus}, doi = {10.1073/pnas.2423057122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2423057122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multiple sources of atmospheric CO2 activated by AMOC recovery at the onset of interglacial MIS 9}, volume = {122}, year = {2025}, }
• (2025). Resilience of deep aquifer microbial communities to seasonal hydrological fluctuations. PNAS, 122(23), e2422608122. (www)

  @article{ , abstract = {The influence of seasonal variations in temperature and precipitation on subsurface biogeochemical processes remains poorly understood. In the Lavey-les-Bains thermal system in the Swiss Alps, annual variations in electrical conductivity are observed to depths of 500 m, suggesting a potential link to surface environmental changes. Here we show, through year-round analyses of stable water isotopes, noble gases, and conductivity, that seasonally varying contributions of shallow groundwater from the Rhône alluvial aquifer mix with deep groundwater. Despite vertically similar fluid geochemical compositions suggesting high hydrological connectivity, microbial communities exhibit significant depth-dependent variation with minimal seasonal change. This decoupling of dynamic water source partitioning and stable microbial community structure has not been previously observed and fills a critical gap in our understanding of geothermal systems and microbial life in the deep subsurface. At 200 m, the communities are dominated by sulfur-disproportionating Bacteria ( Dissulfurispira ) and Micrarchaeota, while at 500 m the major groups include sulfate- and iron-reducers and/or hydrogen-oxidizers (Thermales, Thermodesulfobacteriota, and Bathyarchaeota). Our study highlights the resilience of terrestrial subsurface microbial communities to temporal variations in water sources and fluid composition. We propose that intrinsic environmental properties—such as temperature—are more critical drivers of microbial community structure in hydrologically connected deep aquifers than seasonal hydrological changes.}, archive = {J_PNAS}, author = {Giroud, Sébastien and Deng, Longhui and Lever, Mark A. and Schilling, Oliver S. and Kipfer, Rolf}, doi = {10.1073/pnas.2422608122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2422608122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Resilience of deep aquifer microbial communities to seasonal hydrological fluctuations}, volume = {122}, year = {2025}, }
• (2025). Shared disbelief and shared belief: Belief and disbelief as drivers of interpersonal neural synchronization during narrative processing. PNAS, 122(23), e2422396122. (www)

  @article{ , abstract = {Despite living in an era where the mere concept of truth is increasingly contested, the cognitive processes underlying the processing of information we believe or disbelieve remain largely unexplored. In this fMRI study, we investigated how belief modulates narrative processing through belief context—the initial information indicating the speaker’s credibility—and actual belief—the truth value ultimately assigned by the listener. Across two experiments, participants listened to narratives preceded by contexts explicitly stating whether the speaker was lying or telling the truth. Then, after listening to the narratives, they were asked to rate their actual belief. To investigate the effects of (dis)belief on narrative processing, we analyzed neural synchronization using inter-subject-correlation analysis and inter-subject representational similarity analysis. In both experiments, we successfully differentiated (dis)belief contexts by modeling neural synchronization patterns, despite an actual “belief-bias” at the behavioral level. This indicates a unique neural pattern related to each belief context. Furthermore, our results revealed a dissociation between belief and disbelief in both contextual and actual (dis)belief. Per each narrative, belief and disbelief were associated with increased synchrony within the default mode network, but in distinguishable parcels. These findings highlight the influence of (dis)belief on narrative processing at both behavioral and neural levels. Behaviorally, the observed belief-bias supports the notion of belief as a cognitive default. Neurally, we suggest that belief and disbelief can be understood as fostering qualitatively distinct processing or interpretation of the same narrative, which are then reflected in shared neural responses among individuals who hold similar belief states.}, archive = {J_PNAS}, author = {Braun, Gabriel and Yeshurun, Yaara and Shetreet, Einat}, doi = {10.1073/pnas.2422396122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2422396122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Shared disbelief and shared belief: Belief and disbelief as drivers of interpersonal neural synchronization during narrative processing}, volume = {122}, year = {2025}, }
• (2025). Simpson’s gender-equality paradox. PNAS, 122(23), e2422247122. (www)

  @article{ , abstract = {Several cross-country examinations have found larger gender differences in Western countries. More recently, it has been argued, from an evolutionary standpoint, that equality may paradoxically increase gender differences, because it provides more freedom for men and women to pursue innate preferences. However, this paradox has primarily been examined with this cross-country methodology, opening up for other cultural differences to drive the results. For instance, measures developed in Protestant and Germanic-speaking countries, may not work the same in other cultural clusters of countries, and may not have the same statistical qualities there (e.g., in terms of reliability). Here, we reanalyze the results from multiple studies on the gender-equality paradox with country-level data available. We find that gender differences covary more strongly with cultural regions and data quality than gender equality, and that any variable higher in the West appears to achieve similar correlations as gender equality. Also, controlling for cultural regions consistently and strongly attenuates the association with gender equality, including to become statistically nonsignificant, or to switch direction. In other words, the baseline associations differ between and within cultural clusters (a Simpson’s paradox), suggesting there is no simple causal relation between gender equality and expressed gender differences. Similarly, controlling for data quality indicators strongly attenuates the paradox. Finally, we show that, with and without controls, there is no consistent paradoxical association across many of the largest cross-cultural studies on gender differences, including newly analyzed data. The same is true for other country development variables considered in the gender-equality paradox literature.}, archive = {J_PNAS}, author = {Berggren, Mathias and Bergh, Robin}, doi = {10.1073/pnas.2422247122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2422247122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Simpson’s gender-equality paradox}, volume = {122}, year = {2025}, }
• (2025). Concerted transport and phosphorylation of diacylglycerol at ER–PM contact sites regulate phospholipid dynamics during stress. PNAS, 122(23), e2421334122. (www)

  @article{ , abstract = {A universal response of plants to environmental stresses is the activation of plasma membrane (PM) phospholipase C, which hydrolyzes phosphoinositides to produce soluble inositol phosphate and diacylglycerol (DAG). Because of their conical shape, DAG amounts have to be tightly regulated or they can destabilize membranes. We previously showed that upon stress, Synaptotagmin1 (SYT1) transports DAG from the PM to the endoplasmic reticulum (ER) at ER–PM Contact Sites (CS). Here, we addressed the fate of the incoming DAG in the ER. We show that diacylglycerol kinases (DGKs) DGK1 and DGK2 form a module with SYT1 functionally coupling DAG transport and phosphorylation at ER–PM CS. Although SYT1 and DGK1/DGK2 do not show exclusive ER–PM CS localization, their interaction occurs specifically at ER–PM CS and the removal of ER–PM CS abolishes the interaction. Lipidomic analysis of a dgk1dgk2 double mutant supports that DGK1 and DGK2 phosphorylate DAG at the ER and transcriptomic and phenotypic analyses indicate that SYT1 and DGK1/DGK2 are functionally related. Taken together, our results highlight a mechanism at ER–PM CS that coordinates the transfer of DAG from the PM to the ER by SYT1 upon stress and the concomitant phosphorylation of DAG by DGK1 and DGK2 at the ER. These findings underscore the critical role of spatial coordination in lipid metabolism during stress-induced membrane remodeling.}, archive = {J_PNAS}, author = {Garcia-Hernandez, Selene and Morello-López, Jorge and Haslam, Richard and Amorim-Silva, Vitor and Moya-Cuevas, José and Catalá, Rafael and Michaelson, Louise and Pérez-Sancho, Jessica and Marković, Vedrana and Salinas, Julio and Napier, Johnathan and Jaillais, Yvon and Ruiz-Lopez, Noemí and Botella, Miguel A.}, doi = {10.1073/pnas.2421334122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2421334122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Concerted transport and phosphorylation of diacylglycerol at ER–PM contact sites regulate phospholipid dynamics during stress}, volume = {122}, year = {2025}, }
• (2025). Sequential drug release system: Targeting the tumor ECM for enhanced chemotherapy efficacy. PNAS, 122(23), e2421061122. (www)

  @article{ , abstract = {The dense extracellular matrix (ECM) of stroma-rich solid tumors acts as a significant barrier to effective chemotherapy by hindering drug penetration. In this study, a supramolecular hydrogel was successfully developed, enabling the codelivery and sequential release of hydrophilic and lipophilic drugs designed to target the ECM. The hydrogel is easy to prepare, has self-healing properties and excellent biocompatibility. Upon administration, the hydrogel first releases pirfenidone to inhibit collagen production, weakening the ECM, followed by the release of paclitaxel, which improves tumor penetration. The effectiveness of this sequential drug delivery system was validated in both oral squamous cell carcinoma and pancreatic cancer models, a classic example of a tumor with abundant ECM. In vitro experiments showed controlled sequential release profiles, whereas in vivo experiments using cell-derived and patient-derived xenograft models revealed that the hydrogel was more effective at tumor suppression compared to traditional methods. Single administration of the hydrogel led to long-term localized drug release, maintaining higher concentrations of chemotherapeutic agents in the tumor tissue and effectively reducing the tumor volume. This study provided a promising strategy to enhance chemotherapy in ECM-dense tumors, offering an efficient and minimally invasive method for localized, sustained-release cancer therapy.}, archive = {J_PNAS}, author = {Cao, Lideng and Li, Zaiye and Song, Jian and Xia, Xin and Zhang, Gaowei and Wang, Hang and Zhao, Hang}, doi = {10.1073/pnas.2421061122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2421061122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sequential drug release system: Targeting the tumor ECM for enhanced chemotherapy efficacy}, volume = {122}, year = {2025}, }
• (2025). Pathophysiologically relevant bisphenol s exposure accelerates aging by disrupting brown adipose tissue–regulated energy metabolism. PNAS, 122(23), e2420437122. (www)

  @article{ , abstract = {Bisphenol A (BPA) substitutes are widely used as food contact materials and consumer products, while the effects of pathophysiologically relevant concentrations of BPA substitutes on aging remain unclear. In this study, we used Caenorhabditis elegans ( C. elegans ) to investigate the effects of five BPA substitutes [bisphenol S (BPS), bisphenol B, bisphenol F (BPF), tetramethyl BPF, and 4,4′-(Perfluoropropane-2,2-diyl)diphenol] at pathophysiologically relevant exposure levels during aging and examined the underlying mechanisms using a mouse model. Our results indicated that, among the five BPA substitutes, exposure to pathophysiologically relevant concentrations of BPS (300, 450, and 600 nM) accelerated aging in C. elegans . In mice, exposure to a pathophysiologically relevant concentration of BPS (125 μg/kg/day, from 4 to 20 mo of age) similarly reduces the life and health span and accelerates aging phenotypes in multiple tissues. Further investigations demonstrated that long-term BPS exposure resulted in a significantly higher accumulation of BPS in brown adipose tissue (BAT) than in other organs. RNA sequencing analysis of BAT revealed that BPS accelerates BAT aging through multiple pathways. Importantly, transplantation of BAT from BPS-exposed mice into BPS-naive mice accelerated aging in recipients. Conversely, transplantation of BAT from unexposed mice into BPS-exposed mice significantly improved their metabolic status and delayed aging. These findings elucidate the impact of pathophysiologically relevant concentrations of BPS on the aging process and suggest that these effects are likely mediated through the disruption of BAT function.}, archive = {J_PNAS}, author = {Zhu, Man and Wang, Ru and Yi, Wei and Wu, Beiyi and Deng, Zhizhong and Zhang, Zheng and Wang, Chen and Zhang, Dingkun and Zhang, Tongtong and Wen, Xue}, doi = {10.1073/pnas.2420437122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2420437122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pathophysiologically relevant bisphenol s exposure accelerates aging by disrupting brown adipose tissue–regulated energy metabolism}, volume = {122}, year = {2025}, }
• (2025). Amortized template matching of molecular conformations from cryoelectron microscopy images using simulation-based inference. PNAS, 122(23), e2420158122. (www)

  @article{ , abstract = {Characterizing the conformational ensemble of biomolecular systems is key to understand their functions. Cryoelectron microscopy (cryo-EM) captures two-dimensional snapshots of biomolecular ensembles, giving in principle access to thermodynamics. However, these images are very noisy and show projections of the molecule in unknown orientations, making it very difficult to identify the biomolecule’s conformation in each individual image. Here, we introduce cryo-EM simulation-based inference (cryoSBI) to infer the conformations of biomolecules and the uncertainties associated with the inference from individual cryo-EM images. CryoSBI builds on simulation-based inference, a merger of physics-based simulations and probabilistic deep learning, allowing us to use Bayesian inference even when likelihoods are too expensive to calculate. We begin with an ensemble of conformations, templates from experiments, and molecular modeling, serving as structural hypotheses. We train a neural network approximating the Bayesian posterior using simulated images from these templates and then use it to accurately infer the conformation of the biomolecule from each experimental image. Training is only done once on simulations, and after that, it takes just a few milliseconds to make inference on an image, making cryoSBI suitable for arbitrarily large datasets and direct analysis on micrographs. CryoSBI eliminates the need to estimate particle pose and imaging parameters, significantly enhancing the computational speed compared to explicit likelihood methods. Importantly, we obtain interpretable machine learning models by integrating physics-based approaches with deep neural networks, ensuring that our results are transparent and reliable. We illustrate and benchmark cryoSBI on synthetic data and showcase its promise on experimental single-particle cryo-EM data.}, archive = {J_PNAS}, author = {Dingeldein, Lars and Silva-Sánchez, David and Evans, Luke and D’Imprima, Edoardo and Grigorieff, Nikolaus and Covino, Roberto and Cossio, Pilar}, doi = {10.1073/pnas.2420158122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2420158122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Amortized template matching of molecular conformations from cryoelectron microscopy images using simulation-based inference}, volume = {122}, year = {2025}, }
• (2025). The cell-permeable iron chelator m606 inhibits MYCN-driven neuroblastoma via an E2F3-mediated response. PNAS, 122(23), e2420011122. (www)

  @article{ , abstract = {Despite Myc oncoproteins being major causal factors in human cancer, they remain “undruggable.” The MYCN oncogene is one of the most powerful prognostic markers for the childhood cancer neuroblastoma and represents an important target for developing novel therapeutics. Here, we report the finding and characterization of M606, a selective small molecule inhibitor of MYCN, which was identified by screening a diverse chemical library. M606 reduced MYCN protein levels in neuroblastoma cell lines and upregulated hypoxia-inducible factor 1 alpha (HIF1A). Using siRNA-mediated knockdown of MYCN , c-Myc , or HIF1A in HepG2 and BE(2)-C cells followed by M606 treatment, we demonstrated that Myc downregulation and HIF1A upregulation were two independent effects of M606 treatment. M606 selectively targeted neuroblastoma cell lines expressing higher levels of MYCN protein and delayed neuroblastoma development in the TH-MYCN transgenic mouse model. Metabolomic analysis showed that M606 modulated glucose metabolism, consistent with a hypoxic response and iron deprivation. Biochemical characterization of M606 not only confirmed its iron-chelating properties but also revealed its ability to downregulate MYCN promoter activity, which could be rescued by the addition of iron. Luciferase assays identified the minimal MYCN promoter region required for the M606 response, which contained overlapping E2F transcription factor binding sites. Further evaluation defined a key role for E2F3 in the M606-mediated response. The finding of a potent cell-permeable iron chelator that can chelate iron to directly downregulate MYCN transcription via an E2F3-mediated response represents a potentially valuable therapeutic approach in the treatment of cancers overexpressing Myc oncoproteins.}, archive = {J_PNAS}, author = {Pandher, Ruby and Xue, Chengyuan and Gamble, Laura D. and Milazzo, Giorgio and Di Giacomo, Simone and Murray, Jayne and Cheung, Leanna and Ferrucci, Francesca and Palombo, Marta and Purgato, Stefania and Burkhart, Catherine A. and Fedtsova, Natalia and Gleiberman, Anatoli S. and Purmal, Andrei A. and Korotchkina, Lioubov and Nikiforov, Mikhail A. and Makarov, Sergei S. and Telfer, Thomas J. and Codd, Rachel and Marshall, Glenn M. and Scott, David A. and Osterman, Andrei L. and Gudkov, Andrei V. and Perini, Giovanni and Haber, Michelle and Norris, Murray D.}, doi = {10.1073/pnas.2420011122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2420011122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The cell-permeable iron chelator m606 inhibits MYCN-driven neuroblastoma via an E2F3-mediated response}, volume = {122}, year = {2025}, }
• (2025). Physics of notochord tube expansion in ascidians. PNAS, 122(23), e2419960122. (www)

  @article{ , abstract = {Interaction of cells and the surrounding lumen drives the formation of tubular system that plays the transport and exchange functions within an organism. The physical and biological mechanisms of lumen expansion have been explored. However, how cells communicate and coordinate with the surrounding lumen, leading to continuous tube expansion to a defined geometry, is crucial but remains elusive. In this study, we utilized the ascidian notochord tube as a model to address the underlying mechanisms. We first quantitatively measured and calculated the geometric parameters and found that tube expansion experienced three distinct phases. During the growth processes, we identified and experimentally demonstrated that both Rho GTPase Cdc42 signaling-mediated cell cortex distribution and the stability of tight junctions (TJs) were essential for lumen opening and tube expansion. Based on these experimental data, a conservation-laws-based tube expansion theory was developed, considering critical cell communication pathways, including secretory activity through vesicles, asymmetric cortex tension driven anisotropic lumen geometry, as well as the TJs gate barrier function. Moreover, by estimating the critical tube expansion parameters from experimental observation, we successfully predicted tube growth kinetics under different conditions through the combination of computational and experimental approaches, highlighting the coupling between actomyosin-based active mechanics and hydraulic processes. Taken together, our findings identify the critical cellular regulatory factors that drive the biological tube expansion and maintain its stability.}, archive = {J_PNAS}, author = {Shi, Wenjie and Duclut, Charlie and Xu, Yan and Ma, Yuanting and Qiao, Jinghan and Lin, Boyan and Yang, Dongyu and Prost, Jacques and Dong, Bo}, doi = {10.1073/pnas.2419960122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2419960122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Physics of notochord tube expansion in ascidians}, volume = {122}, year = {2025}, }
• (2025). Anthropogenic iron alters the spring phytoplankton bloom in the north pacific transition zone. PNAS, 122(23), e2418201122. (www)

  @article{ , abstract = {Industrial activities have increased the supply of iron to the ocean, but the magnitude of anthropogenic input and its ecological consequences are not well-constrained by observations. Across four expeditions to the North Pacific transition zone, we document a repeated supply of isotopically light iron from an atmospheric source in spring, reflecting an estimated 39 ± 9 % anthropogenic contribution to the surface ocean iron budget. Expression of iron-stress genes in metatranscriptomes, and evidence for colimitation of ecosystem productivity by iron and nitrogen, indicates that enhanced iron supply should spur spring phytoplankton blooms, accelerating the seasonal drawdown of nitrate delivered by winter mixing. This effect is consistent with regional trends in satellite ocean color, which show a shorter, more intense spring bloom period, followed by an earlier arrival of oligotrophic conditions in summer. Continued iron emissions may contribute to poleward shifts in transitional marine ecosystems, compounding the anticipated impacts from ocean warming and stratification.}, archive = {J_PNAS}, author = {Hawco, Nicholas J. and Conway, Tim M. and Coesel, Sacha N. and Barone, Benedetto and Seelen, Emily A. and Yang, Shun-Chung and Bundy, Randelle M. and Pinedo-Gonzalez, Paulina and Bian, Xiaopeng and Sieber, Matthias and Lanning, Nathan T. and Fitzsimmons, Jessica N. and Foreman, Rhea K. and König, Daniela and Groussman, Mora J. and Allen, James G. and Juranek, Lauren W. and White, Angelicque E. and Karl, David M. and Armbrust, E. Virginia and John, Seth G.}, doi = {10.1073/pnas.2418201122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2418201122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Anthropogenic iron alters the spring phytoplankton bloom in the north pacific transition zone}, volume = {122}, year = {2025}, }
• (2025). Symmetries and synchronization from whole-neural activity in the caenorhabditis elegans connectome: Integration of functional and structural networks. PNAS, 122(23), e2417850122. (www)

  @article{ , abstract = {Understanding the dynamical behavior of complex systems from their underlying network architectures is a long-standing question in complexity theory. Therefore, many metrics have been devised to extract network features like motifs, centrality, and modularity measures. It has previously been proposed that network symmetries are of particular importance since they are expected to underlie the synchronization of a system’s units, which is ubiquitously observed in nervous system activity patterns. However, perfectly symmetrical structures are difficult to assess in noisy measurements of biological systems, like neuronal connectomes. Here, we devise a principled method to infer network symmetries from combined connectome and neuronal activity data. Using nervous system-wide population activity recordings of the Caenorhabditis elegans backward locomotor system, we infer structures in the connectome called fibration symmetries, which can explain which group of neurons synchronize their activity. Our analysis suggests functional building blocks in the animal’s motor periphery, providing testable hypotheses on how descending interneuron circuits communicate with the motor periphery to control behavior. Our approach opens a door to exploring the structure–function relations in other complex systems, like the nervous systems of larger animals.}, archive = {J_PNAS}, author = {Avila, Bryant and Augusto, Pedro and Hashemi, Alireza and Phillips, David and Gili, Tommaso and Zimmer, Manuel and Makse, Hernán A.}, doi = {10.1073/pnas.2417850122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2417850122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Symmetries and synchronization from whole-neural activity in the caenorhabditis elegans connectome: Integration of functional and structural networks}, volume = {122}, year = {2025}, }
• (2025). Targeting of hyperlipid-producing senescent synovial fibroblasts to ameliorate cartilage degeneration. PNAS, 122(23), e2417708122. (www)

  @article{ , abstract = {Osteoarthritis (OA) is one of the most common causes of physical disability among older people and its incidence increases with age. Removal of the senescent cells (SNCs) delays OA pathologies, but little is known about the heterogeneity of SNCs and their roles in OA pathogenesis. Here, we identify a subpopulation of senescent synovial cells and proposed a molecular mechanism governing pathogenic synovium-cartilage crosstalk in OA progression. Using single-cell RNA sequencing and synovial organoids, we demonstrate that RCAN1 + IL1α + senescent synovial fibroblasts, predominantly located in the lining layer of human OA synovium, exhibit proinflammatory phenotype, mitochondrial dysfunction, and promote cartilage degeneration. Mechanistically, RCAN1 stabilizes ATF4 mRNA and mediates saturated fatty acids (SFA) secretion from synovial fibroblasts, which could promote chondrocyte senescence and cartilage matrix degradation. Synovium-targeted delivery of anti-RCAN1 siRNA significantly ameliorated posttraumatic OA development in mice, reducing of SNC accumulation in synovium and increasing cartilage regeneration. Coculture experiments with human OA cartilage explants and synovial organoids confirm that RCAN1 silencing in synovial fibroblasts suppressess chondrocyte senescence and cartilage degradation. Our findings reveal a prodegenerative interaction between RCAN1 + IL1α + senescent synovial fibroblasts and chondrocytes mediated by secreted lipid in OA progression. Targeted RCAN1 knockdown in senescent synovium could be a new treatment strategy for restoring the joint homeostasis.}, archive = {J_PNAS}, author = {Hu, Jiajie and Yu, Dongsheng and Wang, Jiasheng and Guo, Peng and Chen, Mingming and Wu, Dongmei and Cai, Youzhi and Wang, Yixuan and Ji, Junfeng and Yao, Xudong and Ouyang, Hongwei}, doi = {10.1073/pnas.2417708122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2417708122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Targeting of hyperlipid-producing senescent synovial fibroblasts to ameliorate cartilage degeneration}, volume = {122}, year = {2025}, }
• (2025). Macropinosomes are a site of HIV-1 entry into primary CD4+ t cells. PNAS, 122(23), e2417676122. (www)

  @article{ , abstract = {HIV-1 has been observed to enter target cells at both the plasma membrane and endosomes. However, which pathways mediate its entry into primary CD4 + T cells, the major targets of this virus, remains unclear. Here, we show that HIV-1 can enter primary CD4 + T cells through macropinocytosis, a form of endocytosis. We found that HIV-1 can enter primary CD4 + T cells at both the plasma membrane and internal compartments, while entry into common T cell lines occurred primarily at the plasma membrane. Inhibition of macropinocytosis suppressed HIV-1 internalization into and subsequent fusion with primary CD4 + T cells regardless of the viral coreceptor usage. Microscopic analysis of viral contents exposed to the cytosol confirmed that HIV-1 fusion occurs at the macropinosomal membrane. Finally, the inhibition of macropinocytosis blocked HIV-1 infection of primary CD4 + T cells. Altogether, this study identifies macropinocytosis as one pathway for HIV-1 entry into primary CD4 + T cells.}, archive = {J_PNAS}, author = {Murakami, Tomoyuki and Cardoso, Ricardo de Souza and Manivannan, Praveen and Chang, Ya-Ting and Rentchler, Eric and Chou, Kai-Neng and Tang, Yipei and Swanson, Joel A. and King, Philip D. and Ono, Akira}, doi = {10.1073/pnas.2417676122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2417676122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Macropinosomes are a site of HIV-1 entry into primary CD4+ t cells}, volume = {122}, year = {2025}, }
• (2025). Controlling DNA–RNA strand displacement kinetics with base distribution. PNAS, 122(23), e2416988122. (www)

  @article{ , abstract = {DNA–RNA hybrid strand displacement underpins the function of many natural and engineered systems. Understanding and controlling factors affecting DNA–RNA strand displacement reactions is necessary to enable control of processes such as CRISPR-Cas9 gene editing. By combining multiscale modeling with strand displacement experiments, we show that the distribution of bases within the displacement domain has a very strong effect on reaction kinetics, a feature unique to DNA–RNA hybrid strand displacement. Merely by redistributing bases within a displacement domain of fixed base composition, we are able to design sequences whose reaction rates span more than four orders of magnitude. We extensively characterize this effect in reactions involving the invasion of dsDNA by an RNA strand, as well as the invasion of a hybrid duplex by a DNA strand. In all-DNA strand displacement reactions, we find a predictable but relatively weak sequence dependence, confirming that DNA–RNA strand displacement permits far more thermodynamic and kinetic control than its all-DNA counterpart. We show that oxNA, a recently introduced coarse-grained model of DNA–RNA hybrids, can reproduce trends in experimentally observed reaction rates. We also develop a simple kinetic model for predicting strand displacement rates. On the basis of these results, we argue that base distribution effects may play an important role in natural R-loop formation and in the function of the guide RNAs that direct CRISPR-Cas systems.}, archive = {J_PNAS}, author = {Ratajczyk, Eryk J. and Bath, Jonathan and Šulc, Petr and Doye, Jonathan P. K. and Louis, Ard A. and Turberfield, Andrew J.}, doi = {10.1073/pnas.2416988122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2416988122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Controlling DNA–RNA strand displacement kinetics with base distribution}, volume = {122}, year = {2025}, }
• (2025). Transcranial direct current stimulation neuromodulates intracranial cognitive evoked activity in humans. PNAS, 122(23), e2416541122. (www)

  @article{ , abstract = {Transcranial direct current stimulation (tDCS) is an easy to use, noninvasive brain stimulation technique that gained prominence for its potential in cognitive rehabilitation. Electroencephalography (EEG), which records electrical brain activity with a high temporal resolution, is well suited to quantify tDCS-induced neuromodulation in humans. However, most studies relying on scalp EEG recordings or event-related potentials showed low reliability and only indirect correlations. Here, we combined intracranial EEG (iEEG) recordings with a sham-controlled tDCS experiment during fast periodic visual stimulation. Anodal (+2 mA) tDCS was applied over the right occipito-temporal cortex for 20 min using two small ring high-definition electrodes. Through the analysis of iEEG signals of 947 intracerebral contacts in 11 drug-resistant epileptic patients, we quantified the neuromodulation of iEEG cognitive evoked responses during (P2 phase) and after (P3 phase) tDCS by comparison to a control phase before tDCS (P1 phase). Significant neuromodulations of face-selective iEEG activity in anterior & posterior temporal lobe and in the occipital lobe were found, with amplitude increases of 3% and 4%, 16% and 13%, and 36% and 33%, during and after tDCS, respectively. Interestingly, despite a unique tDCS session, the face-selective neuromodulation in the right visual occipito-temporal cortex remained significant ( P = 0.015) after tDCS (P3 vs. P1). This iEEG study demonstrates that using low intensity tDCS and small ring electrodes can induce significant electrophysiological effects on a selective cognitive function in humans.}, archive = {J_PNAS}, author = {Tabikh, Mireille and Quetu, Tom and Maillard, Louis and Colnat-Coulbois, Sophie and Rossion, Bruno and Koessler, Laurent}, doi = {10.1073/pnas.2416541122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2416541122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transcranial direct current stimulation neuromodulates intracranial cognitive evoked activity in humans}, volume = {122}, year = {2025}, }
• (2025). High-frequency monitoring enables machine learning–based forecasting of acute child malnutrition for early warning. PNAS, 122(23), e2416161122. (www)

  @article{ , abstract = {The number of acutely food insecure people worldwide has doubled since 2017, increasing demand for early warning systems (EWS) that can predict food emergencies. Advances in computational methods, and the growing availability of near-real time remote sensing data, suggest that big data approaches might help meet this need. But such models have thus far exhibited low predictive skill with respect to subpopulation-level acute malnutrition indicators. We explore whether updating training data with high frequency monitoring of the predictand can help improve machine learning models’ predictive performance with respect to child acute malnutrition by directly learning the dynamic determinants of rapidly evolving acute malnutrition crises. We combine supervised machine learning methods and remotely sensed feature sets with time series child anthropometric data from EWS’ sentinel sites to generate accurate forecasts of acute malnutrition at operationally meaningful time horizons. These advances can enhance intertemporal and geographic targeting of humanitarian response to impending food emergencies that otherwise have unacceptably high case fatality rates.}, archive = {J_PNAS}, author = {Constenla-Villoslada, Susana and Liu, Yanyan and McBride, Linden and Ouma, Clinton and Mutanda, Nelson and Barrett, Christopher B.}, doi = {10.1073/pnas.2416161122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2416161122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High-frequency monitoring enables machine learning–based forecasting of acute child malnutrition for early warning}, volume = {122}, year = {2025}, }
• (2025). Circuit complexity and functionality: A statistical thermodynamics perspective. PNAS, 122(23), e2415913122. (www)

  @article{ , abstract = {Circuit complexity, defined as the minimum circuit size required for implementing a particular Boolean computation, is a foundational concept in computer science. Determining circuit complexity is believed to be a hard computational problem. Recently, in the context of black holes, circuit complexity has been promoted to a physical property, wherein the growth of complexity is reflected in the time evolution of the Einstein-Rosen bridge (“wormhole”) connecting the two sides of an anti-de Sitter “eternal” black hole. Here, we are motivated by an independent set of considerations and explore links between complexity and thermodynamics for functionally equivalent circuits, making the physics-inspired approach relevant to real computational problems, for which functionality is the key element of interest. In particular, our thermodynamic framework provides an alternative perspective on the obfuscation of programs of arbitrary length—an important problem in cryptography—as thermalization through recursive mixing of neighboring sections of a circuit, which can be viewed as the mixing of two containers with “gases of gates.” This recursive process equilibrates the average complexity and leads to the saturation of the circuit entropy, while preserving functionality of the overall circuit. The thermodynamic arguments hinge on ergodicity in the space of circuits which we conjecture is limited to disconnected ergodic sectors due to fragmentation. The notion of fragmentation has important implications for the problem of circuit obfuscation as it implies that there are circuits of same size and functionality that cannot be connected via a polynomial number of local moves. Furthermore, we argue that fragmentation is unavoidable unless the complexity classes NP and coNP coincide, a statement that implies the collapse of the polynomial hierarchy of computational complexity theory to its first level.}, archive = {J_PNAS}, author = {Chamon, Claudio and Ruckenstein, Andrei E. and Mucciolo, Eduardo R. and Canetti, Ran}, doi = {10.1073/pnas.2415913122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2415913122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Circuit complexity and functionality: A statistical thermodynamics perspective}, volume = {122}, year = {2025}, }
• (2025). Stepwise deactivation of gibberellins during rice internode elongation. PNAS, 122(23), e2415835122. (www)

  @article{ , abstract = {Bioactive gibberellins (GAs) are a class of plant hormones that regulate various aspects of plant growth and development, and several key GA deactivation enzymes have been identified. In rice, non-13-hydroxylated GAs have been shown to be deactivated via 16α,17-epoxidation by a cytochrome P450 monooxygenase, ELONGATED UPPERMOST INTERNODE (EUI/CYP714D1). Although 16,17-dihydro-16α,17-epoxyGA 4 (16α,17-epoxyGA 4 ), the product of EUI from bioactive GA 4 , has shown weak bioactivity on rice seedlings, how 16α,17-epoxyGAs are further deactivated remains elusive. Here, we identify the EUI2 gene, which regulates internode elongation in rice, using a map-based cloning strategy. EUI2 encodes an epoxide hydrolase that hydrolyzes 16α,17-epoxyGAs to 16,17-dihydro-16α,17-dihydroxyGAs. The eui2 mutants are taller than wild-type plants but are shorter than the eui mutants. However, the levels of known bioactive GAs in the uppermost internodes are not significantly increased in the eui2 mutants. Instead, we show that the eui2 mutants accumulate 16α,17-epoxyGA 4 to high levels. We also show that exogenously applied 16α,17-epoxyGA 4 is significantly active in elongating the uppermost internode, although not as potent as GA 4 . Furthermore, we demonstrate that 16α,17-epoxyGA 4 can directly interact with the rice GA receptor, GIBBERELLIN INSENSITIVE DWARF1, in vitro. Taken together, the sequential action of EUI and EUI2 results in the stepwise deactivation of GAs during internode elongation in rice. Our data also suggest that the accumulation of a weakly active GA contributes to the mildly tall phenotype of the eui2 mutants.}, archive = {J_PNAS}, author = {Ishida, Toshiaki and Zhang, Yingying and Zhu, Hongbo and Fudano, Shoko and Peng, Yu and Seto, Yoshiya and Mashiguchi, Kiyoshi and Liu, Jiyun and He, Zuhua and Zhang, Shubiao and Yamaguchi, Shinjiro}, doi = {10.1073/pnas.2415835122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2415835122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stepwise deactivation of gibberellins during rice internode elongation}, volume = {122}, year = {2025}, }
• (2025). Natural dispersal is better than translocation for reducing risks of inbreeding depression in eastern black rhinoceros (Diceros bicornis michaeli). PNAS, 122(23), e2414412122. (www)

  @article{ , abstract = {Due to increasing anthropogenic impacts, many species survive only in small and isolated populations. Active conservation management to reduce extinction risk includes increasing habitat connectivity, translocations from captive populations, or intensive surveillance of highly protected closed populations. Advances in sequencing technology mean that it is now possible to consider the genomic impacts of such strategies, as a proxy for variation in individual fitness. Using whole genome sequences from critically endangered eastern black rhinoceros ( Diceros bicornis michaeli ), we compare the consequences of different types of conservation efforts, based on cohorts of offspring resulting from parents from different sources. Based on the fraction of the genome in runs of homozygosity (ROH) of different lengths, we found lower inbreeding in offspring of individuals that had either been translocated from ex-situ populations (F ROH>1Mb = 0.047) or dispersed between proximate native populations (F ROH>1Mb = 0.065) compared to the intensively managed closed population from which the migrant moved (F ROH>1Mb = 0.112). However, the benefit of such movement was removed after only a few generations of closed breeding (F ROH>1Mb = 0.149). Although sample size restricted power to detect significance of differences, the relative abundance of highly deleterious mutations was higher for offspring resulting from translocation compared to the other cohorts and this load was sheltered by higher heterozygosity, which could increase risks of inbreeding depression if inbreeding subsequently occurs. In contrast, native dispersers reduced the negative effects of inbreeding without compromising the benefits of past purging of deleterious mutations. Our study highlights the importance of natural dispersal and reiterates the importance of maintaining habitat corridors between populations.}, archive = {J_PNAS}, author = {Mellya, Ronald. V. K. and Hopcraft, J. Grant C. and Mwakilema, William and Eblate, Ernest M. and Mduma, Simon and Mnaya, Bakari and Chuma, Idrissa S. and Macha, Emmanuel S. and Wambura, Dickson and Fyumagwa, Robert D. and Kilbride, Elizabeth and Ijaz, Umer Z. and Mable, Barbara K. and Khan, Anubhab}, doi = {10.1073/pnas.2414412122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2414412122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Natural dispersal is better than translocation for reducing risks of inbreeding depression in eastern black rhinoceros (Diceros bicornis michaeli)}, volume = {122}, year = {2025}, }
• (2025). A proteomic signature of healthspan. PNAS, 122(23), e2414086122. (www)

  @article{ , abstract = {The focus of aging research has shifted from increasing lifespan to enhancing healthspan to reduce the time spent living with disability. Despite significant efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. We developed a proteomics-based signature of healthspan [healthspan proteomic score (HPS)] using proteomic data from the Olink Explore 3072 assay in the UK Biobank Pharma Proteomics Project (53,018 individuals and 2,920 proteins). A lower HPS was associated with higher mortality risk and several age-related conditions, such as chronic obstructive pulmonary disease, diabetes, heart failure, cancer, myocardial infarction, dementia, and stroke. HPS showed superior predictive accuracy for these outcomes compared to other biological age measures. Proteins associated with HPS were enriched in hallmark pathways such as immune response, inflammation, cellular signaling, and metabolic regulation. The external validity was evaluated using the Essential Hypertension Epigenetics study with proteomic data also from the Olink Explore 3072 and complementary epigenetic data, making it a valuable tool for assessing healthspan and as a potential surrogate marker to complement existing proteomic and epigenetic biological age measures in geroscience-guided studies.}, archive = {J_PNAS}, author = {Kuo, Chia-Ling and Liu, Peiran and Drouard, Gabin and Vuoksimaa, Eero and Kaprio, Jaakko and Ollikainen, Miina and Chen, Zhiduo and Pilling, Luke C. and Atkins, Janice L. and Fortinsky, Richard H. and Kuchel, George A. and Diniz, Breno S.}, doi = {10.1073/pnas.2414086122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2414086122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A proteomic signature of healthspan}, volume = {122}, year = {2025}, }
• (2025). The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels. PNAS, 122(23), e2413811122. (www)

  @article{ , abstract = {Paracetamol has been used for decades to relieve mild-to-moderate pain. Its analgesic effect is mainly attributed to its metabolite, AM404, acting on cannabinoid receptors or TRPV1 channels in central nervous system (CNS) neurons. Here, we show that AM404 is produced by primary sensory neurons. It inhibits sodium current in nociceptor neurons, blocking action potential (AP) generation and reducing nocifensive behavior in naïve and inflamed rats. We demonstrated that this analgesic effect of AM404 is mediated by its direct inhibition of nociceptive voltage-gated sodium channels (Na V ) 1.8 and 1.7 via the local anesthetic binding site. The Na V 1.8 and 1.7 inhibition was specific for AM404 and not observed with other metabolites of paracetamol. Our findings suggest that the analgesic effect of paracetamol is mediated mainly by direct AM404-induced inhibition of nociceptive sodium channels at the peripheral nociceptor neurons. Our findings lay a foundation for the potential development of AM404 as a selective local analgesic.}, archive = {J_PNAS}, author = {Maatuf, Yossef and Kushnir, Yishai and Nemirovski, Alina and Ghantous, Mariana and Iskimov, Ariel and Binshtok, Alexander M. and Priel, Avi}, doi = {10.1073/pnas.2413811122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2413811122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels}, volume = {122}, year = {2025}, }
• (2025). The prevalence of functional limitations in the US workforce. PNAS, 122(23), e2413663122. (www)

  @article{ , abstract = {This research paper investigates the prevalence of functional limitations among employed adults in the United States and the association between these limitations and medical conditions. The authors administered a survey adapted from the Dutch Functional Abilities List to a nationally representative sample of US adults ages 22 and older, finding that nearly three-quarters of working adults report at least one functional limitation, with an average of nearly six functional limitations per working adult. The most common limitations were in upper body strength and torso range of motion, and with respect to the ambient environment. The study also found that mental illness, arthritis, and substance use disorder are associated with the greatest number of functional limitations in working adults. The findings have implications for economic performance, workforce planning, and social policies to support displaced and vulnerable workers with significant functional limitations. Identifying the occupations and industries with large numbers of workers with functional limitations is critical to addressing short-term labor supply disruptions (e.g., public health crises) and preparing for longer-term workforce needs (e.g., long-term care workers for an aging population).}, archive = {J_PNAS}, author = {Clark, Hailey and Ravesteijn, Bastian and Mullen, Kathleen J. and Maestas, Nicole}, doi = {10.1073/pnas.2413663122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2413663122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The prevalence of functional limitations in the US workforce}, volume = {122}, year = {2025}, }
• (2025). Structure–function coupling in the first month of life: Associations with age and attention. PNAS, 122(23), e2412729122. (www)

  @article{ , abstract = {How brain structure relates to function is a critical and open question in neuroscience. Here, we characterize regional variation in structure–function coupling, capturing the degree to which a cortical region’s structural connections relate to patterns of coordinated neural activity in healthy, term-born neonates ( n = 239). Regional structure–function coupling is heterogeneously patterned across the cortex, with higher coupling in the auditory, lateral prefrontal, and inferior parietal cortices. Average structure–function coupling is negatively associated with age during the first month of life, with age-associated decreases seen in primary sensory systems, specifically in auditory and somatomotor regions. Age-associated “decoupling” of structure and function reflects increasingly segregated patterns of functional connectivity and increasingly integrated patterns of white matter connectivity with age. Notably, higher structure–function coupling after accounting for age in the dorsal attention, cingulo-opercular, and visual systems at birth is associated with faster visuospatial attention to faces at one year of age. These results yield valuable insight into the development of structural and functional connectivity across the cortex, including how interregional variation in structure–function coupling during the first month of life might shape later attention.}, archive = {J_PNAS}, author = {Tooley, Ursula A. and Kenley, Jeanette K. and Camacho, M. Catalina and Latham, Aidan and Alexopoulos, Dimitrios and Nielsen, Ashley N. and Smyser, Tara A. and Warner, Barbara B. and Shimony, Joshua S. and Neil, Jeffrey J. and Luby, Joan L. and Barch, Deanna M. and Rogers, Cynthia E. and Smyser, Christopher D.}, doi = {10.1073/pnas.2412729122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2412729122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure–function coupling in the first month of life: Associations with age and attention}, volume = {122}, year = {2025}, }
• (2025). Light at night negatively affects mood in diurnal primate-like tree shrews via a visual pathway related to the perihabenular nucleus. PNAS, 122(23), e2411280122. (www)

  @article{ , abstract = {To better understand the potential health threats and underlying visual pathways of long-term light at night (LAN) exposure, we adopted a widely accepted diurnal animal model tree shrew ( Tupaia belangeri chinensis ), which is a close relative to primates, and evaluated the deleterious effects of long-term LAN exposure. We used an early-night LAN paradigm that was established in mice to examine behavioral and physiological consequences in adult male tree shrews. We found that 3-wk LAN exposure significantly impaired the mood and long-term memory of tree shrews without affecting the general activity pattern. We identified retinal projections to the perihabenular nucleus (pHb), a crucial area in LAN-induced negative mood, and demonstrated that the pHb continues to innervate the nucleus accumbens (NAc) in tree shrews. Moreover, the pHb was required for the LAN effect on mood but not long-term memory. Transcriptomic profiling of brain tissues containing the NAc area revealed drastic changes of several depression-related genes in NAc neurons post-LAN treatment, suggesting that long-term exposure to nighttime light could result in lasting changes in tree shrews. Collectively, we present behavioral and neural structural evidence that LAN exerts depression-inducing effects in diurnal animals via a pHb-related visual pathway, which may facilitate the translation from laboratory findings of excessive LAN exposure to clinical applications in humans.}, archive = {J_PNAS}, author = {Miao, Ying and Zhao, Huan and Li, Yu-Fei and Sun, Yan-Ping and Bi, Rui and Li, Hongli and Fang, Xin and Li, Zi-Shuo and Ma, Yu-Hua and Lv, Long-Bao and An, Kai and Meng, Jian-Jun and Yao, Yong-Gang and Xue, Tian}, doi = {10.1073/pnas.2411280122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2411280122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Light at night negatively affects mood in diurnal primate-like tree shrews via a visual pathway related to the perihabenular nucleus}, volume = {122}, year = {2025}, }
• (2025). Evolution of the real area of contact during laboratory earthquakes. PNAS, 122(23), e2410496122. (www)

  @article{ , abstract = {Empirical slip-rate- and state-dependent friction laws and linear fracture mechanics constitute popular approaches to explaining earthquakes. However, the physics underlying friction laws remain elusive and fracture mechanics does not specify fault strength at the various conditions relevant to crustal faulting. Here, we introduce a physical constitutive framework that augments the traditional approaches by incorporating the real area of contact as the state variable. The physical model explains the dynamics of slow and fast ruptures on transparent materials, as well as the amount of light transmitted across the interface during laboratory ruptures. The constitutive framework elucidates the origin of empirical friction laws, and the simulated ruptures can be described by linear elastic fracture mechanics. Continuous measurements of the physical state variable or its proxies during seismic cycles emerge as a novel tool for probing natural faults and advancing our understanding of the earthquake phenomenon.}, archive = {J_PNAS}, author = {Wu, Baoning and Barbot, Sylvain}, doi = {10.1073/pnas.2410496122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2410496122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolution of the real area of contact during laboratory earthquakes}, volume = {122}, year = {2025}, }
• (2025). Reinforcement generates systematic differences without heterogeneity. PNAS, 122(23), e2408163122. (www)

  @article{ , abstract = {Inequality in outcomes may emerge through a reinforcement process in which stochastic variation in values is determined by prior values but may also originate in preexisting differences in unobserved factors. A common approach toward differentiating between these origins in longitudinal data is to attribute systematic differences between units—differences in means or differences proportional to a time-varying group average—to unobserved heterogeneity. We show that any longitudinal data with systematic differences can also be produced by a reinforcement-driven data generating process. This result reconciles findings in three distinct research areas—science of science, personal culture, and sexual networks—where reinforcement is a strong theoretical prior, yet longitudinal data analyses advance an explanation of interpersonal differences based on heterogeneity. Future studies may bound the role of heterogeneity and reinforcement from below by measuring fixed traits that systematically vary with the outcome and isolating random events that trigger emergent differences.}, archive = {J_PNAS}, author = {Gelastopoulos, Alexandros and Sage, Lucas and van de Rijt, Arnout}, doi = {10.1073/pnas.2408163122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2408163122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reinforcement generates systematic differences without heterogeneity}, volume = {122}, year = {2025}, }
• (2025). Revealing land control dynamics in emerging agricultural frontiers. PNAS, 122(23), e2407916122. (www)

  @article{ , abstract = {The expansion of commodity agriculture into tropical and subtropical woodlands degrades ecosystem functionality, biodiversity, and the livelihood base of millions of people. Understanding where and how agricultural frontiers emerge is thus important. Yet, existing monitoring approaches typically focus on mapping deforestation and do not capture the shifts in land access and ownership that lay the ground for agricultural expansion, thereby missing early stages of frontier development. We develop an approach that captures these early dynamics and apply it to the entire 1,1 million km 2 of the Chaco, a global deforestation hotspot. Through the detection of linear features indicative of land claims and the analysis of their spatial–temporal dynamics, we reveal that the footprint of agricultural frontiers in the region extends far beyond that of deforestation. Most of the Chaco shows signs of land claiming, and although claiming activity is especially concentrated close to active deforestation, emergent claiming in remote parts of the Bolivian and Paraguayan Chaco indicates rapidly growing interest in land in these regions. Finally, the strong spatial correlation between land claiming and the disappearance of smallholder homesteads points to the social repercussions of early agricultural frontier expansion in the Chaco. By offering a transferable template to map land-control indicators at scale, our approach enables a better understanding of frontier processes and more accurate targeting of policy interventions in emerging agricultural frontiers globally.}, archive = {J_PNAS}, author = {del Giorgio, Olivia and Baumann, Matthias and Kuemmerle, Tobias and le Polain de Waroux, Yann}, doi = {10.1073/pnas.2407916122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2407916122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Revealing land control dynamics in emerging agricultural frontiers}, volume = {122}, year = {2025}, }
• (2025). Disrupted diencephalon development and neuropeptidergic pathways in zebrafish with autism-risk mutations. PNAS, 122(23), e2402557122. (www)

  @article{ , abstract = {Hundreds of human mutations are linked to autism and related disorders, yet the functions of many of these mutated genes during vertebrate neurodevelopment are unclear. We generated 27 zebrafish mutants with presumptive protein-truncating mutations or specific missense variants corresponding to autism-risk alleles in 17 human genes. We observed baseline and stimulus-driven behavioral changes at larval stages, as well as social behavior differences in lines tested as juveniles. Imaging whole-brain activity revealed a near identical activity map for mutations in the unrelated genes kmt5b and hdlbpa , defined by increased activity mainly in the thalamus and mesencephalon. Mutating 7 of the 17 risk genes resulted in substantial brain size differences, localized to the diencephalon in three cases and more widespread in others. Using RNA sequencing, we further defined molecular drivers of the observed phenotypes for three mutants, identifying targetable disruptions in neuropeptide signaling, neuronal maturation, and cell proliferation. This multimodal screen nominated brain regions, cell types, and molecular pathways that may contribute to autism susceptibility.}, archive = {J_PNAS}, author = {Capps, Mary E. S. and Moyer, Anna J. and Conklin, Claire L. and Martina, Verdion and Torija-Olson, Emma G. and Klein, Morgan C. and Gannaway, William C. and Calhoun, Caleb C. S. and Vivian, Michael D. and Thyme, Summer B.}, doi = {10.1073/pnas.2402557122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {23}, pages = {e2402557122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Disrupted diencephalon development and neuropeptidergic pathways in zebrafish with autism-risk mutations}, volume = {122}, year = {2025}, }
• (2025). Laser-induced graphene points to sustainable electronics. PNAS, 122(22), e2511902122. (www)

  @article{ , archive = {J_PNAS}, author = {Ornes, Stephen}, doi = {10.1073/pnas.2511902122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2511902122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Laser-induced graphene points to sustainable electronics}, volume = {122}, year = {2025}, }
• (2025). Correction for clark et al., prosocial motives underlie scientific censorship by scientists: A perspective and research agenda. PNAS, 122(22), e2510676122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2510676122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2510676122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for clark et al., prosocial motives underlie scientific censorship by scientists: A perspective and research agenda}, volume = {122}, year = {2025}, }
• (2025). Correction for bonetti et al., quantum oscillations in the hole-doped cuprates and the confinement of spinons. PNAS, 122(22), e2510049122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2510049122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2510049122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for bonetti et al., quantum oscillations in the hole-doped cuprates and the confinement of spinons}, volume = {122}, year = {2025}, }
• (2025). Correction for khademhosseini et al., microscale technologies for tissue engineering and biology. PNAS, 122(22), e2509740122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2509740122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2509740122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for khademhosseini et al., microscale technologies for tissue engineering and biology}, volume = {122}, year = {2025}, }
• (2025). Lynn landmesser (1943–2024): A pioneer in developmental neurobiology. PNAS, 122(22), e2509313122. (www)

  @article{ , abstract = {Lynn Landmesser, whose studies transformed our view of how neurons find the proper partners on which to form synapses, died at the age of 80 in November 2024. Using elegant electrophysiological methods, she showed that specificity is apparent from the earliest times that connections are established in both autonomic and motor systems. Her work overturned the idea that synaptic connectivity arises by gradual refinement of initially nonspecific patterns and thereby laid the groundwork for molecular analysis of the factors that guide axons to and connect them with their targets.}, archive = {J_PNAS}, author = {Landis, Story and Sanes, Joshua R.}, doi = {10.1073/pnas.2509313122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2509313122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lynn landmesser (1943–2024): A pioneer in developmental neurobiology}, volume = {122}, year = {2025}, }
• (2025). Reply to siqueira-batista and gómez: Underscoring the importance of biosafety for the return of martian samples. PNAS, 122(22), e2508447122. (www)

  @article{ , archive = {J_PNAS}, author = {Whetsel, Charles W. and Levine, Joel S. and Hoffman, Stephen J. and Antonsen, Erik L.}, doi = {10.1073/pnas.2508447122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2508447122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to siqueira-batista and gómez: Underscoring the importance of biosafety for the return of martian samples}, volume = {122}, year = {2025}, }
• (2025). The cellular dance that splits vessels. PNAS, 122(22), e2508260122. (www)

  @article{ , archive = {J_PNAS}, author = {Munn, Lance L.}, doi = {10.1073/pnas.2508260122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2508260122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The cellular dance that splits vessels}, volume = {122}, year = {2025}, }
• (2025). Correction for lai et al., CIRCADIAN CLOCK-ASSOCIATED 1 regulates ROS homeostasis and oxidative stress responses. PNAS, 122(22), e2508245122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2508245122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2508245122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for lai et al., CIRCADIAN CLOCK-ASSOCIATED 1 regulates ROS homeostasis and oxidative stress responses}, volume = {122}, year = {2025}, }
• (2025). Martian samples, hazards, and biosecurity: Between science and bioethics. PNAS, 122(22), e2507961122. (www)

  @article{ , archive = {J_PNAS}, author = {Siqueira-Batista, Rodrigo and Gómez, Felipe}, doi = {10.1073/pnas.2507961122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2507961122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Martian samples, hazards, and biosecurity: Between science and bioethics}, volume = {122}, year = {2025}, }
• (2025). Synthesizing decades of research into one tree for birds. PNAS, 122(22), e2507805122. (www)

  @article{ , archive = {J_PNAS}, author = {Stiller, Josefin}, doi = {10.1073/pnas.2507805122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2507805122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synthesizing decades of research into one tree for birds}, volume = {122}, year = {2025}, }
• (2025). Toward elucidating the mechanism of cochlear stimulation by infrared light. PNAS, 122(22), e2507582122. (www)

  @article{ , archive = {J_PNAS}, author = {Moser, Tobias and Roos, Lennart}, doi = {10.1073/pnas.2507582122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2507582122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Toward elucidating the mechanism of cochlear stimulation by infrared light}, volume = {122}, year = {2025}, }
• (2025). The proofreading mechanism of the human leading-strand DNA polymerase ε holoenzyme. PNAS, 122(22), e2507232122. (www)

  @article{ , abstract = {The eukaryotic leading-strand DNA polymerase ε (Polε) is a dual-function enzyme with a proofreading 3′-5′ exonuclease ( exo ) site located 40 Å from the DNA synthesizing pol site. Errors in Polε proofreading can cause various mutations, including C-to-G transversions, the most prevalent mutation in cancers and genetic diseases. Polε interacts with all three subunits of the PCNA ring to assemble a functional holoenzyme. Despite previous studies on proofreading of several Pol’s, how Polε—or any Pol complexed with its sliding clamp—proofreads a mismatch generated in situ has been unknown. We show here by cryo-EM that a template/primer DNA substrate with a preexisting mismatch cannot enter the exo site of Polε–PCNA holoenzyme, but a mismatch generated in situ in the pol site yields three bona fide proofreading intermediates of Polε–PCNA holoenzyme. These intermediates reveal how the mismatch is dislodged from the pol site, how the DNA unwinds six base pairs, and how the unpaired primer 3′-end is inserted into the exo site for cleavage. These results unexpectedly demonstrate that PCNA imposes strong steric constraints that extend unwinding and direct the trajectory of mismatched DNA and that this trajectory is dramatically different than for Polε in the absence of PCNA. These findings suggest a physiologically relevant proofreading mechanism for the human Polε holoenzyme.}, archive = {J_PNAS}, author = {Wang, Feng and He, Qing and O’Donnell, Michael E. and Li, Huilin}, doi = {10.1073/pnas.2507232122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2507232122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The proofreading mechanism of the human leading-strand DNA polymerase ε holoenzyme}, volume = {122}, year = {2025}, }
• (2025). Iñupiat marine mammal science a long time coming. PNAS, 122(22), e2506779122. (www)

  @article{ , archive = {J_PNAS}, author = {Humphries, Murray M. and Menzies, Allyson K. and Langwieder, Alexandra}, doi = {10.1073/pnas.2506779122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2506779122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Iñupiat marine mammal science a long time coming}, volume = {122}, year = {2025}, }
• (2025). Oxr1 and ncoa7 regulate V-ATPase to achieve optimal pH for glycosylation within the golgi apparatus and trans-golgi network. PNAS, 122(22), e2505975122. (www)

  @article{ , abstract = {Maintenance of pH within membranous organelles is crucial for cellular processes such as posttranslational modifications, ligand–receptor interactions, and proteostasis. The precise mechanisms that determine the luminal pH of each organelle are not fully understood. This study investigated the mechanisms that regulate luminal pH to ensure optimal enzymatic activity. We identified Oxr1 and its paralog Ncoa7, which regulate the vacuolar-type proton pump ATPase (V-ATPase) at the Golgi apparatus and trans-Golgi network (TGN). Oxr1 and Ncoa7 were predominantly localized at the Golgi and TGN membranes, dependent on their binding to various GTP-bound Rab proteins. In vitro experiments using purified recombinant proteins indicated that Oxr1 and Ncoa7 directly bind to the catalytic subunit of V-ATPase, inhibiting its ATP hydrolytic activity via their TLDc domains. We observed significant acidification of the Golgi/TGN lumen in Oxr1- and Ncoa7-depleted cells. Lectin blot analysis demonstrated that depletion of Oxr1 and Ncoa7 led to a defect in protein glycosylation, a major enzymatic posttranslational modification in the Golgi and TGN. Furthermore, depletion of Oxr1 and Ncoa7, along with drug-induced inhibition of glycosylation, increased lysosomal pH and sensitivity to silicon dioxide-induced membrane damage. This apparent lysosomal dysfunction suggested that, in addition to the Golgi and TGN, Oxr1 and Ncoa7 also contribute to the integrity of other organelles. Our findings indicate that Oxr1 and Ncoa7 protect the Golgi and TGN lumen from excess acidification by inhibiting V-ATPase activity and providing an optimal environment for enzymatic activity in the Golgi and TGN.}, archive = {J_PNAS}, author = {Yoshimura, Shin-ichiro and Sobajima, Tomoaki and Kunii, Masataka and Harada, Akihiro}, doi = {10.1073/pnas.2505975122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2505975122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Oxr1 and ncoa7 regulate V-ATPase to achieve optimal pH for glycosylation within the golgi apparatus and trans-golgi network}, volume = {122}, year = {2025}, }
• (2025). Ethanol induction of FGF21 in the liver is dependent on histone acetylation and ligand activation of ChREBP by glycerol-3-phosphate. PNAS, 122(22), e2505263122. (www)

  @article{ , abstract = {Ethanol rapidly stimulates the liver to synthesize the hormone fibroblast growth factor 21 (FGF21), which then acts on the brain to elicit a multifaceted protective response. We show that in mice, this induction of FGF21 occurs at the level of gene transcription and is regulated by two byproducts of ethanol metabolism, glycerol-3-phosphate (G3P) and acetyl-CoA. Using cell-based reporter and thermal shift binding assays, we show that G3P binds to a conserved domain and activates the transcription factor carbohydrate-responsive element-binding protein (ChREBP), which regulates the Fgf21 gene promoter. The stimulation of Fgf21 gene transcription by ethanol also requires its metabolism to acetyl-CoA and correlates with histone acetylation. Accordingly, a p300/CBP histone acetyltransferase inhibitor blocks histone acetylation, ChREBP recruitment, and transcriptional activation at the Fgf21 promoter. Together, these findings reveal a dual regulatory mechanism driven by both G3P and acetyl-CoA that explains ethanol’s robust stimulatory effect on Fgf21 and possibly other ChREBP target genes in the liver.}, archive = {J_PNAS}, author = {Cheong, Mi Cheong and Mackowiak, Bryan and Kim, Hyung Bum and Hernandez, Genaro and Nandu, Tulip and Vale, Kevin and Zhang, Yuan and Zacharias, Lauren G. and Mathews, Thomas P. and Gao, Bin and Kraus, W. Lee and Kliewer, Steven A. and Mangelsdorf, David J.}, doi = {10.1073/pnas.2505263122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2505263122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ethanol induction of FGF21 in the liver is dependent on histone acetylation and ligand activation of ChREBP by glycerol-3-phosphate}, volume = {122}, year = {2025}, }
• (2025). Cocrystal structure reveals the mechanism of FSP1 inhibition by FSEN1. PNAS, 122(22), e2505197122. (www)

  @article{ , abstract = {FSP1 is an FAD-dependent oxidoreductase that uses NAD(P)H to regenerate the reduced forms of lipophilic quinone antioxidants, such as coenzyme Q10 and vitamin K. These quinone antioxidants function as radical scavenging agents that prevent the propagation of lipid peroxidation and the induction of ferroptosis. Although several small-molecule inhibitors of FSP1 have been developed and found to sensitize cancer cells to ferroptosis, our understanding of their molecular mechanisms remains limited and no structures of FSP1 in complex with its inhibitors have been solved. Here, we solve the cocrystal structure of FSP1 in complex with the FSP1 inhibitor FSEN1, revealing that FSEN1 binds within the FSP1 substrate-binding pocket. FSEN1 makes key interactions with a critical phenylalanine, which is absent in mouse FSP1, providing an explanation for the selectivity of FSEN1 for human FSP1. These conclusions are supported by mutagenesis of FSP1 and biochemical and cellular assays of FSP1 function. Our findings provide the first cocrystal structure of FSP1 in complex with an inhibitor, enhancing our understanding of the mechanism of FSP1 inhibition and enabling future rational medicinal chemistry efforts to advance FSP1 inhibitors as therapeutics.}, archive = {J_PNAS}, author = {Zhang, Sitao and Megarioti, Amalia H. and Hendricks, Joseph M. and Zhou, Junshu and Sun, Qingxiang and Jia, Da and Olzmann, James A.}, doi = {10.1073/pnas.2505197122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2505197122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cocrystal structure reveals the mechanism of FSP1 inhibition by FSEN1}, volume = {122}, year = {2025}, }
• (2025). Modular arrangement of synaptic and intrinsic homeostatic plasticity within visual cortical circuits. PNAS, 122(22), e2504775122. (www)

  @article{ , abstract = {Neocortical circuits use synaptic and intrinsic forms of homeostatic plasticity to stabilize key features of network activity, but whether these different homeostatic mechanisms act redundantly or can be independently recruited to stabilize different network features is unknown. Here, we used pharmacological and genetic perturbations both in vitro and in vivo to determine whether synaptic scaling and intrinsic homeostatic plasticity (IHP) are arranged and recruited in a hierarchical or modular manner within layer 2/3 (L2/3) pyramidal neurons in the rodent primary visual cortex (V1). Surprisingly, although the expression of synaptic scaling and IHP was dependent on overlapping signaling pathways, they could be independently recruited by manipulating spiking activity or NMDA receptor (NMDAR) signaling, respectively. Further, we found that changes in visual experience that affect NMDAR activation but not mean firing selectively trigger IHP, without recruiting synaptic scaling. These findings support a modular model in which synaptic and IHP respond to and stabilize distinct aspects of network activity.}, archive = {J_PNAS}, author = {Wen, Wei and Prada, Adriana M. and Turrigiano, Gina G.}, doi = {10.1073/pnas.2504775122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2504775122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Modular arrangement of synaptic and intrinsic homeostatic plasticity within visual cortical circuits}, volume = {122}, year = {2025}, }
• (2025). Dynamic early recruitment of GAK–Hsc70 regulates coated pit maturation. PNAS, 122(22), e2503738122. (www)

  @article{ , abstract = {Clathrin-mediated endocytosis (CME) begins with the assembly of clathrin onto the plasma membrane. These structures grow and stabilize to form clathrin-coated pits (CCPs), which invaginate and accumulate cargo. Finally, through membrane fission, CCPs detach to form clathrin-coated vesicles (CCVs). Mechanisms governing the transition of CCPs from flat-to-curved structures have been a matter of debate. GAK and its chaperone protein, Hsc70, are well known to mediate clathrin release from CCVs, and several studies have observed a late burst of GAK recruitment as CCVs form. Other studies have proposed that early recruitment of GAK–Hsc70 could function to provide the necessary energy source to remodel nascent flat clathrin lattices, replacing hexagons with pentagons and enabling a gain of curvature and invagination of the growing CCP; however, direct functional evidence is lacking. Here, we show that GAK knockdown inhibits CCP stabilization and invagination. Furthermore, mutations in the J domain of GAK that abolish Hsc70 recruitment to and activation at CCPs lead to the accumulation of GAK at CCPs, hinder CCP stabilization and invagination, and result in a striking increase in the proportion of highly transient, abortive CCPs. These findings support the hypothesis that GAK–Hsc70 promotes the turnover and remodeling of nascent clathrin assemblies required for curvature development during CME.}, archive = {J_PNAS}, author = {He, Zhangping and Zuo, Peiyao and Xu, Peiliu and Yuan, Haozhi and Bhave, Madhura and Wei, Xiangying and Yang, Ziyan and Han, Lu and Schmid, Sandra L. and Chen, Zhiming}, doi = {10.1073/pnas.2503738122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2503738122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic early recruitment of GAK–Hsc70 regulates coated pit maturation}, volume = {122}, year = {2025}, }
• (2025). Label-free high-throughput live-cell sorting of genome-wide random mutagenesis libraries for metabolic traits by raman flow cytometry. PNAS, 122(22), e2503641122. (www)

  @article{ , abstract = {A full spontaneous single-cell Raman spectrum captures the metabolic phenome in a label-free and noninvasive manner. However, Raman-activated cell sorting (RACS) of rare target cells from highly heterogeneous systems has remained largely conceptual. Here, we present a positive dielectrophoresis-induced deterministic lateral displacement (pDEP-DLD)-based RACS (pDEP-DLD-RACS), in which a modulated pDEP-DLD force is applied to focus, trap, and functionally sort fast-moving single cells in a wide channel. For pigment- and oil-producing yeasts, pDEP-DLD-RACS shows high sorting accuracy (>90%), high throughput (~600 events min −1 ), high yield (>85%), and long stable running time (~10 h), and can sort rare cells while preserving full cellular vitality. Moreover, label-free sorting directly from a genome-wide random mutagenesis library with >10 5 Aurantiochytrium sp. Mutants, based on intracellular docosahexaenoic acid (DHA) content, produces mutant cells with 58% higher DHA productivity in just two RACS runs over two days, representing two-orders-of-magnitude higher time- and cost-efficiency than conventional approaches. This superior trait arises from global remolding of transcriptomes, including enhanced carbon metabolism, reduced intracellular NADPH synthesis rates, and increased triacylglycerol (TAG) synthesis. By enabling direct screening of metabolic traits from genome-wide mutagenesis libraries, pDEP-DLD-RACS is a powerful platform for synthetic biology.}, archive = {J_PNAS}, author = {Wang, Xixian and Wang, Sen and Diao, Zhidian and Hou, Xibao and Gong, Yanhai and Sun, Qing and Zhang, Jiaping and Ren, Lihui and Li, Yuandong and Ji, Yuetong and Shen, Wei and Yin, Yifeng and Huang, Shi and Song, Xiaojin and Cui, Qiu and Feng, Yingang and Xu, Jian and Ma, Bo}, doi = {10.1073/pnas.2503641122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2503641122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Label-free high-throughput live-cell sorting of genome-wide random mutagenesis libraries for metabolic traits by raman flow cytometry}, volume = {122}, year = {2025}, }
• (2025). Modulation of human dorsal root ganglion neuron firing by the nav1.8 inhibitor suzetrigine. PNAS, 122(22), e2503570122. (www)

  @article{ , abstract = {Nav1.8 voltage-gated sodium channels are strongly expressed in human primary pain-sensing neurons (nociceptors) and a selective Nav1.8 inhibitor VX-548 (suzetrigine) has shown efficacy for treating acute pain in clinical trials. Nociceptors also express other sodium channels, notably Nav1.7, raising the question of how effectively excitability of the neurons is reduced by inhibition of Nav1.8 channels alone. We used VX-548 to explore this question, recording from dissociated human dorsal root ganglion neurons at 37 °C. Applying VX-548 at 10 nM (about 25 times the IC 50 determined using cloned human Nav1.8 channels at 37 °C) had only small effects on action potential threshold and upstroke velocity but substantially reduced the peak and shoulder. Counterintuitively, VX-548 shortened the refractory period—likely reflecting reduced potassium channel activation by the smaller, narrower action potential—sometimes resulting in faster firing. Generally, repetitive firing during depolarizations was diminished but not eliminated by VX-548. Voltage clamp analysis suggested two reasons that repetitive firing often remains in 10 to 100 nM VX-548. First, many neurons had such large Nav1.8 currents that even 99% inhibition leaves nA-level Nav1.8 current that could help drive repetitive firing. Second, Nav1.7 current dominated during initial spikes and could also contribute to repetitive firing. The ability of human neurons to fire repetitively even with >99% inhibition of Nav1.8 channels may help explain the incomplete analgesia produced by even the largest concentrations of VX-548 in clinical studies.}, archive = {J_PNAS}, author = {Stewart, Robert G. and Osorno, Tomás and Fujita, Akie and Jo, Sooyeon and Ferraiuolo, Alyssa and Carlin, Kevin and Bean, Bruce P.}, doi = {10.1073/pnas.2503570122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2503570122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Modulation of human dorsal root ganglion neuron firing by the nav1.8 inhibitor suzetrigine}, volume = {122}, year = {2025}, }
• (2025). Two endogenous dictyostelium discoideum chemorepellents use different mechanisms to induce repulsion. PNAS, 122(22), e2503168122. (www)

  @article{ , abstract = {The directed movement of eukaryotic cells is critical for processes such as development and immune responses. While much is known about chemoattraction, much less is known about chemorepulsion. The eukaryotic amoeba Dictyostelium discoideum secretes a 60 kDa chemorepellent protein called AprA to cause cells at the edge of a colony to move away from the colony. In addition to AprA, cells secrete a <10 kDa chemorepellent. Here, we show that the <10 kDa chemorepellent is a polymer of phosphates (polyphosphate; polyP). D. discoideum cells move by activating cortical Ras at one edge of the cell to initiate pseudopod formation. AprA induces repulsion by inhibiting Ras activation and pseudopod formation on the side of the cell closest to the source of AprA, without affecting the overall frequency of pseudopod formation. In contrast, polyP activates Ras at multiple regions of the cortex and increases pseudopod formation frequency, especially at the side of the cell furthest from the source of polyP. At least 20 signal transduction proteins are needed for both AprA and polyP repulsion, 9 are needed by polyP but not AprA, and 4 are needed by AprA but not polyP. Together, these results indicate that proliferating D. discoideum cells use two different chemorepellents, that one of the repellents is the unusual molecule polyphosphate, and that the two repellents activate partially overlapping and partially different pathways to induce repulsion by two basically different mechanisms.}, archive = {J_PNAS}, author = {El-Sobky, Mohanad H. and Rijal, Ramesh and Gomer, Richard H.}, doi = {10.1073/pnas.2503168122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2503168122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Two endogenous dictyostelium discoideum chemorepellents use different mechanisms to induce repulsion}, volume = {122}, year = {2025}, }
• (2025). X and y gene dosage effects are primary contributors to human sexual dimorphism: The case of height. PNAS, 122(22), e2503039122. (www)

  @article{ , abstract = {Many human phenotypic traits vary between the sexes, including adult height for which males are, on average, 13 cm taller than females. The biological mechanisms for this sexual dimorphism are not entirely understood. One hypothesis to explain the sexual dimorphism in height relates to differential expression in males and females of SHOX , a height-related gene in the pseudoautosomal region 1 (PAR1) on the X and Y sex chromosomes. SHOX expression is reduced on the inactive X chromosome (Xi), compared to the active X in females. Sex chromosome aneuploidies (SCAs), characterized by an atypical number of X and/or Y chromosomes, serve as informative models for investigating PAR1-related gene dosage effects. Here, we leveraged three large biobanks to study 928,605 individuals, including 1,225 adults with SCAs: 45,X (n = 95), 47,XXY (n = 505), 47,XYY (n = 290), and 47,XXX (n = 335). By modeling height across individuals with various sex chromosome complements, we quantified the contributions of five sex-related genomic contributors to height, including Xi chromosome dosage, Y chromosome dosage, male sex hormones, and effects of Klinefelter and Turner syndromes. We found that a unit increase in Y chromosome dosage confers 3.1cm (95% CI, 1.9 to 4.3) more to height than a unit increase in Xi chromosome dosage, independent of hormonal variables. The larger increase in height conferred by the Y chromosome explained 22.6% of the observed difference in height between 46,XY males and 46,XX females. This finding is consistent with the hypothesis that reduced SHOX expression in females results in a net difference in height between the sexes.}, archive = {J_PNAS}, author = {Berry, Alexander S. F. and Finucane, Brenda M. and Myers, Scott M. and Martin, Christa L. and Ledbetter, David H. and Willard, Huntington F. and Oetjens, Matthew T.}, doi = {10.1073/pnas.2503039122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2503039122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {X and y gene dosage effects are primary contributors to human sexual dimorphism: The case of height}, volume = {122}, year = {2025}, }
• (2025). CRISPR screen reveals a simultaneous targeted mechanism to reduce cancer cell selenium and increase lipid oxidation to induce ferroptosis. PNAS, 122(22), e2502876122. (www)

  @article{ , abstract = {Ferroptosis is a cell death mechanism distinguished by its dependence on iron-mediated lipid oxidation. Cancer cells highly resistant to conventional therapies often demonstrate lipid metabolic and redox vulnerabilities that sensitize them to cell death by ferroptosis. These include a unique dependency on the lipid antioxidant selenoenzyme, glutathione peroxidase 4 (GPx4), that acts as a ferroptosis inhibitor. Synthetic high-density lipoprotein-like nanoparticle (HDL NP) targets the high-affinity HDL receptor scavenger receptor class B type 1 (SR-B1) and regulates cell and cell membrane lipid metabolism. Recently, we reported that targeting cancer cell SR-B1 with HDL NP depleted cell GPx4, which is accompanied by increased cell membrane lipid peroxidation and cancer cell death. These data suggest that HDL NP may induce ferroptosis. Thus, we conducted an unbiased CRISPR-based positive selection screen and target validation studies in ovarian clear cell carcinoma (OCCC) cell lines to ascertain the mechanism through which HDL NP regulates GPx4 and kills cancer cells. The screen revealed two genes, acyl-CoA synthetase long chain family member 4 (ACSL4) and thioredoxin reductase 1 (TXNRD1), whose loss conferred resistance to HDL NP. Validation of ACSL4 supports that HDL NP induces ferroptosis as the predominant mechanism of cell death, while validation of TXNRD1 revealed that HDL NP reduces cellular selenium and selenoprotein production, most notably, GPx4. Accordingly, we define cancer cell metabolic targets that can be simultaneously actuated by a multifunctional, synthetic HDL NP ligand of SR-B1 to kill cancer cells by ferroptosis.}, archive = {J_PNAS}, author = {Lamperis, Sophia M. and McMahon, Kaylin M. and Calvert, Andrea E. and Rink, Jonathan S. and Vasan, Karthik and Pandkar, Madhura R. and Crentsil, Eliana U. and Chalmers, Zachary R. and McDonald, Natalie R. and Kosmala, Cameron J. and Bonini, Marcelo G. and Matei, Daniela and Gordon, Leo I. and Chandel, Navdeep S. and Thaxton, C. Shad}, doi = {10.1073/pnas.2502876122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2502876122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CRISPR screen reveals a simultaneous targeted mechanism to reduce cancer cell selenium and increase lipid oxidation to induce ferroptosis}, volume = {122}, year = {2025}, }
• (2025). ATP8B1 regulates PIP2 localization and cleavage of pyroptotic executioner gasdermin d. PNAS, 122(22), e2502798122. (www)

  @article{ , abstract = {Mutations in ATP8B1 cause progressive familial intrahepatic cholestasis, with symptoms including pruritus, pancreatitis, fat malabsorption, intestinal inflammation, and failure to thrive. High-throughput studies showed interconnection between ATP8B1 and phosphoinositide (PIPs), but the mechanism linking ATP8B1, lipid metabolism, and inflammation remains unclear. Atp8b1 G308V/G308V mouse model, unbiased RNAseq, high-resolution-stimulation emission depltion (STED)-microscopy, and Crispr-Cas9 generated ATP8B1 −/− knockouts in hepatocytes/monocytes/macrophages were used to determine role of ATP8B1 in phosphatidylinositol,4-5-bisphosphate (PIP2) trafficking and inflammation. Human ATP8B1, purified from Sf9 insect cells and reconstituted in proteoliposomes, was used to test cell-free PIP2 flip. Various in-vitro techniques were used for testing direct interaction between PIP2 and ATP8B1. ATP8B1 maintains PIP2 at the inner leaflet of plasma membrane (PM). ATP8B1 flips PIP2 in cells, without altering flip of PE or bulk-endocytosis. ATP8b1 flips PIP2 in a cell-free system. ATP8B1 deletion promotes bile-salt-mediated cholesterol extraction from hepatocytes in a PIP2-dependent manner. PIP2 directly binds to the P-loop of ATP8B1. Unbiased RNAseq showed upregulation of inflammatory cytokines in ATP8b1 −/− immune cells. ATP8B1 −/− monocytes/macrophages showed aberrant lipopolysaccharide (LPS)-induced cleavage of GSDMD, formation of GSDMD pores, and interleukin-1beta (IL1β) release. Inflammation-resolving efferocytosis was impaired in ATP8B1 −/− macrophages. Biophysical properties of PM were altered in ATP8b1 −/− cells, with the mechanism being disrupted localization of PIP2. Atp8b1 G308V/G308V mice exposed to LPS showed higher plasma IL1β and lower survival rates vs. WT mice. ATP8B1 maintains PIP2 at the inner leaflet of PM. ATP8b1 directly flips and binds PIP2. ATP8B1 regulates LPS-induced GsdmD cleavage, formation of GsdmD pores, IL1β release, and mortality in mice.}, archive = {J_PNAS}, author = {Bhandari, Nilam and Prince, Ashutosh and Khan, Mariam R. and Traughber, C. Alicia and Neupane, Kalash and Lorkowski, Shuhui W. and Brubaker, Gregory and Ertugral, Elif G. and Kothapalli, Chandrasekhar R. and Dubyak, George R. and Smith, Jonathan D. and Gulshan, Kailash}, doi = {10.1073/pnas.2502798122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2502798122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ATP8B1 regulates PIP2 localization and cleavage of pyroptotic executioner gasdermin d}, volume = {122}, year = {2025}, }
• (2025). Rhomboid-mediated cleavage of the immune receptor XA21 protects grain set and male fertility in rice. PNAS, 122(22), e2502025122. (www)

  @article{ , abstract = {To maintain growth and to successfully reproduce, organisms must protect key functions in specific tissues, particularly when countering pathogen invasion using internal defensive proteins that may disrupt their own developmental processes. The rice immune receptor XA21 confers race-specific resistance against Xanthomonas oryzae pv. oryzae , which causes the deadly disease bacterial leaf blight. Here, we demonstrate that XA21 is cleaved by the rhomboid-like protease OsRBL3b, likely within its transmembrane domain. OsRBL3b mRNA transcripts are preferentially expressed in rice spikelets. Rice plants expressing Xa21 but lacking a functional OsRBL3b displayed impaired anther dehiscence and pollen viability, resulting in male sterility and yield reduction with high levels of XA21 protein present in spikelets during anthesis. In leaves, osrbl3b mutants expressing XA21 had normal levels of this resistance protein and disease immunity. This balance between reproduction and disease resistance through the specific expression of a rhomboid protease may be key to limiting the detrimental effects of an active immune response and may be useful in future for genetic improvement of crops.}, archive = {J_PNAS}, author = {Vergish, Satyam and Huang, Xiaoen and Zhang, Guiyun and de Toledo Franceschi, Beatriz and Li, Jian-Liang and Wu, Xiao-Xia and Nuraj, Joana and Huguet-Tapia, Jose C. and Parajuli, Apekshya and Chen, Xiuhua and Shekhar, Ritu and Liu, Dali and Xiao, Wu-Ming and Dou, Shijuan and Liu, Guo-zhen and Goss, Erica M. and Pi, Liya and Chen, Sixue and Koch, Karen E. and Song, Wen-Yuan}, doi = {10.1073/pnas.2502025122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2502025122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rhomboid-mediated cleavage of the immune receptor XA21 protects grain set and male fertility in rice}, volume = {122}, year = {2025}, }
• (2025). Molecular basis for ligand recognition and receptor activation of the prostaglandin d2 receptor DP1. PNAS, 122(22), e2501902122. (www)

  @article{ , abstract = {The prostaglandin D2 receptor 1 (DP1), a rhodopsin-like Class A GPCR, orchestrates critical physiological and pathological processes, ranging from sleep regulation to inflammatory responses and cardiovascular function. Despite its therapeutic significance, structural insights into DP1 activation mechanisms have remained elusive. Here, using cryoelectron microscopy (cryo-EM), we determined high-resolution structures of human DP1 in both inactive and active states, with the latter captured in complex with its endogenous agonist PGD2 or the synthetic agonist BW245C, bound to the stimulatory G protein, Gs. Our structures, coupled with functional and mutagenesis studies, unveiled unique structural features of DP1, including an alternative activation mechanism, ligand-selectivity determinants, and G protein coupling characteristics. These molecular insights provide a rational framework for designing selective DP1-targeted therapeutics, both agonists and antagonists, with enhanced specificity and reduced off-target effects, opening broad avenues for treating DP1-associated disorders.}, archive = {J_PNAS}, author = {Xu, Jiuyin and Wu, Yanli and Xu, Youwei and Li, Yang and He, Xinheng and Zhang, Heng and Wang, James Jiqi and Hou, Jingjing and Li, Junrui and Hu, Wen and Wu, Kai and Yuan, Qingning and Wu, Canrong and Xu, H. Eric}, doi = {10.1073/pnas.2501902122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2501902122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular basis for ligand recognition and receptor activation of the prostaglandin d2 receptor DP1}, volume = {122}, year = {2025}, }
• (2025). Engineering a protease-stable, oral single-domain antibody to inhibit IL-23 signaling. PNAS, 122(22), e2501635122. (www)

  @article{ , abstract = {Interleukin (IL)-23 is a validated therapeutic target in inflammatory bowel disease. While antibodies targeting IL23 demonstrate clinical efficacy, they face challenges such as high costs, safety risks, and the necessity of parenteral administration. Here, we present a workflow to simultaneously enhance the affinity and protease stability of an inhibitory anti-IL23R VHH for oral use. Cocrystal structure analysis reveals that the anti-IL23R VHH employs both CDR and framework residues to achieve picomolar affinity for IL23R. The engineered VHH remains stable for over 8 h in intestinal fluid and 24 h in fecal samples. Oral administration of this VHH achieves deep pathway inhibition in a murine colitis model. Furthermore, a single pill provides sustained IL23R inhibition in nonhuman primate blood for over 24 h. With high potency, gut stability, high production yield, and favorable drug-like properties, oral VHHs offer a promising approach for inflammatory bowel diseases.}, archive = {J_PNAS}, author = {Ota, Naruhisa and Davies, Christopher W. and Kang, Jing and Yan, Donghong and Scherl, Alexis and Wong, Anne and Cook, Ryan and Tao, Xun and Dunlap, Debra and Klabunde, Sha and Mantik, Priscilla and Mohanan, Vishnu and Lin, WeiYu and McBride, Jacqueline and Sadekar, Shraddha and Storek, Kelly M. and Lupardus, Patrick and Ye, Zhengmao and Ackerly Wallweber, Heidi and Kiefer, James R. and Xu, Min and Chan, Pamela and Nagapudi, Karthik and Yi, Tangsheng and Koerber, James T.}, doi = {10.1073/pnas.2501635122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2501635122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Engineering a protease-stable, oral single-domain antibody to inhibit IL-23 signaling}, volume = {122}, year = {2025}, }
• (2025). Can increasing the size and flexibility of a molecule reduce decoherence and prolong charge migration?. PNAS, 122(22), e2501319122. (www)

  @article{ , abstract = {Coherent superposition of electronic states, created by ionizing a molecule, can initiate ultrafast dynamics of the electron density. Correlation between nuclear and electron motions, however, typically dissipates the electronic coherence in only a few femtoseconds, especially in larger and more flexible molecules. We, therefore, use ab initio semiclassical dynamics to study decoherence in a sequence of analogous organic molecules of increasing size and find, surprisingly, that extending the carbon skeleton in propynal analogs slows down decoherence and prolongs charge migration. To elucidate this observation, we decompose the overall decoherence into contributions from individual vibrational modes and show that: 1) The initial decay of electronic coherence is caused by high- and intermediate-frequency vibrations via momentum separation of nuclear wavepackets evolving on different electronic surfaces. 2) At later times, the coherence disappears completely due to the increasing position separation in the low-frequency modes. 3) In agreement with another study, we observe that only normal modes that preserve the symmetry of the molecule induce decoherence. All together, we justify the enhanced charge migration by a combination of increased hole-mixing and the disappearance of decoherence contributions from specific vibrational modes—CO stretching in butynal and various H rockings in pentynal.}, archive = {J_PNAS}, author = {Scheidegger, Alan and Golubev, Nikolay V. and Vaníček, Jiří J. L.}, doi = {10.1073/pnas.2501319122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2501319122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Can increasing the size and flexibility of a molecule reduce decoherence and prolong charge migration?}, volume = {122}, year = {2025}, }
• (2025). Cardiolipin membranes drive myosin VI activation, oligomerization, and processive cargo transport. PNAS, 122(22), e2501022122. (www)

  @article{ , abstract = {Mitochondrial damage determines cell fate, leading to mitochondrial autophagy or cellular apoptosis in health and disease. The molecular mechanisms and role of the acto-myosin cytoskeleton regulating mitochondrial clearance and membrane remodeling are critical in neurodegenerative disease progression including Alzheimer, but remain unclear. To investigate the potential link between full-length Myosin VI (FL-Myo6) recruitment and exposure of the mitochondria-specific lipid cardiolipin (CL), here we adapted a combination of molecular biology, biochemical, high-resolution fluorescence and interferometric light-scattering techniques. We developed analysis tools to reveal the structural Myo6–CL interaction sites, Myo6-oligomerization interfaces and mechanical properties. We found that CL activates backfolded FL-Myo6 and induces Myo6-oligomerization. Myo6 bound to CL cargo-vesicles in vitro mediates processive runs over >500 nm at >90 nm s −1 . We propose a model how CL-interaction regulates backfolded Myo6 activation into a highly processive cargo-bound motor.}, archive = {J_PNAS}, author = {Montanarella, Antonino F. and Hundt, Nikolas and Keim, Dominik and Venczel, Aron and Zierhut, Felix and Langnickel, Simon and Graw, Andreas and Kröss, Markus and Dietrich, Johannes and Saczko-Brack, Dario and Veigel, Claudia}, doi = {10.1073/pnas.2501022122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2501022122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cardiolipin membranes drive myosin VI activation, oligomerization, and processive cargo transport}, volume = {122}, year = {2025}, }
• (2025). Biochemical and structural basis of dicer helicase function unveiled by resurrecting ancient proteins. PNAS, 122(22), e2500825122. (www)

  @article{ , abstract = {A fully functional Dicer helicase, present in the modern arthropod, uses energy from ATP hydrolysis to power translocation on bound dsRNA, enabling the processive dsRNA cleavage required for efficient antiviral defense. However, modern Dicer orthologs exhibit divergent helicase functions that affect their ability to contribute to antiviral defense. Moreover, mechanisms that couple ATP hydrolysis to Dicer helicase movement on dsRNA remain enigmatic. We used biochemical and structural analyses of ancestrally reconstructed Dicer helicases to map evolution of dsRNA binding affinity, ATP hydrolysis and translocation. Loss of affinity for dsRNA occurred early in Dicer evolution, coinciding with a decline in translocation activity, despite preservation of ATP hydrolysis activity. Ancestral nematode Dicer also exhibited significant decline in ATP hydrolysis and translocation, but studies of antiviral activities in the modern nematode Caenorhabditis elegans indicate Dicer retained a role in antiviral defense by recruiting a second helicase. Cryogenic electron microscopy (cryo-EM) analyses of an ancient metazoan Dicer allowed capture of multiple helicase states revealing the mechanism that connects each step of ATP hydrolysis to unidirectional movement along dsRNA. Our study rationalizes the diversity in modern Dicer helicases by connecting ancestral functions to observations in extant enzymes.}, archive = {J_PNAS}, author = {Aderounmu, Adedeji M. and Maus-Conn, Josephine and Consalvo, Claudia D. and Shen, Peter S. and Bass, Brenda L.}, doi = {10.1073/pnas.2500825122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2500825122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biochemical and structural basis of dicer helicase function unveiled by resurrecting ancient proteins}, volume = {122}, year = {2025}, }
• (2025). Reply to liu et al., visualization of cerebral perivascular spaces following administration of intrathecal contrast. PNAS, 122(22), e2500744122. (www)

  @article{ , archive = {J_PNAS}, author = {Piantino, Juan}, doi = {10.1073/pnas.2500744122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2500744122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to liu et al., visualization of cerebral perivascular spaces following administration of intrathecal contrast}, volume = {122}, year = {2025}, }
• (2025). Targeted apoptotic immune modulator for the treatment of metastatic EGFR-positive solid tumors. PNAS, 122(22), e2500489122. (www)

  @article{ , abstract = {Aberrant activation and overexpression of the epidermal growth factor receptor (EGFR) occurs in various solid cancers and often correlates with poor outcome. The clinical benefit from EGFR-targeted therapies is usually short-lived, with resistance being driven by tumor heterogeneity and an immunosuppressive tumor microenvironment (TME). To address these limitations, we developed Targeted Apoptotic Immune Modulators (TAIM), a nonviral nanoparticle platform for the targeted delivery of polyinosine:polycytosine (polyIC), to simultaneously induce tumor cell death and activate antitumor immunity. The first TAIM compound, TAR001, was designed as a systemic treatment against metastatic EGFR-positive solid cancers. Here, we present TAR001’s multifaceted mode of action. We demonstrate that TAR001 is selective toward EGFR-overexpressing cancers, provoking a pattern recognition response, apoptosis, cytokine secretion, and antitumor immunity. TAR001 modulates the TME, recruiting and activating both innate and adaptive immune cells. Systemic delivery of TAR001 markedly extends survival and inhibits tumor growth in multiple murine tumor models. TAR001 represents an innovative, safe, multimodal treatment approach with the potential to benefit patients with metastatic head and neck, non–small cell lung cancer, colorectal, renal, and triple-negative breast cancers. This unique modality utilizes a broad range of mechanisms to overcome the tumor’s ability to escape apoptosis and immune cell activation.}, archive = {J_PNAS}, author = {Broka, Derrick and Klein, Shoshana and Shir, Alexei and Schade, Babette and Saxena, Meera and Dasargyri, Athanasia and Jarzebinska, Anita and De Feyter, Caroline and Bajic, Davor and Colecchia, David and D'Amico, Lucia and Kitas, Eric and Hikri, Elad and Skowicki, Michal Jerzy and Okoniewski, Michal Jerzy and Baldino, Laura and Qeriqi, Besnik and Stanchina, Elisa de and Schreiber, Joerg and Buchi, Melanie and Palivan, Cornelia G. and Benenson, Yaakov and Zippelius, Alfred and Fabbro, Doriano and Scaltriti, Maurizio and Mizrachi, Aviram and Levitzki, Alexander and Pombo-Villar, Esteban and Zigler, Maya}, doi = {10.1073/pnas.2500489122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2500489122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Targeted apoptotic immune modulator for the treatment of metastatic EGFR-positive solid tumors}, volume = {122}, year = {2025}, }
• (2025). Himalayan “S-type” granite generated from I-type sources. PNAS, 122(22), e2500480122. (www)

  @article{ , abstract = {Partial melting of metasedimentary rocks is generally accepted as the source of peraluminous Himalayan leucogranites—they are commonly considered as pure “S-type” (sedimentary source) granites. Here, a uniquely comprehensive geochronological and geochemical dataset shows that partial melting of metaigneous rocks in the eastern Himalaya produced peraluminous leucogranites—these supposed S-type leucogranites have I-type (igneous) sources. Inherited magmatic zircons from leucogranites and metaigneous rocks have indistinguishable ages, trace element compositions, and Hf isotope compositions, distinct from zircons in metasedimentary rocks. Experimentally, partial melting of metagranitic rocks rather than metapelites predicts alkali major element chemistry of these leucogranites better. High δ 18 O, high 87 Sr/ 86 Sr, and low ε Nd (t) for Himalayan leucogranites have been used to argue for a metasedimentary rock source, but overlapping values occur in metaigneous rocks. Although sediment-sourced leucogranites also occur, igneous-sourced leucogranites are likely common in large hot orogens. A survey of leucogranite geochemistry across the Himalaya suggests that ~20% might be I-type, with no apparent spatial or temporal bias. I-type leucogranites appear to be rare-metal poor, however. Unlike prior assertions that I-type granites represent juvenile additions to orogens, metaigneous-sourced Himalayan granites more likely represent crustal reworking.}, archive = {J_PNAS}, author = {Ding, Huixia and Zhang, Zeming and Kohn, Matthew J.}, doi = {10.1073/pnas.2500480122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2500480122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Himalayan “S-type” granite generated from I-type sources}, volume = {122}, year = {2025}, }
• (2025). Maximum spreading of impacting shear-thinning and shear-thickening drops. PNAS, 122(22), e2500163122. (www)

  @article{ , abstract = {The maximum spreading of an impacting liquid drop is a key metric for characterizing the fundamental fluid process of drop impact. While extensively studied for Newtonian liquids, how far a non-Newtonian drop can spread upon impacting a solid substrate remains an open question. Here, by combining simulations, experiments, and scaling analyses, we establish a general framework for predicting the maximum spreading of drops of generalized Newtonian liquids, encompassing both shear-thinning and shear-thickening behaviors. Through an analysis of the energy budget at maximum spreading, we identify a characteristic shear rate that governs the viscous dissipation during drop impact. The finding allows us to map the spreading of non-Newtonian drops onto that of Newtonian drops, revealing the quantitative dependence of the maximum spreading diameter on various impact parameters and rheological properties of liquids. Our study addresses the long-standing challenge of understanding the impact dynamics of non-Newtonian drops, and provides valuable guidance for designing non-Newtonian liquids to achieve desired impact outcomes.}, archive = {J_PNAS}, author = {Mobaseri, Anahita and Kumar, Satish and Cheng, Xiang}, doi = {10.1073/pnas.2500163122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2500163122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Maximum spreading of impacting shear-thinning and shear-thickening drops}, volume = {122}, year = {2025}, }
• (2025). Phylogenomics reveals the slow-burning fuse of diatom evolution. PNAS, 122(22), e2500153122. (www)

  @article{ , abstract = {Evolution is often uneven in its pace and outcomes, with long periods of stasis interrupted by abrupt increases in morphological and ecological disparity. With thousands of gene histories, phylogenomics can uncover the genomic signatures of these broad macroevolutionary trends. Diatoms are a species-rich lineage of microeukaryotes that contribute greatly to the global cycling of carbon, oxygen, and silica, which they use to build elaborately structured cell walls. We combined fossil information with newly sequenced transcriptomes from 181 diverse diatom species to reconstruct the pattern, timing, and genomic context of major evolutionary transitions. Diatoms originated 270 Mya, and after >100 My of relative stasis in morphology and ecology, a radiation near the Jurassic–Cretaceous boundary led to the diversity of habitats and cell wall architectures characteristic of modern diatoms. This transition was marked by a genome duplication and high levels of gene tree discordance. However, short generation times increase the probability of coalescence between speciation events, minimizing the impacts of incomplete lineage sorting and implicating sequence saturation and gene tree error as the main sources of discordance. Nevertheless, a rigorous tree-based approach to ortholog selection resulted in strongly supported relationships, including some that were uncertain previously. Three pulses of accelerated speciation were detected, two of which were associated with the evolution of novel traits and ecological transitions. The first 100 My of diatom evolution was a slow-burning fuse that led to a burst of innovations in ecology, morphology, and life history that are hallmarks of contemporary diatom assemblages.}, archive = {J_PNAS}, author = {Alverson, Andrew J. and Roberts, Wade R. and Ruck, Elizabeth C. and Nakov, Teofil and Ashworth, Matthew P. and Bryłka, Karolina and Downey, Kala M. and Kociolek, J. Patrick and Parks, Matthew and Pinseel, Eveline and Theriot, Edward C. and Tye, Simon P. and Witkowski, Andrzej and Beaulieu, Jeremy M. and Wickett, Norman J.}, doi = {10.1073/pnas.2500153122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2500153122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phylogenomics reveals the slow-burning fuse of diatom evolution}, volume = {122}, year = {2025}, }
• (2025). Manifold fitting reveals metabolomic heterogeneity and disease associations in UK biobank populations. PNAS, 122(22), e2500001122. (www)

  @article{ , abstract = {NMR-based metabolic biomarkers provide comprehensive insights into human metabolism; however, extracting biologically meaningful patterns from such high-dimensional data remains a significant challenge. In this study, we propose a manifold-fitting-based framework to analyze metabolic heterogeneity within the UK Biobank population, utilizing measurements of 251 NMR biomarkers from 212,853 participants. Initially, our method clusters these biomarkers into seven distinct metabolic categories that reflect the modular organization of human metabolism. Subsequent manifold fitting to each category unveils underlying low-dimensional structures, elucidating fundamental variations from basic energy metabolism to hormone-mediated regulation. Importantly, three of these manifolds clearly stratify the population, identifying subgroups with distinct metabolic profiles and associated disease risks. These subgroups exhibit consistent links with specific diseases, including severe metabolic dysregulation and its complications, as well as cardiovascular and autoimmune conditions, highlighting the intricate relationship between metabolic states and disease susceptibility. Supported by strong correlations with demographic factors, clinical measurements, and lifestyle variables, these findings validate the biological relevance of the identified manifolds. By utilizing a geometrically informed approach to dissect metabolic heterogeneity, our framework enhances the accuracy of population stratification and deepens our understanding of metabolic health, potentially guiding personalized interventions and preventive healthcare strategies.}, archive = {J_PNAS}, author = {Li, Bingjie and Su, Jiaji and Lin, Runyu and Yau, Shing-Tung and Yao, Zhigang}, doi = {10.1073/pnas.2500001122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2500001122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Manifold fitting reveals metabolomic heterogeneity and disease associations in UK biobank populations}, volume = {122}, year = {2025}, }
• (2025). Estimating wage disparities using foundation models. PNAS, 122(22), e2427298122. (www)

  @article{ , abstract = {The rise of foundation models marks a paradigm shift in machine learning: instead of training specialized models from scratch, foundation models are trained on massive datasets before being adjusted or fine-tuned to make predictions on smaller datasets. Initially developed for text, foundation models have also excelled at making predictions about social science data. However, while many estimation problems in the social sciences use prediction as an intermediate step, they ultimately require different criteria for success. In this paper, we develop methods for fine-tuning foundation models to perform these estimation problems. We first characterize an omitted variable bias that can arise when a foundation model is fine-tuned in the standard way: to minimize predictive error. We then provide a set of conditions for fine-tuning under which estimates derived from a foundation model are n -consistent. Based on this theory, we develop fine-tuning algorithms that empirically mitigate this omitted variable bias. To demonstrate our ideas, we study gender wage gap estimation. Classical methods for estimating the adjusted wage gap employ simple predictive models of wages, which can induce omitted variable bias because they condition on coarse summaries of career history. Instead, we use a custom-built foundation model, capturing a richer representation of career history. Using data from the Panel Study of Income Dynamics, we find that career history explains more of the gender wage gap than standard econometric models can measure, and we identify elements of career history that are omitted by standard models but are important for explaining the gap.}, archive = {J_PNAS}, author = {Vafa, Keyon and Athey, Susan and Blei, David M.}, doi = {10.1073/pnas.2427298122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2427298122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Estimating wage disparities using foundation models}, volume = {122}, year = {2025}, }
• (2025). Nanoimmunomodulation of the aβ-STING feedback machinery in microglia for alzheimer’s disease treatment. PNAS, 122(22), e2427257122. (www)

  @article{ , abstract = {Imbalanced production and clearance of amyloid-β (Aβ) is a hallmark pathological feature of Alzheimer’s disease (AD). While several monoclonal antibodies targeting Aβ have shown reductions in amyloid burden, their impact on cognitive function remains controversial, with the added risk of inflammatory side effects. Dysregulated stimulator of interferon genes (STING) signaling is implicated in neurodegenerative disorders, yet the biological interaction between this pathway and Aβ, as well as their combined influence on AD progression, is poorly understood. Here, we show that while microglia play a protective role in clearing extracellular Aβ, excessive Aβ engulfment triggers the cytosolic leakage of mitochondrial DNA for cGAS–STING cascade. This creates a negative feedback loop that not only exacerbates neuroinflammation but also impairs further Aβ clearance. To address this, we present a nanomedicine approach termed “Aβ-STING Synergistic ImmunoSilencing Therapy (ASSIST)”. ASSIST comprises STING inhibitors encapsulated within a blood–brain barrier (BBB)-permeable polymeric micelle that also serves as an Aβ scavenger. Through a multivalent interaction mechanism, ASSIST efficiently destabilizes Aβ plaques and prevents monomer aggregation, subsequently promoting the engulfment of the dissociated Aβ by microglia rather than neurocytes. Furthermore, the STING signaling induced by excessive Aβ uptake is blocked, reducing inflammation and restoring microglial homeostatic functions involved in Aβ clearance. Intravenous administration of ASSIST significantly reduces Aβ burden and improves cognition in AD mice, with minimal cerebral amyloid angiopathy or microhemorrhages. We provide a proof-of-concept nanoengineering strategy to target the maladaptive immune feedback loop arising from conventional immunotherapy for AD treatment.}, archive = {J_PNAS}, author = {Tian, Limin and Long, Guangyu and Zhu, Siqi and Wang, Yuelong and Xu, Pengcheng and Liu, Lifeng and Yao, Hong and Fang, Shentong and Chen, Shuqing and Li, Suxin}, doi = {10.1073/pnas.2427257122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2427257122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nanoimmunomodulation of the aβ-STING feedback machinery in microglia for alzheimer’s disease treatment}, volume = {122}, year = {2025}, }
• (2025). Further exploration of the principles and mechanisms of brainwashing. PNAS, 122(22), e2426192122. (www)

  @article{ , archive = {J_PNAS}, author = {Liu, Haitao and Sun, Haogeng and Liu, Yi}, doi = {10.1073/pnas.2426192122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2426192122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Further exploration of the principles and mechanisms of brainwashing}, volume = {122}, year = {2025}, }
• (2025). Exploring diverse supramolecular tessellation through hierarchical assemblies of nonalternant nanographene. PNAS, 122(22), e2426059122. (www)

  @article{ , abstract = {Tessellation, as an ancient and fascinating mathematical pursuit, has not only captivated mathematicians but also has attracted chemists’ increasing attention at the molecular level in recent years. Exploring tessellation at the molecular scale is pivotal for gaining profound insights into the effects of tessellation on materials and elucidating the essential design principles for supramolecular tessellation. In this study, we develop a dynamic fullerene host ( 1 ) with three consecutive heptagons, which promotes diverse supramolecular tessellation via hierarchical assembly. In the solid state, molecule 1 arranges itself into a layered square-shaped tessellation in the crystal superstructure. Interestingly, the co-crystal structures of 1 with C 60 and C 70 exhibit highly ordered triangular and rhombic tessellation patterns, respectively, due to the adaptive regulation of heptagons with different curved guests, demonstrating the first series of layered tessellated framework in supramolecular fullerene chemistry. This work not only enriches the development of in-solution supramolecular tessellation but also facilitates the rational design of tessellated 2D layered molecular materials}, archive = {J_PNAS}, author = {Sun, Jian and Deng, Ziqi and Lee Phillips, David and Liu, Junzhi}, doi = {10.1073/pnas.2426059122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2426059122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exploring diverse supramolecular tessellation through hierarchical assemblies of nonalternant nanographene}, volume = {122}, year = {2025}, }
• (2025). Reversible molecular simulation for training classical and machine-learning force fields. PNAS, 122(22), e2426058122. (www)

  @article{ , abstract = {The next generation of force fields for molecular dynamics will be developed using a wealth of data. Training systematically with experimental data remains a challenge, however, especially for machine-learning potentials. Differentiable molecular simulation calculates gradients of observables with respect to parameters through molecular dynamics trajectories. Here, we improve this approach by explicitly calculating gradients using a reverse-time simulation with effectively constant memory cost and a computation count similar to the forward simulation. The method is applied to learn all-atom water and gas diffusion models with different functional forms and to train a machine-learning potential for diamond from scratch. Comparison to ensemble reweighting indicates that reversible simulation can provide more accurate gradients and train to match time-dependent observables.}, archive = {J_PNAS}, author = {Greener, Joe G.}, doi = {10.1073/pnas.2426058122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2426058122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reversible molecular simulation for training classical and machine-learning force fields}, volume = {122}, year = {2025}, }
• (2025). Solution structure and synaptic analyses reveal determinants of bispecific t cell engager potency. PNAS, 122(22), e2425781122. (www)

  @article{ , abstract = {Bispecific T cell engagers (TcEs) link T cell receptors to tumor-associated antigens on cancer cells, forming cytotoxic immunological synapses (IS). Close membrane-to-membrane contact (≤13 nm) has been proposed as a key mechanism of TcE function. To investigate this and identify potential additional mechanisms, we compared four immunoglobulin G1-based (IgG1) TcE Formats (A–D) targeting CD3ε and Her2, designed to create varying intermembrane distances (A < B < C < D). Small-angle X-ray scattering (SAXS) and modeling of the conformational states of isolated TcEs and TcE–antigen complexes predicted close contacts (≤13 nm) for Formats A and B and far contacts (≥18 nm) for Formats C and D. In supported lipid bilayer (SLB) model interfaces, Formats A and B recruited, whereas Formats C and D repelled, CD2–CD58 interactions. Formats A and B also excluded bulky Quantum dots more effectively. SAXS also revealed that TcE–antigen complexes formed by Formats A and C were less flexible than complexes formed by Formats B and D. Functional data with Her2-expressing tumor cells showed cytotoxicity, surface marker expression, and cytokine release following the order A > B = C > D. In a minimal system for IS formation on SLBs, TcE performance followed the trend A = B = C > D. Addition of close contact requiring CD58 costimulation revealed phospholipase C-γ activation matching cytotoxicity with A > B = C > D. Our findings suggest that when adhesion is equivalent, TcE potency is determined by two parameters: contact distance and flexibility. Both the close/far-contact formation axis and the low/high flexibility axis significantly impact TcE potency, explaining the similar potency of Format B (close contact/high flexibility) and C (far contact/low flexibility).}, archive = {J_PNAS}, author = {Leithner, Alexander and Staufer, Oskar and Mitra, Tanmay and Liberta, Falk and Valvo, Salvatore and Kutuzov, Mikhail and Dada, Hannah and Spaeth, Jacob and Zhou, Weijie and Schiele, Felix and Reindl, Sophia and Nar, Herbert and Hoerer, Stefan and Crames, Maureen and Comeau, Stephen and Young, David and Low, Sarah and Jenkins, Edward and Davis, Simon J. and Klenerman, David and Nixon, Andrew and Pefaur, Noah and Wyatt, David and Dushek, Omer and Kasturirangan, Srinath and Dustin, Michael L.}, doi = {10.1073/pnas.2425781122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2425781122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Solution structure and synaptic analyses reveal determinants of bispecific t cell engager potency}, volume = {122}, year = {2025}, }
• (2025). Arabidopsis HOOKLESS1 acts as a histone acetyltransferase to promote cotyledon greening during seedling de-etiolation. PNAS, 122(22), e2425647122. (www)

  @article{ , abstract = {Greening immediately after etiolated-seedling’s emergence from the soil is critical for plants to initiate their autotrophic life cycle through photosynthesis. The greening process relies on a complex transcriptional network that fine-tunes the biosynthesis of chlorophyll and prevents premature development of chloroplasts. In this study, we identified the Arabidopsis HOOKLESS1 (HLS1) as a key regulator of light-induced cotyledon greening. Our results demonstrated that HLS1 is essential for the proper expression of greening-related genes controlling chlorophyll biosynthesis and chloroplast development. Loss of HLS1 severely disrupts the Pchlide-to-Chlide transition and impairs reactive oxygen species (ROS) scavenging in etiolated seedlings upon light exposure, leading to catastrophic ROS burst and even photobleaching. Biochemical assays revealed that HLS1 is a histone acetyltransferase mediating the deposition of H3K9ac and H3K27ac marks at multiple greening-related genes, thereby promoting their transcriptional activation. Genetic analysis further confirmed that HLS1’s promotive effect on the greening process is fully dependent on its histone acetyltransferase activity. Moreover, the loss of HLS1 also interrupts the promotive effect of ethylene signaling on the greening process by reducing the binding of ETHYLENE-INSENSITIVE 3 to the promoter region of POR genes, thus inhibiting the activation effect of ethylene signaling on the expression of PORs . Collectively, our study reveals that HLS1 acetylates histones to activate greening-related genes, optimizing chlorophyll biosynthesis and chloroplast development during dark-to-light transition in seedlings.}, archive = {J_PNAS}, author = {Peng, Yang and Peng, Tao and Chu, Yishan and Yan, Wei and Yao, Runyi and Wen, Xing and Qiu, Yuping and Wang, Meng and Xiao, Zhina and Zhang, Dan and Chen, Xiaoqian and Yin, Zhujun and Wang, Yichuan and Guo, Hongwei}, doi = {10.1073/pnas.2425647122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2425647122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Arabidopsis HOOKLESS1 acts as a histone acetyltransferase to promote cotyledon greening during seedling de-etiolation}, volume = {122}, year = {2025}, }
• (2025). Specialized molecular pathways drive the formation of light-scattering assemblies in leucophores. PNAS, 122(22), e2424979122. (www)

  @article{ , abstract = {Pigmentation plays a vital role in the survival of organisms, supporting functions such as camouflage, communication, and mate attraction. In vertebrates, these functions are mediated by specialized pigment cells known as chromatophores of which, uric acid crystal–forming leucophores remain the least understood, with little known about their molecular mechanisms. A key question in pigment cell biology is whether different crystal chemistries require distinct molecular pathways, or whether similar cellular processes drive the formation of diverse crystals. This study was designed to unravel the uncharacterized process of uric acid crystallization in leucophores and compare them to guanine crystal formation in iridophores and pterin formation in xanthophores. The results of our transcriptomic, ultrastructural, and metabolomic analyses, demonstrate that leucophores share molecular pathways with iridophores, particularly those connected to organelle organization and purine metabolism, but express discrete genes involved in uric acid biosynthesis and storage. Additionally, leucophores share intracellular trafficking and pterin biosynthesis genes with xanthophores, suggesting universally conserved processes. Ultrastructural studies reveal star-like fibrous structures in leucosomes, which likely serve as scaffolds for unique one-dimensional uric acid assemblies that radiate from the core and act as efficient light scatterers. These findings provide insights into leucophore cell biology and the specialized mechanisms driving molecular crystalline assembly, and reveal that while some cellular processes are conserved, the specific chemistry of each crystal type drives the evolution of distinct molecular pathways.}, archive = {J_PNAS}, author = {Barzilay, Yuval and Eyal, Zohar and Noy, Yael and Varsano, Neta and Olender, Tsviya and Bera, Sourabh and Lerer-Goldshtein, Tali and Kedmi, Merav and Porat, Ziv and Pinkas, Iddo and Levin-Zaidman, Smadar and Dezorella, Nili and Gur, Dvir}, doi = {10.1073/pnas.2424979122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2424979122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Specialized molecular pathways drive the formation of light-scattering assemblies in leucophores}, volume = {122}, year = {2025}, }
• (2025). Deciphering ca2+ permeation and valence selectivity in CaV1: Molecular dynamics simulations reveal the three-ion knock-on mechanism. PNAS, 122(22), e2424694122. (www)

  @article{ , abstract = {Voltage-gated calcium (Ca V ) channels are pivotal in cellular signaling due to their selective calcium ion permeation upon membrane depolarization. While previous studies have established the highly selective permeability of Ca V channels, the detailed molecular mechanism remains elusive. Here, we use extensive atomistic molecular dynamics simulations to elucidate the mechanisms governing ion permeation and valence selectivity in Ca V 1 channels. Employing the electronic continuum correction method, we simulated a calcium conductance of approximately 9 to 11 pS, aligning closely with experimental measurement. Our simulations uncovered a three-ion knock-on mechanism critical for efficient calcium ion permeation, necessitating the binding of at least two calcium ions within the selectivity filter (SF) and the subsequent entry of a third ion. In silico mutation simulations further validated the importance of multi-ion coordination in the SF for efficient ion permeation, identifying two critical residues, D706 and E1101, that are essential for the binding of two calcium ions in the SF. Moreover, we explored the competitive permeation of calcium and sodium ions and obtained a valence selectivity favoring calcium over sodium at a ratio of approximately 35:1 under the bication condition. This selectivity arises from the strong electrostatic interactions of calcium ions in the confined SF and the three-ion knock-on mechanism. Our findings provide quantitative insights into the molecular underpinnings of Ca V channel function, with implications for understanding calcium-dependent cellular processes.}, archive = {J_PNAS}, author = {Xue, Lingfeng and Yan, Nieng and Song, Chen}, doi = {10.1073/pnas.2424694122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2424694122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deciphering ca2+ permeation and valence selectivity in CaV1: Molecular dynamics simulations reveal the three-ion knock-on mechanism}, volume = {122}, year = {2025}, }
• (2025). Host complement c3 promotes malaria transmission by killing symbiotic bacteria in the mosquito midgut. PNAS, 122(22), e2424570122. (www)

  @article{ , abstract = {Host-derived factors ingested during mosquito blood feeding are poorly understood modulators of malaria transmission. Here, we demonstrated that host complement C3, acquired by mosquitoes during Plasmodium infection, significantly enhanced rodent malaria infection in laboratory-reared mosquitoes. This effect was recapitulated in field-caught Anopheles sinensis mosquitoes, confirming its relevance to malaria transmission in a more natural setting. Moreover, host-derived C3 significantly reduced the efficacy of anti-Pfs25 antibodies in blocking malaria transmission. Mechanistically, host-derived C3 lyses the mosquito midgut symbiont Elizabethkingia anophelis ( E. anophelis )—a bacterium that intrinsically suppresses parasite development by blocking the zygote-to-ookinete transition. Strikingly, host-derived C3 in mosquitoes appears to be activated by the alternative pathway, and inhibiting Factor B with Iptacopan (LNP023) reduced Plasmodium falciparum ( P. falciparum ) infection, while increased the efficacy of anti-Pfs25 antibodies to blocking P. falciparum transmission in the standard membrane-feeding assay. Therefore, this study describes a strategy of the malaria parasite to utilize host complement C3 to promote its transmission and provides us with an avenue to block malaria transmission and improve the blocking efficacy of anti-Pfs25 antibodies by the inhibition of C3 activation.}, archive = {J_PNAS}, author = {He, Biao and Li, Meilin and Guo, Shuai and Zhu, Feng and Jiao, Zhiwei and Li, Jianyong and Tan, Nie and Jiao, Shiming and Liu, Taiping and Zhang, Jian and Fan, Yongling and Gao, Yuanli and Zhou, Taoli and Li, Jian and Huang, Wei and Jiang, Lubin and Lin, Zurui and Wang, Sibao and Xu, Wenyue}, doi = {10.1073/pnas.2424570122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2424570122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Host complement c3 promotes malaria transmission by killing symbiotic bacteria in the mosquito midgut}, volume = {122}, year = {2025}, }
• (2025). Microtubule dynamics are defined by conformations and stability of clustered protofilaments. PNAS, 122(22), e2424263122. (www)

  @article{ , abstract = {Microtubules are dynamic cytoskeletal polymers that add and lose tubulin dimers at their ends. Microtubule growth, shortening, and transitions between them are linked to GTP hydrolysis. Recent evidence suggests that flexible tubulin protofilaments at microtubule ends adopt a variety of shapes, complicating structural analysis using conventional techniques. Therefore, the link between GTP hydrolysis, protofilament structure and microtubule polymerization state is poorly understood. Here, we investigate the conformational dynamics of microtubule ends using coarse-grained modeling supported by atomistic simulations and cryoelectron tomography. We show that individual bent protofilaments organize in clusters, transient precursors to the straight microtubule lattice, with GTP-bound ends showing elevated and more persistent cluster formation. Differences in the mechanical properties of GTP- and GDP-protofilaments result in differences in intracluster tension, determining both clustering propensity and protofilament length. We propose that conformational selection at microtubule ends favors long-lived clusters of short GTP-protofilaments that are more prone to forming a straight microtubule lattice and accommodating new tubulin dimers. Conversely, microtubule ends trapped in states with unevenly long and stiff GDP-protofilaments are more prone to shortening. We conclude that protofilament clustering is the key phenomenon that links the hydrolysis state of single tubulins to the polymerization state of the entire microtubule.}, archive = {J_PNAS}, author = {Kalutskii, Maksim and Grubmüller, Helmut and Volkov, Vladimir A. and Igaev, Maxim}, doi = {10.1073/pnas.2424263122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2424263122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Microtubule dynamics are defined by conformations and stability of clustered protofilaments}, volume = {122}, year = {2025}, }
• (2025). Alternative cGAS signaling promotes herpes simplex encephalitis. PNAS, 122(22), e2423873122. (www)

  @article{ , abstract = {During infection, foreign DNA is sensed by cyclic GMP-AMP synthase (cGAS) leading to the production of cGAMP, STING-dependent type I interferon and proinflammatory cytokine expression, and autophagy. To prevent a response to self-DNA, cGAS activity is tightly regulated. Dysregulation of cGAS underpins interferonopathies, such as Aicardi–Goutières syndrome, as well as Lupus and neurodegenerative diseases like Parkinson’s disease. Thus, cGAS and its product cGAMP are therapeutic targets. However, if cGAS functions independently of cGAMP signaling is undefined. Here, we identified an alternative signaling pathway that cGAS engages independent of cGAMP synthesis. We demonstrate that alternative cGAS signaling promotes hyperexpression of CXCL1 and enhanced neutrophil recruitment that facilitates viral dissemination during herpes simplex encephalitis. Our study reports of an alternative cGAS response independent of cGAMP, highlighting a previously uncharacterized scaffold function for cGAS.}, archive = {J_PNAS}, author = {Shmuel-Galia, Liraz and Jiang, Zhaozhao and Stine, Laurel and Cahill, Sara and Ng, Sze-Ling and Wilson, Ruth and Kandasamy, Richard Kumaran and Kurt-Jones, Evelyn A. and Ramanjulu, Joshi M. and Bertin, John and Kasparcova, Viera and Pesiridis, G. Scott and Fitzgerald, Katherine A. and Humphries, Fiachra}, doi = {10.1073/pnas.2423873122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2423873122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Alternative cGAS signaling promotes herpes simplex encephalitis}, volume = {122}, year = {2025}, }
• (2025). Mgat4b-mediated selective N-glycosylation regulates melanocyte development and melanoma progression. PNAS, 122(22), e2423831122. (www)

  @article{ , abstract = {Melanocyte development involves key pathways that are often recapitulated during melanoma initiation, highlighting the importance of understanding these regulatory processes. Our study identifies mgat4b , a glycosyl transferase involved in selective N -glycan branching enriched in pigment progenitors, as a regulator of directional cell migration and establishment of melanocyte stem cell (McSC) pool during early development. Single cell RNA (scRNA) sequencing analysis in zebrafish upon targeted disruption of mgat4b reveals, that migratory melanocyte progenitors marked by galectin expression fail to persist. Lectin affinity proteomic analysis reveals the glycosylation of key melanocyte proteins GPNMB, KIT, and TYRP1 to be under the control of MGAT4B in melanocytic cells. Additionally, mislocalization of Junctional plakoglobin (JUP) explains the observed defects in cell adhesion and migration to be regulated by MGAT4B but not its isozyme MGAT4A. Our meta-analysis further reveals that melanoma patients with both the BRAF V600E mutation and elevated MGAT4B levels have significantly worse survival outcomes compared to those with only the BRAF V600E mutation. By leveraging the zebrafish MAZERATI platform to model BRAF V600E driver mutation in vivo, we show that mgat4b mutant cells fail to aggregate and initiate tumors. RNA profiling of the transformed melanocytes revealed cell–cell junction, adhesion, and ECM binding to be probable contributing factors that resulted in the failure of tumor onset. Using a small-molecule inhibitor we demonstrate that complex N -glycosylation inhibits early-stage melanoma progression. Our study underscores the importance of selective N -glycan branching in both melanocyte development and melanoma initiation, suggesting MGAT4B as a promising therapeutic target for melanoma treatment.}, archive = {J_PNAS}, author = {Sharma, Babita and Aswin, Keerthic and Jain, Tanya and Nasreen, Ayesha and Aggarwal, Ayush and Subramaniam, Yogaspoorthi J. and Rengaraju, Jeyashri and Agrawal, Srashti Jyoti and Bhatt, Mayank and Paul, Bhashkar and Chandrasekaran, Koushika and Yadav, Aanchal and Soni, Jyoti and Ujjainiya, Rajat and Akhter, Md Quasid and Pandey, Rajesh and Suresh, Shruthy and Sampathkumar, Srinivasa-Gopalan and Natarajan, Vivek T.}, doi = {10.1073/pnas.2423831122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2423831122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mgat4b-mediated selective N-glycosylation regulates melanocyte development and melanoma progression}, volume = {122}, year = {2025}, }
• (2025). Phage-induced protection against lethal bacterial reinfection. PNAS, 122(22), e2423286122. (www)

  @article{ , abstract = {Bacteriophages, or phages, are viruses that target and infect bacteria. Due to a worldwide rise in antimicrobial resistance (AMR), phages have been proposed as a promising alternative to antibiotics for the treatment of resistant bacterial infections. Up to this point in history, phage use in preclinical animal studies, clinical trials, and emergency-use compassionate care cases has centered around the original observation from 1915 showing phage as lytic agent, and thus a treatment that kills bacteria. Here, we describe an activity associated with phage therapy that extends beyond lytic activity that results in long-term protection against reinfection. This activity is potent, providing almost complete protection against a second lethal infection for animals treated with phage therapy. The activity also reduced infection burden an astounding billion-fold over the control. Reinfection protection requires phage lytic killing of its target bacterium but is independent of additional phage therapy. The effect is not driven by phage alone, lingering phage resistors, or a sublethal inoculum. In vitro phage-lysed bacteria provide partial protection, suggesting a combination of phage-induced lytic activity and immune stimulation by phage treatment is responsible for the effect. These observations imply certain phages may induce host adaptive responses following the lysis of the infecting bacteria. This work suggests phage therapy may contain a dual-action effect, an initial treatment efficacy followed by a long-term protection against reoccurring infection, a therapeutic-vaccination mechanism of action.}, archive = {J_PNAS}, author = {Xing, Yikun and Hernandez Santos, Haroldo J. and Qiu, Ling and Ritter, Samantha R. and Zulk, Jacob J. and Lahowetz, Rachel and Patras, Kathryn A. and Terwilliger, Austen L. and Maresso, Anthony W.}, doi = {10.1073/pnas.2423286122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2423286122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phage-induced protection against lethal bacterial reinfection}, volume = {122}, year = {2025}, }
• (2025). Proofreading and single-molecule sensitivity in t cell receptor signaling by condensate nucleation. PNAS, 122(22), e2422787122. (www)

  @article{ , abstract = {T cells display the remarkable ability to detect single foreign peptides displayed on target cells, while ignoring highly abundant self-peptides. This selectivity has been explained by kinetic proofreading in the T cell receptor (TCR) signaling pathway, which prevents responses to short-lived binding events regardless of their abundance. However, the biochemical mechanisms that drive kinetic proofreading have remained unclear. Here, using computational modeling, we show that these key signaling properties of the TCR pathway can emerge from the dynamics of linker for activation of T cells (LAT) phosphorylation, diffusion, and condensation following TCR–peptide major histocompatibility complex (pMHC) binding. In this model, time delays in LAT condensate nucleation underlie kinetic proofreading, enabling selective signaling responses to high-affinity pMHC ligands. The cooperativity in the nucleation and growth of LAT condensates also provides a mechanism to amplify weak signals from single high-affinity peptides and for condensates to grow with increasing antigen numbers. In contrast to other models, condensate-nucleation proofreading predicts a dependence of signal strength on pMHC spacing at fixed number, a prediction we validated experimentally using a protein scaffold to present pMHCs at defined intervals. Our results suggest that nucleation-condensation proofreading underlies the remarkable antigen detection capabilities of the TCR signaling pathway.}, archive = {J_PNAS}, author = {White, William L. and Yirdaw, Hailemikael K. and Ben-Sasson, Ariel J. and Groves, Jay T. and Baker, David and Kueh, Hao Yuan}, doi = {10.1073/pnas.2422787122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2422787122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Proofreading and single-molecule sensitivity in t cell receptor signaling by condensate nucleation}, volume = {122}, year = {2025}, }
• (2025). A whole-scale volatile-depleted lunar interior. PNAS, 122(22), e2422726122. (www)

  @article{ , abstract = {The extent of moderately volatile elements (MVE) depletion and its effects on the Moon’s evolutionary history remain contentious, partly due to unintentionally biased sampling by the Apollo missions from the Procellarum KREEP Terrane. In this study, we analyzed the Zn and K isotope compositions of a series of lunar basaltic meteorites, which vary in Th content and are likely to represent a broader sampling range than previous studies, including samples from the far side of the Moon. Our findings indicate remarkably consistent Zn and K isotope compositions across all lunar basalt types, despite significant variations in Th content. This consistency suggests a relatively homogeneous isotopic composition of volatile elements within the Moon, unaffected by subsequent impact events that formed major basins. Our results suggest that the estimates of MVE abundance and isotopic compositions from the Apollo returned samples are likely representative of the bulk Moon, supporting a globally volatile-depleted lunar interior.}, archive = {J_PNAS}, author = {Dai, Wei and Moynier, Frédéric and Long, Zheng-Yu and Fang, Linru and Day, James M. D. and Paquet, Marine and Siebert, Julien}, doi = {10.1073/pnas.2422726122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2422726122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A whole-scale volatile-depleted lunar interior}, volume = {122}, year = {2025}, }
• (2025). Formation of giant ER sheets by pentadecanoic acid causes lipotoxicity in fission yeast. PNAS, 122(22), e2422126122. (www)

  @article{ , abstract = {Excess amounts of saturated fatty acids (FAs) are toxic to organisms, a condition termed lipotoxicity, which is often accompanied by pleiotropic cellular and tissue dysfunction. Here, we show that pentadecanoic acid (C15:0) exerts toxicity on the fission yeast Schizosaccharomyces pombe by generating an aberrantly planar endoplasmic reticulum (ER) structure, which we named a “giant ER sheet.” Untargeted lipidomics revealed that C15:0 is incorporated into complex lipids depending on an acyl-CoA ligase Lcf1 and an acyl-CoA transferase Slc1, thereby increasing the saturation level of the acyl chains. The toxicity and giant ER sheet formation were abolished by deleting lcf1 or slc1 gene, indicating that the incorporation of C15:0 into glycerophospholipids causes giant ER sheet formation. The giant ER sheets disrupted the correct migration of Mid1, a protein determining the cell division site, and physically blocked septum formation, hindering correct cell separation. Our results suggest that the ER is the primary site targeted by saturated FAs, leading to lipotoxicity.}, archive = {J_PNAS}, author = {Hoshikawa, Yojiro and Shirota, Natsuho and Tsugawa, Hiroshi and Kimura, Satoshi and Matsuyama, Akihisa and Yashiroda, Yoko and Kakeya, Hideaki and Arita, Makoto and Iizumi, Reiko and Yoshida, Minoru and Nishimura, Shinichi}, doi = {10.1073/pnas.2422126122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2422126122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Formation of giant ER sheets by pentadecanoic acid causes lipotoxicity in fission yeast}, volume = {122}, year = {2025}, }
• (2025). Freeze-induced crystallization: An overlooked pathway for mineral genesis in natural waters. PNAS, 122(22), e2421822122. (www)

  @article{ , abstract = {Natural ice plays salient roles in making the Earth habitable and sustainable. Previously overlooked, its role in chemical processes is now of emerging interest, particularly due to the freeze concentration effect, which can substantially promote chemical reactions during ice formation. We demonstrate here that ice formation can serve as a dynamic and unique pathway for mineral genesis. Freezing solutions containing dissolved manganese and carbonates produced rhodochrosite (Mn II CO 3 ) even under slightly undersaturated conditions. At room temperature, by contrast, this occurred when the solution saturation level was increased by ca. 30,000 times. The cryogenic rhodochrosite formed spherical aggregates of nano-polycrystallites, distinctly different from the cubic monocrystalline particles observed at room temperature. The distinct feature likely resulted from the combined effects of the intensified supersaturation induced by the freeze concentration effect and the low temperatures within liquid-like layers, conditions that make liquid-like layers an exceptional environment for mineral genesis, unlike typical natural water systems. The cryogenic rhodochrosite formation was successfully demonstrated using in situ, real-time X-ray absorption spectroscopy (XAS), enabling direct observation of freeze-induced solid formation. Our findings reveal that freeze-induced crystallization may be an active mineralization pathway, potentially influencing elemental cycles within the cryosphere and contributing to minerals with distinguishing properties and reactivities in the environment.}, archive = {J_PNAS}, author = {Won, Younghoon and Lee, Sungsik and Lee, Seungyeol and Park, SoHyun and Lim, Jun and Choi, Wonyong and Lee, Giehyeon}, doi = {10.1073/pnas.2421822122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2421822122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Freeze-induced crystallization: An overlooked pathway for mineral genesis in natural waters}, volume = {122}, year = {2025}, }
• (2025). An electrostatic network with strong connectivity is a phospho-sensor for regulating affinity of syk–receptor association. PNAS, 122(22), e2421663122. (www)

  @article{ , abstract = {Spleen tyrosine kinase (Syk) mediates early signaling events in immunity by coupling membrane receptors to immune responses. Syk comprises a tandem SH2 (tSH2) regulatory module—two SH2 domains connected by a structured linker—and a kinase domain. The association of tSH2 with a doubly tyrosine-phosphorylated motif (dpITAM) on membrane immunoreceptors is central to controlling Syk’s signaling activity. tSH2-dpITAM association is regulated by Y131-phosphorylation on linker A, distant from the Syk–immunoreceptor binding sites. A unique thermodynamic signature was reported to control this protein–protein interaction by phosphorylation, yet the molecular mechanism for the phosphorylation effect is unknown. Molecular dynamics (MD) simulation affords the detail needed to fill this knowledge deficiency. Long MD simulations revealed a highly correlated interdomain electrostatic network (distance correlation coefficients > 0.75) that is lost upon Y131-phosphorylation. Some of the strongly correlated interdomain pairs carry the same charge or are separated by distances greater than a salt-bridge pair. The strong interdomain connectivity accounts for the single, narrow free energy basin in the domain-structure conformational landscape for unphosphorylated tSH2. Linker phosphorylation disrupts this network and yields a broader free energy landscape with multiple networks formed by the same group of residues adopting alternative interdomain conformations. A salt dependence of NMR rotational tumbling times substantiates the electrostatic nature of tSH2 domain–domain coupling. Syk tandem SH2 is thus a sensor whose conformational plasticity is sensitive to Y131 phosphorylation. This phospho-sensing response provides the basis for an entropically driven regulatory mechanism that is so-far unique to Syk–immunoreceptor protein–protein association.}, archive = {J_PNAS}, author = {Hua, Duy P. and Kinnun, Jacob J. and Post, Carol Beth}, doi = {10.1073/pnas.2421663122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2421663122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An electrostatic network with strong connectivity is a phospho-sensor for regulating affinity of syk–receptor association}, volume = {122}, year = {2025}, }
• (2025). Robustness revisited: On the neutral evolution of centrality and localization. PNAS, 122(22), e2421006122. (www)

  @article{ , abstract = {This study investigates the intricate interplay among neutral landscape structure, mutation rate, recombination rate, and population dynamics in shaping evolutionary robustness. We provide a comprehensive framework that elucidates how different evolutionary forces interact to influence genotypic robustness and localization within haploid and diploid populations. We demonstrate that in haploid populations, high mutation rates relative to recombination typically drive the population toward regions of increased eigencentrality, a graph-theoretic measure of centrality which is correlated while not identical to mutational robustness. On the other hand, recombination increases the localization of the population to a smaller region of genotypic space, while high values of recombination relative to mutation can introduce shifts in distribution away from regions of high eigencentrality and toward attractors of the recombination dynamics. Diploid dynamics further complicate these interactions, showing reduced alignment with eigencentrality under both high mutation and recombination rates, with the exception of structured diploid landscapes where dynamics are still aligned with increasing eigencentrality. Our findings underscore the nuanced dependencies of evolutionary outcomes on both local and global landscape structures as well as evolutionary parameters.}, archive = {J_PNAS}, author = {Sella, Yehonatan and Bergman, Aviv}, doi = {10.1073/pnas.2421006122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2421006122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Robustness revisited: On the neutral evolution of centrality and localization}, volume = {122}, year = {2025}, }
• (2025). Environmental DNA adsorption to chitin can promote horizontal gene transfer by natural transformation. PNAS, 122(22), e2420708122. (www)

  @article{ , abstract = {Horizontal gene transfer by natural transformation (NT) is induced in Vibrio cholerae upon attachment to chitin surfaces in the aquatic environment. Here, we show that free environmental DNA adsorbs to chitin surfaces under physiologically realistic conditions. Using live-cell imaging and a fluorescent NT reporter, we demonstrate with cellular resolution microscopy that V. cholerae utilizes chitin-bound DNA as a reservoir for genetic exchange. Additionally, we demonstrate that uptake of DNA from this chitin-bound reservoir requires the forceful retraction of competence type IV pili. These findings uncover a role for retraction force in driving pilus-dependent NT and suggest that chitin particle surfaces can act as hotspots for horizontal gene transfer.}, archive = {J_PNAS}, author = {Holt, Jacob D. and Peng, Yixuan and Dalia, Triana N. and Dalia, Ankur B. and Nadell, Carey D.}, doi = {10.1073/pnas.2420708122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2420708122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Environmental DNA adsorption to chitin can promote horizontal gene transfer by natural transformation}, volume = {122}, year = {2025}, }
• (2025). Stimulus representations in visual cortex shaped by spatial attention and microsaccades. PNAS, 122(22), e2420704122. (www)

  @article{ , abstract = {Microsaccades (MSs) are commonly associated with covert spatial attention, yet their impact on cortical processing of visual objects remains unclear. Rhesus macaques, randomly cued to attend to a target object amid distracters, were rewarded for detecting a color change in the target. While spatial attention does not affect the object tuning curves of V4 cells, the direction of MS significantly influenced object representations in V4 throughout the entire trial. Specifically, intervals following an MS toward the target exhibited superior stimulus decoding and sharper tuning curves compared to intervals following an MS away from the target. Furthermore, MSs directed toward the target enhanced neuronal responses to behaviorally relevant color changes, leading to faster reaction times. This sharpening effect stems from both a refreshing of the initial sensory response and an amplification of attention effects. The firing rate enhancement associated with spatial attention is delayed until the occurrence of the first MS directed toward the target. Subsequently, a positive effect of attention on firing rate, influenced by MS direction, was found throughout the trial across deep and superficial layers of V4, lateral pulvinar, and IT cortex. In summary, these findings underscore a crucial link between covert attention, object processing, and their coordination with MSs.}, archive = {J_PNAS}, author = {Srinivasan, Karthik and Lowet, Eric and Gomes, Bruno and Desimone, Robert}, doi = {10.1073/pnas.2420704122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2420704122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stimulus representations in visual cortex shaped by spatial attention and microsaccades}, volume = {122}, year = {2025}, }
• (2025). A viral necrosome mediates direct RIPK3 activation to promote inflammatory necroptosis. PNAS, 122(22), e2420245122. (www)

  @article{ , abstract = {Necroptosis is an inflammatory programmed cell death pathway triggered by RIPK3 activation through one of the upstream RHIM-domain-containing proteins including RIPK1, TRIF, and ZBP1. Whether necroptosis can be activated independent of the upstream signaling pathways leading to inflammatory pathogenesis remains ambiguous. Here, we revealed a mechanism in which a viral protein mediates direct RIPK3 activation resulting in severe inflammatory pathogenesis in patients. The nonstructural protein NSs of a pathogenic hemorrhagic virus, SFTSV, interacts with the RIPK3 kinase domain and forms biocondensate to promote RIPK3 autophosphorylation and necroptosis activation in an RHIM-independent manner. In parallel, sequestration of RIPK3 within the NSs–RIPK3 condensate inhibited RIPK3-mediated apoptosis and promoted viral replication. Infection with an SFTSV NSs mutant virus not forming NSs condensate triggered pronounced apoptosis resulting in reduced viral replication and decreased fatality in vivo. Blocking SFTSV-triggered necroptosis through depletion of MLKL or treatment with a RIPK3-kinase inhibitor reduced viral inflammatory pathogenesis and fatality in vivo. In contrast, blocking SFTSV-triggered apoptosis through depletion of RIPK3 resulted in enhanced viral replication and increased fatality in vivo. The virus-triggered necroptosis correlated with severe inflammatory pathogenesis and lethality in virus-infected patients. The NSs–RIPK3 condensate may represent a necroptosis activation mechanism that promotes viral pathogenesis.}, archive = {J_PNAS}, author = {Li, Shufen and Li, Hao and Zhou, Zhenxing and Ye, Meidi and Wang, Yifei and Li, Wenqin and Guan, Zhenqiong and Guan, Zihan and Zhang, Chongtao and Zhang, Yulan and Liu, Wei and Peng, Ke}, doi = {10.1073/pnas.2420245122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2420245122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A viral necrosome mediates direct RIPK3 activation to promote inflammatory necroptosis}, volume = {122}, year = {2025}, }
• (2025). Longitudinal associations between birth-to-six cortical growth and childhood neurocognitive function. PNAS, 122(22), e2418176122. (www)

  @article{ , abstract = {The human cortex undergoes immense change in the first years of life, doubling in thickness within the first year and evidencing the greatest change within the first 5 y. While substantial research has identified the early postnatal period as a sensitive period in cortical development, research to date lacks the temporal resolution necessary to identify which aspects of cortical change predict later neural and cognitive function. This study leveraged a rich longitudinal dataset of cortical thickness in 50 children who were scanned up to 11 times between birth and 6 y. We used nonlinear multilevel modeling to explore patterns of cortical change across the brain during this period and distinguish whether different phases of change would predict performance and brain activation during a working memory task children completed at approximately 9 y. Cortical thickness across the brain showed a large increase from birth through 12 mo, a decrease from 12 to 18 mo, and a small increase from 18 mo to 6 y, mirroring patterns of early neural proliferation, pruning, and sustained growth. Performance and neural activation during the working memory task were associated with smaller peak (i.e., 12 mo) thickness and a marginally less steep 12 to 18-mo decline in thickness in the middle frontal gyrus (MFG) of the frontal lobe, in line with evidence demonstrating concurrent links between frontal lobe structure and working memory. These findings validate theories of cortical growth developed in preclinical models using human data and demonstrate that prefrontal cortex development in infancy uniquely predicts neurocognitive function 9 y later.}, archive = {J_PNAS}, author = {Davis, Megan M. and Woodburn, Mackenzie and Nugiel, Tehila and Rakesh, Divyangana and Tate, Maresa and Asciutto, William and Lin, Weili and Cohen, Jessica R. and Sheridan, Margaret A.}, doi = {10.1073/pnas.2418176122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2418176122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Longitudinal associations between birth-to-six cortical growth and childhood neurocognitive function}, volume = {122}, year = {2025}, }
• (2025). Allelic variations and gene cluster modularity act as nonlinear bottlenecks for cholera emergence. PNAS, 122(22), e2417915122. (www)

  @article{ , abstract = {The underlying factors that lead to specific strains within a species to emerge as human pathogens remain mostly enigmatic. The diarrheal disease cholera is caused by strains from a phylogenetically confined group within the Vibrio cholerae species, the pandemic cholera group (PCG), making it an ideal model system to tackle this puzzling phenomenon. Comprehensive analyses of over 1,840 V. cholerae genomes, including environmental isolates from this study, reveal that the species consists of eleven groups, with the PCG belonging to the largest and located within a lineage shared with environmental strains. This hierarchical classification provided us with a framework to unravel the ecoevolutionary dynamics of the genetic determinants associated with the emergence of toxigenic V. cholerae . Our analyses indicate that this phenomenon is largely dependent on the acquisition of unique modular gene clusters and allelic variations that confer a competitive advantage during intestinal colonization. We determined that certain PCG-associated alleles are essential for successful colonization whereas others provide a nonlinear competitive advantage, acting as a critical bottleneck that clarifies the isolated emergence of PCG. For instance, toxigenic strains encoding non-PCG alleles of a) tcpF or b) a sextuple allelic exchange mutant for genes tcpA , toxT , VC0176 , VC1791 , rfbT, and ompU , lose their ability to colonize the intestine. Interestingly, these alleles do not play a role in the colonization of newly established model environmental reservoirs. Our study uncovers the evolutionary roots of toxigenic V. cholerae offering a tractable approach for investigating the emergence of pathogenic clones within an environmental population.}, archive = {J_PNAS}, author = {López-Pérez, Mario and Balasubramanian, Deepak and Campos-Lopez, Alicia and Crist, Cole and Grant, Trudy-Ann and Haro-Moreno, Jose M. and Zaragoza-Solas, Asier and Almagro-Moreno, Salvador}, doi = {10.1073/pnas.2417915122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2417915122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Allelic variations and gene cluster modularity act as nonlinear bottlenecks for cholera emergence}, volume = {122}, year = {2025}, }
• (2025). The IL-18 receptor is expressed on murine small-intestinal enterochromaffin cells and executes a recovery program upon injury. PNAS, 122(22), e2417149122. (www)

  @article{ , abstract = {Upon injury, epithelial-derived IL-18 is released and induces an inflammatory response in underlying IL18R1 + lamina propria cells. Notably, Il18r1 is also predicted to be expressed and functional in intestinal epithelial cells (IECs), since epithelial IL18R1 deficiency contributes to worsened outcomes upon inflammatory challenge. However, the nature of Il18r1 + IECs, and their subsequent role in epithelial-intrinsic IL-18 signaling is poorly characterized. Here, we show that, in the murine small intestine, the IL-18 receptor is expressed by rare IECs that we identified to be a subset of enterochromaffin cells (ECC). While these cells are the major producers of serotonin in the intestine, we found no evidence that IL-18 regulated serotonin metabolism or release. Rather, upon radiation-induced injury, Il18r1 + cells appeared in the crypt base and took on a revival stem cell (revSC) program, marked by mixed expression of YAP/TAZ and enteroendocrine genes signatures. Functionally, irradiated Il18 −/− mice display reduced epithelial proliferation and altered differentiation in the small intestine, characterized by increased Paneth cells (PC) and elevated Wnt3 levels, which was partially recapitulated in Il18 −/− ileal organoids. In sum, we identified an Il18r1 + population in the epithelium and revealed a role for IEC-intrinsic IL-18 signaling during injury.}, archive = {J_PNAS}, author = {Winsor, Nathaniel J. and Tsang, Derek K. and Ranger, Adrienne and Singh, Ojas and Goyal, Shawn and Philpott, Dana J. and Girardin, Stephen E.}, doi = {10.1073/pnas.2417149122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2417149122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The IL-18 receptor is expressed on murine small-intestinal enterochromaffin cells and executes a recovery program upon injury}, volume = {122}, year = {2025}, }
• (2025). Genomic analyses identify 15 risk loci and reveal HDAC2, SOX2-OT, and IGF2BP2 in a naturally occurring canine model of gastric cancer. PNAS, 122(22), e2416723122. (www)

  @article{ , abstract = {Gastric cancer ranks as the fifth most common human cancer worldwide and has a poor survival rate and limited treatment options. Despite the high prevalence and mortality rate, the genetic etiology is largely unknown. In dogs, a clinically and histologically similar disease disproportionately affects two breeds, the Belgian Tervuren and Belgian Sheepdog, which develop the intestinal and diffuse tumor subtypes observed in humans. We performed a Bayesian genome-wide association study and selection analyses in this naturally occurring canine model to elucidate underlying genetic risk factors for gastric cancer and identified 15 associated loci. Variant filtering revealed germline putative regulatory variants for the EPAS1 ( HIF2A ) and PTEN genes and a coding variant in CD101 . Two loci are overrepresented among cases of intestinal tumor subtype. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop gastric cancer. Across-breed analyses uncovered haplotypes enriched in Malinois at SOX2-OT and IGF2BP2 that are at significantly higher frequency among genome-wide association study controls. Among Tervuren and Sheepdogs, HDAC2 putative regulatory variants were present at comparatively high frequency and were associated with risk of gastric cancer. Here, we describe a complex genetic architecture governing gastric cancer in a dog model, including genes such as PDZRN3 and KLHL29 , that have not been associated with human gastric cancer.}, archive = {J_PNAS}, author = {Cook, Shawna R. and Hugen, Sanne and Hayward, Jessica J. and Famula, Thomas R. and Belanger, Janelle M. and McNiel, Elizabeth and Fieten, Hille and Oberbauer, Anita M. and Leegwater, Peter A. J. and Ostrander, Elaine A. and Mandigers, Paul J. J. and Evans, Jacquelyn M.}, doi = {10.1073/pnas.2416723122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2416723122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genomic analyses identify 15 risk loci and reveal HDAC2, SOX2-OT, and IGF2BP2 in a naturally occurring canine model of gastric cancer}, volume = {122}, year = {2025}, }
• (2025). Task difficulty modulates the effect of mind wandering on phase dynamics. PNAS, 122(22), e2416387122. (www)

  @article{ , abstract = {Mind wandering attenuates widespread sensory and motor processing, both of which are mediated by phase coherence. However, it remains unclear i) whether mind wandering impacts both sensory input and motor output processing by modulating ii) neural entrainment to external stimuli, as measured by intertrial phase coherence (ITPC), and specifically iii) whether task difficulty with different degrees of attentional demands moderates the impact of mind wandering on phase coherence. Using the thought-probe method, we assessed participants’ attentional states during different sensory and motor tasks with varying task difficulty. We found that mind wandering decreased ITPC exclusively in less demanding tasks but not in difficult ones, regardless of whether the tasks involved visual input or motor output processing. Our results suggest that external task difficulty may modulate the balance between external and internal cognitive processing (e.g., mind wandering), with simpler tasks facilitating internally oriented cognition and increasing mind wandering. This balance between internal mind wandering and external task difficulty is mediated, in part, by phase coherence, which serves as an underlying neural mechanism. Collectively, our findings support the hypothesis that phase coherence and its dynamics (ITPC) play a key role in mediating the reciprocal balance of internal and external cognition—this suggests their partly shared cognitive-executive resources as entailed by the recently proposed Baseline model of cognition.}, archive = {J_PNAS}, author = {Long, Zhengkun and Northoff, Georg and Fu, Xiaolan}, doi = {10.1073/pnas.2416387122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2416387122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Task difficulty modulates the effect of mind wandering on phase dynamics}, volume = {122}, year = {2025}, }
• (2025). Viral and host network analysis of the human cytomegalovirus transcriptome in latency. PNAS, 122(22), e2416114122. (www)

  @article{ , abstract = {The human cytomegalovirus (HCMV) UL135 and UL138 genes play opposing roles regulating latency and reactivation in CD34 + human progenitor cells. We designed an RNA sequencing study to compare the transcriptional profile of HCMV infection in the presence and absence of these genes using the Tohoku Hospital Pediatrics-1 (THP-1) monocytic cell line model for latency. Relative to primary cell models, THP-1 cells offer the strength of a homogenous population that uniformly silences gene expression and will synchronously reexpress viral genes following stimulation to differentiate, which models early phases of viral reactivation. The loss of UL138 resulted in elevated levels of viral gene expression and in spontaneous adhesion of distinct cell populations that support HCMV gene expression and genome synthesis. The loss of UL135 resulted in diminished viral gene expression during an initial burst that occurs as latency is established and in no expression of eleven viral genes from the UL b ′ region even following differentiation and reexpression of viral genes. Transcriptional network analysis revealed host transcription factors (TFs) with potential to regulate the UL b ′ genes in coordination with pUL135. We show that the cellular TF peroxisome proliferator-activated receptor gamma binds to the viral genome and influences the expression of UL133-UL138 locus genes. Our results define roles for UL135 and UL138 in regulation of patterns of viral gene expression for the establishment of latency and reexpression of viral genes for reactivation and reveal insights into differentiation-linked mechanisms of transcriptional control of the HCMV genome.}, archive = {J_PNAS}, author = {Collins-McMillen, Donna and De Oliveira Pessoa, Diogo and Zarrella, Kristen and Parkins, Christopher J. and Daily, Michael and McKinzey, David R. and Moorman, Nathaniel J. and Kamil, Jeremy P. and Caposio, Patrizia and Padi, Megha and Goodrum, Felicia D.}, doi = {10.1073/pnas.2416114122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2416114122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Viral and host network analysis of the human cytomegalovirus transcriptome in latency}, volume = {122}, year = {2025}, }
• (2025). Evolution of the essential gene MN1 during the macroevolutionary transition toward patterning the vertebrate hindbrain. PNAS, 122(22), e2416061122. (www)

  @article{ , abstract = {The tight link between brain and skull formation is a fundamental aspect of vertebrate evolution and embryogenesis. Their developmental synchronization is essential for structural and functional integration. The brain and skull shape coevolution is evident along the vertebrate phylogeny; however, the genetic basis underlying their close evolutionary and developmental relationship remains little explored. Here, we reveal the evolution and function of the MN1 gene that was previously found to be associated with significant shape variation in the mouse skull and the formation of cranial bones. We show that the vertebrate MN1 gene evolved from an ancestral deuterostome sequence. In vertebrates, the MN1 gene structure, synteny, and spatiotemporal expression pattern are remarkably conserved, indicating that the gene carries out a core function. Using a newly generated mouse knock-out model, we demonstrate in vivo that Mn1 integrated into an ancient molecular machinery and controls the expression of the Cyp26 genes in the developing hindbrain, thereby tuning the retinoic acid levels and patterning of the developing central nervous system. This study thus showcases the emergence of a novel gene function from an ancestral sequence and its role in generating a macroevolutionary innovation. The data expand our knowledge of brain and skull codevelopment and coevolution and highlight the role of this regulatory loop in craniofacial human syndromes.}, archive = {J_PNAS}, author = {Escamilla-Vega, Elio and Seton, Louk W. G. and Kyomen, Stella and Murillo-Rincón, Andrea P. and Petersen, Julian and Tautz, Diethard and Kaucká, Markéta}, doi = {10.1073/pnas.2416061122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2416061122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolution of the essential gene MN1 during the macroevolutionary transition toward patterning the vertebrate hindbrain}, volume = {122}, year = {2025}, }
• (2025). Independent transitions to fully planktonic life cycles shaped the global distribution of medusozoans in the epipelagic zone. PNAS, 122(22), e2415979122. (www)

  @article{ , abstract = {Life history traits influence marine species dispersal and habitat colonization. Medusozoans (jellyfish and siphonophores) exhibit diverse life cycles, evolved from an ancestral cycle alternating between a benthic polyp and a pelagic medusa. Despite their ecological importance, factors shaping medusozoan distribution remain poorly understood. By integrating metabarcoding and environmental data from the Tara Oceans expedition with life history traits, we provide global evidence supporting the longstanding hypothesis that benthic polyp presence/absence is a key factor influencing the distribution and abundance of planktonic medusozoans in the surface ocean. We inferred on a time-calibrated phylogeny of Medusozoa multiple transitions to a fully planktonic (holoplanktonic) life cycle, either through polyp loss, acquisition of drifting polyps, or development of polyps parasitizing pelagic organisms. We could associate each transition with a shift toward offshore habitats and the emergence of globally dominant Operational Taxonomic Units (OTUs), whose abundance far exceeds that of any nonholoplanktonic medusozoans in the planktonic realm. The prevalence of holoplanktonic medusozoans in terms of abundance and diversity is broadly observed in coastal and offshore environments, peaking over greater bathymetric depths in tropical and subtropical regions. We show that holoplanktonic and nonholoplanktonic groups interact with distinct yet compositionally similar planktonic communities. Holoplanktonic OTUs occupy more peripheral positions in a plankton interactome, suggesting greater flexibility in biotic interactions, an adaptive trait in rapidly changing planktonic ecosystems. These findings highlight how life cycle evolution shaped the global distribution of medusozoans and suggest that variations in life history may significantly influence how medusozoans respond to global environmental changes.}, archive = {J_PNAS}, author = {Boosten, Manon and Sant, Camille and Da Silva, Ophélie and Chaffron, Samuel and Guidi, Lionel and Leclère, Lucas}, doi = {10.1073/pnas.2415979122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2415979122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Independent transitions to fully planktonic life cycles shaped the global distribution of medusozoans in the epipelagic zone}, volume = {122}, year = {2025}, }
• (2025). The benefits and dangers of anthropomorphic conversational agents. PNAS, 122(22), e2415898122. (www)

  @article{ , abstract = {A growing body of research suggests that the recent generation of large language model (LLMs) excel, and in many cases outpace humans, at writing persuasively and empathetically, at inferring user traits from text, and at mimicking human-like conversation believably and effectively—without possessing any true empathy or social understanding. We refer to these systems as “anthropomorphic conversational agents” to aptly conceptualize the ability of LLM-based systems to mimic human communication so convincingly that they become increasingly indistinguishable from human interlocutors. This ability challenges the many efforts that caution against “anthropomorphizing” LLMs, attaching human-like qualities to nonhuman entities. When the systems themselves exhibit human-like qualities, calls to resist anthropomorphism will increasingly fall flat. While the AI industry directs much effort into improving the reasoning abilities of LLMs—with mixed results—the progress in communicative abilities remains underappreciated. In this perspective, we aim to raise awareness for both the benefits and dangers of anthropomorphic agents. We ask: should we lean into the human-like abilities, or should we aim to dehumanize LLM-based systems, given concerns over anthropomorphic seduction? When users cannot tell the difference between human interlocutors and AI systems, threats emerge of deception, manipulation, and disinformation at scale. We suggest that we must engage with anthropomorphic agents across design and development, deployment and use, and regulation and policy-making. We outline in detail implications and associated research questions.}, archive = {J_PNAS}, author = {Peter, Sandra and Riemer, Kai and West, Jevin D.}, doi = {10.1073/pnas.2415898122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2415898122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The benefits and dangers of anthropomorphic conversational agents}, volume = {122}, year = {2025}, }
• (2025). Nucleoporins cooperate with polycomb silencers to promote transcriptional repression and repair at DNA double-strand breaks. PNAS, 122(22), e2415069122. (www)

  @article{ , abstract = {DNA double-strand breaks (DSBs) are harmful lesions and major sources of genomic instability. Studies have suggested that DSBs induce local transcriptional silencing that consequently promotes genomic stability. Several factors have been proposed to actively participate in this process, including Ataxia-telangiectasia mutated (ATM) and Polycomb repressive complex 1 (PRC1). Here, we found that disrupting PRC1 clustering disrupts DSB-induced gene silencing. Interactome analysis of PHC2, a PRC1 subunit that promotes the PRC1 clustering, found several nucleoporins found in the nuclear pore complex (NPC). Similar to PHC2, depleting the nucleoporins also disrupted the DSB-induced gene silencing. We found that some of these nucleoporins, such as NUP107 and NUP43, which are members of the Y-complex of NPC, localize to DSB sites. The presence of nucleoporins and PHC2 at DSB regions was interdependent, suggesting that they act cooperatively in the DSB-induced gene silencing. We further found two structural components within NUP107 to be necessary for the transcriptional repression at DSBs: ATM/ Ataxia telangiectasia and Rad3-related-mediated phosphorylation at the Serine37 residue within the N-terminal disordered tail and the NUP133-binding surface at the C-terminus. These results provide a functional interplay among nucleoporins, ATM, and the Polycomb proteins in the DSB metabolism and underscore their emerging roles in genome stability maintenance.}, archive = {J_PNAS}, author = {Song, Hongseon and Bae, Yubin and Kim, Sangin and Deascanis, Dante and Lee, Yujin and Rona, Gergely and Lane, Ethan and Lee, Seo-yeoung and Kim, Su-Jung and Pagano, Michele and Myung, Kyungjae and Kee, Younghoon}, doi = {10.1073/pnas.2415069122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2415069122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nucleoporins cooperate with polycomb silencers to promote transcriptional repression and repair at DNA double-strand breaks}, volume = {122}, year = {2025}, }
• (2025). Histone variant H2A.W7 represses meiotic crossover formation in arabidopsis heterochromatin. PNAS, 122(22), e2414166122. (www)

  @article{ , abstract = {In eukaryotic genomes, DNA is packaged into nucleosomes to form chromatin. The incorporation of canonical or variant histones into nucleosomes confers different properties and influences chromatin structure to regulate cellular processes, including recombination. During meiosis, DNA double-strand breaks (DSBs) are formed and repaired as interhomolog crossovers. Nucleosome occupancy is generally associated with low crossover frequency, but it remains unclear which histone variants are involved in this process. In Arabidopsis , three variants of H2A coexist: H2A.X, H2A.Z, and H2A.W. Here, we show that H2A.W7 has a suppressive role on meiotic recombination. Genome-wide mapping of the crossover landscape revealed increased centromere-proximal recombination in h2a.w7 . Moreover, H2A.W7 can be recruited to the 3a crossover hotspot via 21-24-nucleotide siRNAs during RNA-directed DNA methylation, causing increased nucleosome occupancy and decreased crossover frequency. Cytological analysis reveals that H2A.W7 restricts heterochromatin clustering during meiosis, which can form a mechanism to limit interhomolog recombination. Conversely, the linker histone H1, of which its loading is known to be restricted by H2A.W, promotes heterochromatin clustering and crossover on a heterochromatic genetic interval. Our study reveals a role for H2A.W7 in repressing crossover formation in Arabidopsis .}, archive = {J_PNAS}, author = {Kuo, Pallas and Tock, Andrew J. and Liu, Xuexia and Topp, Stephanie D. and Zhong, Zhenhui and Henderson, Ian R. and Lambing, Christophe}, doi = {10.1073/pnas.2414166122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2414166122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Histone variant H2A.W7 represses meiotic crossover formation in arabidopsis heterochromatin}, volume = {122}, year = {2025}, }
• (2025). Surface melting–driven hydrogen absorption for high-pressure polyhydride synthesis. PNAS, 122(22), e2413480122. (www)

  @article{ , abstract = {The synthesis of new polyhydrides with high superconducting T c is challenging owing to the high pressures and temperatures required. In this study, we used machine-learning potential molecular dynamics simulations to investigate the initial stage of polyhydride formation in calcium hydrides. Upon contact with high-pressure H 2 , the surface of CaH 2 melts, leading to CaH 4 formation. This surface melting proceeds via CaH 4 liquid phase as an intermediate state. High pressure reduces not only the hydrogenation (CaH 2 (s) + H 2 (l) ↔ CaH 4 (s)) enthalpy but also the enthalpy for liquid polyhydride formation (CaH 2 (s) + H 2 (l) ↔ CaH 4 (l)). Consequently, this surface melting process becomes more favorable than the fusion of the polyhydride bulk. Thus, high pressure not only shifts the equilibrium toward the polyhydride product but also lowers the activation energy, thereby promoting the hydrogenation reaction. From these thermodynamic insights, we propose structure-search criteria for polyhydride synthesis that are both computationally effective and experimentally relevant. These criteria are based on bulk properties, such as polyhydride (product) melting temperature and pressure-dependent hydrogenation enthalpy, readily determined through supplementary calculations during structure prediction workflows.}, archive = {J_PNAS}, author = {Sato, Ryuhei and Conway, Lewis J. and Zhang, Di and Pickard, Chris J. and Akagi, Kazuto and Sau, Kartik and Li, Hao and Orimo, Shin-ichi}, doi = {10.1073/pnas.2413480122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2413480122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Surface melting–driven hydrogen absorption for high-pressure polyhydride synthesis}, volume = {122}, year = {2025}, }
• (2025). A universally applicable definition for domestication. PNAS, 122(22), e2413207122. (www)

  @article{ , abstract = {The process of domestication is commonly perceived as a human achievement, and domestic species are typically assumed to be those under human control. Domestic species have emerged from a greater diversity of interactions than this perspective allows, and none of the many definitions proposed for domestication can readily, reliably, and consistently distinguish domestic and nondomestic populations. Here, we propose that the process of domestication should instead be defined solely as evolution of a nonhuman population in response to an anthropogenic niche and that a domestic population is one that cannot sustain itself outside of an anthropogenic niche. As a result, this definition does not require comparisons with a presumed and largely unobservable ancestor. Instead, it focuses on the observable relationship between a nonhuman population and humans. It also avoids making assumptions about how domestication happens, thus enabling an exploration of the mechanisms underlying the process of adaptation to an anthropogenic niche. By applying this definition to plants, animals, and microbes, we illustrate its utility for investigating the evolution of the relationship between humans and other species and for anticipating which species are likely to survive in an increasingly human-influenced world. Domestication is simply an evolutionary process resulting from the interaction between two species, one of which is human. As we work to protect Earth’s biodiversity, this definition allows us to understand why, in response to the conditions human societies create, some species survive and thrive, while others struggle and go extinct.}, archive = {J_PNAS}, author = {Lord, Kathryn A. and Larson, Greger and Allaby, Robin G. and Karlsson, Elinor K.}, doi = {10.1073/pnas.2413207122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2413207122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A universally applicable definition for domestication}, volume = {122}, year = {2025}, }
• (2025). Self-reproduction as an autonomous process of growth and reorganization in fully abiotic, artificial and synthetic cells. PNAS, 122(22), e2412514122. (www)

  @article{ , abstract = {We investigate mechanisms for the observed nonlinear growth in the number of polymer vesicles generated during a photo-Reversible Addition-Fragmentation Chain Transfer-based polymerization-induced self-assembly (PISA) reaction. Our experimental results reveal the presence of a self-reproduction process during which chemically active polymer protocells are chemically and autonomously generated in a light-stimulated one-pot reaction that starts from a homogeneous blend of non-self-assembling molecules and which, as observed microscopically, form vesicular objects that grow and multiply (reproduce) during irradiation with green light (530 nm) as the reaction proceeds. By using a filtration-based protocol, our experiments demonstrate that the self-reproduction process occurs concomitantly with the PISA process and results in a nonlinear increase in the number of polymer vesicles during photopolymerization which can only be ascribed to their reproduction via polymeric spores ejected from previously existing first-generation vesicles. The second and subsequent generations’ vesicles also self-reproduce and continue the process of population growth.}, archive = {J_PNAS}, author = {Katla, Sai Krishna and Lin, Chenyu and Pérez-Mercader, Juan}, doi = {10.1073/pnas.2412514122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2412514122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Self-reproduction as an autonomous process of growth and reorganization in fully abiotic, artificial and synthetic cells}, volume = {122}, year = {2025}, }
• (2025). Transcription-templated assembly of the nucleolus in the caenorhabditis elegans embryo. PNAS, 122(22), e2411964122. (www)

  @article{ , abstract = {The nucleolus is a multicomponent structure made of RNA and proteins that serves as the site of ribosome biogenesis within the nucleus. It has been extensively studied as a prototype of a biomolecular condensate whose assembly is driven by phase separation. While the steady-state size of the nucleolus is quantitatively accounted for by the thermodynamics of phase separation, we show that experimental measurements of the assembly dynamics are inconsistent with a simple model of a phase-separating system relaxing to its equilibrium state. Instead, we show that the dynamics are well described by a model in which the transcription of ribosomal RNA actively drives nucleolar assembly. We find that our model of active transcription-templated assembly quantitatively accounts for the rapid kinetics observed in early embryos at different developmental stages, and for different RNA interference (RNAi) perturbations of embryo size. Our model predicts a scaling of the time to assembly with the volume of the nucleus to the one-third power, which is confirmed by experimental data. Our study highlights the role of active processes such as transcription in controlling the placement and timing of assembly of membraneless organelles.}, archive = {J_PNAS}, author = {Kodan, Nishant and Hussaini, Rabeya and Weber, Stephanie C. and Kondev, Jane and Mohapatra, Lishibanya}, doi = {10.1073/pnas.2411964122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2411964122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transcription-templated assembly of the nucleolus in the caenorhabditis elegans embryo}, volume = {122}, year = {2025}, }
• (2025). High-affinity detection of biotinylated endogenous neuroligin-1 at excitatory and inhibitory synapses using a tagged knock-in mouse. PNAS, 122(22), e2411669122. (www)

  @article{ , abstract = {Neuroligins (NLGNs) are important cell adhesion molecules mediating trans-synaptic contacts between neurons. However, the high-yield biochemical isolation and visualization of endogenous NLGNs is hampered by the lack of efficient antibodies. Thus, to reveal their subcellular distribution, binding partners, and synaptic function, NLGNs were extensively manipulated using knock-down, knock-out, or overexpression approaches, leading to controversial results. As an alternative to the manipulation of NLGN expression level, we describe here the generation of a knock-in (KI) mouse strain in which native NLGN1 was N-terminally tagged with a small biotin acceptor peptide (bAP) that can be enzymatically biotinylated by the exogenous delivery of biotin ligase. After showing that KI mice exhibit normal behavior as well as similar synaptic number, ultrastructure, transmission properties, and protein expression levels when compared to wild type counterparts, we exploited the fact that biotinylated bAP-NLGN1 can be selectively isolated or visualized using high-affinity streptavidin conjugates. Using immunoblotting and immunofluorescence, we show that bAP-NLGN1 binds PSD-95 and gephyrin and populates both excitatory and inhibitory synapses, challenging the historical view that NLGN1 is exclusively localized at excitatory synapses. Using superresolution optical and electron microscopy, we further highlight that bAP-NLGN1 forms in the synaptic cleft a subset of nanodomains, which contain each a few NLGN1 dimers and whose number positively scales with the postsynapse size. Overall, our study not only provides an extensively characterized KI mouse model which will be available to the scientific community but also an unprecedented view of the nanoscale organization of endogenous NLGN1.}, archive = {J_PNAS}, author = {Ducrot, Charles and Drouet, Adèle and Tessier, Béatrice and Desquines, Chloé and Cloâtre, Tiffany and Mazouzi, Rania-Cérine and Levet, Florian and Favereaux, Alexandre and Letellier, Mathieu and Thoumine, Olivier}, doi = {10.1073/pnas.2411669122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2411669122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High-affinity detection of biotinylated endogenous neuroligin-1 at excitatory and inhibitory synapses using a tagged knock-in mouse}, volume = {122}, year = {2025}, }
• (2025). Ecological restructuring of north tethyan marine vertebrate communities triggered by the end-cretaceous extinction. PNAS, 122(22), e2409366122. (www)

  @article{ , abstract = {The ecological upheavals produced by the Cretaceous–Paleogene mass extinction event (K-Pg, −66 Ma) have been mostly studied at large scale with emphasis on clades’ diversity dynamics. How this event affected the structure of paleocommunities is comparatively less investigated, especially within large vertebrate clades like fish. Here, we quantified changes in the contribution of elasmobranchs (sharks, skates, rays) and actinopterygians (ray-finned fishes) to the fish community across the K-Pg extinction by analyzing ichthyolith (fossil teeth and denticles) abundance through time. Based on extensive sampling of 20 horizons from two outcrops spanning the K-Pg event in Austria (>4 tons of rock, >9,000 ichthyoliths), we show that the K-Pg event fostered elasmobranch abundance while reducing actinopterygian density in the Tethys Ocean. Elasmobranch ichthyolith dominance in postextinction communities is not driven by estimated local environmental change (paleobathymetry, bottom-water oxygenation) and may relate to the greater independence of this clade from lower trophic levels in their ecology and early life stages than actinopterygians. We further measured the size structure of ichthyolith assemblages and found that the K-Pg event initiated an increase in the range of ecological niche space occupied by elasmobranchs simultaneously to the demise of actinopterygians in postextinction communities. Finally, using the fine taxonomic resolution of the elasmobranch fossil record, we demonstrate that local environmental fluctuations controlled elasmobranch community structure and richness, which are decoupled from global-scale upheavals. Our results challenge previous hypotheses and provide insights into global and regional environmental forcing over the structure of fish communities across a mass extinction event.}, archive = {J_PNAS}, author = {Feichtinger, Iris and Harzhauser, Mathias and Pollerspöck, Jürgen and Auer, Gerald and Ćorić, Stjepan and Kranner, Matthias and Kallanxhi, Mădălina-Elena and Weinmann, Anna E. and Guinot, Guillaume}, doi = {10.1073/pnas.2409366122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2409366122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ecological restructuring of north tethyan marine vertebrate communities triggered by the end-cretaceous extinction}, volume = {122}, year = {2025}, }
• (2025). Micropipette aspiration reveals differential RNA-dependent viscoelasticity of nucleolar subcompartments. PNAS, 122(22), e2407423122. (www)

  @article{ , abstract = {The nucleolus is a multiphasic biomolecular condensate that facilitates ribosome biogenesis, a complex process involving hundreds of proteins and RNAs. The proper execution of ribosome biogenesis likely depends on the material properties of the nucleolus. However, these material properties remain poorly understood due to the challenges of in vivo measurements. Here, we use micropipette aspiration (MPA) to directly characterize the viscoelasticity and interfacial tensions of nucleoli within transcriptionally active Xenopus laevis oocytes. We examine the major nucleolar subphases, the outer granular component (GC) and the inner dense fibrillar component (DFC), which itself contains a third small phase known as the fibrillar center (FC). We show that the behavior of the GC is more liquid-like, while the behavior of the DFC/FC is consistent with that of a partially viscoelastic solid. To determine the role of ribosomal RNA in nucleolar material properties, we degrade RNA using RNase A, which causes the DFC/FC to become more fluid-like and alters interfacial tension. Together, our findings suggest that RNA underlies the partially solid-like properties of the DFC/FC and provide insights into how material properties of nucleoli in a near-native environment are related to their RNA-dependent function.}, archive = {J_PNAS}, author = {Cheng, Holly H. and Roggeveen, James V. and Wang, Huan and Stone, Howard A. and Shi, Zheng and Brangwynne, Clifford P.}, doi = {10.1073/pnas.2407423122}, journal = {Proceedings of the National Academy of Sciences}, month = {6}, number = {22}, pages = {e2407423122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Micropipette aspiration reveals differential RNA-dependent viscoelasticity of nucleolar subcompartments}, volume = {122}, year = {2025}, }
• (2025). Where do fish go and why? for many species, nobody knows. PNAS, 122(21), e2510827122. (www)

  @article{ , archive = {J_PNAS}, author = {McDermott, Amy}, doi = {10.1073/pnas.2510827122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2510827122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Where do fish go and why? for many species, nobody knows}, volume = {122}, year = {2025}, }
• (2025). Correction for christos et al., a model of d-wave superconductivity, antiferromagnetism, and charge order on the square lattice. PNAS, 122(21), e2510054122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2510054122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2510054122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for christos et al., a model of d-wave superconductivity, antiferromagnetism, and charge order on the square lattice}, volume = {122}, year = {2025}, }
• (2025). Correction for eggertsen et al., logic-based machine learning predicts how escitalopram attenuates cardiomyocyte hypertrophy. PNAS, 122(21), e2510011122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2510011122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2510011122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for eggertsen et al., logic-based machine learning predicts how escitalopram attenuates cardiomyocyte hypertrophy}, volume = {122}, year = {2025}, }
• (2025). Correction for masliah et al., β-amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking alzheimer’s disease and parkinson’s disease. PNAS, 122(21), e2509530122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2509530122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2509530122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for masliah et al., β-amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking alzheimer’s disease and parkinson’s disease}, volume = {122}, year = {2025}, }
• (2025). Correction for garaizar et al., toward understanding lipid reorganization in RNA lipid nanoparticles in acidic environments. PNAS, 122(21), e2509443122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2509443122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2509443122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for garaizar et al., toward understanding lipid reorganization in RNA lipid nanoparticles in acidic environments}, volume = {122}, year = {2025}, }
• (2025). Correction for fernandez velasco et al., expert navigators deploy rational complexity–based decision precaching for large-scale real-world planning. PNAS, 122(21), e2509414122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2509414122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2509414122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for fernandez velasco et al., expert navigators deploy rational complexity–based decision precaching for large-scale real-world planning}, volume = {122}, year = {2025}, }
• (2025). Reply to füller et al.: Exome-wide genetic associations with socioeconomic status and their pleiotropy among health outcomes. PNAS, 122(21), e2508030122. (www)

  @article{ , archive = {J_PNAS}, author = {Wu, Xin-Rui and Yang, Liu and Wu, Bang-Sheng and Cheng, Wei and Yu, Jin-Tai}, doi = {10.1073/pnas.2508030122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2508030122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to füller et al.: Exome-wide genetic associations with socioeconomic status and their pleiotropy among health outcomes}, volume = {122}, year = {2025}, }
• (2025). Engineered chemokines, resistant to cancer-mediated post-transcriptional modifications, as drugs to improve cancer immunotherapy. PNAS, 122(21), e2507821122. (www)

  @article{ , archive = {J_PNAS}, author = {Mandelboim, Ofer and Porgador, Angel}, doi = {10.1073/pnas.2507821122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2507821122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Engineered chemokines, resistant to cancer-mediated post-transcriptional modifications, as drugs to improve cancer immunotherapy}, volume = {122}, year = {2025}, }
• (2025). Immune perturbation by the ileal microbiota in multiple sclerosis. PNAS, 122(21), e2506777122. (www)

  @article{ , archive = {J_PNAS}, author = {Jensen, Lise Torp and Fugger, Lars}, doi = {10.1073/pnas.2506777122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2506777122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Immune perturbation by the ileal microbiota in multiple sclerosis}, volume = {122}, year = {2025}, }
• (2025). Resonant valence bond coulomb phase: From spins to phonons. PNAS, 122(21), e2506041122. (www)

  @article{ , archive = {J_PNAS}, author = {Castelnovo, Claudio}, doi = {10.1073/pnas.2506041122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2506041122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Resonant valence bond coulomb phase: From spins to phonons}, volume = {122}, year = {2025}, }
• (2025). Nonenzymatic RNA copying with a potentially primordial genetic alphabet. PNAS, 122(21), e2505720122. (www)

  @article{ , abstract = {Nonenzymatic RNA copying is thought to have been responsible for the replication of genetic information during the origin of life. However, chemical copying with the canonical nucleotides (A, U, G, and C) strongly favors the incorporation of G and C and disfavors the incorporation of A and especially U because of the stronger G:C vs. A:U base pair and the weaker stacking interactions of U. Recent advances in prebiotic chemistry suggest that the 2-thiopyrimidines were precursors to the canonical pyrimidines, raising the possibility that they may have played an important early role in RNA copying chemistry. Furthermore, 2-thiouridine (s 2 U) and inosine (I) form by deamination of 2-thiocytidine (s 2 C) and A, respectively. We used thermodynamic and crystallographic analyses to compare the I:s 2 C and A:s 2 U base pairs. We find that the I:s 2 C base pair is isomorphic and isoenergetic with the A:s 2 U base pair. The I:s 2 C base pair is weaker than a canonical G:C base pair, while the A:s 2 U base pair is stronger than the canonical A:U base pair, so that a genetic alphabet consisting of s 2 U, s 2 C, I, and A generates RNA duplexes with uniform base pairing energies. Consistent with these results, kinetic analysis of nonenzymatic template-directed primer extension reactions reveals that s 2 C and s 2 U substrates bind similarly to I and A in the template, and vice versa. Our work supports the plausibility of a potentially primordial genetic alphabet consisting of s 2 U, s 2 C, I, and A and offers a potential solution to the long-standing problem of biased nucleotide incorporation during nonenzymatic template copying.}, archive = {J_PNAS}, author = {Fang, Ziyuan and Jia, Xiwen and Xing, Yanfeng and Szostak, Jack W.}, doi = {10.1073/pnas.2505720122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2505720122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nonenzymatic RNA copying with a potentially primordial genetic alphabet}, volume = {122}, year = {2025}, }
• (2025). Genetic associations with socioeconomic status are limited in explaining the socioeconomic health gradient. PNAS, 122(21), e2505061122. (www)

  @article{ , archive = {J_PNAS}, author = {Füller, David and Sasko, Benjamin and Ritter, Oliver}, doi = {10.1073/pnas.2505061122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2505061122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genetic associations with socioeconomic status are limited in explaining the socioeconomic health gradient}, volume = {122}, year = {2025}, }
• (2025). Environmental resistome–guided development of resistance-tolerant antibiotics. PNAS, 122(21), e2504781122. (www)

  @article{ , abstract = {Failure to anticipate new forms of antibiotic resistance has led to resistance developing rapidly to virtually all antibiotics that have entered clinical use. Many of the most problematic types of resistance originated in the environment, where ancient arms races between antibiotic-producing microbes and their competitors have created vast arsenals of antibiotics and resistance. Seizing on the knowledge that resistance in nature is frequently a harbinger of future clinical resistance, we propose introducing an additional step into the antibiotic development process that exploits the susceptibility of development candidates to environmental resistance as a metric for prioritizing lead compounds and as a roadmap for their structural optimization. Using the antibiotic albicidin as a model, we show how the environmental resistome can guide the development of more resistance-tolerant leads. We used metagenomic surveys to identify resistance vulnerabilities for albicidin and guide the synthesis of analogs that evade the resistance threats. We found that natural albicidin analogs (congeners) were especially enriched in structural features that escape resistance, which inspired our syntheses and provided compelling evidence for the evolution of families of antibiotics in response to resistance in nature. The coupling of metagenomics-based resistance surveillance with structural optimizations of new antibiotics is a broadly applicable approach that is easily integrated into antibiotic development programs to generate compounds that are more resilient in the face of resistance.}, archive = {J_PNAS}, author = {Peek, James and Bhattacharjee, Abir and Burian, Ján and Hsieh, David Chun-Cheng and Hernandez, Yozen and Ternei, Melinda and Panfil, Cecilia and Brady, Sean F.}, doi = {10.1073/pnas.2504781122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2504781122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Environmental resistome–guided development of resistance-tolerant antibiotics}, volume = {122}, year = {2025}, }
• (2025). CD83 suppresses endogenous march-I-dependent MHC class II ubiquitination, endocytosis, and degradation. PNAS, 122(21), e2504077122. (www)

  @article{ , abstract = {MHC class II glycoproteins (MHC-II) bind peptides derived from exogenous antigens and dendritic cells (DCs) present these peptide MHC-II (pMHC-II) complexes to antigen-specific CD4 T cells during immune responses. The turnover of surface pMHC-II on antigen-presenting cells (APCs) is controlled by ubiquitin-mediated degradation of pMHC-II by the E3 ubiquitin ligase March-I. To study March-I protein expression, we have generated a mouse in which a V5 epitope-tag was knocked-in to the endogenous March-I gene, thereby allowing us to follow the fate of March-I using high-affinity anti-V5 antibodies. Quantitative analysis revealed that resting spleen DCs and B cells express only ~500 and 125 March-I molecules/cell, respectively. Endogenous March-I protein has a very short half-life in DCs and March-I mRNA, March-I protein, and MHC-II ubiquitination are rapidly terminated upon activation of both DCs and B cells. Like March-I, CD83 is a known regulator of MHC-II expression in APCs and we also show that CD83 suppresses endogenous March-I-dependent MHC-II ubiquitination, endocytosis, and degradation in mouse spleen DCs. Thus, our study reveals molecular mechanisms for both March-I- and CD83-dependent regulation of MHC-II expression in APCs.}, archive = {J_PNAS}, author = {Kaul, Sunil and Cole, Nelson B. and Bandola-Simon, Joanna and Lu, Ying and Tondini, Elena and Walseng, Even and Roche, Paul A.}, doi = {10.1073/pnas.2504077122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2504077122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CD83 suppresses endogenous march-I-dependent MHC class II ubiquitination, endocytosis, and degradation}, volume = {122}, year = {2025}, }
• (2025). Reply to tauzin: How to implement novelty in theory of mind tasks. PNAS, 122(21), e2503973122. (www)

  @article{ , archive = {J_PNAS}, author = {Townrow, Luke A. and Krupenye, Christopher}, doi = {10.1073/pnas.2503973122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2503973122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to tauzin: How to implement novelty in theory of mind tasks}, volume = {122}, year = {2025}, }
• (2025). AI assistance improves people’s ability to distinguish correct from incorrect eyewitness lineup identifications. PNAS, 122(21), e2503971122. (www)

  @article{ , abstract = {Mistaken eyewitness identification is one of the leading causes of false convictions. Improving law enforcement’s ability to identify correct identifications could have profound implications for criminal justice. Across two experiments, we show that AI-assistance can improve people’s ability to distinguish between accurate and inaccurate eyewitness lineup identifications. Participants (Experiment 1: N = 1,092, Experiment 2: N = 1,809) saw an eyewitness’s lineup identification, accompanied by the eyewitness’s verbal confidence statement (e.g., “I’m pretty sure”) and either a featural (“I remember his eyes”), recognition (“I remember him”), or familiarity (“He looks familiar”) justification. They then judged the accuracy of the eyewitness’s identification. AI-assistance (vs. no assistance) improved people’s ability to distinguish between correct identifications and misidentifications, but only when they evaluated lineup identifications based on recognition or featural justifications. Discrimination of identifications based on familiarity justifications showed little improvement with AI-assistance. This project is a critical step in evaluating human-algorithm interactions before widespread use of AI-assistance by law enforcement.}, archive = {J_PNAS}, author = {Kelso, Lauren E. and Dobolyi, David G. and Grabman, Jesse H. and Dodson, Chad S.}, doi = {10.1073/pnas.2503971122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2503971122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {AI assistance improves people’s ability to distinguish correct from incorrect eyewitness lineup identifications}, volume = {122}, year = {2025}, }
• (2025). The distribution of highly deleterious variants across human ancestry groups. PNAS, 122(21), e2503857122. (www)

  @article{ , abstract = {A major focus of human genetics is to map severe disease mutations. Increasingly, that goal is understood as requiring huge numbers of people to be sequenced from every broadly defined genetic ancestry group, so as not to miss “ancestry-specific variants.” Here, we consider whether this focus is warranted. We start from first principles considerations, based on models of mutation–drift-selection balance, which suggest that since severe disease mutations tend to be strongly deleterious, and thus evolutionarily young, they will be kept at relatively constant frequency through recurrent mutation. Therefore, highly pathogenic alleles should be shared identically by descent within extended families, not broad ancestry groups, and sequencing more people should yield similar numbers regardless of ancestry. We test the model predictions using gnomAD genetic ancestry groupings and show that they provide a good fit to the classes of variants most likely to be highly pathogenic, notably sets of loss of function alleles at strongly constrained genes. These findings clarify that strongly deleterious alleles will be found at comparable rates in people of all ancestries, and the information they provide about human biology is shared across ancestries.}, archive = {J_PNAS}, author = {Stolyarova, Anastasia and Coop, Graham and Przeworski, Molly}, doi = {10.1073/pnas.2503857122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2503857122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The distribution of highly deleterious variants across human ancestry groups}, volume = {122}, year = {2025}, }
• (2025). Little bites out of a big reef problem. PNAS, 122(21), e2503843122. (www)

  @article{ , archive = {J_PNAS}, author = {MacNeil, M. Aaron}, doi = {10.1073/pnas.2503843122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2503843122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Little bites out of a big reef problem}, volume = {122}, year = {2025}, }
• (2025). Calcineurin controls the cytokinesis machinery during thermal stress in cryptococcus deneoformans. PNAS, 122(21), e2503751122. (www)

  @article{ , abstract = {Calcineurin is a highly conserved phosphatase that plays a central role in sensing calcium and governing transcriptional, posttranscriptional, and posttranslational signaling networks. Calcineurin is a heterodimer consisting of a catalytic A subunit and a regulatory B subunit. Through downstream effectors, calcineurin signaling drives myriad responses in different organisms. In the fungal pathogenic Cryptococcus species complex that infects humans, calcineurin governs thermotolerance and is essential for growth at high temperature and pathogenesis. In Cryptococcus deneoformans , the underlying molecular functions of this critical signaling cascade are not well understood. In this study, we conducted a genetic screen and identified genetic changes that suppress the requirement for calcineurin during high-temperature growth. Our results identified two mechanisms that bypass the requirement for calcineurin function. The first mechanism involves segmental aneuploidy via both amplification as well as loss of chromosome fragments. The second mechanism involves dominant amino acid substitution mutations in the genes encoding three proteins, Chs6, Imp2, and Cts1, orthologs of components of the Ingression Progression Complex required for septation and budding in Saccharomyces cerevisiae . Loss of calcineurin activity causes chitin and chitosan accumulation and severe budding defects, whereas suppressor mutations largely restore growth and cytokinesis in the absence of calcineurin. These findings reveal that the calcineurin signaling cascade controls a conserved cytokinesis machinery at the mitotic exit network during thermal stress.}, archive = {J_PNAS}, author = {Yadav, Vikas and Floyd Averette, Anna and Upadhya, Rajendra and Heitman, Joseph}, doi = {10.1073/pnas.2503751122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2503751122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Calcineurin controls the cytokinesis machinery during thermal stress in cryptococcus deneoformans}, volume = {122}, year = {2025}, }
• (2025). Physical exercise activates a PVN–NAc oxytocin circuit to relieve stress-induced depressive-like behaviors. PNAS, 122(21), e2503675122. (www)

  @article{ , abstract = {Physical exercise is known to reduce depression, but the underlying brain mechanisms remain unclear. Based on a chronic restraint stress model in mice, we showed that 4-wk treadmill exercise profoundly maintained normal neural activity in the nucleus accumbens (NAc), in association with the prevention of depressive-like behaviors. Microarray analysis conducted in the NAc revealed that the oxytocin (OT) receptor displayed the most significant differential expression, implying a crucial involvement of OT signaling in exercise-induced antidepressant effects. In vivo fiber photometry revealed disrupted OT release in the NAc and altered activity of OT neurons in the paraventricular nucleus (PVN) and their projections to the NAc in stressed mice, which were restored by exercise. Moreover, we found that stress-induced depressive-like behaviors were prevented by activation of the PVN–NAc OT circuit. Additional inhibition of the PVN–NAc OT circuit blocked the antidepressant effects of exercise in stressed mice. In summary, our findings reveal a critical role of the PVN–NAc OT circuit in regulating depressive-like behaviors, which is required for the antidepressant effects of exercise. This neural circuit mechanism provides an explanation for brain network adaptations upon exercise and also suggests a promising therapeutic target for depression.}, archive = {J_PNAS}, author = {Xia, Jie and Zou, Yong and Cui, Yuqing and Zhang, Sen and Huo, Konglin and Liu, Wenbin and Huang, Zhuochun and Zhang, Qiang and Qi, Zhengtang and Liu, Weina}, doi = {10.1073/pnas.2503675122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2503675122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Physical exercise activates a PVN–NAc oxytocin circuit to relieve stress-induced depressive-like behaviors}, volume = {122}, year = {2025}, }
• (2025). Flamingos use their L-shaped beak and morphing feet to induce vortical traps for prey capture. PNAS, 122(21), e2503495122. (www)

  @article{ , abstract = {Flamingos feature one of the most sophisticated filter-feeding systems among birds, characterized by upside-down feeding, comb-like lamellae, and a piston-like tongue. However, the hydrodynamic functions of their L-shaped chattering beak, S-curved neck, and distinct behaviors such as stomping and feeding against the flow remain a mystery. Combining live flamingo experiments with live brine shrimp and passive particles, bioinspired physical models, and 3D CFD simulations, we show that flamingos generate self-induced vortical traps using their heads, beaks, and feet to capture agile planktonic prey in harsh fluid environments. When retracting their heads rapidly (~40 cm/s), flamingos generate tornado-like vortices that stir up and upwell bottom sediments and live shrimp aided by their L-shaped beak. Remarkably, they also induce directional flows (~7 cm/s) through asymmetric beak chattering underwater (~12 Hz). Their morphing feet create horizontal eddies during stomping, lifting, and concentrating sediments and brine shrimp, while trapping fast-swimming invertebrates, as confirmed by using a 3D-printed morphing foot model. During interfacial skimming, flamingos produce a vortical recirculation zone at the beak’s tip, aiding in prey capture. Experiments using a flamingo-inspired particle collection system indicate that beak chattering improves capture rates by ~7×. These findings offer design principles for bioinspired particle collection systems that may be applied to remove pollutants and harmful microorganisms from water bodies.}, archive = {J_PNAS}, author = {Ortega-Jimenez, Victor M. and Yee, Tien and Rohilla, Pankaj and Seleb, Benjamin and Belair, Jake and Bhamla, Saad}, doi = {10.1073/pnas.2503495122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2503495122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Flamingos use their L-shaped beak and morphing feet to induce vortical traps for prey capture}, volume = {122}, year = {2025}, }
• (2025). Communicative mentalization is limited in nonhuman great apes. PNAS, 122(21), e2503448122. (www)

  @article{ , archive = {J_PNAS}, author = {Tauzin, Tibor}, doi = {10.1073/pnas.2503448122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2503448122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Communicative mentalization is limited in nonhuman great apes}, volume = {122}, year = {2025}, }
• (2025). Arteries are finely tuned thermosensors regulating myogenic tone and blood flow. PNAS, 122(21), e2503186122. (www)

  @article{ , abstract = {In response to changing blood pressure, arteries adjust their caliber to control blood flow. This vital autoregulatory property, termed vascular myogenic tone, stabilizes downstream capillary pressure. Here, we reveal that tissue temperature, combined with intraluminal pressure, critically determines myogenic tone. Heating steeply activates tone in skeletal muscle, gut, brain, and skin arteries with temperature coefficients ( Q 10 ) of ~11 to 20. Each of these tissues has a distinct resting temperature, and we find that arterial thermosensitivity is tuned to this temperature, making myogenic tone sensitive to small thermal fluctuations. Interestingly, temperature and intraluminal pressure are sensed largely independently and the signals integrated to trigger myogenic tone. We demonstrate that thermosensitive channels TRPV1 and TRPM4 mediate heat-induced tone in skeletal muscle arteries with discrete temperature sensitivities. Similarly, TRPM4 contributes to heat-induced tone in gut and brain arteries. The half-maximal responses occur at approximately 31 °C for TRPV1 and 33 °C for TRPM4. Variations in tissue temperature are known to alter blood fluidity and therefore vascular conductance; remarkably, thermosensitive tone counterbalances this effect, thus protecting capillary integrity and fluid balance. In conclusion, thermosensitive myogenic tone is a fundamental homeostatic mechanism regulating tissue perfusion.}, archive = {J_PNAS}, author = {Phan, Thieu X. and Sahibzada, Niaz and Freichel, Marc and Miyares, Rosa L. and Ahern, Gerard P.}, doi = {10.1073/pnas.2503186122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2503186122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Arteries are finely tuned thermosensors regulating myogenic tone and blood flow}, volume = {122}, year = {2025}, }
• (2025). Stathmin-2 enhances motor axon regeneration after injury independent of its binding to tubulin. PNAS, 122(21), e2502294122. (www)

  @article{ , abstract = {Stathmin-2 (also known as SCG10 ) is encoded by the STMN2 gene, whose mRNA is one of the most abundantly expressed in human motor neurons. In almost all instances of ALS and other TDP-43 proteinopathies, stathmin-2 encoding mRNAs are cryptically spliced and polyadenylated in motor neurons, a pathogenic consequence of nuclear loss of function of the RNA binding protein TDP-43. While stathmin-2 has been shown to enhance regeneration after axonal injury to axons of cultured motor neurons, here, we show that after crush injury within the adult murine nervous system of wild-type or stathmin-2-null mice, the presence of stathmin-2 reduces axonal and neuromuscular junction degeneration and stimulates reinnervation and functional recovery. Mechanistically, although stathmin-2 has been proposed to function through direct binding to α/β tubulin heterodimers and correspondingly to affect microtubule assembly and dynamics, stathmin-2’s role in axon regeneration after axotomy is shown to be independent of its tubulin binding abilities.}, archive = {J_PNAS}, author = {Beccari, Melinda S. and Arnold-Garcia, Olatz and Baughn, Michael W. and Artates, Jonathan W. and McAlonis-Downes, Melissa and Lim, Jaisen and Leyva-Cázares, Dulce Fernanda and Rubio-Lara, Hugo Isaac and Ramirez-Rodriguez, Andrea and Bernal-Buenrostro, Carol N. and Murgia-Bay, Brian and Rangel, Carolina K. and Kim, Dong Hyun and Melamed, Ze’ev and Lutz, Cathleen M. and Lagier-Tourenne, Clotilde and Corbett, Kevin D. and López-Erauskin, Jone and Cleveland, Don W.}, doi = {10.1073/pnas.2502294122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2502294122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stathmin-2 enhances motor axon regeneration after injury independent of its binding to tubulin}, volume = {122}, year = {2025}, }
• (2025). Knowledge of politician stock trading reduces congressional legitimacy and compliance with the law. PNAS, 122(21), e2501822122. (www)

  @article{ , abstract = {Institutional legitimacy is essential for democracies, yet public trust and confidence in the United States Congress are at an all-time low. A significant predictor of attitudes toward Congress is perceptions of corruption, with perceptions of corruption in government linked to less legitimacy. This study tests whether knowledge of Congressional stock trading affects legitimacy and compliance with Congressional authority. In a preregistered experiment with US citizens ( n = 506), participants who read a report detailing how Congressmembers made higher-than-expected profits from stock trading in 2024 reported increased perceptions of corruption and decreased legitimacy in Congress. They also viewed laws passed by Congress as less fair and were less willing to comply with such laws. Perceptions of Congressional legitimacy mediated the effect of stock trading knowledge on willingness to comply with congressional laws and perceptions of congressional laws as fair. A preregistered follow-up experiment ( n = 664) shows that these effects are not driven by how much Congressmembers profit but by how trading negatively affects broader perceptions of legitimacy. These findings highlight the detrimental effects of Congressional stock trading on perceptions of legitimacy and respect for the law.}, archive = {J_PNAS}, author = {Alam, Raihan and Rai, Tage S.}, doi = {10.1073/pnas.2501822122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2501822122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Knowledge of politician stock trading reduces congressional legitimacy and compliance with the law}, volume = {122}, year = {2025}, }
• (2025). Food rx: Integrating horticulture research to improve nutrition and health. PNAS, 122(21), e2501723122. (www)

  @article{ , abstract = {It is clear that the escalating epidemic of insulin resistance and type 2 diabetes has reached a crisis level in the United States, that overweight and obesity are drivers, and that diets and the food system have major roles. It is also clear that nutrition and medical research point to increased healthful fruit and vegetable intake as a key part of any strategy to manage the crisis. But although increasing healthful intake entails both expanding production of fruits and vegetables and improving their healthful characteristics, horticulture has generally been sidelined or taken for granted when strategies are envisioned. This article makes the case that horticulture research and practice can and should be equal partners with nutrition and medicine in the pressing search for effective crisis-management strategies. To do so, it first “runs the numbers” for the scale of the crisis, for trends in fruit and vegetable intake and production, for the scant federal support for horticultural crop production and research, and for horticulture research’s high return on investment. The article then sketches a roadmap to integrate horticulture research and community outreach with nutrition and healthcare, stressing new opportunities. The goal is a US food system that i) makes healthful fruits and vegetables accessible, affordable, and appealing for all and ii) complements a healthcare system spanning patient-based to population-based nutrition.}, archive = {J_PNAS}, author = {Gunter, Christopher C. and Treadwell, Danielle D. and Resende, Marcio F. R. and Whitaker, Vance M. and Balmant, Kelly M. and Shelnutt, Karla P. and Borum, Peggy R. and Andrade, Juan E. and Goodrich-Schneider, Renée and Bernier, Angelina V. and Donahoo, William T. and Jaffee, Michael S. and Angle, J. Scott and Hanson, Andrew D.}, doi = {10.1073/pnas.2501723122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2501723122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Food rx: Integrating horticulture research to improve nutrition and health}, volume = {122}, year = {2025}, }
• (2025). Cross-reactive sarbecovirus antibodies induced by mosaic RBD nanoparticles. PNAS, 122(21), e2501637122. (www)

  @article{ , abstract = {Broad immune responses are needed to mitigate viral evolution and escape. To induce antibodies against conserved receptor-binding domain (RBD) regions of SARS-like betacoronavirus (sarbecovirus) spike proteins that recognize SARS-CoV-2 variants of concern and zoonotic sarbecoviruses, we developed mosaic-8b RBD nanoparticles presenting eight sarbecovirus RBDs arranged randomly on a 60-mer nanoparticle. Mosaic-8b immunizations protected animals from challenges from viruses whose RBDs were matched or mismatched to those on nanoparticles. Here, we describe neutralizing mAbs isolated from mosaic-8b-immunized rabbits, some on par with Pemgarda, the only currently FDA-approved therapeutic mAb. Deep mutational scanning, in vitro selection of spike resistance mutations, and single-particle cryo-electron microscopy structures of spike–antibody complexes demonstrated targeting of conserved RBD epitopes. Rabbit mAbs included critical D-gene segment RBD-recognizing features in common with human anti-RBD mAbs, despite rabbit genomes lacking an equivalent human D-gene segment, thus demonstrating that the immune systems of humans and other mammals can utilize different antibody gene segments to arrive at similar modes of antigen recognition. These results suggest that animal models can be used to elicit anti-RBD mAbs with similar properties to those raised in humans, which can then be humanized for therapeutic use, and that mosaic RBD nanoparticle immunization coupled with multiplexed screening represents an efficient way to generate and select broadly cross-reactive therapeutic pan-sarbecovirus and pan-SARS-CoV-2 variant mAbs.}, archive = {J_PNAS}, author = {Fan, Chengcheng and Keeffe, Jennifer R. and Malecek, Kathryn E. and Cohen, Alexander A. and West, Anthony P. and Baharani, Viren A. and Rorick, Annie V. and Gao, Han and Gnanapragasam, Priyanthi N. P. and Rho, Semi and Alvarez, Jaasiel and Segovia, Luisa N. and Hatziioannou, Theodora and Bieniasz, Paul D. and Bjorkman, Pamela J.}, doi = {10.1073/pnas.2501637122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2501637122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cross-reactive sarbecovirus antibodies induced by mosaic RBD nanoparticles}, volume = {122}, year = {2025}, }
• (2025). Loss of insulin signaling in microglia impairs cellular uptake of aβ and neuroinflammatory response exacerbating AD-like neuropathology. PNAS, 122(21), e2501527122. (www)

  @article{ , abstract = {Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimer’s disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in the brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprogramming with an increase in glycolysis and impaired uptake of Aβ. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of Aβ plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism and the ability of the cells to take up Aβ, such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together, these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.}, archive = {J_PNAS}, author = {Chen, Wenqiang and Liu, Xiangyu and Muñoz, Vitor Rosetto and Kahn, C. Ronald}, doi = {10.1073/pnas.2501527122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2501527122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Loss of insulin signaling in microglia impairs cellular uptake of aβ and neuroinflammatory response exacerbating AD-like neuropathology}, volume = {122}, year = {2025}, }
• (2025). Mechanisms of photoreceptor protection upon targeting the Nrl–Nr2e3 pathway. PNAS, 122(21), e2500446122. (www)

  @article{ , abstract = {Acute knockout of the rod photoreceptor transcription factor Nrl delays retinal degeneration in multiple mouse models of blindness, but the downstream transcriptomic changes that mediate these therapeutic effects are unknown. Here, we show that acute Nrl knockout causes upregulation of a subset of cone genes in rods as well as downregulation of rod genes, including the rod-specific transcriptional repressor Nr2e3 . We hypothesized that Nr2e3 downregulation might mediate some of the therapeutic effects of Nrl knockout. Indeed, acute knockout of Nr2e3 prevents photoreceptor degeneration and preserves visual function in mice with mutations in the catalytic subunit of the rod-specific phosphodiesterase ( Pde6b rd10/rd10 ). Upregulation of Pde6c , the cone-specific paralog of Pde6b , in Nr2e3 -knockout rods is required to prevent degeneration in Pde6b rd10/rd10 mice, suggesting that this therapeutic effect is mediated, at least in part, by a gene-replacement mechanism. In contrast, acute Nr2e3 knockout fails to prevent degeneration caused by loss- or gain-of-function mutations in Rhodopsin ( Rho −/− and Rho P23H/P23H ), whereas acute Nrl knockout delays degeneration in both models. Surprisingly, the therapeutic effect of acute Nrl knockout in Pde6b rd10/rd10 mice does not depend on Pde6c upregulation. These results suggest that acute Nrl knockout may exert its therapeutic effects via a mechanism independent of Nr2e3 downregulation, perhaps by downregulating other rod genes. We conclude that acute NRL knockout may be a promising gene-independent strategy for preventing photoreceptor degeneration in human patients.}, archive = {J_PNAS}, author = {Murphy, Daniel P. and Kolesnikov, Alexander V. and Montana, Cynthia L. and Khaja, Zaid M. and Liu, Yu and Kefalov, Vladimir J. and Corbo, Joseph C.}, doi = {10.1073/pnas.2500446122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2500446122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mechanisms of photoreceptor protection upon targeting the Nrl–Nr2e3 pathway}, volume = {122}, year = {2025}, }
• (2025). Autophagy-mediated downregulation of AXL and TIM-1 promotes sustained zika virus infection. PNAS, 122(21), e2427241122. (www)

  @article{ , abstract = {Zika virus (ZIKV) infection can lead to a variety of clinical outcomes, including severe congenital abnormalities. The phosphatidylserine receptors AXL and TIM-1 are recognized as critical entry factors for ZIKV in vitro. However, it remains unclear whether and how ZIKV regulates these receptors during infection. In this study, we investigated AXL and TIM-1 expression in human lung adenocarcinoma epithelial A549 cells, glioblastoma U87 cells, and embryonic stem cell-derived trophoblasts following ZIKV infection. We found that both the Asian strain FSS13025 and the African strain MR766 of ZIKV downregulate AXL, with a milder effect on TIM-1. We identified several ZIKV proteins, notably envelope (E), NS2A, NS3, and NS4B, that contribute to this downregulation. Notably, treatment with lysosomal inhibitor NH 4 Cl or the autophagy inhibitor 3-methyladenine mitigated the AXL/TIM-1 downregulation, indicating autophagy’s involvement in the process. Importantly, this downregulation facilitates sustained viral replication and promotes viral spread by preventing superinfection and limiting cell death, which is also associated with impaired innate immune signaling. Our findings uncover a mechanism by which ZIKV downregulates entry factors to enhance prolonged viral replication and spread.}, archive = {J_PNAS}, author = {Yu, Jingyou and Zheng, Yi-Min and Sheridan, Megan A. and Li, Pei and Ezashi, Toshihiko and Roberts, R. Michael and Liu, Shan-Lu}, doi = {10.1073/pnas.2427241122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2427241122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Autophagy-mediated downregulation of AXL and TIM-1 promotes sustained zika virus infection}, volume = {122}, year = {2025}, }
• (2025). The GRAS protein RAM1 interacts with WRI transcription factors to regulate plant genes required for arbuscule development and function. PNAS, 122(21), e2427021122. (www)

  @article{ , abstract = {During arbuscular mycorrhiza (AM) symbiosis AM fungi form tree-shaped structures called arbuscules in root cortex cells of host plants. Arbuscules and their host cells are central for reciprocal nutrient exchange between the symbionts. REQUIRED FOR ARBUSCULAR MYCORRHIZATION1 ( RAM1 ) encodes a GRAS protein crucial for transcriptionally regulating plant genes needed for arbuscule development and nutrient exchange. Similar to other GRAS proteins, RAM1 likely does not bind to DNA and how RAM1 activates its target promoters remained elusive. Here, we demonstrate that RAM1 interacts with five AM-induced APETALA 2 (AP2) transcription factors of the WRINKLED1-like family called CTTC MOTIF-BINDING TRANSCRIPTION FACTOR1 (CBX1), WRI3, WRI5a, WRI5b, and WRI5c via a C-terminal domain containing the M2/M2a motif. This motif is conserved and enriched in WRI proteins encoded by genomes of AM-competent plants. RAM1 together with any of these WRI proteins activates the promoters of genes required for symbiotic nutrient exchange, namely RAM2 , STUNTED ARBUSCULES (STR), and PHOSPHATE TRANSPORTER 4 (PT4) , in Nicotiana benthamiana leaves. This activation as well as target promoter induction in Lotus japonicus hairy roots depends on MYCS ( MYCORRHIZA SEQUENCE )-elements and AW -boxes, previously identified as WRI-binding sites. The WRI genes are activated in two waves: Transcription of RAM1 , CBX1, and WRI3 is coregulated by calcium- and calmodulin-dependent protein kinase-activated CYCLOPS, through the AMCYC-RE in their promoter, and DELLA, while WRI5a , b, and c promoters contain MYCS -elements and AW -boxes and can be activated by RAM1 heterocomplexes with CBX1 or WRI3. We propose that RAM1 provides an activation domain to DNA-binding WRI proteins to activate genes with central roles in AM development and function.}, archive = {J_PNAS}, author = {Paries, Michael and Hobecker, Karen and Hernandez Luelmo, Sofia and Binci, Filippo and Guercio, Angelica and Usländer, Annika and Cardoso, Catarina and Si, Yang and Wankner, Lotta and Bashyal, Sagar and Troycke, Philip and Brückner, Franziska and Pimprikar, Priya and Shabek, Nitzan and Gutjahr, Caroline}, doi = {10.1073/pnas.2427021122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2427021122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The GRAS protein RAM1 interacts with WRI transcription factors to regulate plant genes required for arbuscule development and function}, volume = {122}, year = {2025}, }
• (2025). Macrophages release neuraminidase and cleaved calreticulin for programmed cell removal. PNAS, 122(21), e2426644122. (www)

  @article{ , abstract = {Calreticulin (CALR) is primarily an endoplasmic reticulum chaperone protein that also plays a key role in facilitating programmed cell removal (PrCR) by acting as an “eat-me” signal for macrophages, directing their recognition and engulfment of dying, diseased, or unwanted cells. Recent findings have demonstrated that macrophages can transfer their own CALR onto exposed asialoglycans on target cells, marking them for PrCR. Despite the critical role CALR plays in this process, the molecular mechanisms behind its secretion by macrophages and the formation of binding sites on target cells remain unclear. Our findings show that CALR undergoes C-terminal cleavage upon secretion, producing a truncated form that functions as the active eat-me signal detectable on target cells. We identify cathepsins as potential proteases involved in this cleavage process. Furthermore, we demonstrate that macrophages release neuraminidases, which modify the surface of target cells and facilitate CALR binding. These insights reveal a coordinated mechanism through which lipopolysaccharide (LPS)-activated macrophages regulate CALR cleavage and neuraminidase activity to mark target cells for PrCR. How they recognize the cells to be targeted remains unknown.}, archive = {J_PNAS}, author = {Banuelos, Allison and Baez, Michelle and Zhang, Allison and Yılmaz, Leyla and Kasberg, William and Volk, Regan and Georgeos, Nardin and Koren-Sedova, Elle and Le, Uyen and Burden, Andrew T. and Marjon, Kristopher D. and Lippincott-Schwartz, Jennifer and Zaro, Balyn W. and Weissman, Irving L.}, doi = {10.1073/pnas.2426644122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2426644122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Macrophages release neuraminidase and cleaved calreticulin for programmed cell removal}, volume = {122}, year = {2025}, }
• (2025). Activation dynamics of ubiquitin-specific protease 7. PNAS, 122(21), e2426632122. (www)

  @article{ , abstract = {Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme that plays a crucial role in cellular processes, including the maintenance of genome stability and regulation of antiviral and immune responses. Its dysfunction is linked to various cancers and neurodevelopmental disorders such as Hao-Fountain syndrome. Unlike other USP-family enzymes, the triad of catalytic residues in USP7 adopts an inactive conformation and undergoes rearrangement into the active state upon substrate binding. Despite its potential importance for regulating the enzyme’s activity, the dynamics of USP7 have not been explored. In this study, we combine advanced CPMG NMR relaxation dispersion measurements with the analysis of enzyme kinetics to investigate the conformational dynamics of USP7 in solution and its role in enzyme activation. Our results suggest that apo-USP7 exists in a dynamic equilibrium, transiently switching between inactive and low-populated active conformations, indicating that enzyme activation can occur spontaneously, even in the absence of a substrate. Furthermore, we show that the Hao-Fountain syndrome-associated variant G392D enhances the conformational dynamics of the enzyme, leading to a significant increase in its catalytic activity. This study captures the sparsely populated, "invisible" active conformation of USP7 and demonstrates how changes in enzyme dynamics can contribute to activity, offering broader insights into enzyme function and disease mechanisms.}, archive = {J_PNAS}, author = {Valles, Gabrielle J. and Korchak, Emilie J. and Geddes-Buehre, Dane H. and Jaiswal, Nancy and Korzhnev, Dmitry M. and Bezsonova, Irina}, doi = {10.1073/pnas.2426632122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2426632122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Activation dynamics of ubiquitin-specific protease 7}, volume = {122}, year = {2025}, }
• (2025). Ultraviolet and biological effective dose observations at gale crater, mars. PNAS, 122(21), e2426611122. (www)

  @article{ , abstract = {The incident ultraviolet (UV) irradiance on the surface of Mars is strongly sterilizing and plays a critical role in atmospheric and near-surface photochemistry. The Rover Environmental Monitoring Station (REMS) instrument, which includes the first UV sensor sent to Mars on board the Curiosity rover, has been measuring the UV irradiance at Gale Crater since 2012, providing ground-truth data regarding seasonal and short-term variability of the UV radiation at the surface of another planet. Here, we analyze the REMS UV measurements for a period of >5 Martian years to retrieve biological effective doses and other UV radiation quantities on the planetary surface that are key for different physicochemical processes. Our results reveal a previously unidentified complex UV radiation environment on the Martian surface, with dramatic short-term fluctuations capable of changing UV radiation doses by >30% in a few sols. We assess the viability of terrestrial microorganisms exposed to this UV radiation field and dispersed through the Martian atmosphere from a robotic spacecraft or human habitat. Our findings show that reducing microbial viability by 99% would require several hours of exposure to the Martian environment including during the daytime, a finding that may call for a reinforcement of planetary protection policies.}, archive = {J_PNAS}, author = {Viúdez-Moreiras, Daniel and Zorzano, Maria-Paz and Lemmon, Mark T. and Fairén, Alberto G. and Saiz-Lopez, Alfonso and Smith, Michael D.}, doi = {10.1073/pnas.2426611122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2426611122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ultraviolet and biological effective dose observations at gale crater, mars}, volume = {122}, year = {2025}, }
• (2025). Multiparametric functional characterization of individual lipid nanoparticles using surface-sensitive light-scattering microscopy. PNAS, 122(21), e2426601122. (www)

  @article{ , abstract = {The most efficient lipid nanoparticles (LNPs) for gene therapeutics rely on specific lipids that protect the oligonucleotide cargo and aid cellular uptake and subsequent endosomal escape. Yet, the efficacy of current state-of-the-art LNP formulations remains low, a few percent at best. A deeper understanding of how LNP cargo, lipid composition, stoichiometry, size, structure, and pH-induced conformational changes influence their efficiency is therefore necessary for improved design. Given the variability of these properties, preferred screening methods should offer single-particle-resolved multiparametric characterization. In this work, we employ combined surface-sensitive fluorescence and label-free scattering microscopy with single LNP resolution, which when integrated with microfluidics for liquid exchange between media of varying refractive index, enables quantification of LNP size, refractive index, and cargo content. We investigate two LNP formulations that, while similar in size and mRNA content, exhibit differences in functional mRNA delivery. Correlating size with the content of Cy5-labeled mRNA revealed that the cargo scaled with LNP volume for both types of LNPs, while the refractive index varied marginally across LNP size. While this multiparametric fingerprinting alone could not distinguish the two LNP formulations, we use the same experimental platform to show that their difference in fusogenicity to a supporting lipid bilayer under early endosomal conditions (drop in pH from 7.4 to 6.0) correlates with observed differences in in vitro cellular data. This highlights a limitation of the current state-of-the-art toolbox for in situ LNP characterization, which generally focuses on structural properties of suspended LNPs, which may not adequately capture functional performance.}, archive = {J_PNAS}, author = {Sjöberg, Mattias and Olsén, Erik and Mapar, Mokhtar and Parkkila, Petteri and Niederkofler, Simon and Mohammadi, Sara and Jing, Yujia and Emilsson, Gustav and Lindfors, Lennart and Agnarsson, Björn and Höök, Fredrik}, doi = {10.1073/pnas.2426601122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2426601122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multiparametric functional characterization of individual lipid nanoparticles using surface-sensitive light-scattering microscopy}, volume = {122}, year = {2025}, }
• (2025). Stability of general cognitive ability from infancy to adulthood: A combined twin and genomic investigation. PNAS, 122(21), e2426531122. (www)

  @article{ , abstract = {Measures of general cognitive ability (GCA) are highly stable from adolescence onward, particularly at the level of genetic influences. In contrast, measurement of GCA in early life (before 3 y old) is less reliable and less is known about the stability of GCA across this period, including its relation to adult GCA. Using data from the Colorado Longitudinal Twin study (N = 1,098), we examined the stability of GCA measures across 5 time-points (years 1 to 2, 3, 7, 16, and 29), including how an array of cognitive measures given at 7 and 9 mo relate to later GCA. We then examined the genetic and environmental stability of GCA across the first 30 y of life using complementary methods: twin analyses and polygenic scores (PGSs). Two infant cognition measures, object novelty and tester-rated task orientation, predicted GCA in adulthood ( r = 0.16 and 0.18, respectively). Correlational analyses were consistent with a pattern of increasing stability across development for GCA measures between year 1 to 2 and adulthood ( r = 0.39 to 0.85). Subsequent twin analyses revealed that 22% of variance in adulthood GCA was captured by genetic influences on GCA from year 3 or earlier, with an additional 10% explained by shared environmental influences on GCA at year 1 to 2. PGSs for adulthood GCA and educational attainment predicted GCA from 1 to 2 y onward ( β s = 0.09 to 0.44) but not infant cognition. Findings suggest that genetic and environmental influences on GCA demonstrate considerable stability as early as age 3 y, but that measures of infant cognition are less predictive of later cognitive ability.}, archive = {J_PNAS}, author = {Gustavson, Daniel E. and Borriello, Giulia A. and Karhadkar, Mohini A. and Rhee, Soo Hyun and Corley, Robin P. and Rhea, Sally-Ann and DiLalla, Lisabeth F. and Wadsworth, Sally J. and Friedman, Naomi P. and Reynolds, Chandra A.}, doi = {10.1073/pnas.2426531122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2426531122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stability of general cognitive ability from infancy to adulthood: A combined twin and genomic investigation}, volume = {122}, year = {2025}, }
• (2025). Experimental and theoretical evidence of universality in superfluid vortex reconnections. PNAS, 122(21), e2426064122. (www)

  @article{ , abstract = {The minimum separation between reconnecting vortices in fluids and superfluids obeys a universal scaling law with respect to time. The prereconnection and the postreconnection prefactors of this scaling law are different, a property related to irreversibility and to energy transfer and dissipation mechanisms. In the present work, we determine the temperature dependence of these prefactors in superfluid helium from experiments and a numeric model which fully accounts for the coupled dynamics of the superfluid vortex lines and the thermal normal fluid component. At all temperatures, we observe a pre- and postreconnection asymmetry similar to that observed in other superfluids and in classical viscous fluids, indicating that vortex reconnections display a universal behavior independent of the small-scale regularizing dynamics. We also numerically show that each vortex reconnection event represents a sudden injection of energy in the normal fluid. Finally we argue that in a turbulent flow, these punctuated energy injections can sustain the normal fluid in a perturbed state, provided that the density of superfluid vortices is large enough.}, archive = {J_PNAS}, author = {Stasiak, Piotr Z. and Xing, Yiming and Alihosseini, Yousef and Barenghi, Carlo F. and Baggaley, Andrew and Guo, Wei and Galantucci, Luca and Krstulovic, Giorgio}, doi = {10.1073/pnas.2426064122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2426064122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Experimental and theoretical evidence of universality in superfluid vortex reconnections}, volume = {122}, year = {2025}, }
• (2025). A direct computational assessment of vinculin–actin unbinding kinetics reveals catch-bonding behavior. PNAS, 122(21), e2425982122. (www)

  @article{ , abstract = {Vinculin forms a catch bond with the cytoskeletal polymer actin, displaying an increased bond lifetime upon force application. Notably, this behavior depends on the direction of the applied force, which has significant implications for cellular mechanotransduction. In this work, we present a comprehensive molecular dynamics simulation study, employing enhanced sampling techniques to investigate the thermodynamic, kinetic, and mechanistic aspects of this phenomenon at physiologically relevant forces. We dissect a catch bond mechanism in which force shifts vinculin between either a weakly or strongly bound state. Our results demonstrate that models for these states have unbinding times consistent with those from single-molecule studies, and suggest that both have some intrinsic catch-bonding behavior. We provide atomistic insight into this behavior, and show how a directional pulling force can promote the strong or weak state. Crucially, our strategy can be extended to measure the difficult-to-capture effects of small mechanical forces on biomolecular systems in general, and those involved in mechanotransduction more specifically.}, archive = {J_PNAS}, author = {Peña Ccoa, Willmor J. and Mukadum, Fatemah and Ramon, Aubin and Stirnemann, Guillaume and Hocky, Glen M.}, doi = {10.1073/pnas.2425982122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2425982122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A direct computational assessment of vinculin–actin unbinding kinetics reveals catch-bonding behavior}, volume = {122}, year = {2025}, }
• (2025). Trait-space patterning is dictated by the tempo and mode of mutation. PNAS, 122(21), e2425607122. (www)

  @article{ , abstract = {In large, natural ecosystems, many ( ≳ 1) phenotypically relevant mutants can emerge over the characteristic turnover time of the population. When this is the case, there can be ‘eco-evolutionary feedback’ between the dynamical processes that underlie mutation, selection and ecology. We show that, owing to such feedback, the precise details of the mutational process can have a qualitative impact on the long-term behavior of an eco-evolutionary system, in contrast to the classical population genetic assumption that all mutations can be modeled with an effective, homogeneous rate. We demonstrate this in the context of a version of MacArthur’s consumer-resource model in which consumers mutate along a resource preference trait-space. Starting from a stochastic individual-based model, we simulate the system in the case where mutations are exogenously generated at a fixed rate (e.g. via external mutagens) and in the case where mutations are coupled to replication (e.g. via DNA copying errors). We find that, surprisingly, replication-coupled mutations are capable of generating a patterned phase in the limit of fast ecological relaxation – precisely the regime where classical population genetic models are expected to operate. We derive a mean-field description of the stochastic model and show that the patterned phase comes about due to a Turing-like mechanism driven by the non-reciprocal and nonlinear nature of replicative mutations. Furthermore, we show that additional interactions like those due to host defense mechanisms can extend the patterned regime to arbitrarily high dimensional phenotype spaces. We demonstrate that these results are robust to demographic noise and model choices and we discuss systems in which this phenomenology might be relevant.}, archive = {J_PNAS}, author = {Martis, Stephen and Schwab, David J. and GrandPre, Trevor}, doi = {10.1073/pnas.2425607122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2425607122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Trait-space patterning is dictated by the tempo and mode of mutation}, volume = {122}, year = {2025}, }
• (2025). Partner dependency alters patterns of coevolutionary selection in mutualisms. PNAS, 122(21), e2424983122. (www)

  @article{ , abstract = {Coevolution is a ubiquitous driver of diversification in both mutualistic and antagonistic interactions between species. In mutualisms, coevolution can result in trait complementarity between partners that facilitates their persistence. Despite its importance, most of what we know about coevolution in mutualism comes from obligate interactions, whereas we know comparatively little about facultative interactions, arguably the most common type of mutualism. To evaluate coevolutionary dynamics in facultative mutualism and test how it compares with obligate mutualisms, we used a synthetic yeast mutualism where the partners exchange essential nutrient resources. We manipulated mutualism dependency by controlling the availability of mutualistic resources in the environment and measured coevolution via time-shift assays and tracking the evolution of mutualistic traits over time. In addition, we genotyped the evolved and ancestral mutualists to test for differences in the strength of coevolutionary selection between facultative and obligate mutualisms. We found evidence of coevolution in both facultative and obligate mutualisms, but coevolution was weaker and slower in facultative mutualisms. We also found evidence for evolution of trait complementarity in obligate mutualisms but not in facultative mutualisms. Furthermore, obligate mutualists had more SNPs under positive selection than facultative mutualists. Together, these results provide strong evidence that mutualism dependency impacts both the strength of coevolution and the rate of trait evolution.}, archive = {J_PNAS}, author = {Vidal, Mayra C. and Liu, Cong and Wang, Shengpei and Segraves, Kari A.}, doi = {10.1073/pnas.2424983122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2424983122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Partner dependency alters patterns of coevolutionary selection in mutualisms}, volume = {122}, year = {2025}, }
• (2025). Framework to identify innovative sources of value creation from platform technologies. PNAS, 122(21), e2424665122. (www)

  @article{ , abstract = {Platform technologies are fundamentally reshaping the pharmaceutical industry, offering unprecedented potential for innovation across multiple therapeutic areas. However, traditional valuation models, focused on single-asset metrics, struggle to capture the full spectrum of value these technologies create. This paper presents a comprehensive framework for evaluating the innovative sources of value creation enabled by platform technologies throughout the drug development lifecycle. Through a systematic literature review, in-depth case studies, and framework development, we provide a structured methodology for capturing the diverse benefits of these technologies. Our findings reveal that platform technologies generate value across strategic, technical, and adaptive dimensions, requiring a multifaceted valuation approach. The proposed Platform Value Identification across Strategic, Technical, and Adaptive domains Framework defines key value drivers, specifies quantitative assessment metrics, and provides implementation guidance to inform strategic decision-making in research and development investment, portfolio management, and business development. Application of the framework to case studies of Alnylam’s RNAi platform, Genentech’s therapeutic antibody platform, and Moderna’s mRNA platform demonstrates its broad utility and impact potential. By adopting this holistic, data-driven approach, stakeholders can better assess the long-term value and competitive advantages of well-implemented platform technologies, accelerating the development of transformative therapies for patients.}, archive = {J_PNAS}, author = {Jones, Charles H. and Beitelshees, Marie and Hill, Andrew and Griffiths, Dean and Murphy, Matthew and Kapadia, Ketan and Dolsten, Mikael and True, Jane M.}, doi = {10.1073/pnas.2424665122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2424665122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Framework to identify innovative sources of value creation from platform technologies}, volume = {122}, year = {2025}, }
• (2025). Physical activity stimulates clock neurons of the day-active rodent arvicanthis ansorgei. PNAS, 122(21), e2424545122. (www)

  @article{ , abstract = {Our biological clock, located in the suprachiasmatic nucleus (SCN), controls behavioral activity rhythms by producing circadian rhythms in SCN electrical activity. Behavioral studies in humans suggest that the clock is sensitive not only to light but also to physical activity. Here, we examined the effect of physical activity on the brain’s clock in the diurnal rodent, Arvicanthis ansorgei . We found that the electrical activity of SCN neurons in vitro is high during the day and low during the night. Recordings via stationary microelectrodes in freely moving Arvicanthis revealed that the SCN baseline rhythm in discharge was superimposed by increments in electrical activity. These increments in electrical activity occurred during brief (seconds) or long (hours) periods of spontaneous activity of the animal and were observed at each phase of the cycle, i.e., both day and night. To establish the causal relation, we manipulated the animal’s activity by providing it with a running wheel. The voluntary use of the wheel resulted in direct and significant increments in SCN electrical activity. We conclude that behavioral activity triggers the increments in SCN electrical activity, rather than vice versa. Consequently, physical activity during the day will raise the amplitude of the SCN electrical discharge rhythm, thereby strengthening clock function. In contrast, night-time activity will be countereffective and attenuate the rhythm in electrical activity. The data elucidate the route via which daytime exercise supports clock function.}, archive = {J_PNAS}, author = {Caputo, Rosanna and Schoonderwoerd, Robin A. and Ramkisoensing, Ashna and Janse, Jan A. M. and van Diepen, Hester C. and Raison, Sylvie and Pévet, Paul and Sage-Ciocca, Dominique and Deboer, Tom and Challet, Etienne and Meijer, Johanna H.}, doi = {10.1073/pnas.2424545122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2424545122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Physical activity stimulates clock neurons of the day-active rodent arvicanthis ansorgei}, volume = {122}, year = {2025}, }
• (2025). Click-constructed modular signal aptamer chimeras enable receptor-independent degradation of membrane proteins. PNAS, 122(21), e2424500122. (www)

  @article{ , abstract = {Cell-membrane proteins are critical mediators of signal transduction, playing essential roles in disease occurrence and progression. The emerging LYTACs (Lysosome-targeting chimeras) technology combines drug-targeting strategies with lysosomal degradation, providing a novel approach to drug development and offering new possibilities for disease therapy. However, the clinical applicability of current LYTAC degraders is limited by the variable expression of lysosome-targeting receptors (LTRs) in tissues. To overcome this limitation, we herein hijacked a YXXØ sorting signal that derived from lysosome-associated membrane protein 2a (LAMP-2a) to develop a signal aptamer platform (SApt), which exhibits high specificity for targeting membrane proteins and inducing efficient lysosomal degradation. SApts were synthesized by conjugating the YXXØ signal peptide to the aptamer’s terminus through a click reaction. Our study demonstrated that SApts efficiently degrade disease-associated membrane proteins, such as PTK7, Met, and NCL, based on the inherent signals rather than specific LTR. The potent antitumor efficacy of SApts was further confirmed in a xenograft tumor model, where in vivo degradation of PTK7 was observed. Collectively, our work provides insights into the development of a simple and universal lysosomal degradation platform with potential translational value in clinical treatment.}, archive = {J_PNAS}, author = {Xie, Wanlin and Sun, Weidi and Li, Qin and Dang, Yang and Ma, Lele and Liu, Yuan and Zhang, Hui and Qu, Fengli and Tan, Weihong}, doi = {10.1073/pnas.2424500122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2424500122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Click-constructed modular signal aptamer chimeras enable receptor-independent degradation of membrane proteins}, volume = {122}, year = {2025}, }
• (2025). Identification of the lydiamycin biosynthetic gene cluster in a plant pathogen guides structural revision and identification of molecular target. PNAS, 122(21), e2424388122. (www)

  @article{ , abstract = {The natural products actinonin and matlystatin feature an N -hydroxy-2-pentyl-succinamyl (HPS) chemophore that facilitates metal chelation and confers their metalloproteinase inhibitory activity. Actinonin is the most potent natural inhibitor of peptide deformylase (PDF) and exerts antimicrobial and herbicidal bioactivity by disrupting protein synthesis. Here, we used a genomics-led approach to identify candidate biosynthetic gene clusters (BGCs) hypothesized to produce HPS-containing natural products. We show that one of these BGCs is on the pathogenicity megaplasmid of the plant pathogen Rhodococcus fascians and produces lydiamycin A, a macrocyclic pentapeptide. The presence of genes predicted to make an HPS-like chemophore informed the structural recharacterization of lydiamycin via NMR and crystallography to show that it features a rare 2-pentyl-succinyl chemophore. We demonstrate that lydiamycin A inhibits bacterial PDF in vitro and show that a cluster-situated PDF gene confers resistance to lydiamycin A, representing an uncommon self-immunity mechanism associated with the production of a PDF inhibitor . In planta competition assays showed that lydiamycin enhances the fitness of R. fascians during plant colonization. This study highlights how a BGC can inform the structure, biochemical target, and ecological function of a natural product.}, archive = {J_PNAS}, author = {Ford, Jonathan J. and Santos-Aberturas, Javier and Hems, Edward S. and Sallmen, Joseph W. and Bögeholz, Lena A. K. and Polturak, Guy and Osbourn, Anne and Wright, Joseph A. and Rodnina, Marina V. and Vereecke, Danny and Francis, Isolde M. and Truman, Andrew W.}, doi = {10.1073/pnas.2424388122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2424388122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identification of the lydiamycin biosynthetic gene cluster in a plant pathogen guides structural revision and identification of molecular target}, volume = {122}, year = {2025}, }
• (2025). Effective polarization in potassium channel simulations: Ion conductance, occupancy, voltage response, and selectivity. PNAS, 122(21), e2423866122. (www)

  @article{ , abstract = {Potassium (K + ) channels are widely distributed in many types of organisms. They combine high efficiency (~100 pS) and K + /Na + selectivity by a conserved selectivity filter (SF). Molecular Dynamics (MD) simulations can provide detailed, atomistic mechanisms of this sophisticated ion permeation. However, currently there are clear inconsistencies between computational predictions and experimental results. First, the ion occupancy of the SF in simulations is lower than expected (~2.5 in MD compared to ~4 in X-ray crystallography). Second, in many reported MD simulations of K + channels, K + conductance is typically an order of magnitude lower than experimental values. This discrepancy is in part because the force fields used in MD simulations of potassium channels do not account for polarization. One of the proposed solutions is the Electronic Continuum Correction (ECC), a force field modification that scales down formal charges, to introduce the polarization in a mean-field way. When the ECC is used in conjunction with the Charmm36m force field, the simulated K + conductance increases 13-fold. Following the analysis of ion occupancy states using Hamiltonian Replica Exchange simulations, we propose a parameter set for Amber14sb, that also leads to a similar increase in conductance. These two force fields are then used to compute the full current–voltage (I-V) curves from MD simulations, approaching quantitative agreement with experiments at all voltages. In general, the ECC-enabled simulations are in excellent agreement with experiment, in terms of ion occupancy, conductance, current–voltage response, and K + /Na + selectivity.}, archive = {J_PNAS}, author = {Hui, Chenggong and de Vries, Reinier and Kopec, Wojciech and de Groot, Bert L.}, doi = {10.1073/pnas.2423866122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2423866122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Effective polarization in potassium channel simulations: Ion conductance, occupancy, voltage response, and selectivity}, volume = {122}, year = {2025}, }
• (2025). Energetics and evolutionary fitness. PNAS, 122(21), e2423684122. (www)

  @article{ , abstract = {It has long been recognized that energy is the currency of evolution, but contrasting conceptions of the relationship between energy and adaptation have yielded different interpretations. In the equal fitness paradigm (EFP), fitness (defined as the energetic equivalent of surviving offspring per generation) is held to be a constant within and between species in a steady-state, zero-sum closed system of constant energy availability. The fossil record, however, indicates that living space and energy availability and access have increased over time in response to pervasive natural selection that favors traits conferring as much power (energy per unit time) as possible, given the constraints imposed by external conditions and other organisms. Through various collaborative relationships and power-enhancing innovations, the inevitable tradeoffs among reproductive parameters envisioned in the EFP are relaxed enough that allocation to offspring can vary in space and time. We suggest that the EFP applies only under highly specific conditions of local constancy of energy availability and not to the biosphere as a whole. We note that fitness, however defined, need therefore not be constant and is difficult to measure in extant species and to infer with proxies in fossil taxa.}, archive = {J_PNAS}, author = {Vermeij, Geerat J. and Grosberg, Richard K. and Roopnarine, Peter D.}, doi = {10.1073/pnas.2423684122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2423684122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Energetics and evolutionary fitness}, volume = {122}, year = {2025}, }
• (2025). Population size interacts with reproductive longevity to shape the germline mutation rate. PNAS, 122(21), e2423311122. (www)

  @article{ , abstract = {Mutation rates vary across the tree of life by many orders of magnitude, with fewer mutations occurring each generation in species that reproduce quickly and maintain large effective population sizes. A compelling explanation is that large effective population sizes facilitate selection against weakly deleterious “mutator alleles” such as variants that modulate cell division or interfere with the molecular efficacy of DNA repair. However, while the fidelity of a single cell division largely determines microorganisms’ mutation rates, the relationship of the mutation rate to the molecular determinants of DNA damage and repair is more complex in multicellular species with long generation times. Since long generations leave more time for mutations to accrue each generation, we posit that a long generation time likely amplifies the fitness consequences of any damage agent or DNA repair defect that creates extra mutations in the spermatogonia or oocytes. This leads to the counterintuitive prediction that the species with the highest germline mutation rates per generation are also the species with most effective mechanisms for avoiding and repairing mutations in their reproductive cells. Consistent with this, we show that mutation rates in the reproductive cells are inversely correlated with generation time; in contrast, the number of germline mutations that occur during prepuberty development trends weakly upward as generation time increases. Our results parallel recent findings that the longest-lived species have the lowest mutation rates in adult somatic tissues, potentially due to selection to keep the lifetime mutation load below a harmful threshold.}, archive = {J_PNAS}, author = {Zhu, Luke and Beichman, Annabel and Harris, Kelley}, doi = {10.1073/pnas.2423311122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2423311122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Population size interacts with reproductive longevity to shape the germline mutation rate}, volume = {122}, year = {2025}, }
• (2025). The evolution of thermal performance curves in response to rising temperatures across the model genus yeast. PNAS, 122(21), e2423262122. (www)

  @article{ , abstract = {The maintenance of biodiversity crucially depends on the evolutionary potential of populations to adapt to environmental change. Accelerating climate change and extreme temperature events urge us to better understand and forecast evolutionary responses. Here, we harnessed the power of experimental evolution with the microbial model system yeast ( Saccharomyces spp. ) to measure the evolutionary potential of populations to adapt to future warming, in real-time and across the entire phylogenetic diversity of the genus. We tracked the evolution of thermal performance curves (TPCs) in populations of eight genetically and ecologically diverse species under gradually increasing temperature conditions, from 25 to 40 °C, for up to 600 generations. We found that evolving toward higher critical thermal limits generally came at a cost, causing a decrease in both thermal tolerance and maximum growth performance. The evolution of TPCs varied significantly between species with strong genotype-by-environment interactions, revealing two main trajectories: i) Warm-tolerant species showed an increase in both optimum growth temperature and thermal tolerance, consistent with the “hotter is wider” hypothesis. ii) Cold-tolerant species on the other hand evolved larger thermal breadth and higher thermal limits, but suffered from reduced maximum performance overall, consistent with the generalist or “a jack of all temperatures is a master of none” hypothesis. In addition, cold-tolerant species never reached the warm-tolerant species’ upper thermal limits. Our results show that adaptive strategies to increasing temperatures are complex, highlighting the need to consider both within and between species diversity when predicting and managing the impacts of climate change on populations.}, archive = {J_PNAS}, author = {Molinet, Jennifer and Stelkens, Rike}, doi = {10.1073/pnas.2423262122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2423262122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The evolution of thermal performance curves in response to rising temperatures across the model genus yeast}, volume = {122}, year = {2025}, }
• (2025). Cancer-associated fibroblast-derived SEMA3C facilitates colorectal cancer liver metastasis via NRP2-mediated MAPK activation. PNAS, 122(21), e2423077122. (www)

  @article{ , abstract = {Liver metastasis remains the predominant cause of mortality in patients with colorectal cancer (CRC). Nevertheless, the mechanisms underlying the initiation of colorectal cancer liver metastasis remain poorly elucidated. During the metastatic process of CRC cells from the primary site to the liver, we performed time-resolved analyses and identified a subset of tumor cells spatially located in the primary tumor and temporally distributed in the early stages of liver metastasis. These cells were termed liver metastasis-initiating cells (LMICs). LMICs exhibit high stemness, low proliferation, active interaction with surrounding stromal components, and a close association with liver metastasis. Notably, we found significant interactions between cancer-associated fibroblasts (CAFs) and LMICs via the SEMA3C–NRP2 receptor–ligand pair. Further in vivo and in vitro experiments confirmed that CAF-secreted SEMA3C could bind to the NRP2 receptor, which activates the MAPK pathway and promotes colorectal cancer liver metastasis. Our findings suggest potential therapeutic strategies for the early prevention of colorectal cancer liver metastasis.}, archive = {J_PNAS}, author = {Zhang, Yuyuan and Zuo, Anning and Ba, Yuhao and Liu, Shutong and Chen, Jingqi and Yang, Shuaixi and Weng, Siyuan and Chen, Yukang and Xu, Hui and Luo, Peng and Cheng, Quan and Tang, Bufu and Liu, Benyu and Zhang, Chuhan and Yang, Jingkuan and Han, Xinwei and Liu, Zaoqu}, doi = {10.1073/pnas.2423077122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2423077122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cancer-associated fibroblast-derived SEMA3C facilitates colorectal cancer liver metastasis via NRP2-mediated MAPK activation}, volume = {122}, year = {2025}, }
• (2025). A circuit model for transsaccadic space updating and mislocalization. PNAS, 122(21), e2422911122. (www)

  @article{ , abstract = {We perceive a stable, continuous world despite drastic changes of retinal images across saccades. However, while persistent objects in daily life appear stable across saccades, stimuli flashed around saccades can be grossly mislocalized. We address this puzzle with our recently proposed circuit model for perisaccadic receptive-field (RF) remapping in the lateral interparietal area (LIP) and frontal eye fields (FEF). The model uses center-excitation/surround-inhibition connections to store a relevant stimulus’ retinal location in memory as a population activity. This activity profile is updated across each saccade by directional connections gated by the corollary discharge (CD) of the saccade command. The updating is a continuous backward (against the saccade) shift of the population activity (equivalent to continuous forward remapping of the RFs), whose cumulative effect across the saccade is a subtraction of the saccade vector. The model that correctly updates persistent stimuli, and flashes well before and after saccades, produces the observed forward and backward translational mislocalization for flashes around the saccade onset and offset, respectively, because of insufficient and unnecessary cumulative updating after the saccade, caused by visual response latency and sluggish CD time course. We confirm the model prediction that for perisaccadic RFs measured with flashes before the saccades, the forward remapping magnitudes across the saccades are smaller for later flashes. Our work suggests that transsaccadic perception is stable because the presaccadic retinal position of an object is updated to match the postsaccadic (reafferent) retinal position of the same object, and that the brain uses “unaware” decoders which do not distinguish between different origins of neurons’ activities.}, archive = {J_PNAS}, author = {Wang, Xiao and Tsien, Sophia J. and Jin, Min and Goldberg, Michael E. and Zhang, Mingsha and Qian, Ning}, doi = {10.1073/pnas.2422911122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2422911122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A circuit model for transsaccadic space updating and mislocalization}, volume = {122}, year = {2025}, }
• (2025). Inflammatory cytokine upd3 induces axon length–dependent synapse removal by glia. PNAS, 122(21), e2422752122. (www)

  @article{ , abstract = {Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors but the cellular and molecular bases for neurite length-dependent vulnerability of neurons to degeneration is largely unknown. Using Drosophila sensory neurons as a model system we show that neuronal activation of the integrated stress response triggers expression of the Interleukin-6 homolog unpaired 3 ( upd3 ), which is both necessary and sufficient for axon length–dependent degeneration of presynapses. Upd3 activates phagocytic glia, triggering phagocytic removal of presynapses preferentially on neurons with long axons, thus revealing an intrinsic axon length–dependent vulnerability to glial insult. Finally, we found that axon length–dependent presynapse loss in fly models of human NDDs utilized this pathway, requiring upd3 and glial expression of the phagocytic receptor draper. Our studies identify inflammatory cytokine signaling and glial phagocytosis as key determinants of axon length–dependent vulnerability, thus mechanistically linking these hallmarks of NDDs.}, archive = {J_PNAS}, author = {Tenedini, Federico Marcello and Yin, Chang and Huang, Jessica M. and Dhiman, Neena and Soba, Peter and Parrish, Jay Z.}, doi = {10.1073/pnas.2422752122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2422752122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inflammatory cytokine upd3 induces axon length–dependent synapse removal by glia}, volume = {122}, year = {2025}, }
• (2025). Engineering spin coherence in core-shell diamond nanocrystals. PNAS, 122(21), e2422542122. (www)

  @article{ , abstract = {Fluorescent diamond nanocrystals can host spin qubit sensors capable of probing the physical properties of biological systems with nanoscale spatial resolution. Sub-100 nm diamond nanosensors can readily be delivered into intact cells and even living organisms. However, applications beyond current proof-of-principle experiments require a substantial increase in sensitivity, which is limited by surface induced charge instability and electron-spin dephasing. In this work, we utilize engineered core-shell structures to achieve a drastic increase in qubit coherence times ( T 2 ) from 1.1 to 35 μs in bare nanodiamonds to upward of 52 to 87 μs. We use electron-paramagnetic-resonance results to present a band bending model and connect silica encapsulation to the removal of deleterious mid-gap surface states that are negatively affecting the qubit’s spin properties. Combined with a 1.9-fold increase in particle luminescence these advances correspond to up to two-order-of-magnitude reduction in integration time. Probing qubit dynamics at a single particle level further reveals that the noise characteristics fundamentally change from a bath with spins that rearrange their spatial configuration during the course of an experiment to a more dilute static bath. The observed results shed light on the underlying mechanisms governing fluorescence and spin properties in diamond nanocrystals and offer an effective noise mitigation strategy based on engineered core-shell structures.}, archive = {J_PNAS}, author = {Zvi, Uri and Candido, Denis R. and Weiss, Adam M. and Jones, Aidan R. and Chen, Lingjie and Golovina, Iryna and Yu, Xiaofei and Wang, Stella and Talapin, Dmitri V. and Flatté, Michael E. and Esser-Kahn, Aaron P. and Maurer, Peter C.}, doi = {10.1073/pnas.2422542122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2422542122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Engineering spin coherence in core-shell diamond nanocrystals}, volume = {122}, year = {2025}, }
• (2025). Phase separation in mitochondrial fate and mitochondrial diseases. PNAS, 122(21), e2422255122. (www)

  @article{ , abstract = {Mitochondria are central metabolic organelles that control cell fate and the development of mitochondrial diseases. Traditionally, phase separation directly regulates cell functions by driving RNA, proteins, or other molecules to concentrate into lipid droplets. Recent studies show that phase separation regulates cell functions and diseases through the regulation of subcellular organelles, particularly mitochondria. In fact, phase separation is involved in various mitochondrial activities including nucleoid assembly, autophagy, and mitochondria-related inflammation. Here, we outline the key mechanisms through which phase separation influences mitochondrial activities and the development of mitochondrial diseases. Insights into how phase separation regulates mitochondrial activities and diseases will help us develop interventions for related diseases.}, archive = {J_PNAS}, author = {Chen, Qingyi and An, Sanqi and Wang, Chuanlong and Zhou, Yanshuang and Liu, Xingguo and Ren, Wenkai}, doi = {10.1073/pnas.2422255122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2422255122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phase separation in mitochondrial fate and mitochondrial diseases}, volume = {122}, year = {2025}, }
• (2025). Forecasting range shifts of dioecious plants under climate change. PNAS, 122(21), e2422162122. (www)

  @article{ , abstract = {Global climate change has triggered an urgent need for predicting the reorganization of Earth’s biodiversity. For dioecious species (those with separate sexes), it is unclear how commonly unique climate sensitivities of females and males could influence projections for species-level responses to climate change. We developed demographic models of range limitation, parameterized from geographically distributed common garden experiments, with females and males of a dioecious grass species ( Poa arachnifera ) throughout and beyond its range in the south-central U.S. We contrasted predictions of a standard female-dominant model with those of a two-sex model that accounts for feedbacks between sex ratio and vital rates. Both model versions predict that future climate change will induce a poleward shift of niche suitability beyond current northern limits. However, the magnitude of the poleward shift was underestimated by the female-dominant model because females have broader temperature tolerance than males but become mate-limited under female-biased sex ratios, which are forecasted to become more common under future climate. Our results illustrate how explicitly accounting for both sexes can enhance population viability forecasts and conservation planning for dioecious species in response to climate change.}, archive = {J_PNAS}, author = {Moutouama, Jacob K. and Compagnoni, Aldo and Miller, Tom E. X.}, doi = {10.1073/pnas.2422162122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2422162122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Forecasting range shifts of dioecious plants under climate change}, volume = {122}, year = {2025}, }
• (2025). HCK regulates NLRP12-mediated PANoptosis. PNAS, 122(21), e2422079122. (www)

  @article{ , abstract = {NOD-like receptors (NLRs) are a highly conserved family of cytosolic pattern recognition receptors that drive innate immune responses against pathogens, pathogen-associated molecular patterns, damage-associated molecular patterns, and homeostatic disruptions. Within the NLR family, NLRP12 was recently identified as a key regulator of PANoptosis, which is an innate immune, lytic cell death pathway initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosome complexes. While NLRP12 activation is critical for maintaining homeostasis, aberrant activation has been implicated in a broad range of disorders, including cancers and metabolic, infectious, autoinflammatory, and hemolytic diseases. However, the molecular mechanisms of NLRP12 activation remain poorly understood. Here, we identified hematopoietic cell kinase (HCK) as a regulator of NLRP12-mediated PANoptosis. HCK expression was significantly upregulated in response to NLRP12-PANoptosome triggers. Moreover, Hck knockdown inhibited NLRP12-mediated PANoptosis. Computational analyses identified residues in the putative interaction interface between NLRP12 and HCK, suggesting that HCK likely binds NLRP12 in the region between its NACHT domain and pyrin domain (PYD); removal of the NLRP12 PYD abrogated this interaction in vitro. Overall, our work identifies HCK as a regulator of NLRP12-mediated PANoptosis, suggesting that it may serve as a potential therapeutic target for mitigating inflammation and pathology.}, archive = {J_PNAS}, author = {Nadendla, Eswar Kumar and Alluri, Priyanshu and Sundaram, Balamurugan and Kumar, Sivakumar Prasanth and Chadchan, Sangappa B. and Sarkar, Roman and Kanneganti, Thirumala-Devi}, doi = {10.1073/pnas.2422079122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2422079122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {HCK regulates NLRP12-mediated PANoptosis}, volume = {122}, year = {2025}, }
• (2025). Barremian tricolpate pollen from Portugal—New evidence for the age of eudicot-related angiosperms. PNAS, 122(21), e2421470122. (www)

  @article{ , abstract = {New evidence on the timing of early angiosperm evolution is presented through the discovery of four well-dated tricolpate pollen grains from the Early Cretaceous midlatitudes. Recovered from nearshore marine sediments in the Lusitanian Basin of Portugal, these fossils significantly expand the pre-Aptian tricolpate pollen record and document a greater number of pre-Aptian tricolpate grains in the midlatitudes than previously recognized. The fossil evidence was obtained through the innovative application of advanced microscopy techniques and was precisely dated through biostratigraphy and strontium isotope stratigraphy on material from the same section. These findings extend the first occurrence of tricolpate pollen to the early late Barremian (~123.0 Ma) in Portugal and possibly worldwide. Our findings provide fossil evidence with minimal dating uncertainty, as both the fossils and their age determination come from the same well-constrained sections, eliminating the need for cross-correlation. This establishes the most reliable age for the first occurrence of tricolpate pollen, unequivocally linked to the eudicot clade—an early derived lineage within angiosperms. These fossils serve as a robust calibration point for phylogenetic studies. Additionally, our study emphasizes the importance of methodological advancements in refining the fossil plant record. The newly applied fluorescence screening method when adapted also in future research could further enhance the detection of rare fossils, offering insights into the diversification of angiosperms.}, archive = {J_PNAS}, author = {Gravendyck, Julia and Krencker, François-Nicolas and Riding, James B. and Coimbra, Rute and Heimhofer, Ulrich}, doi = {10.1073/pnas.2421470122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2421470122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Barremian tricolpate pollen from Portugal—New evidence for the age of eudicot-related angiosperms}, volume = {122}, year = {2025}, }
• (2025). Induction of the ISR by AB5 subtilase cytotoxin drives type-I IFN expression in pDCs via STING activation. PNAS, 122(21), e2421258122. (www)

  @article{ , abstract = {We demonstrate that exposure to the AB5 subtilase cytotoxin (SubAB) induces the unfolded protein response (UPR) in human peripheral blood mononuclear cells, concomitant with a proinflammatory response across distinct cell subsets. Notably, SubAB selectively induces type-I interferon (IFN) expression in plasmacytoid dendritic cells, acting synergistically with Toll-like receptor 7 stimulation. The induction of type-I IFN in response to SubAB relies on stimulator of interferon genes (STING) activation, coupled with protein synthesis inhibition mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) and phosphorylation of the eukaryotic translation initiation factor 2 subunit-alpha. By impeding mRNA translation through the integrated stress response, SubAB precipitates the downregulation of the negative innate signaling feedback regulator Tax1-binding protein 1. This downregulation is necessary to unleash TANK-binding kinase 1 signaling associated with STING activation. These findings shed light on how UPR-inducing conditions may regulate the immune system during infection or pathogenesis.}, archive = {J_PNAS}, author = {Barros, Daniela and Ferreira, Beatriz H. and Garcia-Gonzalez, Paulina and Carbone, Francesco and Luka, Marine and Leite-Pinheiro, Fátima and Machado, Mariana D. and Nikolaou, Theopisti and Pilotti, Angelo and Goguet, Eliot and Antas, Paulo and Mendes, Andreia and Zhang, Lichen and Cresci, Marina and Galliot, Lou and Gigan, Julien P. and Reverendo, Marisa and Su, Bing and Narita, Miwako and Paton, Adrienne W. and Paton, James C. and Rocchi, Stéphane and Rieux-Laucat, Frédéric and Argüello, Rafael J. and Nal, Béatrice and Liang, Yinming and Ménager, Mickaël and Gatti, Evelina and Almeida, Catarina R. and Pierre, Philippe}, doi = {10.1073/pnas.2421258122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2421258122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Induction of the ISR by AB5 subtilase cytotoxin drives type-I IFN expression in pDCs via STING activation}, volume = {122}, year = {2025}, }
• (2025). Phase separation of RXRγ drives tumor chemoresistance and represents a therapeutic target for small-cell lung cancer. PNAS, 122(21), e2421199122. (www)

  @article{ , abstract = {Small-cell lung cancer (SCLC) is the most lethal type of lung cancer, characterized by rapid evolution from chemosensitivity to chemoresistance and limited treatment options. However, the mechanisms underlying this evolution remain poorly understood. Here, we show that Retinoid X receptor γ (RXRγ) is uniquely overexpressed in chemo-resistant SCLC tumors, and that RXRγ serves as an essential factor driving chemoresistance in SCLC. RXRγ forms phase-separated droplets with LSD1 in the nucleus, which enhances RXRγ-mediated gene transcription activity and reprograms gene expression, promoting tumor stemness and metastasis, and eventually driving SCLC chemoresistance. In turn, RXRγ antagonist disrupts RXRγ–LSD1 interaction, reducing their binding to the target gene locus, markedly suppressing the expression of the RXRγ target gene network. Finally, RXRγ antagonists strongly suppress tumor growth and metastasis and restore SCLC vulnerability to chemotherapy in multiple preclinical SCLC models, resulting in a substantial extension of survival in mouse models. Thus, these results establish RXRγ as a key player in SCLC by phase separation and as a potential therapeutic target for this deadly disease.}, archive = {J_PNAS}, author = {Wang, Hong and Huang, Jie and Zhang, Zhenhua and An, Yana and Sun, Huizi and Chen, Jianghe and Feng, Weineng and Duan, Hao and Mou, Yonggao and Wang, Yuanxiang and Liu, Peiqing and Zhou, Huihao and Chen, Hong-Wu and Zhang, Jian and Lu, Xiaoyun and Wang, Junjian}, doi = {10.1073/pnas.2421199122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2421199122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phase separation of RXRγ drives tumor chemoresistance and represents a therapeutic target for small-cell lung cancer}, volume = {122}, year = {2025}, }
• (2025). Can AI weather models predict out-of-distribution gray swan tropical cyclones?. PNAS, 122(21), e2420914122. (www)

  @article{ , abstract = {Predicting gray swan weather extremes, which are possible but so rare that they are absent from the training dataset, is a major concern for AI weather models and long-term climate emulators. An important open question is whether AI models can extrapolate from weaker weather events present in the training set to stronger, unseen weather extremes. To test this, we train independent versions of the AI weather model FourCastNet on the 1979–2015 ERA5 dataset with all data, or with Category 3–5 tropical cyclones (TCs) removed, either globally or only over the North Atlantic or Western Pacific basin. We then test these versions of FourCastNet on 2018–2023 Category 5 TCs (gray swans). All versions yield similar accuracy for global weather, but the one trained without Category 3–5 TCs cannot accurately forecast Category 5 TCs, indicating that these models cannot extrapolate from weaker storms. The versions trained without Category 3–5 TCs in one basin show some skill forecasting Category 5 TCs in that basin, suggesting that FourCastNet can generalize across tropical basins. This is encouraging and surprising because regional information is implicitly encoded in inputs. Given that current state-of-the-art AI weather and climate models have similar learning strategies, we expect our findings to apply to other models. Other types of weather extremes need to be similarly investigated. Our work demonstrates that novel learning strategies are needed for AI models to reliably provide early warning or estimated statistics for the rarest, most impactful TCs, and, possibly, other weather extremes.}, archive = {J_PNAS}, author = {Sun, Y. Qiang and Hassanzadeh, Pedram and Zand, Mohsen and Chattopadhyay, Ashesh and Weare, Jonathan and Abbot, Dorian S.}, doi = {10.1073/pnas.2420914122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2420914122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Can AI weather models predict out-of-distribution gray swan tropical cyclones?}, volume = {122}, year = {2025}, }
• (2025). Dinucleotide preferences underlie apparent codon preference reversals in the drosophila melanogaster lineage. PNAS, 122(21), e2419696122. (www)

  @article{ , abstract = {We employ fine-scale population genetic analyses to reveal dynamics among interacting forces that act at synonymous sites and introns among closely related Drosophila species. Synonymous codon usage bias has proven to be well suited for population genetic inference. Under major codon preference (MCP), translationally superior “major” codons confer fitness benefits relative to their less efficiently and/or accurately decoded synonymous counterparts. Our codon family and lineage-specific analyses expand on previous findings in the Drosophila simulans lineage; patterns in naturally occurring polymorphism demonstrate fixation biases toward GC-ending codons that are consistent in direction, but heterogeneous in magnitude, among synonymous families. These forces are generally stronger than fixation biases in intron sequences. In contrast, population genetic analyses reveal unexpected evidence of codon preference reversals in the Drosophila melanogaster lineage. Codon family-specific polymorphism patterns support reduced efficacy of natural selection in most synonymous families but indicate reversals of favored states in the four codon families encoded by NAY. Accelerated synonymous fixations in favor of NAT and greater differences for both allele frequencies and fixation rates among X-linked, relative to autosomal, loci bolster support for fitness effect reversals. The specificity of preference reversals to codons whose cognate tRNAs undergo wobble position queuosine modification is intriguing. However, our analyses reveal prevalent dinucleotide preferences for ApT over ApC that act in opposition to GC-favoring forces in both coding and intron regions. We present evidence that changes in the relative efficacy of translational selection and dinucleotide preference underlie apparent codon preference reversals.}, archive = {J_PNAS}, author = {Yamashita, Haruka and Matsumoto, Tomotaka and Kawashima, Kent and Abdulla Daanaa, Hassan Sibroe and Yang, Ziheng and Akashi, Hiroshi}, doi = {10.1073/pnas.2419696122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2419696122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dinucleotide preferences underlie apparent codon preference reversals in the drosophila melanogaster lineage}, volume = {122}, year = {2025}, }
• (2025). Pattern formation along signaling gradients driven by active droplet behavior of cell swarms. PNAS, 122(21), e2419152122. (www)

  @article{ , abstract = {Gradients of extracellular signals organize cells in tissues. Although there are several models for how gradients can pattern cell behavior, it is not clear how cells react to gradients when the population is undergoing 3D morphogenesis, in which cell–cell and cell–signal interactions are continually changing. Dictyostelium cells follow gradients of their nutritional source to feed and maintain their undifferentiated state. Using lightsheet imaging to simultaneously monitor signaling, single-cell, and population dynamics, we show that the cells migrate toward nutritional gradients in swarms. As swarms advance, they deposit clumps of cells at the rear, triggering differentiation. Clump deposition is explained by a physical model in which cell swarms behave as active droplets: cells proliferate within the swarm, with clump shedding occurring at a critical population size, at which cells at the rear no longer perceive the gradient and are not retained by the emergent surface tension of the swarm. The model predicts vortex motion of the cells within the swarm emerging from the local transfer of propulsion forces, a prediction validated by 3D tracking of single cells. This active fluid behavior reveals a developmental mechanism we term “musical chairs” decision-making, in which the decision to proliferate or differentiate is determined by the position of a cell within the group as it bifurcates.}, archive = {J_PNAS}, author = {Ford, Hugh Z. and Celora, Giulia L. and Westbrook, Elizabeth R. and Dalwadi, Mohit P. and Walker, Benjamin J. and Baumann, Hella and Weijer, Cornelis J. and Pearce, Philip and Chubb, Jonathan R.}, doi = {10.1073/pnas.2419152122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2419152122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pattern formation along signaling gradients driven by active droplet behavior of cell swarms}, volume = {122}, year = {2025}, }
• (2025). BRD9 functions as an HIV-1 latency regulatory factor. PNAS, 122(21), e2418467122. (www)

  @article{ , abstract = {A major challenge for HIV type 1 (HIV-1) cure is the presence of viral latent reservoirs. The “Shock & Kill” strategy involves the combined use of latency reversal agents (LRA) and antiretroviral treatment (ART) to reactivate HIV-1 latent reservoirs, followed by elimination of infected cells. However, current LRAs are insufficient in fully reactivating the latent reservoirs. Therefore, investigation on novel HIV-1 latency regulators will be crucial to the success of HIV-1 cure research. Here, we identify bromodomain-containing protein 9 (BRD9) as an HIV-1 latency regulator. BRD9 inhibition induces HIV-1 latency reactivation in T cell lines, human resting memory CD4 + T cells, and PBMCs derived from people living with HIV-1 (PWH) on ART. BRD9 inhibition, gene depletion, and protein degradation consistently reactivate HIV-1 latency. Moreover, BRD9 inhibition synergizes with BRD4 inhibition in inducing HIV-1 production. Mechanistically, BRD9 binds to HIV-1 LTR promoter and competes with HIV-1 Tat protein for binding to the HIV-1 genome. Additionally, our integrated CUT&RUN DNA sequencing, transcriptomics, and pharmacological analysis revealed downstream host targets of BRD9, including ATAD2 and MTHFD2, that modulate HIV-1 latency.}, archive = {J_PNAS}, author = {Luk, Tsz-Yat and Yim, Lok-Yan and Zhou, Runhong and Mo, Yufei and Huang, Huarong and Zhao, Meiqing and Dai, Jie and Lau, Thomas Tsz-Kan and Huang, Xiner and Lui, Grace Chung-Yan and Yuen, Kwok-Yung and Chan, Jasper Fuk-Woo and Cheng, Alfred Sze-Lok and Chen, Zhiwei and Chu, Hin}, doi = {10.1073/pnas.2418467122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2418467122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {BRD9 functions as an HIV-1 latency regulatory factor}, volume = {122}, year = {2025}, }
• (2025). The white lupin CCR1 receptor-like kinase controls systemic autoregulation of cluster root and nodule development. PNAS, 122(21), e2418411122. (www)

  @article{ , abstract = {Root development is tightly regulated in plants to optimize nutrient acquisition and interactions with soil microorganisms. In legumes, the Autoregulation of Nodulation (AoN) pathway systemically controls the proliferation of root nodules, which are energy-intensive organs. Mutations affecting the AoN pathway result in a hypernodulation phenotype accompanied by altered root development. However, it remains unclear whether this modification of root development is also systemic and coordinated with nodulation. In this study, we report the identification of the constitutive cluster root 1 (ccr1) mutant in white lupin ( Lupinus albus ), which exhibits constitutive production of an excessive number of cluster roots. We demonstrate that CCR1 is an ortholog of HAR1/SUNN/NARK leucin-rich repeat-receptor like kinases (LRR-RLKs), which are key regulators of the AoN pathway. Furthermore, we show that CCR1 negatively regulates both nodule and cluster root development. Interspecific grafting experiments between white and narrow-leaved lupin ( Lupinus angustifolius ), a species incapable of producing cluster roots, show that ccr1 shoots can induce the formation of cluster-like roots in narrow-leaved lupin rootstocks. This highlights the conservation of a CCR1-dependent signaling cascade. Transcriptome analyses reveal that CCR1 targets the conserved NIN/LBD16-NFYA regulatory module, which connects nodule and lateral root development through a shared inhibitory systemic pathway. We propose that this pathway represents a broader developmental control mechanism of root organogenesis, termed Autoregulation of Cluster Root and Nodule Development (AoDev).}, archive = {J_PNAS}, author = {Marquès, Laurence and Divol, Fanchon and Boultif, Alexandra and Garcia, Fanny and Soriano, Alexandre and Maurines-Carboneill, Cléa and Fernandez, Virginia and Verstraeten, Inge and Pidon, Hélène and Izquierdo, Esther and Hufnagel, Bárbara and Péret, Benjamin}, doi = {10.1073/pnas.2418411122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2418411122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The white lupin CCR1 receptor-like kinase controls systemic autoregulation of cluster root and nodule development}, volume = {122}, year = {2025}, }
• (2025). The cortical critical power law balances energy and information in an optimal fashion. PNAS, 122(21), e2418218122. (www)

  @article{ , abstract = {A recent study has suggested that the stimulus responses of cortical neural populations follow a critical power law. More precisely, the power spectrum of the covariance matrix of neural responses follows a power law with an exponent indicating that the neural manifold lies on the edge of differentiability. This criticality is hypothesized to balance expressivity and robustness in neural encoding, as population responses on a nondifferential fractal manifold are thought to be overly sensitive to perturbations. However, contrary to this hypothesis, we prove that neural coding is far more robust than previously assumed. We develop a theoretical framework that provides an analytical expression for the Fisher information of population coding under the small noise assumption. Our results reveal that, due to its intrinsic high dimensionality, population coding maintains reliability even on a nondifferentiable fractal manifold, despite its sensitivity to perturbations. Furthermore, the theory reveals that the trade-off between energetic cost and information makes the critical power-law coding the optimal neural encoding of sensory information for a wide range of conditions. In this derivation, we highlight the essential role of a neural correlation, known as differential correlation, in power-law population coding. By uncovering the nontrivial nature of high-dimensional information coding, this work deepens our understanding of criticality and power laws in both biological and artificial neural computation.}, archive = {J_PNAS}, author = {Tatsukawa, Tsuyoshi and Teramae, Jun-nosuke}, doi = {10.1073/pnas.2418218122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2418218122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The cortical critical power law balances energy and information in an optimal fashion}, volume = {122}, year = {2025}, }
• (2025). Neuron–astrocyte associative memory. PNAS, 122(21), e2417788122. (www)

  @article{ , abstract = {Astrocytes, the most abundant type of glial cell, play a fundamental role in memory. Despite most hippocampal synapses being contacted by an astrocyte, there are no current theories that explain how neurons, synapses, and astrocytes might collectively contribute to memory function. We demonstrate that fundamental aspects of astrocyte morphology and physiology naturally lead to a dynamic, high-capacity associative memory system. The neuron–astrocyte networks generated by our framework are closely related to popular machine learning architectures known as Dense Associative Memories. Adjusting the connectivity pattern, the model developed here leads to a family of associative memory networks that includes a Dense Associative Memory and a Transformer as two limiting cases. In the known biological implementations of Dense Associative Memories, the ratio of stored memories to the number of neurons remains constant, despite the growth of the network size. Our work demonstrates that neuron–astrocyte networks follow a superior memory scaling law, outperforming known biological implementations of Dense Associative Memory. Our model suggests an exciting and previously unnoticed possibility that memories could be stored, at least in part, within the network of astrocyte processes rather than solely in the synaptic weights between neurons.}, archive = {J_PNAS}, author = {Kozachkov, Leo and Slotine, Jean-Jacques and Krotov, Dmitry}, doi = {10.1073/pnas.2417788122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2417788122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neuron–astrocyte associative memory}, volume = {122}, year = {2025}, }
• (2025). Inferring neural population codes for drosophila acoustic communication. PNAS, 122(21), e2417733122. (www)

  @article{ , abstract = {Social communication between animals is often mediated by sequences of acoustic signals, sometimes spanning long timescales. How auditory neural circuits respond to extended input sequences to guide behavior is not understood. We address this problem using Drosophila acoustic communication, a behavior involving the male’s production of and female’s response to long, highly variable courtship songs. Here we ask whether female neural and behavioral responses to song are better described by a linear–nonlinear feature detection model vs. a nonlinear accumulation model. Comparing both models against head-fixed neural recordings and pure-behavioral recordings of unrestrained courtship, we found that while both models could explain the neural data, the accumulation model better predicted female locomotion during courtship, outperforming several alternative predictors. To understand how the accumulation model encoded song to predict locomotion, we analyzed the relationship between neural activity simulated by the model and female locomotion during courtship—this revealed the model’s reliance on heterogeneous nonlinear adaptation and slow integration. Finally, we asked how adaptation and integration processes could cooperate across the model neural population to encode temporal patterns in song. Simulations revealed how adaptation can transform song inputs prior to integration, allowing fine-scale song information to be retained in the population code for long periods. Thus, modeling fly auditory responses as a nonlinearly adaptive, accumulating population code accounts for female locomotor responses to song during courtship and suggests a biologically plausible mechanism for the online encoding of extended communication sequences.}, archive = {J_PNAS}, author = {Pang, Rich and Baker, Christa A. and Murthy, Mala and Pillow, Jonathan}, doi = {10.1073/pnas.2417733122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2417733122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inferring neural population codes for drosophila acoustic communication}, volume = {122}, year = {2025}, }
• (2025). Inhibiting 15-PGDH blocks blood–brain barrier deterioration and protects mice from alzheimer’s disease and traumatic brain injury. PNAS, 122(21), e2417224122. (www)

  @article{ , abstract = {Alzheimer’s disease (AD) and traumatic brain injury (TBI) are currently untreatable neurodegenerative disorders afflicting millions of people worldwide. These conditions are pathologically related, and TBI is one of the greatest risk factors for AD. Although blood–brain barrier (BBB) disruption drives progression of both AD and TBI, strategies to preserve BBB integrity have been hindered by lack of actionable targets. Here, we identify 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that catabolizes eicosanoids and other anti-inflammatory mediators, as a therapeutic candidate that protects the BBB. We demonstrate that 15-PGDH is enriched in BBB-associated myeloid cells and becomes markedly elevated in human and mouse models of AD and TBI, as well as aging, another major risk factor for AD. Pathological increase in 15-PGDH correlates with pronounced oxidative stress, neuroinflammation, and neurodegeneration, alongside profound BBB structural degeneration characterized by astrocytic endfeet swelling and functional impairment. Pharmacologic inhibition or genetic reduction of 15-PGDH in AD and TBI models strikingly mitigates oxidative damage, suppresses neuroinflammation, and restores BBB integrity. Most notably, inhibiting 15-PGDH not only halts neurodegeneration but also preserves cognitive function at levels indistinguishable from healthy controls. Remarkably, these neuroprotective effects in AD are achieved without affecting amyloid pathology, underscoring a noncanonical mechanism for treating AD. In a murine microglia cell line exposed to amyloid beta oligomer, major protection was demonstrated by multiple anti-inflammatory substrates that 15-PGDH degrades. Thus, our findings position 15-PGDH inhibition as a broad-spectrum strategy to protect the BBB and thereby preserve brain health and cognition in AD and TBI.}, archive = {J_PNAS}, author = {Koh, Yeojung and Vázquez-Rosa, Edwin and Gao, Farrah and Li, Hongyun and Chakraborty, Suwarna and Tripathi, Sunil Jamuna and Barker, Sarah and Bud, Zea and Bangalore, Anusha and Kandjoze, Uapingena P. and León-Alvarado, Rose A and Sridharan, Preethy S. and Cordova, Brittany A. and Yu, Youngmin and Hyung, Jiwon and Fang, Hua and Singh, Salendra and Katabathula, Ramachandra and LaFramboise, Thomas and Kasturi, Lakshmi and Lutterbaugh, James and Beard, Lydia and Cordova, Erika and Cintrón-Pérez, Coral J. and Franke, Kathryn and Fragoso, Mariana Franco and Miller, Emiko and Indrakumar, Vidya and Noel, Kamryn L. and Dhar, Matasha and Ajroud, Kaouther and Zamudio, Carlos and Lopes, Filipa Blasco Tavares Pereira and Bambakidis, Evangeline and Zhu, Xiongwei and Wilson, Brigid and Flanagan, Margaret E. and Gefen, Tamar and Fujioka, Hisashi and Fink, Stephen P. and Desai, Amar B. and Dawson, Dawn and Williams, Noelle S. and Kim, Young-Kwang and Ready, Joseph M. and Paul, Bindu D. and Shin, Min-Kyoo and Markowitz, Sanford D. and Pieper, Andrew A.}, doi = {10.1073/pnas.2417224122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2417224122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inhibiting 15-PGDH blocks blood–brain barrier deterioration and protects mice from alzheimer’s disease and traumatic brain injury}, volume = {122}, year = {2025}, }
• (2025). Galvanotactic directionality of cell groups depends on group size. PNAS, 122(21), e2416440122. (www)

  @article{ , abstract = {Motile cells migrate directionally in the electric field (EF) in a process known as galvanotaxis, an important phenomenon in wound healing and development. We previously reported that individual fish keratocyte cells migrate to the cathode in EFs, that inhibition of PI3 kinase (PI3K) reverses single cells to the anode, and that large cohesive groups of either unperturbed or PI3K-inhibited cells migrate to the cathode. Here, we report that small uninhibited cell groups move to the cathode, while small groups of PI3K-inhibited cells move to the anode. Small groups move faster than large groups, and groups of unperturbed cells move faster than PI3K-inhibited cell groups of comparable sizes. The shapes and sizes of large groups change little when they start migrating, while size and shapes of small groups change significantly, and lamellipodia disappear from the rear edges of these groups. The computational model, according to which cells inside and at the edge of the group interpret directional signals differently, explains the observations. Namely, cells in the group interior are directed to the cathode independently whether they are PI3K-inhibited or not. Meanwhile, the edge cells behave like individual cells: They are directed to the cathode in uninhibited groups and to the anode in PI3K-inhibited groups. As a result, all cells drive uninhibited groups to the cathode, while larger PI3K-inhibited groups are directed by cell majority in the group interior to the cathode, while majority of the edge cells in small groups win the tug-of-war driving these groups to the anode.}, archive = {J_PNAS}, author = {Copos, Calina and Sun, Yao-Hui and Zhu, Kan and Zhang, Yan and Reid, Brian and Draper, Bruce and Lin, Francis and Yue, Haicen and Bernadskaya, Yelena and Zhao, Min and Mogilner, Alex}, doi = {10.1073/pnas.2416440122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2416440122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Galvanotactic directionality of cell groups depends on group size}, volume = {122}, year = {2025}, }
• (2025). Horizontal transmission of functionally diverse transposons is a major source of new introns. PNAS, 122(21), e2414761122. (www)

  @article{ , abstract = {Since the discovery of spliceosomal introns in eukaryotic genomes, the proximate molecular and evolutionary processes that generate new introns have remained a critical mystery. Specialized transposable elements (TEs), introners, are thought to be one of the major drivers of intron gain in diverse eukaryotes. However, the molecular mechanism(s) and evolutionary processes driving introner propagation within and between lineages remain elusive. Here, we analyze 8,716 genomes, revealing 1,093 introner families in 201 species spanning 1.7 billion years of evolution. Introners are derived from functionally diverse TEs including families of terminal-inverted-repeat DNA TEs, retrotransposons, cryptons, and helitrons as well as mobile elements with unknown molecular mechanisms. We identify eight cases where introners recently transferred between divergent host species and show that giant viruses that integrate into genomes may facilitate introner transfer across lineages. We propose that ongoing intron gain is primarily a consequence of TE activity in eukaryotes, thereby resolving a key mystery of genome structure evolution.}, archive = {J_PNAS}, author = {Gozashti, Landen and Nakamoto, Anne and Russell, Shelbi and Corbett-Detig, Russell}, doi = {10.1073/pnas.2414761122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2414761122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Horizontal transmission of functionally diverse transposons is a major source of new introns}, volume = {122}, year = {2025}, }
• (2025). A tethering mechanism underlies pin1-catalyzed proline cis–trans isomerization at a noncanonical site. PNAS, 122(21), e2414606122. (www)

  @article{ , abstract = {The prolyl isomerase Pin1 catalyzes the cis – trans isomerization of proline peptide bonds, a noncovalent posttranslational modification that influences cellular and molecular processes, including protein–protein interactions. Pin1 is a two-domain enzyme containing a WW domain that recognizes phosphorylated serine/threonine-proline (pS/pT-P) canonical motifs and an enzymatic PPIase domain that catalyzes proline cis – trans isomerization of pS/pT-P motifs. Here, we show that Pin1 uses a tethering mechanism to bind and catalyze proline cis – trans isomerization of a noncanonical motif in the disordered N-terminal activation function-1 (AF-1) domain of the human nuclear receptor PPARγ. NMR reveals multiple Pin1 binding regions within the PPARγ AF-1, including a canonical motif (pS112-P113) that when phosphorylated by the kinase ERK2 binds the Pin1 WW domain with high affinity. NMR methods reveal that Pin1 also binds and accelerates cis – trans isomerization of a noncanonical motif containing a tryptophan-proline motif (W39-P40) previously shown to be involved in an interdomain interaction with the C-terminal ligand-binding domain (LBD) of PPARγ. Cellular transcription studies combined with mutagenesis and Pin1 inhibitor treatment reveal a functional role for Pin1-mediated acceleration of cis – trans isomerization of the PPARγ W39-P40 motif. Our data inform a refined model of the Pin1 catalytic mechanism where the WW domain can bind a canonical pS/T-P motif and tether Pin1 to a target, which enables the PPIase domain to exert catalytic cis – trans isomerization at a distal noncanonical site.}, archive = {J_PNAS}, author = {Williams, Christopher C. and Chuck, Jonathan and Munoz-Tello, Paola and Kojetin, Douglas J.}, doi = {10.1073/pnas.2414606122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2414606122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A tethering mechanism underlies pin1-catalyzed proline cis–trans isomerization at a noncanonical site}, volume = {122}, year = {2025}, }
• (2025). Imaging a concussion and the ensuing immune response at the blood–brain barrier. PNAS, 122(21), e2414316122. (www)

  @article{ , abstract = {Concussions can cause debilitating symptoms despite no evidence of structural changes on diagnostic imaging. The cellular events occurring in the brain parenchyma following concussion, especially repetitive concussion, are not well elucidated. We developed a concussion model to induce a confined area of injury without causing frank hemorrhage. Using intravital microscopy, we observe activation of the vasculature that supported neutrophil rolling and platelet adhesion but no overt cellular recruitment from blood into brain parenchyma. Activated resident, not monocyte-derived, macrophages relocated to the injury site via Cx3cr1 and phagocytosed dysfunctional/detached astrocytes via scavenger receptors and TLR4, particularly after repetitive concussion. Additionally, microglia sealed areas of blood–brain barrier (BBB) disruption via purinergic pathways. Using a splitCre approach to dissect microglia and perivascular macrophages, we show that microglial invasion into the injury site is key to reducing BBB disruption. Our data suggest that microglia repair the BBB following concussion, but in doing so significantly alter the cellular ultrastructure of the brain milieu.}, archive = {J_PNAS}, author = {Nguyen, Rita H. and Newton, Michelle and Kratofil, Rachel M. and Scott, Brittney N.V. and Castanheira, Fernanda and Kim, Jung-seok and Ginhoux, Florent and Jung, Steffen and Kubes, Paul}, doi = {10.1073/pnas.2414316122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2414316122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Imaging a concussion and the ensuing immune response at the blood–brain barrier}, volume = {122}, year = {2025}, }
• (2025). Cave records reveal recent origin of north america’s deepest canyon. PNAS, 122(21), e2413069122. (www)

  @article{ , abstract = {We explore how and when Hells Canyon, North America’s deepest river gorge (~2,400 m deep), formed, addressing these fundamental questions first posed by W. Lindgren [ The Gold Belt of the Blue Mountains of Oregon (1901)]. Existing hypotheses about the canyon’s formation and timing of incision remain speculative due to a lack of direct constraints and geomorphic analysis in the canyon. Herein, we combine cosmogenic nuclide dating of cave-bound river deposits, river profile analysis, and numerical modeling to provide the first direct age constraints and systematic analysis of incision processes at work in Hells Canyon. Our study reveals a significant drainage capture triggered rapid incision at ~2.1 ± 1.0 Ma, establishing the Snake River’s modern route into the Columbia River system. The increased drainage area and subsequent increase in stream power resulted in the rapid incision of Hells Canyon and the formation of tributary knickpoints (KPs) that decrease in elevation away from the capture location. Cosmogenic dating of cave deposits indicates incision rates increased from ~0.01 to ~0.16 mm y −1 . Numerical modeling of the stream capture supports these observations, demonstrating how abrupt drainage area increase drives rapid river incision. Our findings from Hells Canyon provide a well-constrained example of how drainage capture can dramatically shape the evolution of a major river gorge.}, archive = {J_PNAS}, author = {Morriss, Matthew C. and Mitchell, Nate A. and Yanites, Brian J. and Staisch, Lydia M. and Korup, Oliver}, doi = {10.1073/pnas.2413069122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2413069122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cave records reveal recent origin of north america’s deepest canyon}, volume = {122}, year = {2025}, }
• (2025). Near-zero photon bioimaging by fusing deep learning and ultralow-light microscopy. PNAS, 122(21), e2412261122. (www)

  @article{ , abstract = {Enhancing the reliability and reproducibility of optical microscopy by reducing specimen irradiance continues to be an important biotechnology target. As irradiance levels are reduced, however, the particle nature of light is heightened, giving rise to Poisson noise, or photon sparsity that restricts only a few (0.5%) image pixels to comprise a photon. Photon sparsity can be addressed by collecting approximately 200 photons per pixel; this, however, requires long acquisitions and, as such, suboptimal imaging rates. Here, we introduce near-zero photon bioimaging, a method that operates at kHz rates and 10,000-fold lower irradiance than standard microscopy. To achieve this level of performance, we uniquely combined a judiciously designed epifluorescence microscope enabling ultralow background levels and AI that learns to reconstruct biological images from as low as 0.01 photons per pixel. We demonstrate that near-zero photon bioimaging captures the structure of multicellular and subcellular features with high fidelity, including features represented by nearly zero photons. Beyond optical microscopy, the near-zero photon bioimaging paradigm can be applied in remote sensing, covert applications, and biomedical imaging that utilize damaging or quantum light.}, archive = {J_PNAS}, author = {Sheneman, Lucas and Balogun, Sulaimon and Johnson, Jill L. and Harrison, Maria J. and Vasdekis, Andreas E.}, doi = {10.1073/pnas.2412261122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2412261122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Near-zero photon bioimaging by fusing deep learning and ultralow-light microscopy}, volume = {122}, year = {2025}, }
• (2025). Learning to estimate sample-specific transcriptional networks for 7,000 tumors. PNAS, 122(21), e2411930122. (www)

  @article{ , abstract = {Cancers are shaped by somatic mutations, microenvironment, and patient background, each altering gene expression and regulation in complex ways, resulting in heterogeneous cellular states and dynamics. Inferring gene regulatory networks (GRNs) from expression data can help characterize this regulation-driven heterogeneity, but network inference requires many statistical samples, limiting GRNs to cluster-level analyses that ignore intracluster heterogeneity. We propose to move beyond coarse analyses of predefined subgroups by using contextualized learning, a multitask learning paradigm that uses multiview contexts including phenotypic, molecular, and environmental information to infer personalized models. With sample-specific contexts, contextualization enables sample-specific models and even generalizes at test time to predict network models for entirely unseen contexts. We unify three network model classes (Correlation, Markov, and Neighborhood Selection) and estimate context-specific GRNs for 7,997 tumors across 25 tumor types, using copy number and driver mutation profiles, tumor microenvironment, and patient demographics as model context. Our generative modeling approach allows us to predict GRNs for unseen tumor types based on a pan-cancer model of how somatic mutations affect gene regulation. Finally, contextualized networks enable GRN-based precision oncology by providing a structured view of expression dynamics at sample-specific resolution, explaining known biomarkers in terms of network-mediated effects and leading to subtypings that improve survival prognosis. We provide a SKLearn-style Python package https://contextualized.ml for learning and analyzing contextualized models, as well as interactive plotting tools for pan-cancer data exploration at https://github.com/cnellington/CancerContextualized .}, archive = {J_PNAS}, author = {Ellington, Caleb N. and Lengerich, Benjamin J. and Watkins, Thomas B. K. and Yang, Jiekun and Adduri, Abhinav K and Mahbub, Sazan and Xiao, Hanxi and Kellis, Manolis and Xing, Eric P.}, doi = {10.1073/pnas.2411930122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2411930122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Learning to estimate sample-specific transcriptional networks for 7,000 tumors}, volume = {122}, year = {2025}, }
• (2025). Ancient DNA suggests a historical demographic decline and genetic erosion in the atlantic bluefin tuna. PNAS, 122(21), e2409302122. (www)

  @article{ , abstract = {Overexploitation has depleted fish stocks during the past century; nonetheless, its genomic consequences remain poorly understood for most species. Characterizing the spatiotemporal patterns of these consequences may provide baseline estimates of past diversity and productivity to aid management targets, help predict future dynamics, and facilitate the identification of evolutionary factors limiting fish population recovery. Here, we evaluate human impacts on the evolution of the iconic Atlantic bluefin tuna ( Thunnus thynnus ), one of the longest and most intensely exploited marine fishes, with a tremendous cultural and economic importance. We sequenced whole genomes from modern (n = 49) and ancient (n = 41) specimens dating up to 5,000 y ago, uncovering several findings. First, we identify temporally stable patterns of population admixture, as bluefin tuna caught off Norway and in the eastern Mediterranean share a greater degree of ancestry with Gulf of Mexico bluefin tuna than western and central Mediterranean bluefin tuna. This suggests that Atlantic spawning areas are important mixing grounds for the genetic diversity of Mediterranean bluefin tuna. We model effective population size to show that Mediterranean bluefin tuna began to undergo a demographic decline by the year 1900 to an extent not observed across the previous millennia. Coinciding with this, we found that heterozygosity and nucleotide diversity were significantly lower in modern (2013 to 2020) than ancient (pre-1941) Mediterranean bluefin tuna, suggesting that bluefin tuna underwent a genetic bottleneck. With this work, we show how ancient DNA provides unique perspectives on ecological complexity with the potential to inform the management and conservation of fishes.}, archive = {J_PNAS}, author = {Andrews, Adam Jon and Eriksen, Emma Falkeid and Star, Bastiaan and Præbel, Kim and Di Natale, Antonio and Malca, Estrella and Onar, Vedat and Aniceti, Veronica and Carenti, Gabriele and Piquès, Gäel and Nielsen, Svein Vatsvåg and Persson, Per and Piattoni, Federica and Fontani, Francesco and Atmore, Lane M. and Kersten, Oliver and Tinti, Fausto and Cilli, Elisabetta and Cariani, Alessia}, doi = {10.1073/pnas.2409302122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2409302122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ancient DNA suggests a historical demographic decline and genetic erosion in the atlantic bluefin tuna}, volume = {122}, year = {2025}, }
• (2025). Empowering safer socially sensitive autonomous vehicles using human-plausible cognitive encoding. PNAS, 122(21), e2401626122. (www)

  @article{ , abstract = {Autonomous vehicles (AVs) will soon cruise our roads as a global undertaking. Beyond completing driving tasks, AVs are expected to incorporate ethical considerations into their operation. However, a critical challenge remains. When multiple road users are involved, their impacts on AV ethical decision-making are distinct yet interrelated. Current AVs lack social sensitivity in ethical decisions, failing to enable both differentiated consideration of road users and a holistic view of their collective impact. Drawing on research in AV ethics and neuroscience, we propose a scheme based on social concern and human-plausible cognitive encoding. Specifically, we first assess the individual impact that each road user poses to the AV based on risk. Then, social concern can differentiate these impacts by weighting the risks according to road user categories. Through cognitive encoding, these independent impacts are holistically encoded into a behavioral belief, which in turn supports ethical decisions that consider the collective impact of all involved parties. A total of two thousand benchmark scenarios from CommonRoad are used for evaluation. Empirical results show that our scheme enables safer and more ethical decisions, reducing overall risk by 26.3%, with a notable 22.9% decrease for vulnerable road users. In accidents, we enhance self-protection by 8.3%, improve protection for all road users by 17.6%, and significantly boost protection for vulnerable road users by 51.7%. As a human-inspired practice, this work renders AVs socially sensitive to overcome future ethical challenges in everyday driving.}, archive = {J_PNAS}, author = {Lu, Hongliang and Zhu, Meixin and Lu, Chao and Feng, Shuo and Wang, Xuesong and Wang, Yinhai and Yang, Hai}, doi = {10.1073/pnas.2401626122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {21}, pages = {e2401626122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Empowering safer socially sensitive autonomous vehicles using human-plausible cognitive encoding}, volume = {122}, year = {2025}, }
• (2025). A half-century of climate change in major agricultural regions: Trends, impacts, and surprises. PNAS, 122(20), e2502789122. (www)

  @article{ , abstract = {Efforts to anticipate and adapt to future climate can benefit from historical experiences. We examine agroclimatic conditions over the past 50 y for five major crops around the world. Most regions experienced rapid warming relative to interannual variability, with 45% of summer and 32% of winter crop area warming by more than two SD (σ). Vapor pressure deficit (VPD), a key driver of plant water stress, also increased in most temperate regions but not in the tropics. Precipitation trends, while important in some locations, were generally below 1σ. Historical climate model simulations show that observed changes in crops’ climate would have been well predicted by models run with historical forcings, with two main surprises: i) models substantially overestimate the amount of warming and drying experienced by summer crops in North America, and ii) models underestimate the increase in VPD in most temperate cropping regions. Linking agroclimatic data to crop productivity, we estimate that climate trends have caused current global yields of wheat, maize, and barley to be 10, 4, and 13% lower than they would have otherwise been. These losses likely exceeded the benefits of CO 2 increases over the same period, whereas CO 2 benefits likely exceeded climate-related losses for soybean and rice. Aggregate global yield losses are very similar to what models would have predicted, with the two biases above largely offsetting each other. Climate model biases in reproducing VPD trends may partially explain the ineffectiveness of some adaptations predicted by modeling studies, such as farmer shifts to longer maturing varieties.}, archive = {J_PNAS}, author = {Lobell, David B. and Di Tommaso, Stefania}, doi = {10.1073/pnas.2502789122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {20}, pages = {e2502789122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A half-century of climate change in major agricultural regions: Trends, impacts, and surprises}, volume = {122}, year = {2025}, }
• (2025). Quadruple adenine base–edited allogeneic CAR t cells outperform CRISPR/Cas9 nuclease–engineered t cells. PNAS, 122(20), e2427216122. (www)

  @article{ , abstract = {Genome-editing technologies have enabled the clinical development of allogeneic cellular therapies, yet the optimal gene-editing modality for multiplex editing of therapeutic T cell product manufacturing remains elusive. In this study, we conducted a comprehensive comparison of CRISPR/Cas9 nuclease and adenine base editor (ABE) technologies in generating allogeneic chimeric antigen receptor (CAR) T cells, utilizing extensive in vitro and in vivo analyses. Both methods achieved high editing efficiencies across four target genes, critical for mitigating graft-versus-host disease and allograft rejection: TRAC or CD3E , B2M , CIITA , and PVR . Notably, ABE demonstrated higher manufacturing yields and distinct off-target profiles compared to Cas9, with translocations observed exclusively in Cas9-edited products. Functionally, ABE-edited CAR T cells exhibited superior in vitro effector functions under continuous antigen stimulation, including enhanced proliferative capacity and increased surface CAR expression. Transcriptomic analysis revealed that ABE editing resulted in reduced activation of p53 and DNA damage response pathways at baseline, along with sustained activation of metabolic pathways during antigen stress. Consistently, Assay for Transposase-Accessible Chromatin using sequencing data indicated that Cas9-edited, but not ABE-edited, CAR T cells showed enrichment of chromatin accessibility peaks associated with double-strand break repair and DNA damage response pathways. In a preclinical leukemia model, ABE-edited CAR T cells demonstrated improved tumor control and extended overall survival compared to their Cas9-edited counterparts. Collectively, these findings position ABE as superior to Cas9 nucleases for multiplex gene editing of therapeutic T cells.}, archive = {J_PNAS}, author = {Engel, Nils W. and Steinfeld, Israel and Ryan, Daniel and Anupindi, Kusala and Kim, Samuel and Wellhausen, Nils and Chen, Linhui and Wilkins, Katherine and Baker, Daniel J. and Rommel, Philipp C. and Jarocha, Danuta and Gohil, Mercy and Zhang, Qian and Milone, Michael C. and Fraietta, Joseph A. and Davis, Megan and Young, Regina M. and June, Carl H.}, doi = {10.1073/pnas.2427216122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {20}, pages = {e2427216122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quadruple adenine base–edited allogeneic CAR t cells outperform CRISPR/Cas9 nuclease–engineered t cells}, volume = {122}, year = {2025}, }
• (2025). A vetiver-specific terpene synthase VzTPS9 contributes to the high attractiveness of vetiver to rice stem borer. PNAS, 122(20), e2424863122. (www)

  @article{ , abstract = {Vetiver ( Vetiveria zizanioides ) is highly attractive to the rice stem borer ( Chilo suppressalis , RSB) and is widely utilized as a trap plant for RSB control in East Asia. However, the underlying mechanism driving this high level of attractiveness remains unclear. In this study, we identified volatiles emitted by vetiver using SPME/GC–MS and found that cedrol constitutes 12.15% of the total volatile profile. Both Y-tube olfactometer and electroantennography assays revealed that cedrol is highly attractive to female RSB moths at a concentration of 200 μg/μL. To investigate the mechanism responsible for the high level of cedrol in vetiver, we sequenced and assembled a chromosome-level genome of vetiver, identifying a vetiver-specific terpene synthase, VzTPS9, which is responsible for the synthesis of cedrol from farnesyl pyrophosphate (FPP). Subsequently, we constructed a transgenic rice line by integrating VzTPS9 into the rice genome. Enzyme assays and gene expression analyses demonstrated that the transgenic rice produced higher levels of cedrol, which were positively correlated with VzTPS9 expression levels, and consequently, with increased attractiveness to female RSB moths. These findings suggest that increased expression of VzTPS9 in vetiver leads to elevated cedrol synthesis, contributing to its enhanced attractiveness to RSB. This work uncovers the molecular mechanism behind vetiver’s high attractiveness to RSB and provides valuable insights for developing more effective strategies for utilizing vetiver as a trap plant in RSB control.}, archive = {J_PNAS}, author = {Li, Qiang and He, Kang and Lu, Yanhui and He, Bingbing and Zheng, Xusong and Lu, Zhongxian and Li, Fei and Xu, Hongxing}, doi = {10.1073/pnas.2424863122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {20}, pages = {e2424863122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A vetiver-specific terpene synthase VzTPS9 contributes to the high attractiveness of vetiver to rice stem borer}, volume = {122}, year = {2025}, }
• (2025). Group traits moderate the relationship between individual social traits and fitness in gorillas. PNAS, 122(20), e2421539122. (www)

  @article{ , abstract = {Evidence across a broad range of disciplines has demonstrated how individuals’ social environments can impact their health, lifespan, reproduction, and ultimately their evolutionary fitness. Past research has primarily focused on either traits specific to individuals or wider traits of social groups, linking these with a component of fitness. In this study, we examined how both individual- and group-level social traits in 164 wild mountain gorillas combine to influence multiple pathways impacting fitness over 21 y. First, we highlight key sex differences in the costs and benefits of social bonds, with strong and stable social bonds linked with lower risk of illness in females, but higher risk of illness in males. Second, we demonstrate important trade-offs in the fitness consequences of sociality, with strong and stable bonds in males linked with decreases in injury but increases in illness. Finally, we show the extensive moderating effects of group-level traits on the fitness consequences of individual-level social traits. For example, in small groups, females with strong bonds benefitted from lower rates of illness, but also showed lower birth rates, while in large groups, females with strong bonds experienced higher rates of illness but also higher birth rates. These findings highlight the complexity of selection acting on social traits, where the fitness consequences of individual’s social phenotypes are highly context dependent. We argue that this variability in the fitness benefits of sociality has likely played a fundamental role in maintaining the wide diversity of social phenotypes observed within species.}, archive = {J_PNAS}, author = {Morrison, Robin E. and Ellis, Samuel and Martignac, Victoire and Stoinski, Tara S. and Eckardt, Winnie}, doi = {10.1073/pnas.2421539122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {20}, pages = {e2421539122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Group traits moderate the relationship between individual social traits and fitness in gorillas}, volume = {122}, year = {2025}, }
• (2025). The fate of south america’s endemic mammalian fauna in response to the most dramatic cenozoic climate disruption. PNAS, 122(20), e2419520122. (www)

  @article{ , abstract = {Around 34 Mya, the Eocene−Oligocene transition (EOT) marked the most dramatic global climatic cooling of the Cenozoic. On a planetary scale, paleontological evidence suggests that this transition was associated with major faunal turnovers, sometimes even regarded as a mass extinction crisis. In South America, there is no consensus on the response of the endemic mammals to this transition. Here, using a vetted fossil dataset and cutting-edge Bayesian methods, we analyzed the dynamics of South American mammal (SAM) diversification and their possible drivers across latitude (tropical vs. extratropical), taxonomic groups, and trophic guilds throughout the Eocene−Oligocene ( ca. 56 to 23 Ma). Our results did not evidence any mass extinction among SAM at the EOT. Instead, they experienced a gradual and long-term diversity decline from the middle Eocene to the early Oligocene, followed by a sudden waxing-and-waning diversity associated with a large taxonomic—but not ecological—turnover. Tropical and extratropical lineages have had very distinct macroevolutionary histories. No effective change in the pace at which tropical lineages diversify was found, thus favoring the tropical stability hypothesis proposed by Wallace. Diversity-dependent effects, temperature, and Andean uplift were recovered as probable drivers of SAM diversification across the period. Contrasting evidence casts doubt on the common hypothesis primarily linking Oligocene faunal changes to grassland expansion. Our findings illustrate the uniqueness of the deep-time interplay between endemic SAM and their physical environment in a context of climatic shift, highlighting the need to consider regional idiosyncrasies for understanding the coevolution of life and climate.}, archive = {J_PNAS}, author = {Buffan, Lucas and Condamine, Fabien L. and Stutz, Narla S. and Pujos, François and Antoine, Pierre-Olivier and Marivaux, Laurent}, doi = {10.1073/pnas.2419520122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {20}, pages = {e2419520122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The fate of south america’s endemic mammalian fauna in response to the most dramatic cenozoic climate disruption}, volume = {122}, year = {2025}, }
• (2025). Ecosystem relocation on snowball earth: Polar−alpine ancestry of the extant surface biosphere?. PNAS, 122(20), e2414059122. (www)

  @article{ , abstract = {Geological observations informed by climate dynamics imply that the oceans were 99.9% covered by light-blocking ice shelves during two discrete, self-reversing Snowball Earth epochs spanning a combined 60 to 70 Myr of the Cryogenian Period (720 to 635 Ma). The timescale for initial ice advances across the tropical oceans is ~300 y in an ice−atmosphere−ocean general circulation model in Cryogenian paleogeography. Areas of optically thin oceanic ice are usually invoked to account for fossil marine phototrophs, including macroscopic multicellular eukaryotes, before and after each Snowball, but different taxa. Ecosystem relocation is a scenario that does not require thin marine ice. Assume that long before Cryogenian Snowballs, diverse supra- and periglacial biomes were established in polar−alpine regions. When the Snowball onsets occurred, those biomes migrated in step with their ice margins to the equatorial zone of net sublimation. There, they prospered and evolved, their habitat areas expanded, and the cruelty of winter reduced. Nutrients were supplied by dust (loess) derived from cozonal ablative lands where surface winds were strong. When each Snowball finally ended, those biomes were mostly inundated by the meltwater-dominated and rapidly warming lid of a nutrient-rich but depauperate ocean. Some taxa returned to the mountaintops while others restocked the oceans. This ecosystem relocation scenario makes testable predictions. The lineages required for post-Cryogenian biotic radiations should be present in modern polar−alpine biomes. Legacies of polar−alpine ancestry should be found in the genomes of living organisms. Examples of such tests are highlighted herein.}, archive = {J_PNAS}, author = {Hoffman, Paul F.}, doi = {10.1073/pnas.2414059122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {20}, pages = {e2414059122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ecosystem relocation on snowball earth: Polar−alpine ancestry of the extant surface biosphere?}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for jensen et al., Bcl2L13 is a ceramide synthase inhibitor in glioblastoma. PNAS, 122(19), e2507673122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2507673122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2507673122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for jensen et al., Bcl2L13 is a ceramide synthase inhibitor in glioblastoma}, volume = {122}, year = {2025}, }
• (2025). Reply to compton et al.: Paradoxical misunderstanding. PNAS, 122(19), e2507210122. (www)

  @article{ , archive = {J_PNAS}, author = {Butler, George and Baker, Joanna and Amend, Sarah R. and Pienta, Kenneth J. and Venditti, Chris}, doi = {10.1073/pnas.2507210122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2507210122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to compton et al.: Paradoxical misunderstanding}, volume = {122}, year = {2025}, }
• (2025). MiR218-5p tips the scales. PNAS, 122(19), e2506039122. (www)

  @article{ , archive = {J_PNAS}, author = {Diering, Graham H.}, doi = {10.1073/pnas.2506039122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2506039122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MiR218-5p tips the scales}, volume = {122}, year = {2025}, }
• (2025). Refining the role of the paraventricular hypothalamus in feeding behavior. PNAS, 122(19), e2506038122. (www)

  @article{ , archive = {J_PNAS}, author = {Fang, Lisa Z. and Hirasawa, Michiru}, doi = {10.1073/pnas.2506038122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2506038122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Refining the role of the paraventricular hypothalamus in feeding behavior}, volume = {122}, year = {2025}, }
• (2025). Eat, flee, freeze: Division of labor in the larval zebrafish visuomotor system. PNAS, 122(19), e2506018122. (www)

  @article{ , archive = {J_PNAS}, author = {Wang, Qing and Baier, Herwig}, doi = {10.1073/pnas.2506018122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2506018122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Eat, flee, freeze: Division of labor in the larval zebrafish visuomotor system}, volume = {122}, year = {2025}, }
• (2025). Structural insights into the ubiquitin-independent midnolin-proteasome pathway. PNAS, 122(19), e2505345122. (www)

  @article{ , abstract = {The protein midnolin (MIDN) augments proteasome activity in lymphocytes and dramatically facilitates the survival and proliferation of B-lymphoid malignancies. MIDN binds both to proteasomes and to substrates, but the mode of interaction with the proteasome is unknown, and the mechanism by which MIDN facilitates substrate degradation in a ubiquitin-independent manner is incompletely understood. Here, we present cryoelectron microscopy (cryo-EM) structures of the substrate-engaged, MIDN-bound human proteasome in two conformational states. MIDN induces proteasome conformations similarly to ubiquitinated substrates by using its ubiquitin-like domain to bind to the deubiquitinase RPN11 (PSMD14). By simultaneously binding to RPN1 (PSMD2) with its C-terminal α-helix, MIDN positions its substrate-carrying Catch domain above the proteasome ATPase channel through which substrates are translocated before degradation. Our findings suggest that both ubiquitin-like domain and C-terminal α-helix must bind to the proteasome for MIDN to stimulate proteasome activity.}, archive = {J_PNAS}, author = {Peddada, Nagesh and Zhong, Xue and Yin, Yan and Lazaro, Danielle Renee and Wang, Jianhui and Lyon, Stephen and Choi, Jin Huk and Bai, Xiao-chen and Moresco, Eva Marie Y. and Beutler, Bruce}, doi = {10.1073/pnas.2505345122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2505345122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural insights into the ubiquitin-independent midnolin-proteasome pathway}, volume = {122}, year = {2025}, }
• (2025). Reply to wang and wang: Exploring TCM evolution from the perspective of recombinant inventions and the data. PNAS, 122(19), e2505067122. (www)

  @article{ , archive = {J_PNAS}, author = {Wu, Min and Ma, Tieju and Zhu, Yan and Ren, Hongtao and Fu, Lu}, doi = {10.1073/pnas.2505067122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2505067122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to wang and wang: Exploring TCM evolution from the perspective of recombinant inventions and the data}, volume = {122}, year = {2025}, }
• (2025). Architecture of pseudomonas aeruginosa glutamyl-tRNA synthetase defines a subfamily of dimeric class ib aminoacyl-tRNA synthetases. PNAS, 122(19), e2504757122. (www)

  @article{ , abstract = {The aminoacyl-tRNA synthetases (AaRSs) are an ancient family of structurally diverse enzymes that are divided into two major classes. The functionalities of most AaRSs are inextricably linked to their oligomeric states. While GluRSs were previously classified as monomers, the current investigation reveals that the form expressed in Pseudomonas aeruginosa is a rotationally pseudosymmetrical homodimer featuring intersubunit tRNA binding sites. Both subunits display a highly bent, “pipe strap” conformation, with the anticodon binding domain directed toward the active site. The tRNA binding sites are similar in shape to those of the monomeric GluRSs, but are formed through an approximately 180-degree rotation of the anticodon binding domains and dimerization via the anticodon and D-arm binding domains. As a result, each anticodon binding domain is poised to recognize the anticodon loop of a tRNA bound to the adjacent protomer. Additionally, the anticodon binding domain has an α-helical C -terminal extension containing a conserved lysine-rich consensus motif positioned near the predicted location of the acceptor arm, suggesting dual functions in tRNA recognition. The unique architecture of Pa GluRS broadens the structural diversity of the GluRS family, and member synthetases of all bacterial AaRS subclasses have now been identified that exhibit oligomerization.}, archive = {J_PNAS}, author = {Fenwick, Michael K. and Mayclin, Stephen J. and Seibold, Steve and DeRocher, Amy E. and Subramanian, Sandhya and Phan, Isabelle Q. and Dranow, David M. and Lorimer, Donald D. and Abramov, Ariel B. and Choi, Ryan and Hewitt, Stephen Nakazawa and Edwards, Thomas E. and Bullard, James M. and Battaile, Kevin P. and Wower, Iwona K. and Soe, Aimee C. and Tsutakawa, Susan E. and Lovell, Scott and Myler, Peter J. and Wower, Jacek and Staker, Bart L.}, doi = {10.1073/pnas.2504757122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2504757122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Architecture of pseudomonas aeruginosa glutamyl-tRNA synthetase defines a subfamily of dimeric class ib aminoacyl-tRNA synthetases}, volume = {122}, year = {2025}, }
• (2025). Paradoxical indeed. PNAS, 122(19), e2504512122. (www)

  @article{ , archive = {J_PNAS}, author = {Compton, Zachary T. and Vincze, Orsolya and Mellon, Walker and Tollis, Marc and Abegglen, Lisa and Schiffman, Joshua D. and Giraudeau, Mathieu and Boddy, Amy M. and Maley, Carlo C.}, doi = {10.1073/pnas.2504512122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2504512122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Paradoxical indeed}, volume = {122}, year = {2025}, }
• (2025). Mechanism and application of thiol–disulfide redox biosensors with a fluorescence-lifetime readout. PNAS, 122(19), e2503978122. (www)

  @article{ , abstract = {Genetically encoded biosensors with changes in fluorescence lifetime (as opposed to fluorescence intensity) can quantify small molecules in complex contexts, even in vivo. However, lifetime-readout sensors are poorly understood at a molecular level, complicating their development. Although there are many sensors that have fluorescence-intensity changes, there are currently only a few with fluorescence-lifetime changes. Here, we optimized two biosensors for thiol–disulfide redox (RoTq-Off and RoTq-On) with opposite changes in fluorescence lifetime in response to oxidation. Using biophysical approaches, we showed that the high-lifetime states of these sensors lock the chromophore more firmly in place than their low-lifetime states do. Two-photon fluorescence lifetime imaging of RoTq-On fused to a glutaredoxin (Grx1) enabled robust, straightforward monitoring of cytosolic glutathione redox state in acute mouse brain slices. The motional mechanism described here is probably common and may inform the design of other lifetime-readout sensors; the Grx1-RoTq-On fusion sensor will be useful for studying glutathione redox in physiology.}, archive = {J_PNAS}, author = {Rosen, Paul C. and Glaser, Andrew and Martínez-François, Juan R. and Lim, Daniel C. and Brooks, Daniel J. and Fu, Panhui and Kim, Erica and Kern, Dorothee and Yellen, Gary}, doi = {10.1073/pnas.2503978122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2503978122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mechanism and application of thiol–disulfide redox biosensors with a fluorescence-lifetime readout}, volume = {122}, year = {2025}, }
• (2025). Methodological and conceptual considerations of the TCM evolution. PNAS, 122(19), e2503785122. (www)

  @article{ , archive = {J_PNAS}, author = {Wang, Haiyan and Wang, Yanbing}, doi = {10.1073/pnas.2503785122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2503785122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Methodological and conceptual considerations of the TCM evolution}, volume = {122}, year = {2025}, }
• (2025). Early development of navigationally relevant location information in the retrosplenial complex. PNAS, 122(19), e2503569122. (www)

  @article{ , abstract = {Representing the locations of places so that we can use them as landmarks is critical to our ability to navigate through large-scale spaces—a process referred to as “map-based navigation.” While many neuroimaging studies in adults have revealed that this ability involves the retrosplenial complex (RSC)—a scene-selective region in the medial parietal cortex—nothing is known about how this cortical system develops. So, does it develop only late in childhood, as generally assumed from some behavioral studies? Or is it, perhaps counterintuitively, present in the first few years of life? To test this question, using functional magnetic resonance imaging (fMRI) multivoxel pattern analysis and a virtual town paradigm, we investigated the representation of location information in the RSC of 5-y-olds. We found that i) the RSC in 5-y-olds already represents the locations of particular buildings in the town (e.g., the ice cream store by the mountain versus by the lake), but not their category membership (e.g., ice cream store, regardless of location), and ii) this neural representation is correlated with their performance on a location task. Using multidimensional scaling, we also found that the neural representation of the buildings in RSC reflects the actual layout of the virtual town. Finally, the parahippocampal place area—a scene-selective region implicated in scene categorization, not map-based navigation—did not represent location information, but instead category information, the exact opposite of RSC. Taken together, these findings reveal the early development of navigationally relevant location information in RSC and thus the early origins of map-based navigation.}, archive = {J_PNAS}, author = {Jung, Yaelan and Dilks, Daniel D.}, doi = {10.1073/pnas.2503569122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2503569122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Early development of navigationally relevant location information in the retrosplenial complex}, volume = {122}, year = {2025}, }
• (2025). Inheritance of extraordinary metabolic activity from parental bacteria individuals. PNAS, 122(19), e2502818122. (www)

  @article{ , abstract = {Many phenotypic traits, such as fermentation activity, have been shown to be instable due to stochastic gene expression and environmental influence. While previous studies only have obtained understanding at the level of the microbial community, the fate of extraordinary traits of an individual through generations of reproduction has yet to be adequately investigated. This work uses the lactic acid bacteri Lactiplantibacillus plantarum as a research model to study the activity inheritance between parental generations and filial generations. An integrated single-cell manipulation strategy is established, including fluorescent screening using an extracellular pH probe and a microwell array, micropicking using a micropipette, and amplifying an individual bacterium via single-cell culture. Consequently, it is found that daughter bacteria can well inherit the strong acid-producing activity from their parental bacterial individuals, although as the reproduction proceeds over 30 generations, the offspring gradually regresses to the mediocre, thus setting a caveat for the limiting generations for desired inheritance. This is likely due to the deterioration of the cell living environment. This work illustrates the inheritable features of bacterial metabolic traits at the level of individual bacteria and is therefore fundamentally insightful for biotechnological applications like bioenergy production that require consistent or at least predictable metabolic performance.}, archive = {J_PNAS}, author = {Lu, Yuyang and Gao, Jia and Xie, Ruo-Chen and Su, Hua and Zhang, Yaoyao and Wang, Wei}, doi = {10.1073/pnas.2502818122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2502818122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inheritance of extraordinary metabolic activity from parental bacteria individuals}, volume = {122}, year = {2025}, }
• (2025). Molecular insights into de novo small-molecule recognition by an intron RNA structure. PNAS, 122(19), e2502425122. (www)

  @article{ , abstract = {Despite the promise of vastly expanding the druggable genome, rational design of RNA-targeting ligands remains challenging as it requires the rapid identification of hits and visualization of the resulting cocomplexes for guiding optimization. Here, we leveraged high-throughput screening, medicinal chemistry, and structural biology to identify a de novo splicing inhibitor against a large and highly folded fungal group I intron. High-resolution cryoEM structures of the intron in different liganded states not only reveal molecular interactions that rationalize experimental structure–activity relationship but also shed light on a unique strategy whereby RNA-associated metal ions and RNA conformation exhibit exceptional plasticity in response to small-molecule binding. This study reveals general principles that govern RNA–ligand recognition, the interplay between chemical bonding specificity, and dynamic responses within an RNA target.}, archive = {J_PNAS}, author = {Liu, Tianshuo and Xu, Ling and Chung, Kevin and Sisto, Luke J. and Hwang, Jimin and Zhang, Chengxin and Van Zandt, Michael C. and Pyle, Anna Marie}, doi = {10.1073/pnas.2502425122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2502425122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular insights into de novo small-molecule recognition by an intron RNA structure}, volume = {122}, year = {2025}, }
• (2025). Persistent pseudopod splitting is an effective chemotaxis strategy in shallow gradients. PNAS, 122(19), e2502368122. (www)

  @article{ , abstract = {Single-cell organisms and various cell types use a range of motility modes when following a chemical gradient, but it is unclear which mode is best suited for different gradients. Here, we model directional decision-making in chemotactic amoeboid cells as a stimulus-dependent actin recruitment contest. Pseudopods extending from the cell body compete for a finite actin pool to push the cell in their direction until one pseudopod wins and determines the direction of movement. Our minimal model provides a quantitative understanding of the strategies cells use to reach the physical limit of accurate chemotaxis, aligning with data without explicit gradient sensing or cellular memory for persistence. To generalize our model, we employ reinforcement learning optimization to study the effect of pseudopod suppression, a simple but effective cellular algorithm by which cells can suppress possible directions of movement. Different pseudopod-based chemotaxis strategies emerge naturally depending on the environment and its dynamics. For instance, in static gradients, cells can react faster at the cost of pseudopod accuracy, which is particularly useful in noisy, shallow gradients where it paradoxically increases chemotactic accuracy. In contrast, in dynamics gradients, cells form de novo pseudopods. Overall, our work demonstrates mechanical intelligence for high chemotaxis performance with minimal cellular regulation.}, archive = {J_PNAS}, author = {Alonso, Albert and Kirkegaard, Julius B. and Endres, Robert G.}, doi = {10.1073/pnas.2502368122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2502368122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Persistent pseudopod splitting is an effective chemotaxis strategy in shallow gradients}, volume = {122}, year = {2025}, }
• (2025). Hdac1 as an early determinant of intermediate-exhausted CD8+ t cell fate in chronic viral infection. PNAS, 122(19), e2502256122. (www)

  @article{ , abstract = {The exhausted CD8 + T (T EX ) cells consist of distinct subsets including Tcf1 + stem-like, Tcf1 – Cx3cr1 + intermediate (T EX -int) and Tcf1 – Cx3cr1 – terminally exhausted cells; yet, epigenetic determinants of T EX subset differentiation remain incompletely understood. Using chronic viral infection, we show that histone deacetylase 1 (Hdac1) was specifically required for the formation of antigen-specific T EX -int cells at the effector phase of responses. Single-cell transcriptomics validated that Hdac1 deficiency depleted T EX -int cells and revealed that Hdac1 was critical for positive regulation of T EX -int-characteristic genes, including Cx3cr1 , Cxcr6 , and Klf2 . Furthermore, profiling chromatin accessibility landscape in T EX subsets demonstrated that loss of Hdac1 resulted in a prevalent increase in chromatin open state, as evidently observed at the exhaustion program genes, which were linked to induced expression of exhaustion-inducing Tox transcription factor, PD1 and Lag3 coinhibitory receptors in T EX cells. Hdac1 thus has dual regulatory functions: promoting T EX -int cell fate and preventing excessive activation of the exhaustion program to curtail uncontrolled virus replication.}, archive = {J_PNAS}, author = {Hu, Wei and Shawn Hu, Shengen and Zhu, Shaoqi and Peng, Weiqun and Badovinac, Vladimir P. and Zang, Chongzhi and Zhao, Xudong and Xue, Hai-Hui}, doi = {10.1073/pnas.2502256122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2502256122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hdac1 as an early determinant of intermediate-exhausted CD8+ t cell fate in chronic viral infection}, volume = {122}, year = {2025}, }
• (2025). Conversion of social organization in fire ants induced by few colony members: Unmasking indirect genetic effects. PNAS, 122(19), e2501740122. (www)

  @article{ , abstract = {Genes and the environment jointly shape individual traits, but the influence of indirect genetic effects (IGEs), arising from the genetic composition of interacting conspecific individuals, is often ignored or underemphasized. Moreover, because of practical challenges in characterizing IGEs, empirical research has fallen behind theoretical advancement. The fire ant Solenopsis invicta offers a uniquely suitable study system due to its distinct colony-level phenotypic variation (monogyne and polygyne social forms) attributed to IGEs of a social-supergene variant ( b allele). A minority of b -carrying workers ( Bb genotype) can trigger colony-level conversion from monogyne (single queen per colony) to polygyne (multiple queens per colony) behavior. This study investigated the mechanisms underlying this process via 400-ant microcolonies. We first showed that assimilated Bb workers reduce aggression by host BB workers toward Bb queens, thus inducing polygyny, at rates observed earlier in experiments that used full-size (>20,000 ants) colonies. We then demonstrated that social conversion is facilitated by cuticular contact between the worker types, and verified the presence of nonvolatile cuticular pheromones that are necessary but not sufficient components underpinning this process. Follow-up experiments suggested that a second, polygyne worker-produced pheromone that is only released once such workers detect a Bb queen is also necessary but again insufficient, for full expression of the conversion phenomenon. Thus, multiple pheromonal components linked to presence of the b supergene allele in colony workers appear to be involved in shaping social environments and thereby inducing, via IGEs, the transformation from monogyne to polygyne fire ant societies.}, archive = {J_PNAS}, author = {Zeng, Haolin and Ross, Kenneth G. and Sasaki, Takao}, doi = {10.1073/pnas.2501740122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2501740122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Conversion of social organization in fire ants induced by few colony members: Unmasking indirect genetic effects}, volume = {122}, year = {2025}, }
• (2025). Population imaging of enterochromaffin cell activity reveals regulation by somatostatin. PNAS, 122(19), e2501525122. (www)

  @article{ , abstract = {Sensory enteroendocrine cells in the intestinal epithelium detect and relay information about the luminal environment to other cells within and outside the gut. Serotonergic enterochromaffin (EC) cells are a subset of enteroendocrine cells that detect noxious stimuli within the gut lumen, such as chemical irritants and microbial byproducts, and transduce this information to sensory nerve fibers to elicit defensive responses such as nausea and visceral pain. While much has recently been learned about the pharmacological and biophysical characteristics of EC cells, a more broadscale investigation of their properties has been hindered by their relatively low prevalence and sparse anatomical distribution within the gut epithelium. Here, we introduce a method for large-scale parallel analysis of individual EC cell activity within a physiologically relevant epithelial context. Using this approach, we identify somatostatin-28 as a potent inhibitor of both basal and stimulus-evoked serotonin release from EC cells and delineate the signaling pathway that underlies this modulatory response. Our analysis suggests that targeting this inhibitory signaling pathway may offer therapeutic avenues for treating gastrointestinal disorders associated with EC cell function and dysregulated serotonin signaling. Together with the ongoing development of specific biosensors, this platform provides a template for the efficient characterization of other rare sensory cell types and their pharmacological modulators.}, archive = {J_PNAS}, author = {Rossen, Nathan D. and Touhara, Kouki K. and Castro, Joel and Harrington, Andrea M. and Caraballo, Sonia Garcia and Deng, Fei and Li, Yulong and Brierley, Stuart M. and Julius, David}, doi = {10.1073/pnas.2501525122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2501525122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Population imaging of enterochromaffin cell activity reveals regulation by somatostatin}, volume = {122}, year = {2025}, }
• (2025). Coupling between electrons’ spin and proton transfer in chiral biological crystals. PNAS, 122(19), e2500584122. (www)

  @article{ , abstract = {Proton transport plays a fundamental role in many biological and chemical systems. In life, proton transport is crucial for biochemical and physiological functions. It is usually accepted that the main mechanism of proton transfer is a result of hopping between neighboring water molecules and amino acid side chains. It was recently suggested that the proton transfer can be simultaneously coupled with electron transfer. As life is homochiral, proton transfer in biology is occurring in a chiral environment. In this environment, the chiral-induced spin selectivity effect relating to electron transfer and chirality is expected to occur. The present work establishes that the proton transfer is coupled to a specific electron spin polarization in lysozyme crystals, associating proton transfer to electron movement and polarization. To preserve total angular momentum, this motion may be coupled to chiral phonons that propagate in the crystal. Our work shows that the interaction of the electrons’ spin and phonons is very significant in proton transfer through lysosome crystals. Injecting the opposite electron spin into the lysosome crystal results in a significant change in proton transfer impedance. This study presents the support for the proton-coupled electron transfer mechanism and indicates the importance of spin polarization in the process.}, archive = {J_PNAS}, author = {Goren, Naama and Pandurangan, Perumal and Eisenberg-Domovich, Yael and Yochelis, Shira and Keren, Nir and Ansermet, Jean-Philippe and Naaman, Ron and Livnah, Oded and Ashkenasy, Nurit and Paltiel, Yossi}, doi = {10.1073/pnas.2500584122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2500584122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Coupling between electrons’ spin and proton transfer in chiral biological crystals}, volume = {122}, year = {2025}, }
• (2025). Accurate, scalable, and fully automated inference of species trees from raw genome assemblies using ROADIES. PNAS, 122(19), e2500553122. (www)

  @article{ , abstract = {Current genome sequencing initiatives across a wide range of life forms offer significant potential to enhance our understanding of evolutionary relationships and support transformative biological and medical applications. Species trees play a central role in many of these applications; however, despite the widespread availability of genome assemblies, accurate inference of species trees remains challenging due to the limited automation, substantial domain expertise, and computational resources required by conventional methods. To address this limitation, we present ROADIES, a fully automated pipeline to infer species trees starting from raw genome assemblies. In contrast to the prominent approach, ROADIES incorporates a unique strategy of randomly sampling segments of the input genomes to generate gene trees. This eliminates the need for predefining a set of loci, limiting the analyses to a fixed number of genes, and performing the cumbersome gene annotation and/or whole genome alignment steps. ROADIES also eliminates the need to infer orthology by leveraging existing discordance-aware methods that allow multicopy genes. Using the genomic datasets from large-scale sequencing efforts across four diverse life forms (placental mammals, pomace flies, birds, and budding yeasts), we show that ROADIES infers species trees that are comparable in quality to the state-of-the-art studies but in a fraction of the time and effort, including on challenging datasets with rampant gene tree discordance and complex polyploidy. With its speed, accuracy, and automation, ROADIES has the potential to vastly simplify species tree inference, making it accessible to a broader range of scientists and applications.}, archive = {J_PNAS}, author = {Gupta, Anshu and Mirarab, Siavash and Turakhia, Yatish}, doi = {10.1073/pnas.2500553122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2500553122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Accurate, scalable, and fully automated inference of species trees from raw genome assemblies using ROADIES}, volume = {122}, year = {2025}, }
• (2025). Synergistic regulation of metal–organic cage architectures via temperature- and solvent-driven atropisomerism. PNAS, 122(19), e2500357122. (www)

  @article{ , abstract = {Regulating multistimulus responses in artificial systems remains a challenge in smart material development. We present a versatile chemical switching system that precisely controls the self-assembly of metal–organic cages via temperature and solvent changes. The key component, cyclo[2](1,3-(4,6-dimethyl)benzene) (4-pyridine)[6](1,3-(4,6-dimethyl)benzene) ( CP2 ), was generated as three atropisomers ( 1 , 2 , and 3 ) with C s , C 1 , and C 2v symmetries. Thermally, metastable isomers ( 1 and 2 ) convert into the stable isomer ( 3 ), which reacts with Pd 2+ to form specific molecular cages. Depending on the solvent, either rectangular M 2 L 2 cages ( 5′ and 5 ) form in 1,4-dioxane or hexagonal M 3 L 3 cages ( 6 ) in 1,1′,2,2′-tetrachloroethane. The solvent dictates the cage type and enables reversible transformation between cages 5 and 6 . Additionally, cage 5 ′, formed from metastable isomer 1 , can switch to other cage types (i.e., 5 or 6 ) depending on temperature and solvent conditions. This multipathway system offers a precise strategy for controlling self-assembly in smart materials.}, archive = {J_PNAS}, author = {Liang, Jiaqi and Peng, Li-Jun and Zhu, Ke-Lin and Li, Zhi-Ao and Chen, Xu-Lang and Yang, Yu-Dong and Li, Qian and Bi, Qian-Nan and Cui, Jie and Guan, Ai-Jiao and Liang, Tong-Ling and Hao, Xiang and Wang, Heng and Li, Xiaopeng and Gong, Han-Yuan}, doi = {10.1073/pnas.2500357122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2500357122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synergistic regulation of metal–organic cage architectures via temperature- and solvent-driven atropisomerism}, volume = {122}, year = {2025}, }
• (2025). The SIK3-N783Y mutation is associated with the human natural short sleep trait. PNAS, 122(19), e2500356122. (www)

  @article{ , abstract = {Sleep is an essential component of our daily life. A mutation in human salt induced kinase 3 (hSIK3), which is critical for regulating sleep duration and depth in rodents, is associated with natural short sleep (NSS), a condition characterized by reduced daily sleep duration in human subjects. This NSS hSIK3-N783Y mutation results in diminished kinase activity in vitro. In a mouse model, the presence of the NSS hSIK3-N783Y mutation leads to a decrease in sleep time and an increase in electroencephalogram delta power. At the phosphoproteomic level, the SIK3-N783Y mutation induces substantial changes predominantly at synaptic sites. Bioinformatic analysis has identified several sleep-related kinase alterations triggered by the SIK3-N783Y mutation, including changes in protein kinase A and mitogen-activated protein kinase. These findings underscore the conserved function of SIK3 as a critical gene in human sleep regulation and provide insights into the kinase regulatory network governing sleep.}, archive = {J_PNAS}, author = {Chen, Hongmin and Xing, Ye and Wan, Chunyan and Zhang, Zheng and Shi, Zhu and Liang, Yutao and Jin, Chunlai and Chen, Yating and Zhou, Xia and Xu, Junyu and Ptáček, Louis J. and Fu, Ying-Hui and Shi, Guangsen}, doi = {10.1073/pnas.2500356122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2500356122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The SIK3-N783Y mutation is associated with the human natural short sleep trait}, volume = {122}, year = {2025}, }
• (2025). In silico machine learning–enabled detection of polycyclic aromatic hydrocarbons from contaminated soil. PNAS, 122(19), e2427069122. (www)

  @article{ , abstract = {The detection and identification of polycyclic aromatic hydrocarbons (PAHs) and their modified derivatives in contaminated soil is challenging due to the chemical and microbial complexity of soil organic matter. To address these challenges, we developed an innovative analytical approach that combines Surface-enhanced Raman spectroscopy with a Raman spectral library constructed in silico using density functional theory (DFT)-calculated spectra. This method overcomes several limitations associated with traditional experimental libraries, including spectral background interference, solvent effects, and commercially unavailable or challenging to synthesize compounds. Our methodology employs a physics-informed machine learning pipeline that operates in two stages: the characteristic peak extraction (CaPE) algorithm, which isolates distinctive spectral features, and the characteristic peak similarity (CaPSim) algorithm, which identifies analytes with high robustness to spectral shifts and amplitude variations. Validation of this approach showed strong similarity values (>0.6) between DFT-calculated and experimental Surface-enhanced Raman spectra for multiple PAHs, confirming its accuracy and discriminative capability. This study establishes the viability of DFT-calculated spectra as reliable references for identifying analytes that lack experimental reference spectra, including those formed through environmental modification of PAHs. This advancement addresses a critical gap in environmental monitoring, providing a valuable tool for assessing public health risks associated with these contaminants.}, archive = {J_PNAS}, author = {Ju, Yilong and Neumann, Oara and Denison, Sara B. and Jin, Peixuan and Sanchez-Alvarado, Andres B. and Nordlander, Peter and Senftle, Thomas P. and Alvarez, Pedro J. J. and Patel, Ankit and Halas, Naomi J.}, doi = {10.1073/pnas.2427069122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2427069122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In silico machine learning–enabled detection of polycyclic aromatic hydrocarbons from contaminated soil}, volume = {122}, year = {2025}, }
• (2025). Ab initio stability predictions for rare earth oxyphosphates and experimental confirmation of cerium (III) phases. PNAS, 122(19), e2426921122. (www)

  @article{ , abstract = {Rare earth oxyphosphates represent a large family of compounds with the general formula (RE 2 O 3 ) x (REPO 4 ), where RE refers to lanthanides and yttrium. At least four known stoichiometries have been established, each with distinct structures. These compounds have potential applications as refractory coatings, catalysts, and magnetic materials. We modeled the stability of RE 3 PO 7 [RE 3 (PO 4 )O 3 ] with respect to rare earth sesquioxides (RE 2 O 3 ) and orthophosphates (REPO 4 ) using DFT computations with the GGA-PBE and r2SCAN exchange-correlation functionals. Phase stability predictions were consistent between the two functionals, while r2SCAN calculations of formation enthalpies for REPO 4 showed better agreement with experimental data. RE 3 PO 7 phases for La–Dy were predicted to be stable at 0 K, with a space group change from Cm to C 2 /m starting with Sm. RE 3 PO 7 phases for Y, Ho, and Er were found to be stabilized by lattice vibrational entropies at temperatures above 800 K, 1,000 K, and 1,600 K, respectively. The formation of predicted cerium (III) oxyphosphate, isostructural to Nd 3 (PO) 4 O 3 , was confirmed through laser melting of monazite (CePO 4 ). Ce 3 (PO 4 )O 3 is monoclinic (space group Cm ) with experimentally measured cell parameters a = 12.989(1) Å, b = 13.413(1) Å, c = 12.396(1) Å, β = 108.06(1)°. The existence of a Ce member of RE 7 P 3 O 18 family with unknown structure was experimentally established. This work invites further exploration of RE oxyphosphates as functional materials and indicates the possible formation of Ce oxyphosphate upon monazite melting during impact events and their potential use in geothermometry.}, archive = {J_PNAS}, author = {Wang, Edric X. and Ushakov, Sergey V. and Wang, Ligen and Matteucci, Jared and Xu, Hongwu and Opila, Elizabeth J. and Hong, Qi-Jun and Navrotsky, Alexandra}, doi = {10.1073/pnas.2426921122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2426921122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ab initio stability predictions for rare earth oxyphosphates and experimental confirmation of cerium (III) phases}, volume = {122}, year = {2025}, }
• (2025). Evidence of a social evaluation penalty for using AI. PNAS, 122(19), e2426766122. (www)

  @article{ , abstract = {Despite the rapid proliferation of AI tools, we know little about how people who use them are perceived by others. Drawing on theories of attribution and impression management, we propose that people believe they will be evaluated negatively by others for using AI tools and that this belief is justified. We examine these predictions in four preregistered experiments (N = 4,439) and find that people who use AI at work anticipate and receive negative evaluations regarding their competence and motivation. Further, we find evidence that these social evaluations affect assessments of job candidates. Our findings reveal a dilemma for people considering adopting AI tools: Although AI can enhance productivity, its use carries social costs.}, archive = {J_PNAS}, author = {Reif, Jessica A. and Larrick, Richard P. and Soll, Jack B.}, doi = {10.1073/pnas.2426766122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2426766122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evidence of a social evaluation penalty for using AI}, volume = {122}, year = {2025}, }
• (2025). Quantitative spatial analysis of chromatin biomolecular condensates using cryoelectron tomography. PNAS, 122(19), e2426449122. (www)

  @article{ , abstract = {Phase separation is an important mechanism to generate certain biomolecular condensates and organize the cell interior. Condensate formation and function remain incompletely understood due to difficulties in visualizing the condensate interior at high resolution. Here, we analyzed the structure of biochemically reconstituted chromatin condensates through cryoelectron tomography. We found that traditional blotting methods of sample preparation were inadequate, and high-pressure freezing plus focused ion beam milling was essential to maintain condensate integrity. To identify densely packed molecules within the condensate, we integrated deep learning–based segmentation with context-aware template matching. Our approaches were developed on chromatin condensates and were also effective on condensed regions of in situ native chromatin. Using these methods, we determined the average structure of nucleosomes to 6.1 and 12 Å resolution in reconstituted and native systems, respectively, found that nucleosomes form heterogeneous interaction networks in both cases, and gained insight into the molecular origins of surface tension in chromatin condensates. Our methods should be applicable to biomolecular condensates containing large and distinctive components in both biochemical reconstitutions and certain cellular systems.}, archive = {J_PNAS}, author = {Zhou, Huabin and Hutchings, Joshua and Shiozaki, Momoko and Zhao, Xiaowei and Doolittle, Lynda K. and Yang, Shixin and Yan, Rui and Jean, Nikki and Riggi, Margot and Yu, Zhiheng and Villa, Elizabeth and Rosen, Michael K.}, doi = {10.1073/pnas.2426449122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2426449122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantitative spatial analysis of chromatin biomolecular condensates using cryoelectron tomography}, volume = {122}, year = {2025}, }
• (2025). We need better ways to re-evaluate conservation policies when they’re founded on flawed research. PNAS, 122(19), e2426166122. (www)

  @article{ , archive = {J_PNAS}, author = {Shoemaker, Kevin T. and Loope, Kevin J.}, doi = {10.1073/pnas.2426166122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2426166122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {We need better ways to re-evaluate conservation policies when they’re founded on flawed research}, volume = {122}, year = {2025}, }
• (2025). OGG1S326C variant frequent in human populations facilitates inflammatory responses due to its extended interaction with DNA substrate. PNAS, 122(19), e2426102122. (www)

  @article{ , abstract = {8-oxoguanine (8-oxoGua) is one of the most frequent forms of oxidative DNA base lesions, repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) via base excision repair (BER) pathway to maintain genome fidelity. The human allelic variant hOGG1 S326C , prevalent in Caucasians and Asians, has been regarded as a susceptibility factor for various diseases, yet its pathogenic mechanism remains elusive. In this study, we demonstrate that Ogg1 S326C/S326C mice exhibit increased and sustained airway inflammation compared with wild-type (WT) Ogg1 S326/S326 mice. Mechanistically, in response to inflammatory stimulation, OGG1S326C undergoes reactive oxygen species-induced dimerization, which impairs its base excision function, but prolongs its association with promoter-embedded substrate(s), leading to an increase in NF-κB’ DNA occupancy, subsequently the excessive expression of proinflammatory cytokines and chemokines, and the exacerbated lung inflammation. In contrast, Serine at position 326 in WT -OGG1 is constitutively phosphorylated by CDK4. To fulfill the requirement for its function in transcriptional regulation, the phosphorylated OGG1 needs to undergo dephosphorylation to rescue DNA binding ability. In this scenario, OGG1S326C lacks this phosphorylation site, disrupting this regulatory cycle. Notably, administration of a small molecule inhibitor of OGG1 prevents OGG1S326C from binding to DNA and significantly decreases gene expression and inflammatory responses. Our findings elucidate a molecular basis for the increased disease susceptibility of individuals carrying the hOGG1 S326C variant and propose the therapeutic potential of OGG1 inhibitors in mitigating inflammation-driven pathologies.}, archive = {J_PNAS}, author = {Han, Jinling and Zhang, Meichen and Ge, Jiakun and Ji, Zhihua and Zhao, Jianyi and Hu, Yinchao and Li, Chunshuang and Xue, Yaoyao and Li, Xining and Zhao, Haiwang and Cui, Zixu and Tian, Miaomiao and Zheng, Xu and Wang, Dapeng and Wang, Jing and Wei, Min and Radak, Zsolt and Nakabeppu, Yusaku and Boldogh, Istvan and Ba, Xueqing}, doi = {10.1073/pnas.2426102122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2426102122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {OGG1S326C variant frequent in human populations facilitates inflammatory responses due to its extended interaction with DNA substrate}, volume = {122}, year = {2025}, }
• (2025). Structure of the human TWIK-2 potassium channel and its inhibition by pimozide. PNAS, 122(19), e2425709122. (www)

  @article{ , abstract = {The potassium channel TWIK-2 is crucial for ATP-induced activation of the NLRP3 inflammasome in macrophages. The channel is a member of the two-pore domain potassium (K2P) channel superfamily and an emerging therapeutic target to mitigate severe inflammatory injury involving NLRP3 activation. We report the cryo-EM structure of human TWIK-2. In comparison to other K2P channels, the structure reveals an unusual “up” conformation of Tyr111 in the selectivity filter and a resulting SF1-P1 pocket behind the filter. Density for acyl chains is present in fenestrations within the transmembrane region that connects the central cavity of the pore to the lipid membrane. Despite its importance as a drug target, limited pharmacological tools are available for TWIK-2. A previous study suggested that the FDA-approved small molecule pimozide might inhibit TWIK-2. Using a reconstituted system, we show that pimozide directly inhibits the channel and we determine a cryo-EM structure of a complex with the drug. Pimozide displaces the acyl chains within the fenestrations and binds below the selectivity filter where it would impede ion permeation. The drug may access its binding site by lateral diffusion in the membrane, suggesting that other hydrophobic small molecules could have utility for inhibiting TWIK-2. The work defines the structure of TWIK-2 and provides a structural foundation for development of more specific inhibitors with potential utility as anti-inflammatory drugs.}, archive = {J_PNAS}, author = {Khanra, Nandish K. and Wang, Chongyuan and Delgado, Bryce D. and Long, Stephen B.}, doi = {10.1073/pnas.2425709122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2425709122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure of the human TWIK-2 potassium channel and its inhibition by pimozide}, volume = {122}, year = {2025}, }
• (2025). Cross-feeding creates tipping points in microbiome diversity. PNAS, 122(19), e2425603122. (www)

  @article{ , abstract = {A key unresolved question in microbial ecology is how the extraordinary diversity of microbiomes emerges from the interactions among their many functionally distinct populations. This process is driven in part by the cross-feeding networks that help to structure these systems, in which consumers use resources to fuel their metabolism, creating by-products which can be used by others in the community. Understanding the effects of cross-feeding presents a major challenge, as it creates complex interdependencies between populations which can be hard to untangle. We address this problem using the tools of network science to develop a structural microbial community model. Using methods from percolation theory, we identify feasible community states for cross-feeding network structures in which the needs of consumers are met by metabolite production across the community. We identify tipping points at which small changes in structure can cause the catastrophic collapse of cross-feeding networks and abrupt declines in microbial community diversity. Our results are an example of a well-defined tipping point in a complex ecological system and provide insight into the fundamental processes shaping microbiomes and their robustness. We further demonstrate this by considering how network attacks affect community diversity and apply our results to show how the apparent difficulty in culturing the microbial diversity emerges as an inherent property of their cross-feeding networks.}, archive = {J_PNAS}, author = {Clegg, Tom and Gross, Thilo}, doi = {10.1073/pnas.2425603122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2425603122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cross-feeding creates tipping points in microbiome diversity}, volume = {122}, year = {2025}, }
• (2025). Pre-hispanic ritual use of psychoactive plants at chavín de huántar, peru. PNAS, 122(19), e2425125122. (www)

  @article{ , abstract = {Ritual is broadly accepted as an important locus of social interaction in the pre-Hispanic Central Andes, and research into the development of durable sociopolitical inequality in the region often focuses on the social and political roles of public rituals. At the Middle-Late Formative Period (ca. 1200–400 BCE) monumental center of Chavín de Huántar, as well as at contemporary sites, ritual has long been hypothesized to include the use of psychoactive plants. However, neither psychoactive plant remains nor chemical traces of psychoactive compounds in likely ritual contexts have been identified at any of these sites. Recently excavated deposits sealed in an underground gallery at Chavín contained twenty-three artifacts of forms (especially bone tubes) associated with consumption of psychoactive plants elsewhere in the region. We here report, based on independent microbotanical and chemical analyses, two kinds of direct evidence for use of psychoactive plants in institutionalized ritual at Chavín. These results are direct evidence of psychoactive plants in archaeological bone tubes used as inhalers and the northernmost direct evidence of vilca and Nicotiana use in the pre-Hispanic Andes.}, archive = {J_PNAS}, author = {Rick, John W. and Lema, Verónica S. and Echeverría, Javier and Valverde, Giuseppe Alva and Contreras, Daniel A. and Arias Espinoza, Oscar and Rosenfeld, Silvana A. and Sayre, Matthew P.}, doi = {10.1073/pnas.2425125122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2425125122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pre-hispanic ritual use of psychoactive plants at chavín de huántar, peru}, volume = {122}, year = {2025}, }
• (2025). Combining live fluorescence imaging with in situ cryoelectron tomography sheds light on the septation process in deinococcus radiodurans. PNAS, 122(19), e2425047122. (www)

  @article{ , abstract = {Cell division is a fundamental biological process that allows a single mother cell to produce two daughter cells. In walled bacteria, different modes of cell division have been reported that are notably associated with distinctive cell shapes. In all cases, division involves a step of septation, corresponding to the growth of a new dividing cell wall, followed by splitting of the two daughter cells. The radiation-resistant Deinococcus radiodurans is a spherical bacterium protected by a thick and unusual cell envelope. It has been reported to divide using a distinctive mode of septation in which two septa originating from opposite sides of the cell progress with a flat leading edge until meeting and fusing at mid-cell. In the present study, we have combined conventional and superresolution fluorescence microscopy of live bacteria with in situ cryogenic electron tomography of bacterial lamellae to investigate the septation process in D. radiodurans . This work provides important insight into i) the complex architecture and multilayered composition of the cell envelope of this bacterium, ii) the unusual “sliding doors” septation process and iii) the sequence of events and molecular mechanisms underlying septal closure, including the synthesis of a FtsZ-dependent peptidoglycan layer that rigidifies and straightens the growing septa.}, archive = {J_PNAS}, author = {Gaifas, Lorenzo and Kleman, Jean-Philippe and Lacroix, Françoise and Schexnaydre, Erin and Trouve, Jennyfer and Morlot, Cecile and Sandblad, Linda and Gutsche, Irina and Timmins, Joanna}, doi = {10.1073/pnas.2425047122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2425047122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Combining live fluorescence imaging with in situ cryoelectron tomography sheds light on the septation process in deinococcus radiodurans}, volume = {122}, year = {2025}, }
• (2025). METTL3 mediates atheroprone flow–induced glycolysis in endothelial cells. PNAS, 122(19), e2424796122. (www)

  @article{ , abstract = {Atheroprone flow–increased glycolysis in vascular endothelial cells (ECs) is pivotal in EC dysfunction and the initiation of atherosclerosis. Methyltransferase 3 (METTL3) is a major m 6 A methyltransferase for RNA N6-mehtyladenosine (m 6 A) modifications to regulate epitranscriptome and cellular functions. With the atheroprone flow upregulating METTL3 and m 6 A RNA hypermethylation, we investigate the role of METTL3 in atheroprone flow–induced glycolysis in ECs in vitro and in vivo. Compared to pulsatile shear stress (PS, atheroprotective flow), oscillatory shear stress (OS, atheroprone flow) increases METTL3 expression to enhance the m 6 A modifications of mRNAs encoding HK1, PFKFB3, and GCKR, which are rate-limiting enzymes of glycolysis. These augmented m 6 A modifications increase the expressions of HK1 and PFKFB3 while decreasing GCKR, resulting in elevated EC glycolysis, as revealed by seahorse analysis. Moreover, a stimulated Raman scattering (SRS) imaging study demonstrates the elevation of glucose incorporation into de novo synthesized lipids in ECs under atheroprone flow in vitro and in vivo. Empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i) drug, represses METTL3 expression, thereby mitigating OS-induced glycolysis in ECs. These data suggest mechanisms by which METTL3 links EC mechanotransduction with metabolic reprogramming under atherogenic conditions.}, archive = {J_PNAS}, author = {Zhao, Guo-Jun and Han, So Yun and Li, Yajuan and Yuan, Dongqiang and Qin, Shuo and Li, Yuhan and Jang, Hongje and Chen, Li-Jing and Wei, Tong-You Wade and He, Ming and Li, Yi-Shun and Bouman Chen, Zhen and Shi, Lingyan and Chien, Shu and Shyy, John Y-J}, doi = {10.1073/pnas.2424796122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2424796122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {METTL3 mediates atheroprone flow–induced glycolysis in endothelial cells}, volume = {122}, year = {2025}, }
• (2025). Nonequilibrium relaxation exponentially delays the onset of quantum diffusion. PNAS, 122(19), e2424582122. (www)

  @article{ , abstract = {Predicting the exact many-body quantum dynamics of polarons in materials with strong carrier–phonon interactions presents a fundamental challenge, often necessitating one to adopt approximations that sacrifice the ability to predict the transition from nonequilibrium relaxation to thermodynamic equilibrium. Here, we exploit a recent breakthrough that generalizes the concept of memory beyond its conventional temporal meaning to also encompass space. Specifically, we leverage our finding that the dynamics of observables in systems with local couplings satisfy Green’s functions with kernels that are local in time and space. This enables us to employ the dynamics of small lattices over short times to predict the dynamics of thermodynamically large lattices over arbitrarily long timescales while circumventing the deleterious impacts of finite-size effects. We thus interrogate the exact nonequilibrium formation and migration of polarons in one- (1D) and two-dimensional (2D) systems, revealing that their motion approaches diffusive transport only asymptotically in time and system size. We also compare transport in 1D and 2D systems to investigate the effect of dimension in polaron migration physics, illustrating how energy variations can cause localization—a phenomenon observable via current microscopy experiments.}, archive = {J_PNAS}, author = {Bhattacharyya, Srijan and Sayer, Thomas and Montoya-Castillo, Andrés}, doi = {10.1073/pnas.2424582122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2424582122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nonequilibrium relaxation exponentially delays the onset of quantum diffusion}, volume = {122}, year = {2025}, }
• (2025). Durably reducing partisan animosity through multiple scalable treatments. PNAS, 122(19), e2424414122. (www)

  @article{ , abstract = {Recent research has identified several effective strategies for reducing Americans’ animosity toward supporters of opposing political parties. However, whether these strategies can durably reduce partisan animosity in a scalable manner and in everyday life remains unclear. We bridge the gap between prior research and useful application by assessing whether exposure to multiple, scalable treatments that portray inparty and outparty members interacting positively, receiving accurate information about one another’s views, and learning about cross-party similarities can a) durably shift partisans’ sentiments and b) influence partisans’ sentiments toward specific, personally known others encountered in everyday life—not only general, hypothetical, or one-off rival partisans. In a longitudinal survey experiment, we find that exposure to three brief, scalable treatments over a week reduces partisan animosity, with effects persisting for at least a month. Moreover, the treatments durably ameliorate animosity toward both general outparty members and a personally known outparty member, specified prior to the treatments. These findings suggest promising avenues for redressing social divisions in real-world contexts.}, archive = {J_PNAS}, author = {Hall, Matthew E. K. and Solomon, Brittany C. and Voelkel, Jan G. and Stagnaro, Michael N. and Chu, James Y. and Willer, Robb}, doi = {10.1073/pnas.2424414122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2424414122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Durably reducing partisan animosity through multiple scalable treatments}, volume = {122}, year = {2025}, }
• (2025). Activity and structure of human (d)CTP deaminase CDADC1. PNAS, 122(19), e2424245122. (www)

  @article{ , abstract = {Vertebrates have evolved an understudied protein termed CDADC1 (NYD-SP15) that contains an inactive N-terminal and active C-terminal DCTD-like domain. Here, we show that human CDADC1 is a (d)CTP-specific deaminase, with a roughly 2-fold in vitro preference for dCTP over CTP. We determined high-resolution cryo-EM structures of CDADC1 in the absence of substrate and in complex with dCTP and 5-methyl-dCTP. The structures show that CDADC1 forms trimers and dimers of trimers in solution. The (d)CTP substrate is selected by a narrow pocket for the cytosine base and multiple lysine and arginine contacts to the triphosphate. Substrate binding promotes the association of trimers into hexamers and the transition of the hexamers from a loose to a tighter arrangement. Genetic experiments in mice show that loss of Cdadc1 is surprisingly well tolerated, even in the absence of the dCMP deaminase Dctd that is considered as the main source of dUMP, the precursor of dTTP.}, archive = {J_PNAS}, author = {Slyvka, Anton and Rathore, Ishan and Yang, Renbin and Gewartowska, Olga and Kanai, Tapan and Lountos, George T. and Skowronek, Krzysztof and Czarnocki-Cieciura, Mariusz and Wlodawer, Alexander and Bochtler, Matthias}, doi = {10.1073/pnas.2424245122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2424245122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Activity and structure of human (d)CTP deaminase CDADC1}, volume = {122}, year = {2025}, }
• (2025). Distinguishing species boundaries from geographic variation. PNAS, 122(19), e2423688122. (www)

  @article{ , abstract = {In an era of unprecedented biodiversity loss, the need for standardized practices to describe biological variation is becoming increasingly important. As with all scientific endeavors, species delimitation needs to be explicit, testable, and refutable. A fundamental task in species delimitation is distinguishing within-species variation from among-species variation. Many species that are distributed across large geographic areas exhibit levels of genetic variation that are as great or greater than those that exist between well-defined sympatric species. Here, we provide a workflow to distinguish between intra- and interspecific genetic variation and apply the workflow to a taxonomically problematic group of frogs (the Rana pipiens complex, or leopard frogs) that are widely distributed across Mexico and Central America. Our workflow makes use of recent advancements that pair genome-scale datasets with model-based species delimitation methods, while emphasizing the need for positive evidence of reproductive isolation to confirm the validity of geographically contiguous species boundaries. We find that intraspecific geographic variation in widespread leopard frog species has resulted in considerable taxonomic inflation of species. Ten currently recognized species are not supported in our analyses, and we here synonymize them with previously named taxa. Furthermore, we find positive evidence for the presence of three undescribed species. In addition to proposing these taxonomic changes, we provide descriptions of the data or analyses that would be needed to refute and overturn our recommendations. We recommend that all species delimitation studies (especially of geographically variable groups) clarify what new evidence would be sufficient to change the taxonomic recommendations.}, archive = {J_PNAS}, author = {Chambers, E. Anne and Lara-Tufiño, José Daniel and Campillo-García, Gustavo and Cisneros-Bernal, Antonio Yolocalli and Dudek, Daniel J. and León-Règagnon, Virginia and Townsend, Josiah H. and Flores-Villela, Oscar and Hillis, David M.}, doi = {10.1073/pnas.2423688122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2423688122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Distinguishing species boundaries from geographic variation}, volume = {122}, year = {2025}, }
• (2025). Distinct latitudinal patterns of molecular rates across vertebrates. PNAS, 122(19), e2423386122. (www)

  @article{ , abstract = {The latitudinal diversity gradient (LDG) is the most notable global biodiversity pattern, but its underlying mechanisms remain unresolved. The evolutionary speed hypothesis (ESH) posits that molecular rates play a crucial role in shaping the LDG, suggesting that higher temperatures accelerate molecular rates, thereby facilitating rapid speciation and accumulation of biodiversity in the tropics. However, whether ESH can explain the LDG across diverse taxonomic groups remains debated, and systematic examinations of its two key predictions using consistent datasets and methodologies across vertebrates are lacking. Here, we tested ESH using molecular rates from mitochondrial (5,424 species) and nuclear (1,512 species) genomes across major vertebrate groups, including fishes, amphibians, reptiles, mammals, and birds. Our findings revealed distinct latitudinal patterns in the absolute synonymous substitution rate (dS), which were influenced by thermoregulatory strategies. Specifically, the dS increases with ambient temperature and decreases with latitude in ectotherms but shows no correlation in most endotherms. These distinct patterns are likely attributed to different key predictors of dS between thermogroups, with temperature playing a major role only in ectotherms. For mitochondrial genes, absolute nonsynonymous substitution rates (dN) increase with temperature, likely driven by mutation rates in ectotherms and purifying selection in endotherms. However, neither mitochondrial dS nor dN correlates with diversification rates across vertebrates, contradicting the second prediction of ESH. For nuclear rates, the ESH was supported in reptiles and amphibians but not in mammals, birds, or fishes. In conclusion, our results provide limited support for ESH in vertebrates, underscoring the intricate processes that shape the LDG.}, archive = {J_PNAS}, author = {Cai, Tianlong and Wen, Zhixin and Jiang, Zhongguan and Zhen, Ying}, doi = {10.1073/pnas.2423386122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2423386122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Distinct latitudinal patterns of molecular rates across vertebrates}, volume = {122}, year = {2025}, }
• (2025). Interspecies interactions in dual, fibrous gels enable control of gel structure and rheology. PNAS, 122(19), e2423293122. (www)

  @article{ , abstract = {Natural and synthetic multicomponent gels display emergent properties, which implies that they are more than just the sum of their components. This warrants the investigation of the role played by interspecies interactions in shaping gel architecture and rheology. Here, using computer simulations, we investigate the effect of changing the strength of the interactions between two species forming a fibrous double network. Simply changing the strength of interspecies lateral association, we generate two types of gels: one in which the two components demix and another one in which the two species wrap around each other. We show that demixed gels have structure and rheology that are largely unaffected by the strength of attraction between the components. In contrast, architecture and material properties of intertwined gels strongly depend on interspecies “stickiness” and volume exclusion. These results can be used as the basis of a design principle for double networks which are made to emphasize either stability to perturbations or responsiveness to stimuli. Similar ideas could be used to interpret naturally occurring multicomponent gels.}, archive = {J_PNAS}, author = {Mugnai, Mauro L. and Tchuenkam Batoum, Rose and Del Gado, Emanuela}, doi = {10.1073/pnas.2423293122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2423293122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Interspecies interactions in dual, fibrous gels enable control of gel structure and rheology}, volume = {122}, year = {2025}, }
• (2025). Why does AI hinder democratization?. PNAS, 122(19), e2423266122. (www)

  @article{ , abstract = {This paper examines the relationship between democratization and the development of AI and information and communication technology (ICT). Our empirical evidence shows that in the past 10 y, the advancement of AI/ICT has hindered the development of democracy in many countries around the world. Given that both the state rulers and civil society groups can use AI/ICT, the key that determines which side would benefit more from the advancement of these technologies hinges upon “technology complementarity.” In general, AI/ICT would be more complementary to the government rulers because they are more likely than civil society groups to access various administrative big data. Empirically, we propose three hypotheses and use statistical tests to verify our argument. Theoretically, we prove a proposition, showing that when the above-mentioned complementarity assumption is true, the AI/ICT advancements would enable rulers in authoritarian and fragile democratic countries to achieve better control over civil society forces, which leads to the erosion of democracy. Our analysis explains the recent ominous development in some fragile-democracy countries.}, archive = {J_PNAS}, author = {Chu, C. Y. Cyrus and Chang, Juin-Jen and Lin, Chang-Ching}, doi = {10.1073/pnas.2423266122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2423266122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Why does AI hinder democratization?}, volume = {122}, year = {2025}, }
• (2025). Derivational morphology reveals analogical generalization in large language models. PNAS, 122(19), e2423232122. (www)

  @article{ , abstract = {What mechanisms underlie linguistic generalization in large language models (LLMs)? This question has attracted considerable attention, with most studies analyzing the extent to which the language skills of LLMs resemble rules. As of yet, it is not known whether linguistic generalization in LLMs could equally well be explained as the result of analogy. A key shortcoming of prior research is its focus on regular linguistic phenomena, for which rule-based and analogical approaches make the same predictions. Here, we instead examine derivational morphology, specifically English adjective nominalization, which displays notable variability. We introduce a method for investigating linguistic generalization in LLMs: Focusing on GPT-J, we fit cognitive models that instantiate rule-based and analogical learning to the LLM training data and compare their predictions on a set of nonce adjectives with those of the LLM, allowing us to draw direct conclusions regarding underlying mechanisms. As expected, rule-based and analogical models explain the predictions of GPT-J equally well for adjectives with regular nominalization patterns. However, for adjectives with variable nominalization patterns, the analogical model provides a much better match. Furthermore, GPT-J’s behavior is sensitive to the individual word frequencies, even for regular forms, a behavior that is consistent with an analogical account but not a rule-based one. These findings refute the hypothesis that GPT-J’s linguistic generalization on adjective nominalization involves rules, suggesting analogy as the underlying mechanism. Overall, our study suggests that analogical processes play a bigger role in the linguistic generalization of LLMs than previously thought.}, archive = {J_PNAS}, author = {Hofmann, Valentin and Weissweiler, Leonie and Mortensen, David R. and Schütze, Hinrich and Pierrehumbert, Janet B.}, doi = {10.1073/pnas.2423232122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2423232122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Derivational morphology reveals analogical generalization in large language models}, volume = {122}, year = {2025}, }
• (2025). Muscle peripheral circadian clock drives nocturnal protein degradation via raised Ror/Rev-erb balance and prevents premature sarcopenia. PNAS, 122(19), e2422446122. (www)

  @article{ , abstract = {How central and peripheral circadian clocks regulate protein metabolism and affect tissue mass homeostasis has been unclear. Circadian shifts in the balance between anabolism and catabolism control muscle growth rate in young zebrafish independent of behavioral cycles. Here, we show that the ubiquitin–proteasome system (UPS) and autophagy, which mediate muscle protein degradation, are each upregulated at night under the control of the muscle peripheral clock. Perturbation of the muscle transcriptional molecular clock disrupts nocturnal proteolysis, increases muscle growth measured over 12 h, and compromises muscle function. Mechanistically, the shifting circadian balance of Ror and Rev-erb regulates nocturnal UPS, autophagy, and muscle growth through altered TORC1 activity. Although environmental zeitgebers initially mitigate defects, lifelong muscle clock inhibition reduces muscle size and growth rate, accelerating aging-related loss of muscle mass and function. Circadian misalignment such as shift work, sleep deprivation, or dementia may thus unsettle muscle proteostasis, contributing to muscle wasting and sarcopenia.}, archive = {J_PNAS}, author = {Kelu, Jeffrey J. and Hughes, Simon M.}, doi = {10.1073/pnas.2422446122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2422446122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Muscle peripheral circadian clock drives nocturnal protein degradation via raised Ror/Rev-erb balance and prevents premature sarcopenia}, volume = {122}, year = {2025}, }
• (2025). Interferon-induced activation of dendritic cells and monocytes by yellow fever vaccination correlates with early antibody responses. PNAS, 122(19), e2422236122. (www)

  @article{ , abstract = {Yellow fever vaccination provides long-lasting protection and is a unique model for studying the immune response to an acute RNA virus infection in humans. To elucidate the early innate immune events preceding the rapid generation of protective immunity, we performed transcriptome analysis of human blood dendritic cell (DC) and monocyte subpopulations before and 3, 7, 14, and 28 d after vaccination. We detected temporary upregulation of IFN-stimulated genes (ISG) in all DC and monocyte subsets on days 3 and 7 after vaccination as well as cell type–specific responses and response kinetics. Single-cell RNA sequencing revealed rapid appearance of activated DC and monocyte clusters dominated by ISGs, inflammatory chemokines, and genes involved in antigen processing and presentation. This was confirmed by flow cytometric analysis in a large cohort of vaccinees. We identified SIGLEC1/CD169 upregulation as a sensitive indicator of the transient IFN-induced activation state elicited in DCs and monocytes by YF17D vaccination correlating with early protective IgM antibody responses.}, archive = {J_PNAS}, author = {Winheim, Elena and Santos-Peral, Antonio and Ehm, Tamara and Rinke, Linus and Riemer, Sandra and Zaucha, Magdalena and Goresch, Sebastian and Lehmann, Lisa and Eisenächer, Katharina and Pritsch, Michael and Barba-Spaeth, Giovanna and Straub, Tobias and Rothenfusser, Simon and Krug, Anne B.}, doi = {10.1073/pnas.2422236122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2422236122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Interferon-induced activation of dendritic cells and monocytes by yellow fever vaccination correlates with early antibody responses}, volume = {122}, year = {2025}, }
• (2025). Exploiting thioether reactivity to label mycobacterial glycans. PNAS, 122(19), e2422185122. (www)

  @article{ , abstract = {Mycobacterium tuberculosis ( Mtb ) is a leading cause of death worldwide. Mtb cell envelope glycans are potent virulence factors that play key roles in mediating infection of host tissues and modulating the host immune response. However, there are few ways to site-selectively modify and label these or any glycans to study their functions in disease. This gap arises because glycans generally lack functional groups amenable to bioconjugation strategies. Methylthioxylofuranose (MTX), a rare monosaccharide in select pathogenic mycobacteria, is an exception. MTX is appended to mannose-capped lipoarabinomannan (ManLAM), an antigenic glycolipid in the Mtb cell envelope implicated in downregulating the host immune system during infection. MTX is unique not only in its prevalence but also in its functionality—it contains a thioether not present in other glycans. We envisioned exploiting the MTX thioether to selectively label ManLAM with an oxaziridine probe. Here, we show that MTX-containing glycans can be labeled selectively in the test tube and live cells, highlighting the reactivity and accessibility of this motif. Our approach labels ManLAM efficiently despite the presence of protein methionine residues and can distinguish between different mycobacterial species. Using an oxaziridine equipped with a reporter, we could visualize ManLAM localization in live cells and a macrophage infection model, highlighting the stability of the label and the cell envelope in this environment. These studies will enable investigations of dynamic changes in a critical Mtb cell envelope component during infection. Moreover, the selective reactivity of thioethers can be leveraged to expand the repertoire of glycan bioconjugation strategies.}, archive = {J_PNAS}, author = {Smelyansky, Stephanie R. and Ma, Chi-Wang and Marando, Victoria M. and Babunovic, Gregory H. and Lee, So Young and Bryson, Bryan D. and Kiessling, Laura L.}, doi = {10.1073/pnas.2422185122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2422185122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exploiting thioether reactivity to label mycobacterial glycans}, volume = {122}, year = {2025}, }
• (2025). Observation of disorder-induced boundary localization. PNAS, 122(19), e2422154122. (www)

  @article{ , abstract = {Bloch wavefunctions in crystals experience localization within the bulk when disorder is introduced, a phenomenon commonly known as Anderson localization. This effect is considered universal, being applicable to all types of waves, quantum or classical. However, the interaction between disorder and topology—a concept that has profoundly transformed many branches of physics—necessitates revisiting the original Anderson localization picture. For instance, in the recently discovered topological Anderson insulator, the introduction of disorder induces topological boundary states that can resist localization due to protection from line-gap topology. While line-gap topology applies to both Hermitian and non-Hermitian systems, non-Hermitian systems uniquely exhibit point-gap topology, which has no Hermitian counterparts and leads to the non-Hermitian skin effect. Here, we experimentally demonstrate disorder-induced point-gap topology in a non-Hermitian acoustic crystal. This crystal, with non-Hermitian disorder in nearest-neighbor couplings, exhibits the non-Hermitian skin effect, where all eigenstates localize at a boundary. Interestingly, the boundary where localization occurs—either the left or right—depends on the strength of the disorder. As the disorder strength increases, the direction of boundary localization can be reversed. Additionally, we observe a “bipolar” skin effect, where boundary localization occurs at both the left and right boundaries when disorder is introduced in next-nearest-neighbor couplings. These findings experimentally reveal a non-Hermitian mechanism of disorder-induced localization that goes beyond the conventional framework of Anderson localization.}, archive = {J_PNAS}, author = {Wang, Bing-Bing and Cheng, Zheyu and Zou, Hong-Yu and Ge, Yong and Zhao, Ke-Qi and Si, Qiao-Rui and Yuan, Shou-Qi and Sun, Hong-Xiang and Xue, Haoran and Zhang, Baile}, doi = {10.1073/pnas.2422154122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2422154122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Observation of disorder-induced boundary localization}, volume = {122}, year = {2025}, }
• (2025). Impact of mg2+ and pH on amorphous calcium carbonate nanoparticle formation: Implications for biomineralization and ocean acidification. PNAS, 122(19), e2421961122. (www)

  @article{ , abstract = {Crystallization by amorphous calcium carbonate (ACC) particle attachment (CPA) is a prevalent biomineralization mechanism among calcifying organisms. A narrow, controlled size distribution of ACC nanoparticles is essential for macroscopic crystal formation via CPA. Using in situ synchrotron small-angle X-ray scattering, we demonstrate that synthetic magnesium-stabilized ACC (Mg-ACC) nanoparticles form with an exceptionally narrow size distribution near the spinodal line during liquid–liquid phase separation. We monitored ACC formation kinetics at pH 8.4 to 8.9 and Mg 2 + contents of 50 to 80%, observing a 2-order magnitude rise in nucleation kinetics for a 0.1 pH increase and a 6-order magnitude rise for a 10% Mg 2 + decrease. Within the binodal region, faster nucleation kinetics result in more monodisperse particles, narrowing the particle size distribution by factors of 2 for a pH increase of merely 0.1 and by a factor of 3 for a 10% Mg 2 + decrease. While the influence of Mg 2 + on calcite biomineralization is well studied, its effect on Mg-ACC formation and particle size distribution-an essential parameter in CPA-based biomineralization pathways-remained unexplored. These findings highlight the delicate interplay of pH and Mg 2 + in controlling the kinetics and thermodynamics of Mg-ACC formation, significantly impacting particle size distribution.}, archive = {J_PNAS}, author = {Kuhrts, Lucas and Shaked, Hadar and Sklar, Johanna and Prudnikov, Elena and Prévost, Sylvain and Manna, Gouranga and Sztucki, Michael and Katsman, Alexander and Pokroy, Boaz}, doi = {10.1073/pnas.2421961122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2421961122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Impact of mg2+ and pH on amorphous calcium carbonate nanoparticle formation: Implications for biomineralization and ocean acidification}, volume = {122}, year = {2025}, }
• (2025). De novo DUOX2 expression in neutrophil subsets shapes the pathogenesis of intestinal disease. PNAS, 122(19), e2421747122. (www)

  @article{ , abstract = {Infiltrating neutrophils are key effector cells in inflammatory bowel disease (IBD) while providing antimicrobial defense and tissue restitution in the intestine. The complexity of neutrophil functions in local environments underscores our limited understanding of how their adaptation in tissues influences disease progression. Here, we demonstrate that neutrophils recruited in murine colitis and infection models, idiopathic IBD, and chronic granulomatous disease-associated IBD undergo extensive transcriptional reprogramming, resulting in the emergence of neutrophil populations that feature unique DUOX2 NADPH oxidase expression. Functional studies utilizing mice with myeloid and neutrophil specific DUOX2 inactivation reveal a vital and dichotomous role for this NADPH oxidase in both colitis and intestinal infection. Niche-directed reprogramming promoted a DUOX2-dependent chemokine and cytokine-rich intestinal environment that amplified and prolonged inflammatory responses, suggesting that selectively suppressing DUOX2 may constitute an anti-inflammatory strategy for IBD treatment. Altering spatiotemporal redox signaling by de novo expression of a ROS-generating enzyme represents an important feature for functional neutrophil diversification in disease, with implications for other neutrophil-driven diseases in specialized niches.}, archive = {J_PNAS}, author = {Singh, Ashish K. and Ainciburu, Marina and Wynne, Kieran and Bhat, Sajad A. and Blanco, Alfonso and Tzani, Ioanna and Akiba, Yasutada and Lalor, Stephen J. and Kaunitz, Jonathan and Bourke, Billy and Kelly, Vincent P. and Doherty, Glen A. and Zerbe, Christa S. and Clarke, Colin and Hussey, Séamus and Knaus, Ulla G.}, doi = {10.1073/pnas.2421747122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2421747122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {De novo DUOX2 expression in neutrophil subsets shapes the pathogenesis of intestinal disease}, volume = {122}, year = {2025}, }
• (2025). Directional water navigation and reallocation in tillandsia capitata. PNAS, 122(19), e2421589122. (www)

  @article{ , abstract = {Liquid manipulation is ubiquitous in nature and engineering, enabling controllable and efficient liquid delivery. Conventional understanding of liquid manipulation relies on inhomogeneous chemical modifications or single-scale structure design. Here, we present how water is directionally navigated and spontaneously reallocated at high efficiency via the cross-scale topology on Tillandsia capitata leaves. These leaves feature transversely curved lanceolate macrostructures decorated by a layer of microtrichomes with varied morphologies. The macrostructure creates a lanceolate effect in the transport direction for fundamental navigation. At the same time, the microtrichomes serve dual functions: constructing a self-wetting superhydrophilic surface to facilitate the water transport speed and implementing water spreading in the opposite direction for autonomous reallocation. We explain the multiscale transport behavior through theoretic analysis and finite element simulations. Our findings demonstrate how cross-scale topographies jointly function in efficient autonomous fluid manipulation, with potential applications such as droplet driving, fog harvesting, and seawater desalination, offering pathways for improving liquid processing efficiency and reducing energy consumption.}, archive = {J_PNAS}, author = {Lian, Jiaoyuan and Li, Wei and Yang, Ling and Li, Hegeng and Deng, Qiyu and Zhu, Hengjia and Zhang, Yiyuan and Fang, Nicholas X. and Wang, Liqiu}, doi = {10.1073/pnas.2421589122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2421589122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Directional water navigation and reallocation in tillandsia capitata}, volume = {122}, year = {2025}, }
• (2025). Circadian clock–gated cell renewal controls time-dependent changes in taste sensitivity. PNAS, 122(19), e2421421122. (www)

  @article{ , abstract = {Circadian regulation of the cell cycle progression generates a diurnal supply of newborn cells to replace those lost in organs and tissues. In this study, we analyzed circadian time-dependent changes in cell types within the mouse tongue epithelium. Using single-cell RNA sequencing, we observed circadian time-dependent changes in the populations of stem/progenitor cells and the differentiated cells in mice tongues. Notably, we observed time-dependent changes in the type II taste cell population, which were abolished by ablation of taste bud stem cells, thereby inhibiting cell proliferation within the taste cell population. Through experiments with taste bud organoids (TBOs), we found a 24-h cell cycle period, which was disrupted by the knockdown of the core-clock gene Bmal1 . In TBOs, both cell divisions and apoptotic cells exhibited circadian time-dependent phenotypes. Interestingly, the time-dependent changes in cell death disappeared in the stem cell–ablated TBOs, indicating that the diurnal supply of newly born cells is essential for the rhythmic cell death phenotype. Additionally, taste tests conducted at different times of the day revealed time-dependent sensitivity changes originating from type II taste cells in mice. These findings suggest that the time-dependent changes in taste cell population are driven by circadian clock–regulated cell cycle progression and control time-dependent physiological regulation in the mouse tongue.}, archive = {J_PNAS}, author = {Matsu-ura, Toru and Nasu, Atsunori and Lee, Suengwon and Yoshida, Naoko and Matsuura, Kaoru and Yasuda, Masaharu and Nakamura, Kae and Hong, Christian I. and Tsuta, Koji}, doi = {10.1073/pnas.2421421122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2421421122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Circadian clock–gated cell renewal controls time-dependent changes in taste sensitivity}, volume = {122}, year = {2025}, }
• (2025). Phylogenomics of the tetraploid hawaiian lobeliads: Implications for their origin, dispersal history, and adaptive radiation. PNAS, 122(19), e2421004122. (www)

  @article{ , abstract = {Hawaiian lobeliads exhibit extensive adaptive radiations and are considered the largest plant clade (143 species) endemic to any oceanic archipelago. Rapid insular radiations are prone to reticulate evolution, yet detecting hybridization is often limited by inadequate sampling of taxa or independent loci. We analyzed 633 nuclear loci (including tetraploid duplications) and whole plastomes for 89% of extant species to derive phylogenies for the Hawaiian lobeliads. Nuclear data provide strong support for nine major clades in both likelihood and ASTRAL analyses. All genera/sections are monophyletic except Clermontia and Cyanea . Nuclear and plastome phylogenies conflict on short, deep branches; the nuclear tree resolves a fleshy-fruited clade of Hawaiian Clermontia/Cyanea-Brighamia/Delissea , sister to Polynesian Sclerotheca , with both sister to a capsular-fruited Hawaiian clade. Incomplete lineage sorting in a rapid radiation starting 8.5–11.3 Ma is sufficient to explain uncertainty and cytonuclear discordance along the backbone. Sequence data support reticulation within Clermontia and especially Cyanea . Nuclear data identify 42 interisland dispersal events: 89% accord with the strict progression rule, involving movement to the next younger island in the hotspot chain, consistent with theory. Plastid data overestimate such events by 17%. Cyanea and Clermontia have undergone parallel adaptive radiations in elevational distribution and flower length on all major islands, with multiple founders and some interisland differences. Hawaiian lobeliad diversification was driven by an early intergeneric divergence in habitat, followed by parallel adaptive radiation and ecological speciation within Clermontia/Cyanea , combined with widespread single-island endemism, frequent interisland dispersal, and occasional hybridization.}, archive = {J_PNAS}, author = {Rose, Jeffrey P. and Li, Bing and Sporck-Koehler, Margaret J. and Stacy, Elizabeth A. and Wood, Kenneth R. and Lemmon, Emily Moriarty and Lemmon, Alan R. and Ané, Cécile and Sytsma, Kenneth J. and Givnish, Thomas J.}, doi = {10.1073/pnas.2421004122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2421004122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phylogenomics of the tetraploid hawaiian lobeliads: Implications for their origin, dispersal history, and adaptive radiation}, volume = {122}, year = {2025}, }
• (2025). NF-κB-mediated developmental delay extends lifespan in drosophila. PNAS, 122(19), e2420811122. (www)

  @article{ , abstract = {Developmental time (or time to maturity) strongly correlates with an animal’s maximum lifespan, with late-maturing individuals often living longer. However, the genetic mechanisms underlying this phenomenon remain largely unknown. This may be because most previously identified longevity genes regulate growth rate rather than developmental time. To address this gap, we genetically manipulated prothoracicotropic hormone (PTTH), the primary regulator of developmental timing in Drosophila , to explore the genetic link between developmental time and longevity. Loss of PTTH delays developmental timing without altering the growth rate. Intriguingly, PTTH mutants exhibit extended lifespan despite their larger body size. This lifespan extension depends on ecdysone signaling, as feeding 20-hydroxyecdysone to PTTH mutants reverses the effect. Mechanistically, loss of PTTH blunts age-dependent chronic inflammation, specifically in fly hepatocytes (oenocytes). Developmental transcriptomics reveal that NF-κB signaling activates during larva-to-adult transition, with PTTH inducing this signaling via ecdysone. Notably, time-restricted and oenocyte-specific silencing of Relish (an NF-κB homolog) at early 3rd instar larval stages significantly prolongs adult lifespan while delaying pupariation. Our study establishes an aging model that uncouples developmental time from growth rate, highlighting NF-κB signaling as a key developmental program in linking developmental time to adult lifespan.}, archive = {J_PNAS}, author = {Kang, Ping and Liu, Peiduo and Hu, Yanhui and Kim, Jinoh and Kumar, Ankur and Dorneich-Hayes, Marlene K. and Murzyn, Wren and Anderson, Zenessa J. and Frank, Lexi N. and Kavlock, Nicholas and Hoffman, Elizabeth and Martin, Chad C. and Miao, Ting and Shimell, MaryJane and Powell-Coffman, Jo Anne and O’Connor, Michael B. and Perrimon, Norbert and Bai, Hua}, doi = {10.1073/pnas.2420811122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2420811122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {NF-κB-mediated developmental delay extends lifespan in drosophila}, volume = {122}, year = {2025}, }
• (2025). Improved synapsis dynamics accompany meiotic stability in arabidopsis arenosa autotetraploids. PNAS, 122(19), e2420115122. (www)

  @article{ , abstract = {During meiosis, the correct pairing, synapsis, and recombination of homologous chromosome pairs is critical for fertility of sexual eukaryotes. These processes are challenged in polyploids, which possess additional copies of each chromosome. Polyploidy thus provides a unique context to study how evolution can modify meiotic programs in response to challenges. We previously observed that in newly formed (neo-)polyploids of Arabidopsis arenosa , synapsis defects precede chromosomes associating in aberrant multivalent and univalent configurations. Here, we study synapsis dynamics in genotypes with varying levels of meiotic stability to ask whether efficient synaptic progression is a key component of evolving stable tetraploid meiosis. We develop a method to quantify synapsis dynamics using the progression of foci of the pro-crossover factor HEI10 as a reference. HEI10 initially appears at many small foci before accumulating only at crossover sites. In diploids, this transition begins while significant asynapsis is still present, though it quickly declines as HEI10 accumulates at fewer foci. In neo-tetraploids, suboptimal elongation of synaptic initiation sites and stalled synapsis, perhaps due to defective pairing, occurs before the onset of HEI10 accumulation. In established tetraploids, HEI10 accumulation begins only when synapsis is near complete, suggesting enhanced HEI10/synapsis codynamics (even compared to diploids). Hybrids generated by crossing neo- and established tetraploids exhibit intermediate phenotypes. We find the extent of asynapsis correlates positively with crossover numbers, and the frequency of multivalents and univalents, which can disturb chromosome segregation. Our work supports the hypothesis that improving the efficiency of synapsis is important for evolving polyploid meiotic stability.}, archive = {J_PNAS}, author = {Gonzalo, Adrián and Nayak, Aditya and Bomblies, Kirsten}, doi = {10.1073/pnas.2420115122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2420115122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Improved synapsis dynamics accompany meiotic stability in arabidopsis arenosa autotetraploids}, volume = {122}, year = {2025}, }
• (2025). The developmental factor TBX3 engages with the wnt/β-catenin transcriptional complex in colorectal cancer to regulate metastasis genes. PNAS, 122(19), e2419691122. (www)

  @article{ , abstract = {Wnt signaling orchestrates gene expression in a plethora of processes during development and adult cell homeostasis via the action of nuclear β-catenin. Yet, little is known about how β-catenin generates context-specific transcriptional outcomes. Understanding this will reveal how aberrant Wnt/β-catenin signaling causes neoplasia specifically of the colorectal epithelium. We have previously identified the transcription factor TBX3 as a tissue-specific component of the Wnt/β-catenin nuclear complex during mouse forelimb development. In this study, we show that TBX3 is functionally active in human colorectal cancer (CRC). Here, genome-wide binding and transcriptomics analyses reveal that TBX3 regulates cancer metastasis genes in cooperation with Wnt/β-catenin. Proteomics proximity labeling performed across Wnt pathway activation shows that TBX3 engages with several transcription factors and chromatin remodeling complexes found at Wnt responsive elements (WRE). Protein sequence and structure analysis of TBX3 revealed short motifs, including an exposed Asn-Pro-Phe (NPF), that mediate these interactions. Deletion of these motifs abrogates TBX3’s proximity to its protein partners and its ability to enhance the Wnt-dependent transcription. TBX3 emerges as a key modulator of the oncogenic activity of Wnt/β-catenin in CRC, and its mechanism of action exposes protein-interaction surfaces as putative druggable targets.}, archive = {J_PNAS}, author = {Jauregi-Miguel, Amaia and Söderholm, Simon and Weiss, Tamina and Nordin, Anna and Ghezzi, Valeria and Brütsch, Salome M. and Pagella, Pierfrancesco and van de Grift, Yorick and Zambanini, Gianluca and Ulisse, Jacopo and Mattia, Alessandro and Deviatiiarov, Ruslan and Faustini, Elena and Moparthi, Lavanya and Zhong, Wenjing and Björnsson, Bergthor and Sandström, Per and Lundqvist, Erik and Lottersberger, Francisca and Koch, Stefan and Moor, Andreas E. and Sun, Xiao-Feng and von Castelmur, Eleonore and Sheng, Guojun and Cantù, Claudio}, doi = {10.1073/pnas.2419691122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2419691122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The developmental factor TBX3 engages with the wnt/β-catenin transcriptional complex in colorectal cancer to regulate metastasis genes}, volume = {122}, year = {2025}, }
• (2025). Amplification mechanism with interacting atomic gases. PNAS, 122(19), e2419683122. (www)

  @article{ , abstract = {The use of atoms, molecules, and free electrons in quantum amplifiers has greatly advanced precision measurements, paving the way for the development of extremely-low-noise quantum devices such as masers and lasers. Here, we investigate the signal amplification of interacting spins and observe the amplification of magnetic fields using mixtures of interacting alkali-metal and noble gases. In contrast to noninteracting systems used as amplifiers, we demonstrate that interactions resulting from random atomic collisions give rise to two distinct amplification phenomena. These phenomena provide essential resources for enhancing quantum sensing capabilities. Our results show that magnetic fields can be amplified by at least two orders of magnitude, enhancing magnetic sensitivity to the femtotesla per root hertz level. Additionally, we report a counterpart phenomenon, deamplification, where the magnetic noise response is suppressed by at least one order of magnitude within certain frequency regimes. In this work alkali-metal and noble-gas spins are weakly coupled. We further explore how the performance of amplification changes with the interaction strength as the two spin gases gradually enter the strong-coupling regime, unveiling hitherto unexplored amplification effects that hold promise for enhancing precision measurements.}, archive = {J_PNAS}, author = {Jiang, Min and Qin, Yushu and Wang, Yuanhong and Huang, Ying and Peng, Xinhua and Budker, Dmitry}, doi = {10.1073/pnas.2419683122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2419683122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Amplification mechanism with interacting atomic gases}, volume = {122}, year = {2025}, }
• (2025). Simulating regional workforce impacts of decarbonizing integrated steelmaking. PNAS, 122(19), e2419294122. (www)

  @article{ , abstract = {Global efforts to mitigate climate change are increasing pressure on heavy manufacturing industries to decarbonize production. The iron and steel industry is responsible for 7% of CO 2 emissions globally (2% in the United States) and is often a major employer in the regions where iron and steel is produced. Understanding the future prospects for workers in regions with high CO 2 emitting industries—including impacts of phasing out or evolving such industries—will be critical for informing regional economic and clean energy strategies. We simulate the impact of an “in-place” transition that replaces today’s integrated production with direct reduced iron (DRI) used in electric arc furnaces (EAFs), using Southwest Pennsylvania as an application of our generalizable approach. Our results suggest that the integrated steelmaking workforce today has the skills, knowledge, and abilities (SKAs) to fill over 95% of all jobs required by DRI/EAF facilities, but the number of jobs is only 25% of those at integrated plants. We also find that some occupational groups have greater general transferability into the broader job market, while other groups, such as production workers, are ill-equipped today based on current SKAs to transition out of the iron and steel industry. Our methodology further suggests factors that limit transitions: Around 85% of occupations are more limited by missing skills, while 15% are more limited by insufficient wages. These results may help to improve the design of social policy and the targeting of retraining programs, while the simulation approach can be readily adapted for other regions and industries.}, archive = {J_PNAS}, author = {Miles, Jillian and Combemale, Christophe and Karplus, Valerie J. and Pistorius, P. Chris}, doi = {10.1073/pnas.2419294122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2419294122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Simulating regional workforce impacts of decarbonizing integrated steelmaking}, volume = {122}, year = {2025}, }
• (2025). Healthy sleep durations appear to vary across cultures. PNAS, 122(19), e2419269122. (www)

  @article{ , abstract = {Past research finds that sleep duration is reliably linked with health yet sleep durations differ substantially between countries. We investigated whether countries with shorter sleep durations have worse health. Study 1 analyzed national sleep durations from 14 past investigations ( k = 353) and found that they were not associated with national health. Study 2 collected sleep duration and health data from people from 20 different countries ( N = 4,933). Average sleep durations varied substantially between countries (range = 1.57 h). A quadratic relation between sleep duration and health was found in all countries, although the turning points varied between countries. Individuals whose sleep duration was closer to their country’s perceived ideal reported better health. The results suggest that the amount of sleep associated with optimal health varies across countries.}, archive = {J_PNAS}, author = {Ou, Christine and Lou, Nigel Mantou and Maheshka, Charul and Shi, Marc and Takemura, Kosuke and Cheung, Benjamin and Heine, Steven J.}, doi = {10.1073/pnas.2419269122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2419269122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Healthy sleep durations appear to vary across cultures}, volume = {122}, year = {2025}, }
• (2025). Lateral jaw motion in fish expands the functional repertoire of vertebrates and underpins the success of a dominant herbivore lineage. PNAS, 122(19), e2418982122. (www)

  @article{ , abstract = {The primary function of the vertebrate jaw is the dorsoventral movement that occurs during opening and closing. Yet, several lineages have evolved the ability to move their jaws laterally, enabling major innovations, like chewing. While lateral jaw motions are primarily known in tetrapods, here, we show that an ecologically dominant lineage of reef fishes (Zanclidae and Acanthuridae) has evolved the ability to laterally rotate their jaws during feeding. This unique function substantially expands both the kinematic versatility and known diversity of vertebrate jaw mechanisms, adding to the growing list of innovations that followed the origin of jaws. Within Acanthuridae, this increased kinematic versatility may allow for algal detachment with minimal movement of the rest of the body, facilitating rapid biting within the same microtopographic location, and thus, this lineage having the highest bite rates among biting reef fishes. This innovation may have thus helped create one of the most ecologically diverse and speciose herbivorous reef fish lineages. Our results highlight the ecological and evolutionary impact of lateral jaw rotation within vertebrates, and potentially how this novelty led to a significant change in coral reef trophodynamics.}, archive = {J_PNAS}, author = {Mihalitsis, Michalis and Yamhure-Ramirez, Denise and Beil, Maelan H. and Chan, HoWan and Cole, Nathan J. and Luenenborg, Ava and Paglione, Isabella and Petri, Hallee and Shum, Nicole C. and Wainwright, Dylan K. and Zheng, Bryson and Wainwright, Peter C.}, doi = {10.1073/pnas.2418982122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2418982122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lateral jaw motion in fish expands the functional repertoire of vertebrates and underpins the success of a dominant herbivore lineage}, volume = {122}, year = {2025}, }
• (2025). Cryptic genetic variation in brain gene expression precedes the evolution of cannibalism in spadefoot toad tadpoles. PNAS, 122(19), e2418431122. (www)

  @article{ , abstract = {The origins of novel behaviors are poorly understood, despite behavior’s hypothesized roles in evolution. One model, “genetic accommodation,” proposes that selection on ancestral phenotypic plasticity may precede the evolution of novel traits. A critical assumption of genetic accommodation is that ancestral lineages possess heritable genetic variation for trait plasticity that is revealed in novel environments, thereby providing the raw materials for subsequent refinement of the novel trait in derived lineages. Here, we use a combination of behavioral and RNA-seq approaches to test this assumption in the context of a novel tadpole behavior: predatory cannibalism. Cannibalism evolved in the spadefoot genus Spea , where an invertebrate diet induces a carnivorous tadpole morph capable of consuming live conspecific tadpoles. In contrast, closely related Scaphiopus tadpoles do not induce this carnivorous phenotype. Through species comparisons, we found that ancestral Spea likely expressed behavioral plasticity and harbored latent (i.e., “cryptic”) genetic variation in brain gene expression plasticity associated with cannibalism-inducing cues. Further, we found that this cryptic genetic variation includes genes specifically associated with a dietary response and cannibalism in derived Spea . Our results suggest that novel behaviors, alongside novel morphologies, can evolve via the process of genetic accommodation. More generally, our results provide key evidence for the plausibility of genetic accommodation, revealing that cryptic genetic variation—the raw material for the evolution of novel traits—exists in natural populations at the level of gene expression.}, archive = {J_PNAS}, author = {Nesta, Dante J. and Ledón-Rettig, Cristina C.}, doi = {10.1073/pnas.2418431122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2418431122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryptic genetic variation in brain gene expression precedes the evolution of cannibalism in spadefoot toad tadpoles}, volume = {122}, year = {2025}, }
• (2025). Cyclic peptide inhibitors function as molecular glues to stabilize gq/11 heterotrimers. PNAS, 122(19), e2418398122. (www)

  @article{ , abstract = {Heterotrimeric Gα:Gβγ G proteins function as molecular switches downstream of G protein–coupled receptors (GPCRs). They alternate between a heterotrimeric GDP-bound OFF-state and a GTP-bound ON-state in which Gα GTP is separated from the Gβγ dimer. Consequently, pharmacological tools to securely prevent the OFF-ON transition are of utmost importance to investigate their molecular switch function, specific contribution to GPCR signal transduction, and potential as drug targets. FR900359 (FR) and YM-254890 (YM), two natural cyclic peptides and highly specific inhibitors of Gq/11 heterotrimers, are exactly such tools. To date, their efficient and long-lasting inhibition of Gq/11 signaling has been attributed solely to a wedge-like binding to Gα, thereby preventing separation of the GTPase and α-helical domains and thus GDP release. Here, we use X-ray crystallography, biochemical and signaling assays, and BRET-based biosensors to show that FR and YM also function as stabilizers of the Gα:Gβγ subunit interface. Our high-resolution structures reveal a network of residues in Gα and two highly conserved amino acids in Gβ that are targeted by FR and YM to glue the Gβγ complex to the inactive Gα GDP subunit. Unlike all previously developed nucleotide-state specific inhibitors that sequester Gα in its OFF-state but compete with Gβγ, FR and YM actively promote the inhibitory occlusion of Gα GDP by Gβγ. In doing so, they securely lock the entire heterotrimer, not just Gα, in its inactive state. Our results identify FR and YM as molecular glues for Gα and Gβγ that combine simultaneous binding to both subunits with inhibition of G protein signaling.}, archive = {J_PNAS}, author = {Mühle, Jonas and Alenfelder, Judith and Rodrigues, Matthew J. and Jürgenliemke, Lars and Guixà-González, Ramon and Grätz, Lukas and Andres, Fabio and Bacchin, Arianna and Hennig, Michael and Schihada, Hannes and Crüsemann, Max and König, Gabriele M. and Schertler, Gebhard and Kostenis, Evi and Deupi, Xavier}, doi = {10.1073/pnas.2418398122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2418398122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cyclic peptide inhibitors function as molecular glues to stabilize gq/11 heterotrimers}, volume = {122}, year = {2025}, }
• (2025). Monsoon hysteresis reveals atmospheric memory. PNAS, 122(19), e2418093122. (www)

  @article{ , abstract = {Within Earth’s climate system, the ocean, cryosphere, and vegetation exhibit hysteresis behavior such that their state depends on their past and not merely on their current boundary conditions. The atmosphere’s fast mixing time scales were thought to inhibit the necessary memory effect for such multistability. Here, we show that moisture accumulation within the atmospheric column generates hysteresis in monsoon circulation independent of oceanic heat storage and yields two stable atmospheric states for the same solar insolation. The dynamics of monsoon rainfall is thus that of a seasonal transition between two stable states. The resulting hysteresis is shown in observational data and reproduced in a general circulation model where it increases with decreasing oceanic memory and exhibits the two distinct states that persist for more than 60 y. They are stabilized by moisture accumulation within the atmospheric column that carries information across time scales much longer than those typical for mixing. The possibility of abrupt shifts between these two states has implications for the future evolution of global monsoon rainfall that is crucial for the agricultural productivity currently feeding more than two billion people.}, archive = {J_PNAS}, author = {Katzenberger, Anja and Levermann, Anders}, doi = {10.1073/pnas.2418093122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2418093122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Monsoon hysteresis reveals atmospheric memory}, volume = {122}, year = {2025}, }
• (2025). Intercellular contractile force attenuates chemosensitivity through notch-MVP-mediated nuclear drug export. PNAS, 122(19), e2417626122. (www)

  @article{ , abstract = {Resistance to chemotherapeutics is one major challenge to clinical effectiveness of cancer treatment and is primarily interpreted by various biochemical mechanisms. This study establishes an inverse correlation between tumor cell contractility and chemosensitivity. In both clinical biopsies and cancer cell lines, high/low actomyosin-mediated contractile force attenuates/enhances the vulnerability to chemotherapy, which depends on intercellular force propagation. Cell–cell interaction force activates the mechanosensitive Notch signaling that upregulates the downstream effector major vault protein, which facilitates the export of chemotherapy drugs from nuclei, leading to the reduction of chemosensitivity. Cellular contractility promotes the tolerance of tumor xenografts to chemotherapy and sustains tumor growth in vivo, which can be reversed by the inhibition of contractile force, Notch signaling, or major vault protein. Further, the actomyosin-Notch signaling is associated with drug resistance and cancer recurrence of patients. These findings unveil a regulatory role of intercellular force in chemosensitivity, which could be harnessed as a promising target for cancer mechanotherapeutics.}, archive = {J_PNAS}, author = {Du, Pengyu and Tang, Kai and Chen, Xi and Xin, Ying and Hu, Bin and Meng, Jianfeng and Hu, Guanshuo and Zhang, Cunyu and Li, Keming and Tan, Youhua}, doi = {10.1073/pnas.2417626122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2417626122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intercellular contractile force attenuates chemosensitivity through notch-MVP-mediated nuclear drug export}, volume = {122}, year = {2025}, }
• (2025). DDX24 spatiotemporally orchestrates VEGF and wnt signaling during developmental angiogenesis. PNAS, 122(19), e2417445122. (www)

  @article{ , abstract = {Vascular development is a precisely controlled process, yet how it is spatiotemporally orchestrated remains enigmatic. We previously identified DEAD-box RNA helicase 24 (DDX24) as a pathogenic gene for multiorgan vascular anomalies. Here, we show that DDX24 is expressed in the endothelium during embryonic angiogenesis in zebrafish. DDX24 deficiency causes intersegmental vessel hyperbranching in the trunk, but inhibits central artery angiogenesis in the brain. Mechanistically, DDX24 deficiency enhances VEGFR2 expression by direct binding to its mRNA in nonbrain endothelial cells (ECs), while suppressing GPR124/RECK-mediated Wnt signaling in brain ECs. Additionally, spatial transcriptome analysis profiles DDX24-mediated crosstalk between ECs and neighboring cells. Finally, pharmacological targeting of these two pathways in a temporal manner can rescue the phenotypes induced by DDX24 deficiency. Overall, our findings highlight an essential role for DDX24 in the spatiotemporal regulation of developmental angiogenesis.}, archive = {J_PNAS}, author = {Chen, Fangbin and Deng, Zhaohua and Wang, Xiaoming and Liu, Yuxuan and Zhao, Kaichen and Zhang, Yue and He, Simeng and Ran, Rensen and Dong, Yingying and Guo, Shuang and Zhou, Yitong and Zhou, Bin and Pang, Pengfei and Ge, Wei and Liu, Chang and Shan, Hong and He, Huanhuan}, doi = {10.1073/pnas.2417445122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2417445122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {DDX24 spatiotemporally orchestrates VEGF and wnt signaling during developmental angiogenesis}, volume = {122}, year = {2025}, }
• (2025). Loss of lipid asymmetry facilitates plasma membrane blebbing by decreasing membrane lipid packing. PNAS, 122(19), e2417145122. (www)

  @article{ , abstract = {Membrane blebs have important roles in cell migration, apoptosis, and intercellular communication through extracellular vesicles (EVs). While plasma membranes (PM) typically maintain phosphatidylserine (PS) on their cytoplasmic leaflet, most blebs have PS exposed on their outer leaflet, revealing that loss of steady-state lipid asymmetry often accompanies PM blebbing. How these changes in PM lipid organization regulate membrane properties and affect bleb formation remains unknown. We confirmed that lipid scrambling through the scramblase TMEM16F is essential for chemically induced membrane blebbing across cell types, with the kinetics of PS exposure being tightly coupled to the kinetics of bleb formation. Measurement of lipid packing with environment-sensitive probes revealed that lipid scrambling changes the physical properties of the PM, reducing lipid packing and facilitating the bilayer bending required for bleb formation. Accordingly, reducing lipid packing of the PM through cholesterol extraction, elevated temperature, or treatment with biological amphiphiles promoted blebbing in the absence of TMEM16F. Consistent with these cellular observations, blebbing in Caenorhabditis elegans embryos measured via EV production was significantly reduced by depleting the TMEM16-homolog ANOH-2. Our findings suggest that changing membrane biophysical properties by lipid scrambling is an important contributor to the formation of blebs and EVs and potentially other cellular processes involving PM deformation.}, archive = {J_PNAS}, author = {Wang, Hong-Yin and Rumin, Alissa and Doktorova, Milka and Sputay, Daryna and Chan, Sze Ham and Wehman, Ann M. and Levental, Kandice R. and Levental, Ilya}, doi = {10.1073/pnas.2417145122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2417145122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Loss of lipid asymmetry facilitates plasma membrane blebbing by decreasing membrane lipid packing}, volume = {122}, year = {2025}, }
• (2025). Incorporation of polylactic acid microplastics into the carbon cycle as a carbon source to remodel the endogenous metabolism of the gut. PNAS, 122(19), e2417104122. (www)

  @article{ , abstract = {Biodegradable polylactic acid (PLA) plastics have been praised as an effective solution to the global pollution caused by petroleum-based plastics, and their widespread use in food packaging and disposable tableware has resulted in increased oral exposure to PLA microplastics (PLA-MPs). Despite their eco-friendly and biodegradable reputation, the in vivo behaviors of PLA-MPs concerning fermentation, carbon cycle, and adverse effects remain unknown. Here, we showed that gut microbiota from the colon can effectively degrade the PLA-MPs by secreting esterase FrsA, whereas esterase FrsA-producing bacteria were identified to dominate this behavior in male C57BL/6 mice. Using isotope tracing and multiomics techniques, we uncovered that 13 C-labeled PLA-MPs were incorporated into the carbon cycle of gut microbiota as a carbon source. Meanwhile, these degraded PLA-MPs fragments entered the succinate pathway of the tricarboxylic acid cycle within gut epithelial cells. These processes altered the metabolic phenotype of the gut, resulting in the decreased linear short-chain fatty acids that are primary energy sources of the gut epithelium. Furthermore, we found that exposure of PLA-MPs significantly reduced the appetite and body weight of mice. Our findings present an overall process of biodegradable plastics within hosts, with the focus on the entire double carbon cycle of PLA-MPs in the gut, which offers indispensable insights into the potential impact of exposure to PLA-MPs.}, archive = {J_PNAS}, author = {Bao, Lin and Cui, Xuejing and Zeng, Tao and Liu, Guanyu and Lai, Wenjia and Zhao, Hao and Gao, Fene and Wu, Junguang and Leong, Kam W. and Chen, Chunying}, doi = {10.1073/pnas.2417104122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2417104122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Incorporation of polylactic acid microplastics into the carbon cycle as a carbon source to remodel the endogenous metabolism of the gut}, volume = {122}, year = {2025}, }
• (2025). Acute chromatin decompaction stiffens the nucleus as revealed by nanopillar-induced nuclear deformation in cells. PNAS, 122(19), e2416659122. (www)

  @article{ , abstract = {Chromatin architecture is critical in determining nuclear mechanics. Most studies focus on the mechanical rigidity conferred by chromatin condensation from densely packed heterochromatin, but less is known on how transient chromatin decompaction impinge on nucleus stiffness. Here, we used an array of vertically aligned nanopillars to study nuclear deformability in situ after chromatin decompaction in cells. The nucleus significantly stiffened within 4 h of chromatin decompaction but softened at longer timescales. This acute stiffening of the nucleus was underpinned predominantly by an increase in nucleus volume and nuclear import, and partially by enhanced lamin protein recruitment to the periphery. The coupling between nucleus stiffening and acute chromatin decompaction was observed in low malignancy cancer cell lines (e.g. MCF7, PEO1, A549) but weakened in highly malignant counterparts (e.g. MDA-MB-231, HEYA8, HT1080) due to the capacity to efficiently compact heterochromatin into foci that sustains nucleus deformability required for confined migration. Our work signals how rapid chromatin remodeling is a physiologically relevant pathway to modulate nucleus mechanics and cell migration behavior.}, archive = {J_PNAS}, author = {Mitra, Aninda and Cutiongco, Marie F. A. and Burla, Romina and Zeng, Yongpeng and Na, Qin and Kong, Mengya and Vinod, Benjamin and Nai, Mui Hoon and Hübner, Barbara and Ludwig, Alexander and Lim, Chwee Teck and Shivashankar, G. V. and Saggio, Isabella and Zhao, Wenting}, doi = {10.1073/pnas.2416659122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2416659122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Acute chromatin decompaction stiffens the nucleus as revealed by nanopillar-induced nuclear deformation in cells}, volume = {122}, year = {2025}, }
• (2025). VCP’s nuclear journey: Initiated by interacting with KPNB1 to repair DNA damage. PNAS, 122(19), e2416045122. (www)

  @article{ , abstract = {DNA damage repair (DDR) is essential for cancer cell survival and treatment resistance, making it a critical target for tumor therapy. The eukaryotic AAA+ adenosine triphosphatase valosin-containing protein (VCP), which is transported from the cytoplasm into the nucleus, plays a critical role in the DDR process. However, the nuclear translocation and molecular mechanism of VCP for DDR remain elusive. Here, we define VCP as a KPNB1 interacting protein through a combination of chemical and immunoprecipitation mass spectrometry approaches. Further biochemical studies elucidate that KPNB1 directly transports VCP into the nucleus. We also identify withaferin A (WA) as a small molecule that can retard VCP nuclear localization via covalent binding to CYS 158 of KPNB1. Further studies verify WA as an effective antitumor drug candidate via blocking VCP nuclear localization to impact on the DDR pathway in vivo. Our findings underly the unclear VCP’s role in DDR in a KPNB1-dependent manner and provide an important theoretical basis for developing small-molecule inhibitors targeting this process.}, archive = {J_PNAS}, author = {Xing, Zhichao and Cai, Xiaoying and He, Ting and Li, Peiheng and He, Jun and Qiu, Yuxuan and Li, Na and Mi, Li and Li, Ruixi and Zhu, Jingqiang and Li, Zhihui and Su, Anping and Ye, Haoyu and Wu, Wenshuang}, doi = {10.1073/pnas.2416045122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2416045122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {VCP’s nuclear journey: Initiated by interacting with KPNB1 to repair DNA damage}, volume = {122}, year = {2025}, }
• (2025). Spreading depolarizations exhaust neuronal ATP in a model of cerebral ischemia. PNAS, 122(19), e2415358122. (www)

  @article{ , abstract = {Spreading depolarizations (SDs) have been identified in various brain pathologies. SDs increase the cerebral energy demand and, concomitantly, oxygen consumption, which indicates enhanced synthesis of adenosine triphosphate (ATP) by oxidative phosphorylation. Therefore, SDs are considered particularly detrimental during reduced supply of oxygen and glucose. However, measurements of intracellular neuronal ATP ([ATP] i ), ultimately reporting the balance of ATP synthesis and consumption during SDs, have not yet been conducted. Here, we investigated neuronal ATP homeostasis during SDs using two-photon imaging in acute brain slices from adult mice expressing the ATP sensor ATeam1.03 YEMK in neurons. SDs were induced by application of potassium chloride or by oxygen and glucose deprivation (OGD) and detected by recording the local field potential, extracellular potassium, as well as the intrinsic optical signal. We found that, in the presence of oxygen and glucose, SDs were accompanied by a substantial but transient drop in neuronal ATP sensor signals, corresponding to a drop in ATP. OGD, which prior to SDs was accompanied by only a slight reduction in ATP signals, led to a large, terminal drop in ATP signals during SDs. Subsequently, we investigated whether neurons could still regenerate ATP if oxygen and glucose were promptly resupplied following SD detection, and show that ATP depletion was essentially reversible in most cells. Our findings indicate that SDs are accompanied by a substantial increase in ATP consumption beyond production. This, under conditions that mimic reduced blood supply, leads to a breakdown of [ATP] i . Therefore, our findings support therapeutic strategies targeting SDs after cerebral ischemia.}, archive = {J_PNAS}, author = {Schoknecht, Karl and Baeza-Lehnert, Felipe and Hirrlinger, Johannes and Dreier, Jens P. and Eilers, Jens}, doi = {10.1073/pnas.2415358122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2415358122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spreading depolarizations exhaust neuronal ATP in a model of cerebral ischemia}, volume = {122}, year = {2025}, }
• (2025). Proviral insights of glycolytic enolase in bamboo mosaic virus replication associated with chloroplasts and mitochondria. PNAS, 122(19), e2415089122. (www)

  @article{ , abstract = {Diverse single-stranded RNA viruses employ different host cellular organelles or membrane systems to compartmentalize their replication intermediates and proviral factors, ensuring robust replication. Replication of Bamboo mosaic virus (BaMV), an Alphaflexiviridae family, is tightly associated with chloroplasts and dynamic cytosolic viral replication complex (VRC) clusters. BaMV VRC clusters comprise double-stranded viral RNA, BaMV replicase (Rep BaMV ), and mitochondrial outer membrane protein, voltage-dependent anion channel (VDAC). In this study, we demonstrate that host glycolytic enolase (ENO) binds to untranslated regions of BaMV RNA independently of ENO hydrolytic activity. However, the structural integrity of ENO is essential for its direct interaction with Rep BaMV , and its positive regulating role in BaMV replication and the size of BaMV VRC clusters. Additionally, ENO, pyruvate kinase (PYK), and VDAC colocalize within cytosolic BaMV VRC clusters embedded in the convoluted endomembrane reticulum (ER) along with ER-targeted viral movement proteins under BaMV infection. This association suggests that the ENO-PYK-VDAC metabolon, with ENO serving as a scaffold to link chloroplasts and mitochondria, may play a pivotal role in BaMV robust replication. Collectively, our findings offer significant insights into how glycolytic ENO acts in BaMV replication.}, archive = {J_PNAS}, author = {Lin, Kuan-Yu and Huang, Ying-Wen and Hou, Liang-Yu and Chen, Hsin-Chuan and Wu, Yu and Chen, I-Hsuan and Huang, Ying-Ping and Lee, Shu-Chuan and Hu, Chung-Chi and Tsai, Ching-Hsiu and Hsu, Yau-Heiu and Lin, Na-Sheng}, doi = {10.1073/pnas.2415089122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2415089122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Proviral insights of glycolytic enolase in bamboo mosaic virus replication associated with chloroplasts and mitochondria}, volume = {122}, year = {2025}, }
• (2025). Unbiased mechanical cloaks. PNAS, 122(19), e2415056122. (www)

  @article{ , abstract = {The distinction between “reinforcement” and “cloaking” has been overlooked in optimization-based design of devices intended to conceal a defect in an elastic medium. In the former, a so-called “cloak” is severely biased toward one or a few specific elastic disturbances, whereas in the latter, an “unbiased cloak” is effective under any elastic disturbance. We propose a two-stage approach for optimization-based design of elastostatic cloaks that targets true, unbiased cloaks. First, we perform load-case optimization to find a finite set of worst-case design loads. Then we perform topology optimization of the cloak microstructure under these worst-case loads using a judicious choice of the objective function, formulated in terms of energy mismatch. Although a small subset of the infinite load cases that the cloak must handle, these highly nonintuitive, worst-case loads lead to designs that approach perfect and unbiased elastostatic cloaking. In demonstration, we consider elastic media composed of spinodal architected materials, which provides an ideal testbed for exploring elastostatic cloaks in media with varying anisotropy and porosity, without sacrificing manufacturability. To numerically verify the universal nature of our cloaks, we compare the elastic response of the medium containing the cloaked defect to that of the undisturbed medium under many random load cases not considered during design. By using digital light processing additive manufacturing to realize the elastic media containing cloaked defects and analyzing their response experimentally using compression testing with digital image correlation, this study provides a physical demonstration of elastostatic cloaking of a three-dimensional defect in a three-dimensional medium.}, archive = {J_PNAS}, author = {Senhora, Fernando Vasconcelos and Sanders, Emily D. and Paulino, Glaucio H.}, doi = {10.1073/pnas.2415056122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2415056122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unbiased mechanical cloaks}, volume = {122}, year = {2025}, }
• (2025). Unconventional secretion of PARK7 requires lysosomal delivery via chaperone-mediated autophagy and specialized SNARE complex. PNAS, 122(19), e2414790122. (www)

  @article{ , abstract = {PARK7/DJ-1, a redox-sensitive protein implicated in neurodegeneration, cancer, and inflammation, exhibits increased secretion under stress. We previously demonstrated that, as a leaderless protein, PARK7 relies on an unconventional autophagy pathway for stress-induced secretion. The current study delves deeper into the mechanisms governing PARK7 secretion under oxidative stress triggered by the neurotoxin 6-hydroxydopamine (6-OHDA). Here, we revealed that 6-OHDA-induced autophagic flux is critical for PARK7 secretion. Downregulation of syntaxin 17 (STX17), a SNARE protein crucial for autophagosome-lysosome fusion and cargo degradation, hindered PARK7 secretion. Likewise, impairing lysosomal function with bafilomycin A1 (BafA1) or chloroquine (CQ) diminished PARK7 release, highlighting the importance of functional lysosomes, potentially in the form of secretory autolysosomes, in PARK7 release. We also found that 6-OHDA appeared to promote the unfolding of PARK7, allowing its selective recognition by the chaperone HSPA8 via KFERQ-like motifs, leading to PARK7 translocation to the lysosomal membrane through LAMP2 via chaperone-mediated autophagy (CMA). Additionally, a dedicated SNARE complex comprising Qabc-SNAREs (STX3/4, VTI1B, and STX8) and R-SNARE SEC22B mediates the fusion of PARK7-containing autolysosomes with the plasma membrane, facilitating the extracellular release of PARK7. Hence, this study uncovers a mechanism where 6-OHDA-induced autophagic flux drives the unconventional secretion of PARK7, involving CMA for PARK7 translocation to lysosomes and specialized SNARE complexes for membrane fusion events.}, archive = {J_PNAS}, author = {Dash, Biplab Kumar and Urano, Yasuomi and Mita, Yuichiro and Ashida, Yuki and Hirose, Ryoma and Noguchi, Noriko}, doi = {10.1073/pnas.2414790122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2414790122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unconventional secretion of PARK7 requires lysosomal delivery via chaperone-mediated autophagy and specialized SNARE complex}, volume = {122}, year = {2025}, }
• (2025). Dynamic interplay between niche variation and flight adaptability drove a hundred million years’ dispersion in iconic lacewings. PNAS, 122(19), e2414549122. (www)

  @article{ , abstract = {The form and change of animal biogeography reflects the long-term interplay between organisms and their environment, involving physiological limitation, dispersal capability, and adaptive evolution versus plate tectonics, global climatic shifts, and changing landscapes. This is especially manifest for lineages with extended geological histories, which, therefore, evokes questions as to the associated processes producing such patterns. Insects, as the earliest flying animals, have exceptional abilities for expanding their range and habitats and to avoid detrimental conditions. They are ideal for exploring historical biogeography augmented via adaptation. Here, we employ beaded lacewings as a model to explore such patterns and likely processes, particularly given that they differ notably from the commonly observed pattern of a latitudinal diversity gradient. Furthermore, owing to their good fossil record it can be observed that their distributions varied remarkably through time. Ecological niche modeling and evaluation demonstrate their niche variation and niche breadth expansion intermittently accompanying global climate change. However, different niche relevant variables changed under patterns of either phylogenetic conservatism or evolutionary lability. By assessing wing morphological disparity and modeling flight aerodynamics, we uncovered a continuous improvement of flight efficiency through beaded-lacewing history as well as a Paleogene divergence in strategy, which reveals a long-term associated path with the niche variation. Our results unveil the adaptive evolution and dispersal history of beaded lacewings through 170 My, achieved by dynamic strategies in niche shift and flight adaptation as responses to a changing planet.}, archive = {J_PNAS}, author = {Ou, Haohong and Yang, Jingtao and Wang, Honglong and Kang, Nuoyao and Li, Shumin and Chen, Yuting and Peng, Zihao and Xiang, Xianzhe and Engel, Michael S. and Winterton, Shaun L. and Ren, Dong and Yang, Qiang and Shi, Chaofan}, doi = {10.1073/pnas.2414549122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2414549122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic interplay between niche variation and flight adaptability drove a hundred million years’ dispersion in iconic lacewings}, volume = {122}, year = {2025}, }
• (2025). Cortical signatures linked to behavior quantitatively track arousal levels. PNAS, 122(19), e2413789122. (www)

  @article{ , abstract = {While current arousal level assessments in patients with disorders of consciousness discriminate altered states of consciousness, there are significant limitations in characterizing the transition from one state to another or quantifying the frequent arousal level fluctuations observed in a patient. Here, we identified a repeated, temporally discrete, dynamical pattern evident in the recovery of consciousness from anesthesia and brain injury coma models in rodents. We prospectively validated these features we label “Arousal Units” (AU) in neonatal humans recovering from static hypoxic injuries and senior patients emerging from anesthesia indicating their generalizability. The AUs lawfully link changes in spectral power and breathing frequency and reliably associate with motor changes. Distinctive cortical patterns within AUs can be transformed into arousal indices, determining arousal levels. The reliability of these events is demonstrated across intact and brain-injured states and translates to the human brain; extracting these stereotyped dynamics could aid anesthesia monitoring, tracking coma recovery, and identifying cognitive motor dissociation.}, archive = {J_PNAS}, author = {Gao, Sijia and Bibineyshvili, Yelena and Safavynia, Seyed A. and Calderón-Martínez, Juan and Grinspan, Zachary M. and Calderon, Diany P.}, doi = {10.1073/pnas.2413789122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2413789122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cortical signatures linked to behavior quantitatively track arousal levels}, volume = {122}, year = {2025}, }
• (2025). Bone microstructure supports a mesozoic origin for a semiaquatic burrowing lifestyle in monotremes (Mammalia). PNAS, 122(19), e2413569122. (www)

  @article{ , abstract = {The platypus and four echidna species are the only living egg-laying mammals and the sole extant representatives of Order Monotremata. The platypus and echidnas are very disparate both morphologically and ecologically: The platypus is a specialized semiaquatic burrowing form that forages for freshwater invertebrates, whereas echidnas are fully terrestrial and adapted for feeding on social insects and earthworms. It has been proposed that echidnas evolved from a semiaquatic, platypus-like ancestor, but fossil evidence for such a profound evolutionary transformation has been lacking, and this hypothesis remains controversial. Here, we present original data about the Early Cretaceous (108 to 103 Ma) Australian mammal Kryoryctes cadburyi , currently only known from a single humerus, that provides key information relating to this question. Phylogenetic analysis of a 536-character morphological matrix of mammaliaforms places Kryoryctes as a stem-monotreme. Three-dimensional whole bone comparisons show that the overall shape of the humerus is more similar to that of echidnas than the platypus, but analysis of microstructure reveals specializations found in semiaquatic mammals, including a particularly thick cortex and a highly reduced medullary cavity, present in the platypus but absent in echidnas. The evidence suggests Kryoryctes was a semiaquatic burrower, indicating that monotremes first evolved an amphibious lifestyle in the Mesozoic, and providing support for the hypothesis that this is ancestral for living monotremes as a whole. The lineage leading to the modern platypus appears to have been characterized by extremely long term (>100 My) niche conservatism, with echidnas representing a much later reversion to a fully terrestrial lifestyle.}, archive = {J_PNAS}, author = {Hand, Suzanne J. and Wilson, Laura A. B. and López-Aguirre, Camilo and Houssaye, Alexandra and Archer, Michael and Bevitt, Joseph J. and Evans, Alistair R. and Halim, Amalia Y. and Hung, Tzong and Rich, Thomas H. and Vickers-Rich, Patricia and Beck, Robin M. D.}, doi = {10.1073/pnas.2413569122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2413569122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bone microstructure supports a mesozoic origin for a semiaquatic burrowing lifestyle in monotremes (Mammalia)}, volume = {122}, year = {2025}, }
• (2025). The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity. PNAS, 122(19), e2412854122. (www)

  @article{ , abstract = {Cancer cells frequently reprogram one-carbon metabolic pathways to fulfill their vigorous demands of biosynthesis and antioxidant defense for survival and proliferation. Dysfunction of oncogenes or tumor suppressor genes is critically involved in this process, but the precise mechanisms by which cancer cells actively trigger one-carbon metabolic alterations remain incompletely elucidated. Here, by using untargeted metabolomic analysis, we identify the oncoprotein SE translocation (SET) as a key regulator of one-carbon metabolism in cancer cells. SET physically interacts with mitochondrial SHMT2 and facilitates SHMT2 enzymatic activity. Loss of SET profoundly suppresses serine-derived one-carbon metabolic flux, whereas reexpression of ectopic SET leads to the opposite effect. Notably, although the presence of SHMT2 is critical for SET-mediated one-carbon metabolic alterations, the depletion of SHMT2 alone is insufficient to antagonize SET-induced tumor growth, probably due to functional compensation by its cytosolic isozyme SHMT1 upon SHMT2 knockdown. Instead, pharmacological targeting of cellular SHMT (including both SHMT1 and SHMT2) activity results in dramatic suppression of SET-induced tumor growth. Moreover, by using a Kras/Lkb1 mutation-driven lung tumor mouse model, we demonstrate that the loss of SET compromises both tumor formation and intratumoral SHMT2 enzymatic activity. Clinically, the overexpression of SET and SHMT2 is observed in lung tumors, both of which correlate with poor prognosis. Our study reveals a SET–SHMT2 axis in regulating serine-derived one-carbon metabolism and uncovers one-carbon metabolic reprogramming as a mechanism for SET-driven tumorigenesis.}, archive = {J_PNAS}, author = {Jiao, Zishan and Zhang, Mi and Ning, Jingyuan and Yao, Han and Yan, Xiaojun and Wu, Zhen and Wu, Dexuan and Liu, Yajing and Zhang, Meng and Wang, Lin and Wang, Donglai}, doi = {10.1073/pnas.2412854122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2412854122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity}, volume = {122}, year = {2025}, }
• (2025). Social dominance in rats is a determinant of susceptibility to stress. PNAS, 122(19), e2412314122. (www)

  @article{ , abstract = {Establishing a dominance hierarchy in social organisms is important for access to resources. Stress has been proposed as a major factor influencing an animal’s likely position in a social hierarchy. Although individual differences in vulnerability to stress are increasingly recognized, how social hierarchy affects vulnerability remains relatively understudied. Here, we examined how the social dominance status of adult male Sprague-Dawley rats influences their response to stress in interactions with a familiar animal living in the same cage, and separately when confronting an unfamiliar rat of uncertain dominance status from another cage, using the tube test. Having determined the relatively stable within-cage social dominance status of animals, half were subjected to a single episode of 2-h immobilization stress. Cagemates, both control and stressed rats, again faced one another 1 d and 10 d after stress. First, the predetermined hierarchical rank among familiar cagemates was relatively unaffected by stress. However, second, the same stress had a differential impact in competitions between unfamiliar rats. Socially dominant control rats continued to win competitions but subordinate control rats, that had previously lost, sometimes started to win against previously dominant rats that had been stressed. Strikingly, subordinate stressed rats displayed consistent submissive-like behavior and they alone showed differential effects on dendritic spine density in the amygdala. Thus, an individual’s social rank can influence its response to stress, an effect that is detectable in interactions with unfamiliar animals. These findings provide an additional dimension to animal models of stress used for exploring facets of social anxiety and withdrawal in stress-related psychiatric disorders.}, archive = {J_PNAS}, author = {Srinivasan, Durga J. and Kapgal, Vijayakumar and Morris, Richard G. M. and Chattarji, Sumantra}, doi = {10.1073/pnas.2412314122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2412314122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Social dominance in rats is a determinant of susceptibility to stress}, volume = {122}, year = {2025}, }
• (2025). Single-cell elderly blood–CSF atlas implicates peripherally influenced immune dysregulation in normal pressure hydrocephalus. PNAS, 122(19), e2412159122. (www)

  @article{ , abstract = {We have generated a single-cell RNA sequencing atlas of peripheral blood and ventricular CSF in idiopathic normal pressure hydrocephalus (iNPH) patients totaling 140,207 single-cell transcriptomes. We found proinflammatory alterations in peripheral blood and CSF monocytes in iNPH patients with lower baseline cognitive function. We also identified CSF cell populations likely representing periventricular sloughing of degenerating neuroglial cells. Our findings suggest possible immune dysregulation in the blood and CSF of iNPH patients.}, archive = {J_PNAS}, author = {Duy, Phan Q. and Kiziltug, Emre and Greenberg, Ana B.W. and Mehta, Neel H. and Hao, Le T. and Fortes, Carla and Mullany, Susan and Fan, Baojian and Manichaikul, Ani and Teich, Andrew F. and Chan, Diane and Alper, Seth L. and Hyman, Bradley T. and Arnold, Steven E. and McKhann, Guy M. and Frosch, Matthew P. and Kahle, Kristopher T.}, doi = {10.1073/pnas.2412159122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2412159122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Single-cell elderly blood–CSF atlas implicates peripherally influenced immune dysregulation in normal pressure hydrocephalus}, volume = {122}, year = {2025}, }
• (2025). Differential elimination of marked sex chromosomes enables production of nontransgenic male mosquitoes in a single strain. PNAS, 122(19), e2412149122. (www)

  @article{ , abstract = {Diverse genetic strategies are being pursued to control mosquito-borne infectious diseases. These strategies often rely on the release of nonbiting males to either reduce the target mosquito population or render them resistant to pathogens. Male-only releases are important as any contaminating females can bite and potentially transmit pathogens. Despite significant efforts, it remains a major bottleneck to reliably and efficiently separate males from females, especially when nontransgenic males are preferred. In the yellow fever mosquito Aedes aegypti , sex is determined by a pair of homomorphic sex chromosomes, with the dominant male-determining locus (the M locus) and its counterpart (the m locus) embedded in an M-bearing and an m-bearing chromosome 1, respectively. We utilized both naturally occurring and engineered sex-linked recessive lethal alleles (RLAs) to create sex separation strains for Ae. aegypti on the basis of differential elimination of marked sex chromosomes (DeMark). DeMark strains are self-sustaining and produce nontransgenic males that are readily separated from individuals carrying RLA- and transgene-marked m chromosomes. For example, the marked m chromosome in the heterozygous mother in some strains was only inherited by her female progeny due to RLA-mediated incompatibility with the M-bearing chromosome in the father, producing nontransgenic males and transgenic females, generation after generation. We further explore strategies to conditionally eliminate females that contain marked sex chromosomes. We also discuss DeMark designs that are applicable for efficient sex separation in organisms with well-differentiated X and Y chromosomes, such as the Anopheles mosquitoes.}, archive = {J_PNAS}, author = {Compton, Austin and Sharma, Atashi and Hempel, Melanie and Aryan, Azadeh and Biedler, James K. and Potters, Mark B. and Chandrasegaran, Karthikeyan and Vinauger, Clément and Tu, Zhijian}, doi = {10.1073/pnas.2412149122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2412149122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Differential elimination of marked sex chromosomes enables production of nontransgenic male mosquitoes in a single strain}, volume = {122}, year = {2025}, }
• (2025). Structure and nucleic acid interactions of the sΔ60 domain of the hepatitis delta virus small antigen. PNAS, 122(19), e2411890122. (www)

  @article{ , abstract = {Infection with hepatitis delta virus (HDV) causes the most severe form of viral hepatitis, affecting more than 15 million people worldwide. HDV is a small RNA satellite virus of the hepatitis B virus (HBV) that relies on the HBV envelope for viral particle assembly. The only specific HDV component is the ribonucleoprotein (RNP), which consists of viral RNA (vRNA) associated with the small (S) and large (L) delta antigens (HDAg). While the structure of the HDAg N-terminal assembly domain is known, here we address the structure of the remaining S Δ60 protein using NMR. We show that S Δ60 contains two intrinsically disordered regions separated by a helix–loop–helix motif and that this structure is conserved in the full-length protein. Solution NMR analysis revealed that S Δ60 binds to both full-length and truncated vRNA, highlighting the role of the helical regions in submicromolar affinity interactions. The resulting complex contains approximately 120 S Δ60 proteins per RNA. Our results provide a model for the arginine-rich domains in RNP assembly and RNA interactions. In addition, we show that a cluster of acidic residues within the structured region of S Δ60 is critical for HDV replication, possibly mimicking the nucleosome acidic patch involved in the recruitment of chromatin remodelers. Our work thus provides the molecular basis for understanding the role of the C-terminal RNA-binding domain of S-HDAg in HDV infection.}, archive = {J_PNAS}, author = {Yang, Yang and Delcourte, Loïc and van Belleghem, Carolanne and Fonte, Simone and Gerard, Kassandra and Baconnais, Sonia and Callon, Morgane and Le Cam, Eric and Fogeron, Marie-Laure and Levrero, Massimo and Faivre-Moskalenko, Cendrine and Böckmann, Anja and Lecoq, Lauriane}, doi = {10.1073/pnas.2411890122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2411890122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure and nucleic acid interactions of the sΔ60 domain of the hepatitis delta virus small antigen}, volume = {122}, year = {2025}, }
• (2025). Prioritizing urban heat adaptation infrastructure based on multiple outcomes: Comfort, health, and energy. PNAS, 122(19), e2411144122. (www)

  @article{ , abstract = {Globally, cities face increasing extreme heat, impacting comfort, health, and energy consumption. Infrastructure-based heat adaptation strategies can improve these outcomes, but each strategy has a unique mix of benefits and drawbacks. Here, we apply an urbanized meteorological model (WRF) with the newly integrated multilayer BEP-Tree street tree model to dynamically downscale Earth System Model projections and a 3-D microclimate model (TUF-Pedestrian) to simulate the street-scale radiation environment impacting pedestrians. We evaluate the performance of five heat adaptation strategies (street trees, cool roofs, green roofs, rooftop photovoltaics (PV), and reflective pavements) during extreme heat events in three cities with contrasting background climates (Toronto, Phoenix, and Miami), under contemporary and end-of-century projected climates, based on three metrics: outdoor heat stress, air conditioning (AC) energy use, and ventilation of vehicular air pollution. No single adaptation strategy improves all three outcomes. While street trees inhibit ventilation, they reduce outdoor heat stress four times more effectively than the next best strategy via shade provision, fully offsetting heat stress increases under a high-emissions end-of-century climate scenario in all cities studied. Cool roofs and green roofs moderately reduce heat stress and energy use. Alternatively, rooftop PV with energy storage can generate sufficient power for space cooling but have marginal effects on heat stress. Reflective pavements are the least effective across metrics. Where the ventilation of street-level emissions is of less concern, our results clearly support the combination of street trees and rooftop PV as a highly complementary and effective means of adaptive mitigation across different climates and neighborhood densities.}, archive = {J_PNAS}, author = {Jiang, Timothy and Krayenhoff, E. Scott and Martilli, Alberto and Nazarian, Negin and Stone, Brian and Voogt, James A.}, doi = {10.1073/pnas.2411144122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2411144122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prioritizing urban heat adaptation infrastructure based on multiple outcomes: Comfort, health, and energy}, volume = {122}, year = {2025}, }
• (2025). Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine. PNAS, 122(19), e2410766122. (www)

  @article{ , abstract = {RAS is the most frequently mutated oncogene in cancer. RAS proteins show high sequence similarities in their G-domains but are significantly different in their C-terminal hypervariable regions (HVR). These regions interact with the cell membrane via lipid anchors that result from posttranslational modifications (PTM) of cysteine residues. KRAS4b is unique as it has only one cysteine that undergoes PTM, C185. Small molecule covalent modification of C185 would block any form of prenylation and subsequently inhibit attachment of KRAS4b to the cell membrane, blocking its biological activity. We translated this concept to the discovery and development of disulfide tethering screen hits into irreversible covalent modifiers of C185. These compounds inhibited proliferation of KRAS4b-driven mouse embryonic fibroblasts, but not cells driven by N-myristoylated KRAS4b that harbor a C185S mutation and are not dependent on C185 prenylation. Top–down proteomics was used to confirm target engagement in cells. These compounds bind in a pocket formed when the HVR folds back between helix 3 and 4 in the G-domain (HVR-α3-α4). This interaction can happen in the absence of small molecules as predicted by molecular dynamics simulations and is stabilized in the presence of C185 binders as confirmed by small-angle X-ray scattering and solution NMR. NOESY-HSQC, an NMR approach that measures internuclear distances of 6 Å or less, and structure analysis identified the critical residues and interactions that define the HVR-α3-α4 pocket. Further development of compounds that bind to this pocket could be the basis of a new approach to targeting KRAS cancers.}, archive = {J_PNAS}, author = {Maciag, Anna E. and Yang, Yue and Sharma, Alok K. and Turner, David M. and DeHart, Caroline J. and Abdelkarim, Hazem and Fan, Lixin and Smith, Brian P. and Kumari, Vandana and Dyba, Marcin and Rigby, Megan and Castillo Badillo, Jean A. and Adams, Lauren and Fornelli, Luca and Fox, Stephen and Brafman, Alla and Turbyville, Thomas and Gillette, William and Messing, Simon and Agamasu, Constance and Wolfe, Andrew L. and Gysin, Stephan and Chan, Albert H. and Simanshu, Dhirendra K. and Esposito, Dominic and Chertov, Oleg and Stephen, Andrew G. and Arkin, Michelle and Renslo, Adam and Kelleher, Neil L. and Gaponenko, Vadim and Lightstone, Felice C. and Nissley, Dwight V. and McCormick, Frank}, doi = {10.1073/pnas.2410766122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2410766122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine}, volume = {122}, year = {2025}, }
• (2025). Achievement (not effort) makes people feel entitled to rewards. PNAS, 122(19), e2409131122. (www)

  @article{ , abstract = {It is common to say that people feel entitled to rewards—they think they have earned or deserve them—based on their effort and achievement. However, effort and achievement draw on different principles to justify reward. They can also conflict over when people should feel entitled to rewards. These observations raise the question: In everyday settings, do people feel entitled to rewards because of their effort, achievement, or some combination of the two? To determine how effort and achievement contribute to feelings of entitlement, we hired online workers and varied the feelings of effort and achievement that their work induced. We then let those workers decide how large of a bonus we then paid them. Achievement strongly predicted how much participants paid themselves. Hard work, by contrast, played little-to-no detectable role.}, archive = {J_PNAS}, author = {Cusimano, Corey and Kim, Jin and Wong, Jared}, doi = {10.1073/pnas.2409131122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2409131122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Achievement (not effort) makes people feel entitled to rewards}, volume = {122}, year = {2025}, }
• (2025). Paving the way for social touch at a distance: Sonifying tactile interactions and their underlying emotions. PNAS, 122(19), e2407614122. (www)

  @article{ , abstract = {Social touch is crucial for human well-being, as a lack of tactile interactions increases anxiety, loneliness, and need for social support. To address the detrimental effects of social isolation, we build on cutting-edge research on social touch and movement sonification to investigate whether social tactile gestures could be recognized through sounds, a sensory channel giving access to remote information. Four online experiments investigated participants’ perception of auditory stimuli that were recorded with our “audio-touch” sonification technique, which captures the sounds of touch. In the first experiment, participants correctly categorized sonified skin-on-skin tactile gestures (i.e., stroking, rubbing, tapping, hitting). In the second experiment, the audio-touch sample consisted of the sonification of six socio-emotional intentions conveyed through touch (i.e., anger, attention, fear, joy, love, sympathy). Participants categorized above chance the socio-emotional intentions of skin-on-skin touches converted into sounds and coherently rated their valence. In two additional experiments, the surface involved in the touches (either skin or plastic) was shown to influence participants’ recognition of sonified gestures and socio-emotional intentions. Thus, our research unveils that specific information about social touch (i.e., gesture, emotions, and surface) can be recognized through sounds, when they are obtained with our specific sonifying methodology. This shows significant promise for providing remote access, through the auditory channel, to meaningful social touch interactions.}, archive = {J_PNAS}, author = {de Lagarde, Alexandra and Pelachaud, Catherine and Kirsch, Louise P. and Auvray, Malika}, doi = {10.1073/pnas.2407614122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2407614122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Paving the way for social touch at a distance: Sonifying tactile interactions and their underlying emotions}, volume = {122}, year = {2025}, }
• (2025). Linked nitrogen and carbon dynamics reveal distinct pools and patterns in a deep, weathered bedrock rhizosphere. PNAS, 122(19), e2400452122. (www)

  @article{ , abstract = {Nitrogen is one of the most limiting nutrients to forest productivity worldwide. Recently, it has been established that diverse ecosystems source a substantial fraction of their water from weathered bedrock, leading to questions about whether root-driven nitrogen cycling extends into weathered bedrock as well. In this study, we specifically examined nitrogen dynamics using specialized instrumentation distributed across a 16 m weathered bedrock vadose zone (WBVZ) underlying an old growth forest in northern California where the rhizosphere—composed of plant roots and their associated microbiome—extends meters into rock. We documented total dissolved nitrogen (TDN), dissolved organic carbon (DOC), inorganic nitrogen (ammonium and nitrate), and CO 2 and O 2 gases every 1.5 m to 16 m depth for 2 y. We found that TDN concentrations increased with depth, were an order of magnitude greater at 15 m than in the upper 30 cm, and that the majority of TDN throughout the weathered bedrock vadose zone was organic. We also found that TDN concentrations are influenced by depth, season, and interannual precipitation patterns. Carbon isotope composition of the DOC suggests that dissolved organic matter in the WBVZ is primarily derived from plant sources, and not the nitrogen-rich bedrock. We conclude that nitrogen dynamics in the WBVZ may be driven, in part, by an active rhizosphere, meters below the base of soil, and we argue that weathered bedrock horizons may play a key role in C-N cycling in ecosystems with deep-rooted plants.}, archive = {J_PNAS}, author = {Crutchfield-Peters, Kelsey L. and Rempe, Daniella M. and Tune, Alison K. and Dawson, Todd E.}, doi = {10.1073/pnas.2400452122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {19}, pages = {e2400452122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Linked nitrogen and carbon dynamics reveal distinct pools and patterns in a deep, weathered bedrock rhizosphere}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(18), eiti1825122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti1825122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {eiti1825122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Historians use data science to mine the past. PNAS, 122(18), e2508428122. (www)

  @article{ , archive = {J_PNAS}, author = {Beans, Carolyn}, doi = {10.1073/pnas.2508428122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2508428122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Historians use data science to mine the past}, volume = {122}, year = {2025}, }
• (2025). Retraction for duckworth et al., role of test motivation in intelligence testing. PNAS, 122(18), e2508040122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2508040122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2508040122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Retraction for duckworth et al., role of test motivation in intelligence testing}, volume = {122}, year = {2025}, }
• (2025). Correction for gong et al., jellyfish shape as a mechanical balance. PNAS, 122(18), e2507911122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2507911122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2507911122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for gong et al., jellyfish shape as a mechanical balance}, volume = {122}, year = {2025}, }
• (2025). RAD52’s active form is not a ring. PNAS, 122(18), e2506019122. (www)

  @article{ , archive = {J_PNAS}, author = {Borgstahl, Gloria E. O.}, doi = {10.1073/pnas.2506019122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2506019122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RAD52’s active form is not a ring}, volume = {122}, year = {2025}, }
• (2025). Exposing the role of individual heterogeneity in bighorn sheep population dynamics. PNAS, 122(18), e2505494122. (www)

  @article{ , archive = {J_PNAS}, author = {Forsythe, Amy B.}, doi = {10.1073/pnas.2505494122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2505494122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exposing the role of individual heterogeneity in bighorn sheep population dynamics}, volume = {122}, year = {2025}, }
• (2025). Late cretaceous community structure changed before the asteroid. PNAS, 122(18), e2505486122. (www)

  @article{ , archive = {J_PNAS}, author = {Polly, P. David}, doi = {10.1073/pnas.2505486122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2505486122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Late cretaceous community structure changed before the asteroid}, volume = {122}, year = {2025}, }
• (2025). Total whole-arm chromosome losses predict malignancy in human cancer. PNAS, 122(18), e2505385122. (www)

  @article{ , abstract = {Aneuploidy is observed as gains or losses of whole chromosomes or chromosome arms and is a common hallmark of cancer. Whereas models for the generation of aneuploidy in cancer invoke mitotic chromosome segregation errors, whole-arm losses might occur simply as a result of centromere breakage. We recently showed that elevated RNA Polymerase II level over the S-phase-dependent histone genes predicts rapid recurrence of human meningioma and is correlated with total whole-arm losses relative to gains. To explain this imbalance in arm losses over gains, we have proposed that histone overexpression at S-phase competes with the histone H3 variant CENP-A, resulting in centromere breaks and whole-arm losses. To test whether centromere breaks alone can drive aneuploidy, we ask whether total whole-arm aneuploids can predict outcomes across different cancer types in large RNA and whole-genome sequencing databanks. We find that total whole-arm losses generally predict outcome, suggesting that centromere breakage is a major initiating factor leading to aneuploidy and the resulting changes in the selective landscape that drive most cancers. We also present evidence that centromere breakage alone is sufficient to account for whole-arm losses and gains, contrary to mitotic spindle error models for the generation of aneuploidy. Our results suggest that therapeutic intervention targeting histone overexpression has the potential to reduce aneuploidy and slow cancer progression.}, archive = {J_PNAS}, author = {Zheng, Ye and Ahmad, Kami and Henikoff, Steven}, doi = {10.1073/pnas.2505385122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2505385122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Total whole-arm chromosome losses predict malignancy in human cancer}, volume = {122}, year = {2025}, }
• (2025). Popping the hood of muscle motors using time-resolved, small-angle X-ray diffraction. PNAS, 122(18), e2504453122. (www)

  @article{ , archive = {J_PNAS}, author = {Hessel, Anthony L.}, doi = {10.1073/pnas.2504453122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2504453122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Popping the hood of muscle motors using time-resolved, small-angle X-ray diffraction}, volume = {122}, year = {2025}, }
• (2025). Five-body recombination of identical bosons. PNAS, 122(18), e2503390122. (www)

  @article{ , abstract = {This work treats resonant collisions between five identical ultracold bosons in the framework of the adiabatic hyperspherical representation. The five-body recombination rate coefficient is quantified using a semiclassical description in conjunction with an analysis of the lowest five-body hyperspherical adiabatic potential curves in a scattering length regime with no universal weakly bound tetramers, trimers, or dimers. A comparison is made between these results and the only existing experimental measurement of five-body loss in an ultracold gas of bosonic cesium atoms and with the lone theoretical estimation of the loss rate. The recombination rate for the process B + B + B + B + B → B 4 + B is also computed in a different regime of scattering lengths where there is one universal bound tetramer by implementing a few-channel quantum scattering calculation based on five-body hyperspherical potential curves and nonadiabatic couplings. Our calculations predict regions where five-body recombination can cause decay of the atom cloud in an ultracold gas that is even faster than 3-body and 4-body recombination, which can ideally be tested by using the current generation of box traps having nearly uniform density.}, archive = {J_PNAS}, author = {Higgins, Michael D. and Greene, Chris H.}, doi = {10.1073/pnas.2503390122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2503390122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Five-body recombination of identical bosons}, volume = {122}, year = {2025}, }
• (2025). Resonance-stabilized radical clustering bridges the gap between gaseous precursors and soot in the inception stage. PNAS, 122(18), e2503292122. (www)

  @article{ , abstract = {Carbonaceous particles are widespread in combustion, atmospheric, extraterrestrial, and nanomaterials environments. Resonance-stabilized radicals (RSRs) are commonly identified in fuel combustion and pyrolysis processes and play an essential role in carbonaceous particle formation. Despite their importance, comprehensive experimental and mechanistic understanding of particle inception through RSR reactions is lacking. This work investigated particle size distribution, chemical composition, and thermal behavior of soot particles generated by the flow reactor pyrolysis reactions of typical RSRs, in particular, 1-indenyl, 1-methylnaphthyl, and 2-methylnaphthyl radicals, and by the pyrolysis of hydrocarbons with a variety of structures. Particle size distributions show soot particles with mobility diameters in an incipient-particle range of 1.3 to 1.6 nm. Laser desorption/ionization mass spectrometry results suggest that soot products consist of much larger covalently bound clusters (CBCs) than those observed in the gas phase. Under our experimental conditions, the CBCs exhibit a phase transition for particles with calculated molecular diameters of around 1.5 nm. Evaporation experiments and thermogravimetric analysis of the soot products reveal distinct thermal characteristics for small and large CBCs. These results implicate CBCs as bridges between gas-phase species and soot particles. The present work provides a soot-inception mechanism called RSR clustering (RSRC) that is characterized by the reactive clustering of RSRs. The RSRC mechanism contrasts with conventional soot formation models that attribute soot inception primarily to the aggregation of large-size polycyclic aromatic hydrocarbons.}, archive = {J_PNAS}, author = {Wang, Hong and Guan, Jiwen and Xu, Guangxian and Mercier, Xavier and Zhang, Jinyang and Guo, Haotian and Yu, Tongzhu and Gui, Huaqiao and Huang, Teng and Truhlar, Donald G. and Wang, Zhandong}, doi = {10.1073/pnas.2503292122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2503292122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Resonance-stabilized radical clustering bridges the gap between gaseous precursors and soot in the inception stage}, volume = {122}, year = {2025}, }
• (2025). Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis. PNAS, 122(18), e2502978122. (www)

  @article{ , abstract = {Metabolic dysfunction–associated steatohepatitis (MASH) represents a progressive form of steatotic liver disease which increases the risk for fibrosis and advanced liver disease. The accumulation of discrete species of bioactive lipids has been postulated to activate signaling pathways that promote inflammation and fibrosis. However, the key pathogenic lipid species is a matter of debate. We explored candidates using various dietary, molecular, and genetic models. Mice fed a choline-deficient L-amino acid–defined high-fat diet (CDAHFD) developed steatohepatitis and manifested early markers of liver fibrosis associated with increased cholesterol content in liver lipid droplets within 5 d without any changes in total liver cholesterol content. Treating mice with antisense oligonucleotides against Coenzyme A synthase ( Coasy ) or treatment with bempedoic acid or atorvastatin decreased liver lipid droplet cholesterol content and prevented CDAHFD-induced MASH and the fibrotic response. All these salutary effects were abrogated with dietary cholesterol supplementation. Analysis of human liver samples demonstrated that cholesterol in liver lipid droplets was increased in humans with MASH and liver fibrosis and was higher in PNPLA3 I148M (variants rs738409) than in HSD17B13 variants (rs72613567). Together, these data identify cholesterol in liver lipid droplets as a critical mediator of MASH and demonstrate that Coenzyme A synthase knockdown and bempedoic acid are therapeutic approaches to reduce liver lipid droplet cholesterol content and thereby prevent the development of MASH and liver fibrosis.}, archive = {J_PNAS}, author = {Sakuma, Ikki and Gaspar, Rafael C. and Nasiri, Ali R. and Dufour, Sylvie and Kahn, Mario and Zheng, Jie and LaMoia, Traci E. and Guerra, Mateus T. and Taki, Yuki and Kawashima, Yusuke and Yimlamai, Dean and Perelis, Mark and Vatner, Daniel F. and Petersen, Kitt Falk and Huttasch, Maximilian and Knebel, Birgit and Kahl, Sabine and Roden, Michael and Samuel, Varman T. and Tanaka, Tomoaki and Shulman, Gerald I.}, doi = {10.1073/pnas.2502978122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2502978122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis}, volume = {122}, year = {2025}, }
• (2025). Nonproteolytic ubiquitination regulates chromatin occupancy by the NCoR/SMRT/HDAC3 corepressor complex in MCF-7 breast cancer cells. PNAS, 122(18), e2502805122. (www)

  @article{ , abstract = {Tight regulation of gene expression is achieved through the coordinated action of transcription factors and cofactors that often can act as both repressors and activators in response to regulatory signals, with their activity modulated by context-specific signal transduction pathways that also impinge on their transient and cyclical recruitment to chromatin. However, the mechanisms underlying the intricate interplay between the regulatory strategies controlling cofactors’ activity and localization across subcellar domains remain poorly understood. Here, we investigated the role of G-Protein Pathway Suppressor 2 (GPS2), a transcriptional cofactor critical for maintaining cellular homeostasis via regulation of mitochondrial biogenesis, stress response, lipid metabolism, insulin signaling, and inflammation, in MCF-7 breast cancer cells. By integration of biochemical assays with genome-wide RNA sequencing and Chromatin immunoprecipitation-Seq analyses, we show that nuclear GPS2 is required for licensing histone deacetylase 3 recruitment to chromatin via restricted ubiquitination by tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase previously shown to regulate the switch from repressive to activating functions of the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) complex and here unexpectedly found to translocate to the nucleus in response to IL-1β stimulation. Nuclear TRAF6 is recruited to chromatin via direct interaction with the corepressors NCoR/SMRT, and TRAF6-mediated ubiquitination of TGF-beta activated kinase 1 (MAP3K7) binding protein 2 (TAB2), a facultative component of the NCoR/SMRT complex, contributes to corepressor clearance from target regulatory regions. Together, these results reveal an exquisite mechanism for coordinating the local regulation of cofactor activity with proinflammatory signaling pathways.}, archive = {J_PNAS}, author = {Ferrero, Giulio and Cardamone, Maria Dafne and Luca, Francesca and Bourk, Eliot and Ricci, Laura and Liu, Wen and Gao, Yuan and Burrone, Giulia and Muhammad, Akhirah and Chan, Stefanie and Smith, Emma and Fan, Ting-Yu Claire and Cutrupi, Santina and Garcia-Bassets, Ivan and De Bortoli, Michele and Rosenfeld, Michael G. and Perissi, Valentina}, doi = {10.1073/pnas.2502805122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2502805122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nonproteolytic ubiquitination regulates chromatin occupancy by the NCoR/SMRT/HDAC3 corepressor complex in MCF-7 breast cancer cells}, volume = {122}, year = {2025}, }
• (2025). Bayesian phylodynamic inference of population dynamics with dormancy. PNAS, 122(18), e2501394122. (www)

  @article{ , abstract = {Many organisms employ reversible dormancy, or seedbank, in response to environmental fluctuations. This life-history strategy alters fundamental ecoevolutionary forces, leading to distinct patterns of genetic diversity. Two models of dormancy have been proposed based on the average duration of dormancy relative to coalescent timescales: weak seedbank, induced by scheduled seasonality (e.g., plants, invertebrates), and strong seedbank, where individuals stochastically switch between active and dormant states (e.g., bacteria, fungi). The weak seedbank coalescent is statistically equivalent to the Kingman coalescent with a scaled mutation rate, allowing the use of existing inference methods. In contrast, the strong seedbank coalescent differs fundamentally, as only active lineages can coalesce, while dormant lineages cannot. Additionally, dormant individuals typically mutate at a slower rate than active ones. Consequently, despite the significant role of dormancy in the ecoevolutionary dynamics of many organisms, no methods currently exist for inferring population dynamics involving dormancy and associated parameters. We present a Bayesian framework for jointly inferring a latent genealogy, seedbank parameters, and evolutionary parameters from molecular sequence data under the strong seedbank coalescent. We derive the exact probability density of genealogies sampled under the strong seedbank coalescent, characterize the corresponding likelihood function, and present efficient computational algorithms for its evaluation based on our theoretical framework. We develop a tailored Markov chain Monte Carlo sampler and implement our inference framework as a package SeedbankTree within BEAST2. Our work provides both a theoretical foundation and practical inference framework for studying the population genetic and genealogical impacts of dormancy.}, archive = {J_PNAS}, author = {Cappello, Lorenzo and Lo, Wai Tung ‘Jack’ and Zhang, Joy Z. and Xu, Peiyu and Barrow, Daniel and Chopra, Ishani and Clark, Andrew G. and Wells, Martin T. and Kim, Jaehee}, doi = {10.1073/pnas.2501394122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2501394122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bayesian phylodynamic inference of population dynamics with dormancy}, volume = {122}, year = {2025}, }
• (2025). Dopamine induces fear extinction by activating the reward-responding amygdala neurons. PNAS, 122(18), e2501331122. (www)

  @article{ , abstract = {The extinction of conditioned fear responses is crucial for adaptive behavior, and its impairment is a hallmark of anxiety disorders such as posttraumatic stress disorder. Fear extinction takes place when animals form a new memory that suppresses the original fear memory. In the case of context-dependent fear memory, the new memory is formed within the reward-responding posterior subset of basolateral amygdala (BLA) that is genetically marked by Ppp1r1b + neurons. These memory engram cells suppress the activity of the original fear-responding Rspo2 + engram cells present in the anterior BLA, hence fear extinction. However, the neurological nature of the teaching signal that instructs the formation of fear extinction memory in the Ppp1r1b + neurons is unknown. Here, we demonstrate that ventral tegmental area (VTA) dopaminergic signaling drives fear extinction in distinct BLA neuronal populations. We show that BLA fear and extinction neuronal populations receive topographically divergent inputs from VTA dopaminergic neurons via differentially expressed dopamine receptors. Fiber photometry recordings of dopaminergic activity in the BLA reveal that dopamine (DA) activity is time-locked to freezing cessation in BLA fear extinction neurons, but not BLA fear neurons. Furthermore, this dopaminergic activity in BLA fear extinction neurons correlates with extinction learning. Finally, using projection-specific optogenetic manipulation, we find that activation of the VTA DA projections to BLA reward and fear neurons accelerated or impaired fear extinction, respectively. Together, this work demonstrates that dopaminergic activity bidirectionally controls fear extinction by distinct patterns of activity at BLA fear and extinction neurons.}, archive = {J_PNAS}, author = {Zhang, Xiangyu and Flick, Katelyn and Rizzo, Marianna and Pignatelli, Michele and Tonegawa, Susumu}, doi = {10.1073/pnas.2501331122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2501331122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dopamine induces fear extinction by activating the reward-responding amygdala neurons}, volume = {122}, year = {2025}, }
• (2025). Induced b cell receptor diversity predicts PD-1 blockade immunotherapy response. PNAS, 122(18), e2501269122. (www)

  @article{ , abstract = {Immune checkpoint inhibitors such as anti-Programmed Death-1 antibodies (aPD-1) can be effective in treating advanced cancers. However, many patients do not respond, and the mechanisms underlying these differences remain incompletely understood. In this study, we profile a cohort of patients with locally advanced or metastatic basal cell carcinoma undergoing aPD-1 therapy using single-cell RNA sequencing, high-definition spatial transcriptomics in tumors and draining lymph nodes, and spatial immunoreceptor profiling, with long-term clinical follow-up. We find that successful responses to PD-1 inhibition are characterized by an induction of B cell receptor (BCR) clonal diversity after treatment initiation. These induced BCR clones spatially colocalize with T cell clones, facilitate their activation, and traffic alongside them between tumor and draining lymph nodes to enhance tumor clearance. Furthermore, we validated aPD-1-induced BCR diversity as a predictor of clinical response in a larger cohort of glioblastoma, melanoma, and head and neck squamous cell carcinoma patients, suggesting that this is a generalizable predictor of treatment response across many types of cancers. We find that pretreatment tumors harbor a characteristic gene expression signature that portends a higher probability of inducing BCR clonal diversity after aPD-1 therapy, and we develop a machine learning model that predicts PD-1-induced BCR clonal diversity from baseline tumor RNA sequencing. These findings underscore a dynamic role of B cell diversity during immunotherapy, highlighting its importance as a prognostic marker and a potential target for intervention in non-responders.}, archive = {J_PNAS}, author = {Che, Yonglu and Lee, Jinwoo and Abou-Taleb, Farah and Rieger, Kerri E. and Satpathy, Ansuman T. and Chang, Anne Lynn S. and Chang, Howard Y.}, doi = {10.1073/pnas.2501269122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2501269122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Induced b cell receptor diversity predicts PD-1 blockade immunotherapy response}, volume = {122}, year = {2025}, }
• (2025). Antiviral resistance and barrier integrity at the maternal-fetal interface restrict hepatitis e virus from crossing the placental barrier. PNAS, 122(18), e2501128122. (www)

  @article{ , abstract = {Hepatitis E virus (HEV) genotype 1 (HEV-1) infection in pregnant women is associated with adverse outcomes of pregnancy including fulminant hepatic failure, fetal loss, premature birth, and neonatal mortality, although the underlying mechanisms remain largely unclear. In this study, we first demonstrated that HEV-1 robustly infects pregnant gerbils and causes pregnancy-associated adverse outcomes, which were recorded in 4/6 HEV-1-infected but only 1/5 in PBS-inoculated pregnant gerbils. However, vertical transmission of HEV-1 from mothers to newborns is not evident, as HEV-1 RNA was not detected in uterus tissues or in newborn pups. To further determine whether HEV-1 can cross the placental barrier, we established an in vitro blood–placental barrier by coculturing human placental trophoblast cells (BeWo) and umbilical vein endothelial cells (HUVEC) in Transwell inserts. By using the placental barrier under the conditions in this study, we showed that quasi-enveloped or nonenveloped HEV-1, HEV-3, or HEV-4 virions do not readily cross the barrier prior to 4 d postinoculation when it has high barrier integrity. Importantly, we demonstrated that the placental barrier induces local antiviral resistance at the maternal-fetal interface, that interactions between maternal- and fetal-derived cocultured cells are important for induction of antiviral resistance, and that anti-HEV resistance can be transferred to nonplacental HepG2 liver cells. We also revealed that the main effectors of antiviral resistance at the placental barrier are type III interferons (IFN-λ1, λ2/3) and the chemokine CXCL10. The findings have important implications in understanding the mechanisms leading to HEV-1-associated maternal and fetal adverse outcomes in pregnant women.}, archive = {J_PNAS}, author = {Tian, Debin and Li, Wen and Heffron, C. Lynn and Mahsoub, Hassan M. and Wang, Bo and LeRoith, Tanya and Meng, Xiang-Jin}, doi = {10.1073/pnas.2501128122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2501128122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Antiviral resistance and barrier integrity at the maternal-fetal interface restrict hepatitis e virus from crossing the placental barrier}, volume = {122}, year = {2025}, }
• (2025). Twinfilin is a nonprocessive depolymerase which synergizes with formin to dramatically accelerate actin filament uncapping by 300-fold. PNAS, 122(18), e2501078122. (www)

  @article{ , abstract = {For over four decades, our understanding of cellular actin dynamics has been guided by the concept of treadmilling. However, this paradigm has been challenged by the evidence that twinfilin can uncap and promote depolymerization of filament barbed ends, though its precise mechanism remains debated. Using single-molecule microscopy and microfluidics-assisted TIRF imaging, we demonstrate that twinfilin transiently associates with barbed ends for ~0.2 to 0.5 s, acting as a nonprocessive depolymerase that likely removes one or both terminal actin subunits. Furthermore, we show that twinfilin’s barbed-end residence time and its ability to uncap CP-capped filaments (both alone and with formin mDia1) are significantly influenced by filament age. The synergistic enhancement in uncapping by twinfilin and mDia1 ranges from 11-fold for newly assembled to ~318-fold for aged actin filaments. These represent the fastest uncapping rates measured in vitro and approach CP turnover rates in vivo. Our study thus reinforces twinfilin’s central role as a multifunctional barbed-end regulator which nonprocessively depolymerizes actin filaments, transiently caps barbed ends, and synergizes with formin to destabilize CP, thereby facilitating rapid actin turnover that depends on filament age.}, archive = {J_PNAS}, author = {Reddy, Vishal and Arya, Ankita and Shekhar, Shashank}, doi = {10.1073/pnas.2501078122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2501078122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Twinfilin is a nonprocessive depolymerase which synergizes with formin to dramatically accelerate actin filament uncapping by 300-fold}, volume = {122}, year = {2025}, }
• (2025). Metasurface-assisted multimodal quantum imaging. PNAS, 122(18), e2500760122. (www)

  @article{ , abstract = {Traditional quantum imaging is featured by remarkable sensitivity and signal-to-noise ratio, but limited by bulkiness and static function (either phase contrast imaging or edge detection). Our report synergizes a polarization-entangled source with a metasurface consisting of various sophisticatedly engineered spatial frequency segments. By tuning polarization, we demonstrate multiple “on”-state quantum imaging modes, enabling flexible switching between phase contrast, edge, and arbitrary superimposed imaging mode. Furthermore, the “off”-state, which characterizes the background noise, enables self-calibration of the system by subtracting this noise in “on”-state modes, resulting in self-enhanced edge detection. Our approach performs phase contrast imaging with a phase difference of π/4 present in the target object, and edge imaging capable of detecting tiny (radius about 2 μm) defects, maintaining high image contrast (phase contrast of 0.726, and enhanced edge contrast of 0.902). Our results provide insights into constructive duet between quantum imaging and metaoptics.}, archive = {J_PNAS}, author = {Zhou, Yifan and Zhu, Xiaoshu and Li, Tianyue and Zhou, Zhou and Bi, Qianhui and Liu, Jun and Chen, Jian and Fu, Boyan and He, Juanzi and Feng, Xiaojing and Feng, Xinyang and Liu, Xingyu and Wang, Qianjin and Wang, Shuming and Wang, Zhenlin and Qiu, Cheng-Wei and Zhu, Shining}, doi = {10.1073/pnas.2500760122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2500760122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Metasurface-assisted multimodal quantum imaging}, volume = {122}, year = {2025}, }
• (2025). Dissociation of SYNGAP1 enzymatic and structural roles: Intrinsic excitability and seizure susceptibility. PNAS, 122(18), e2427288122. (www)

  @article{ , abstract = {SYNGAP1 is a key Ras-GAP protein enriched at excitatory synapses, with mutations causing intellectual disability and epilepsy in humans. Recent studies have revealed that in addition to its role as a negative regulator of G-protein signaling through its GAP enzymatic activity, SYNGAP1 plays an important structural role through its interaction with postsynaptic density proteins. Here, we reveal that intrinsic excitability deficits and seizure phenotypes in heterozygous Syngap1 knockout (KO) mice are differentially dependent on Syngap1 GAP activity. Cortical excitatory neurons in heterozygous KO mice displayed reduced intrinsic excitability, including lower input resistance, and increased rheobase, a phenotype recapitulated in GAP-deficient Syngap1 mutants. However, seizure severity and susceptibility to pentylenetetrazol (PTZ)-induced seizures were significantly elevated in heterozygous KO mice but unaffected in GAP-deficient mutants, implicating the structural rather than enzymatic role of Syngap1 in seizure regulation. These findings highlight the complex interplay between SYNGAP1 structural and catalytic functions in neuronal physiology and disease.}, archive = {J_PNAS}, author = {Brill, Julia and Clarke, Blaise and Hong, Ingie and Huganir, Richard L.}, doi = {10.1073/pnas.2427288122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2427288122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dissociation of SYNGAP1 enzymatic and structural roles: Intrinsic excitability and seizure susceptibility}, volume = {122}, year = {2025}, }
• (2025). Compatibility of intracellular binding: Evolutionary design principles for metal sensors. PNAS, 122(18), e2427151122. (www)

  @article{ , abstract = {In the common cellular space, hundreds of binding reactions occur reliably and simultaneously without disruptive mutual interference. The design principles that enable this remarkable compatibility have not yet been adequately elucidated. In order to delineate these principles, we consider the intracellular sensing of transition metals in bacteria—an integral part of cellular metal homeostasis. Protein cytosolic sensors typically interact with metals through three types of lateral chain residues, containing oxygen, nitrogen, or sulfur. The very existence of complete sets of mutually compatible sensors is a nontrivial problem solved by evolution, since each metal sensor has to bind to its cognate metal without being “mismetallated” by noncognate competitors. Here, based solely on theoretical considerations and limited information about binding constants for metal-amino acid interactions, we are able to predict possible “sensor compositions,” i.e., the residues forming the binding sites. We find that complete transition-metal sensor sets are severely limited in their number by compatibility requirements, leaving only a handful of possible sensor compositions for each transition metal. Our theoretical results turn out to be broadly consistent with experimental data on known bacterial sensors. If applicable to other cytosolic binding interactions, the results generated by our approach imply that compatibility requirements may play a crucial role in the organization and functioning of intracellular processes.}, archive = {J_PNAS}, author = {Lenner, Nicolas and Chariker, Logan and Leibler, Stanislas}, doi = {10.1073/pnas.2427151122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2427151122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Compatibility of intracellular binding: Evolutionary design principles for metal sensors}, volume = {122}, year = {2025}, }
• (2025). Radiation protection and structural stability of fungal melanin polylactic acid biocomposites in low earth orbit. PNAS, 122(18), e2427118122. (www)

  @article{ , abstract = {Materials in low Earth orbit (LEO) face radiation, atomic oxygen erosion, and extreme temperature fluctuations, which can severely compromise their structural and functional integrity. Developing lightweight, multifunctional materials capable of withstanding these harsh conditions is critical for long-term space exploration and sustainable extraterrestrial settlements. This study evaluates the structural stability and radiation shielding efficacy of polylactic acid (PLA) and biocomposites, including PLA infused with fungal melanin, synthetic melanin, or animal melanin, and a compressed mycelium (CMy) coated with PLA (PLA-CMy), after exposure to the LEO environment. Samples were deployed on the Materials International Space Station Experiment–Flight Facility platform for approximately 6 mo in zenith- and wake-facing orientations. Postflight analyses comparing flight-exposed samples to Earth controls revealed composition- and orientation-dependent differences in mass loss, optical properties, and surface morphology. Notably, fungal melanin reduced mass loss and surface wrinkle formation, indicating a protective effect against PLA degradation in LEO. Biocomposites also demonstrated shielding effects by protecting an underlying polyvinyl chloride backing layer from damage. These findings demonstrate PLA’s performance in space and highlight fungal melanin as a bioderived additive to enhance PLA resilience under LEO conditions, advancing the development of sustainable materials for future space missions.}, archive = {J_PNAS}, author = {Cordero, Radames J. B. and de Groh, Kim K. and Dragotakes, Quigly and Singla, Saranshu and Maurer, Christopher and Trunek, Andrew and Chiu, Arlene and Hwang, Jonghyun and Crowell, Sylvie and Benyo, Theresa and Thon, Susanna M. and Rothschild, Lynn J. and Dhinojwala, Ali and Casadevall, Arturo}, doi = {10.1073/pnas.2427118122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2427118122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Radiation protection and structural stability of fungal melanin polylactic acid biocomposites in low earth orbit}, volume = {122}, year = {2025}, }
• (2025). Distantly related bacteria share a rigid proteome allocation strategy with flexible enzyme kinetics. PNAS, 122(18), e2427091122. (www)

  @article{ , abstract = {Bacteria are known to allocate their proteomes according to how fast they grow, and the allocation strategies employed strongly affect bacterial adaptation to different environments. Much of what is currently known about proteome allocation is based on extensive studies of the model organism Escherichia coli . It is not clear how much of E. coli ’s proteome allocation strategy is applicable to other species, particularly since different species can grow at vastly different rates even in the same growth condition. In this study, we investigate differences in nutrient-dependent proteome allocation programs adopted by several distantly related bacterial species, including Vibrio natriegens , one of the fastest-growing bacteria known. Extensive quantitative proteome characterization across conditions reveals an invariant allocation program in response to changing nutrients despite systemic, species-specific differences in enzyme kinetics. This invariant program is not organized according to the growth rate but is based on a common internal metric of nutrient quality after scaling away species-specific differences in enzyme kinetics, with the faster species behaving as if it is growing under a higher temperature. The flexibility of enzyme kinetics and the rigidity of proteome allocation programs across species defy common notions of evolvability and resource optimization. Our results suggest the existence of a blueprint of proteome allocation shared by diverse bacterial species, with implications on common underlying regulatory strategies. Further knowledge on the existence and organization of such phylogeny-transcending relations also promises to simplify the bottom–up description and understanding of bacterial behaviors in ecological communities.}, archive = {J_PNAS}, author = {Zhu, Manlu and Mori, Matteo and Hwa, Terence and Dai, Xiongfeng}, doi = {10.1073/pnas.2427091122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2427091122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Distantly related bacteria share a rigid proteome allocation strategy with flexible enzyme kinetics}, volume = {122}, year = {2025}, }
• (2025). A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity. PNAS, 122(18), e2427073122. (www)

  @article{ , abstract = {Glioblastoma (GBM) is the most aggressive form of brain cancer, with limited therapeutic options. While microglia contribute to GBM progression, the mechanisms by which they foster a protumorigenic immune environment remain poorly understood. We identify the zinc transporter Zrt- And Irt-Like Protein 4 (ZIP4) as a pivotal regulator of the GBM immune landscape. In orthotopic mouse models, ZIP4 drives tumor growth and behavioral changes. Mechanistically, ZIP4 modulates microglial plasticity through tumor-derived extracellular vesicles carrying triggering receptor expressed on myeloid cells-1 (TREM1), a process regulated by the zinc-dependent transcription factor Zinc Finger E-box Binding Homeobox 1 in GBM cells. TREM1 enhances microglial plasticity through the spleen associated tyrosine kinase-Pyruvate dehydrogenase kinase-signal transducer and activator of transcription 3 (SYK-PDK-STAT3) signaling axis, ultimately promoting an immune environment favorable to tumor progression. ZIP4 depletion or TREM1 inhibition attenuates tumor growth and behavioral effects in vivo by disrupting the tumor–microglia interaction. These findings establish ZIP4 as a key modulator of the GBM immune landscape and suggest a promising therapeutic target to counteract microglia-mediated tumor progression.}, archive = {J_PNAS}, author = {Zhang, Liyang and Yang, Jingxuan and Zhou, Zhijun and Ren, Yu and Chen, Bo and Tang, Anliu and Zhang, Kailiang and Li, Chuntao and Zhou, Hongshu and Fung, Kar-Ming and Xu, Chao and Kang, Chunsheng and Battiste, James D. and Bronze, Michael S. and Houchen, Courtney W. and Liu, Zhixiong and Dunn, Ian F. and Cavenee, Webster K. and Li, Min}, doi = {10.1073/pnas.2427073122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2427073122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity}, volume = {122}, year = {2025}, }
• (2025). Structural basis for substrate selectivity by site-one protease revealed by studies with a small-molecule inhibitor. PNAS, 122(18), e2426931122. (www)

  @article{ , abstract = {Site-one protease (S1P) carries out the first proteolytic step to activate membrane-bound effector proteins in the Golgi. S1P matures through an autocatalytic process that begins in the endoplasmic reticulum (ER) and culminates with the displacement of its inhibitory pro-domain by its cofactor, sterol regulatory element binding protein-regulating gene (SPRING). Spatial control of S1P activity and substrate localization underpins signaling pathways governing, among others, lipogenesis, ER stress, and lysosome biogenesis. The factors governing these pathways are activated by S1P-mediated proteolysis upon their regulated transport from the ER to the Golgi. S1P cleaves substrates with the recognition sequence RX(L/I/V)Z, where X is any residue other than Cys or Pro and Z is preferably Leu or Lys. However, the structural basis for substrate recognition by S1P has remained unknown. Here, we used the small molecule PF-429242, a competitive inhibitor of S1P, to investigate substrate recognition by the S1P/SPRING complex. We determined the structure of S1P/SPRING bound to PF-429242 and found that PF-429242 binds S1P in the same pocket that recognizes the substrate’s conserved P 4 Arg. Further structural analysis suggests that S1P requires a conformation change to accommodate the substrate’s P 2 (L/I/V) residue. We designed an S1P mutation (I308A) to reduce the steric clash at the P 2 position and generated an S1P that was resistant to PF-429242 in biochemical and cell culture assays. Our findings reveal selectivity in the recognition of substrates by S1P and provide a roadmap for the rational design of improved S1P inhibitors.}, archive = {J_PNAS}, author = {Bullington, Ashley V. and Micallo, Ilaria and Bajaj, Bilkish and Kumar, Pankaj and Schlamowitz, Netanya and Silva, Aurora and Hendrix, Sebastian and Zelcer, Noam and Kober, Daniel L.}, doi = {10.1073/pnas.2426931122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2426931122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis for substrate selectivity by site-one protease revealed by studies with a small-molecule inhibitor}, volume = {122}, year = {2025}, }
• (2025). Global modulation of gene expression and transcriptome size in aneuploid combinations of maize. PNAS, 122(18), e2426749122. (www)

  @article{ , abstract = {Genomic imbalance refers to the more severe phenotypic consequences of changing a single chromosome compared to changing the whole genomic set. Previous genomic imbalance studies in maize have identified gene expression modulation in aneuploids of single chromosome arms. Here, the modulation of gene expression in more complex aneuploids, e.g., monosomy of one chromosome arm and trisomy of another was examined to determine the extent that combination aneuploids were additive, multiplicative, or rebalanced in terms of their effect on gene expression. A series of genetic crosses was performed to produce one, two, and three copies of one arm with independent one, two, and three copies of the other arm in each of the three genotypes for the opposite arm. In total, 31 combinations were analyzed. By examining RNA modulation, we found that cis genes on varied chromosome arms are generally more dosage-compensated in aneuploid combinations than in single aneuploidy even though some showed a clear dosage effect. For genes on the unvaried chromosomes ( trans ), there is greater modulation in most of the aneuploidy combinations. Finally, 22 of the 31 combinations were found to have an altered transcriptome size, suggesting that extensive stoichiometric changes of genomic regions upset global messenger RNA (mRNA) transcription. Overall, these results have important implications for understanding the role of genomic stoichiometry for mechanisms of gene expression, the evolution of dosage-sensitive duplicated genes, the evolution of sex chromosomes, the rapid growth adaptation of aneuploid cancer cells, and the control of quantitative traits.}, archive = {J_PNAS}, author = {Yang, Hua and Brennan, Vincent and Gao, Zhi and Liu, Jian and Boadu, Frimpong and Cheng, Jianlin and Birchler, James A.}, doi = {10.1073/pnas.2426749122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2426749122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global modulation of gene expression and transcriptome size in aneuploid combinations of maize}, volume = {122}, year = {2025}, }
• (2025). Mass-independent fractionation of oxygen isotopes during high-temperature condensation in cosmochemical plasmas. PNAS, 122(18), e2426711122. (www)

  @article{ , abstract = {Contrary to all terrestrial rocks, planets and meteorites exhibit oxygen isotope variations decorrelated with the mass difference of their atomic nuclei. It has been proposed that, in the protosolar nebula (PSN), these variations could result from mass independent isotopic fractionation (MIF) either during specific chemical reactions similar to those responsible for the formation of ozone in the Earth’s atmosphere or during ultraviolet (UV)-photolysis of carbon monoxide (CO) gas in the PSN. However, these potential chemical MIF reactions (Chem-MIFs) are not identified in conditions close to the PSN, and there is no experimental demonstration that large MIF signature can be transferred to solids forming in the PSN. Here, we show that MIFs, up to 60‰ depletion in 16 O, are produced by high-temperature reactions in a plasma during the condensation of carbonaceous solids from a gas containing two of the most abundant PSN molecular species (H 2 O and CH 4 ). This effect is attributed to the formation in the plasma of the activated complex H 2 O 2 * followed by its stabilization by reactions with CH x • radicals. Although it is premature to assert that this reaction represents the main process resulting in MIF of oxygen isotopes in the solar system, our result demonstrates the potential importance of a Chem-MIF effect in a PSN where plasma zones develop.}, archive = {J_PNAS}, author = {Asset, Nathan and Chaussidon, Marc and Lombardi, Guillaume and Villeneuve, Johan and Tartèse, Romain and Mostefaoui, Smail and Robert, François}, doi = {10.1073/pnas.2426711122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2426711122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mass-independent fractionation of oxygen isotopes during high-temperature condensation in cosmochemical plasmas}, volume = {122}, year = {2025}, }
• (2025). Stereoselective construction of coconformational mechanically helical and topologically chiral [2]catenanes induced by point chirality. PNAS, 122(18), e2426356122. (www)

  @article{ , abstract = {Supported by chiral stationary phase high-performance liquid chromatography HPLC (CSP-HPLC), examples of chiral mechanically interlocked organic molecules, including knots, rotaxanes, and catenanes, have been reported. However, the exploration of stereoselective construction of chiral cationic complexes, particularly those induced by point chirality, has been notably limited due to the constraints posed by the type of chiral chromatographic columns and separation efficiency. To address this, we have developed a construction strategy for generating coconformational mechanically helical and topologically chiral [2]catenanes through the induction of point chirality. In this study, by adjusting the symmetry of the ligand, we have easily realized the efficient construction of high-yield crystalline coconformational mechanically helical and topologically chiral [2]catenanes. Moreover, within the enantiomerically pure chiral environment of molecular self-assembly driven by L -alanine and L -valine residues in bidentate ligands, the coconformational mechanically helical and topologically chiral [2]catenanes exist exclusively as a single enantiomer, thus eliminating the need for laborious CSP-HPLC separation from racemic mixtures. The generation of the opposite enantiomer can be realized by employing unsymmetrical ligands containing corresponding D -alanine and D -valine residues, as confirmed through single-crystal X-ray diffraction, elemental analysis, electrospray-ionization time-of-flight mass spectrometry, solution-state NMR spectroscopy, and circular dichroism spectroscopy.}, archive = {J_PNAS}, author = {Tang, Haitong and Zou, Yan and Zhang, Hai-Ning and Jin, Guo-Xin}, doi = {10.1073/pnas.2426356122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2426356122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stereoselective construction of coconformational mechanically helical and topologically chiral [2]catenanes induced by point chirality}, volume = {122}, year = {2025}, }
• (2025). The expanded immunoregulatory protease network in mosquitoes is governed by gene coexpression. PNAS, 122(18), e2425863122. (www)

  @article{ , abstract = {Serine protease cascades regulate key innate immune responses. Their activation cleaves a series of inactive protease zymogens, which then activate downstream effector enzymes, ensuring a rapid response. In mosquitoes, these cascades involve clip-domain serine proteases and their noncatalytic homologs (CLIPs), whose make-up and structural organization are not fully understood. Here, we systematically assessed the contribution of individual CLIPs to humoral immunity in Anopheles gambiae , by performing gene knockdown of 85 of the 110 CLIPs in adult females and assessing their individual contribution to humoral immunity regulation. By coupling RNAi with assays measuring antimicrobial activity and melanization, we identified 27 immunoregulatory CLIPs. Only one CLIP contributed to both immune responses, thus providing evidence for largely distinct protease subnetworks controlling melanization and antimicrobial activity. CLIPs regulating antimicrobial activity were found to contribute to antimicrobial peptide expression and to control infection resistance, as knockdowns reduced bacterial load and improved survival. Furthermore, our analysis of CLIP gene expression unveiled a immunoregulatory mechanism reliant on protease baseline coexpression rather than infection-induced upregulation. Together, results from this study improve our understanding of immune system regulation by proteolysis and identify a layer of regulation that could be manipulated for mosquito control purposes.}, archive = {J_PNAS}, author = {Morejon, Bianca and Michel, Kristin}, doi = {10.1073/pnas.2425863122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2425863122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The expanded immunoregulatory protease network in mosquitoes is governed by gene coexpression}, volume = {122}, year = {2025}, }
• (2025). Comparative single-cell analysis of transcriptional bursting reveals the role of genome organization in de novo transcript origination. PNAS, 122(18), e2425618122. (www)

  @article{ , abstract = {Spermatogenesis is a key developmental process underlying the origination of newly evolved genes. However, rapid cell type–specific transcriptomic divergence of the Drosophila germline has posed a significant technical barrier for comparative single-cell RNA-sequencing studies. By quantifying a surprisingly strong correlation between species- and cell type–specific divergence in three closely related Drosophila species, we apply a statistical procedure to identify a core set of 198 genes that are highly predictive of cell type identity while remaining robust to species-specific differences that span over 25 to 30 My of evolution. We then utilize cell type classifications based on the 198-gene set to show how transcriptional divergence in cell type increases throughout spermatogenic developmental time. After validating these cross-species cell type classifications using RNA fluorescence in situ hybridization and imaging, we then investigate the influence of genome organization on the molecular evolution of spermatogenesis vis-a-vis transcriptional bursting. We first show altering transcriptional burst size contributes to premeiotic transcription and altering bursting frequency contributes to postmeiotic expression. We then report global differences in autosomal vs. X chromosomal transcription may arise in a developmental stage preceding full testis organogenesis by showing evolutionarily conserved decreases in X-linked transcription bursting kinetics in all examined somatic and germline cell types. Finally, we provide evidence supporting the cultivator model of de novo gene origination by demonstrating how the appearance of newly evolved testis-specific transcripts potentially provides short-range regulation of neighboring genes’ transcriptional bursting properties during key stages of spermatogenesis.}, archive = {J_PNAS}, author = {Lee, UnJin and Li, Cong and Langer, Christopher B. and Svetec, Nicolas and Zhao, Li}, doi = {10.1073/pnas.2425618122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2425618122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Comparative single-cell analysis of transcriptional bursting reveals the role of genome organization in de novo transcript origination}, volume = {122}, year = {2025}, }
• (2025). The diffused evolutionary dynamics of morphological novelty. PNAS, 122(18), e2425573122. (www)

  @article{ , abstract = {Rates of evolution are fundamental to understand the processes that shaped the history of life. The predominant view holds that high rates of phenotypic evolution result from lineage transitions across peaks in an adaptive landscape, with subsequent slow-downs, but evidence remains debated. I developed a phylogenetic “diffused Brownian motion” model that characterizes nuanced variations in evolutionary rates and use it to comprehensively assess body size evolution and its underlying rates for 2,950 extinct and 792 extant species that span over 450 Mys of evolution. I find that evolutionary rates do not conform to expectations from adaptive landscape theory, but rather have been stable, unaffected by the accumulation of phenotypic disparity. Long-term evolutionary trends, such as several net increases in clade-average body size, result both from sustained evolution at the lineage level and the sorting of species phenotypes and their underlying evolutionary rates at the clade level, sometimes acting in opposite directions. These findings substantiate an active role of species in shaping their environment that generate continuous novelty of life forms.}, archive = {J_PNAS}, author = {Quintero, Ignacio}, doi = {10.1073/pnas.2425573122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2425573122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The diffused evolutionary dynamics of morphological novelty}, volume = {122}, year = {2025}, }
• (2025). Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel KCa3.1. PNAS, 122(18), e2425494122. (www)

  @article{ , abstract = {The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery disease. Every 1,4-dihydropyridine in clinical use blocks L-type voltage-gated calcium channels. We now report our development, using selective optimization of a side activity (SOSA), of a class of 1,4-dihydropyridines that selectively and potently inhibit the intermediate-conductance calcium-activated K + channel K Ca 3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K Ca 3.1 with an IC 50 of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of >100 additional molecular targets. Using high-resolution structure determination by cryogenic electron microscopy together with mutagenesis and electrophysiology, we delineated the drug binding pocket for DHP-103 within the water-filled central cavity of the K Ca 3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant K Ca 3.1 channels that cause hereditary xerocytosis, suggesting its potential use as a therapeutic for this hemolytic anemia. In a rat model of acute ischemic stroke, the second leading cause of death worldwide, DHP-103 administered 12 h postischemic insult in proof-of-concept studies reduced infarct volume, improved balance beam performance (measure of proprioception) and decreased numbers of activated microglia in infarcted areas. K Ca 3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which K Ca 3.1 has been experimentally confirmed as a therapeutic target.}, archive = {J_PNAS}, author = {Ong, Seow Theng and Nam, Young-Woo and Nasburg, Joshua A. and Ramanishka, Alena and Ng, Xuan Rui and Zhuang, Zhong and Goay, Stephanie Shee Min and Nguyen, Hai M. and Singh, Latika and Singh, Vikrant and Rivera, Alicia and Eyster, M. Elaine and Xu, Yang and Alper, Seth L. and Wulff, Heike and Zhang, Miao and Chandy, K. George}, doi = {10.1073/pnas.2425494122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2425494122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel KCa3.1}, volume = {122}, year = {2025}, }
• (2025). Synthesized dispersion-engineered elastic metasurfaces for achromatic focusing and harvesting across the audible to ultrasound ranges. PNAS, 122(18), e2425407122. (www)

  @article{ , abstract = {Metasurfaces have garnered significant attention for unnatural abilities to modulate waves across various physics domains, including elastics. However, existing elastic metasurfaces are limited to narrowband operations due to chromatic aberrations; moreover, these exhibit highly discrete phase profiles due to the empty spaces required for each meta-atom to function as an individual waveguide. Herein, to address these, we propose a synthesized dispersion engineering that compensates for higher-order wave dispersion, and considers both diffraction and refraction. This approach allows for the design of an elastic metasurface with achromatic focusing capability across an ultrabroadband range, from audible to ultrasound frequencies. By exploiting Kirchhoff–Love plate theory, we demonstrate achromatic focusing with a quasi-continuous phase profile. Additionally, we harness the amplified electrical energy generated by piezoelectric elements attached at the confocal point. Our precise yet straightforward design strategy can be extended to other wave dynamics, including photonics and acoustics, and applied to various scenarios.}, archive = {J_PNAS}, author = {Lee, Geon and Choi, Wonjae and Seung, Hong Min and Kim, Seokwoo and Rho, Junsuk}, doi = {10.1073/pnas.2425407122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2425407122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synthesized dispersion-engineered elastic metasurfaces for achromatic focusing and harvesting across the audible to ultrasound ranges}, volume = {122}, year = {2025}, }
• (2025). Increased flood exposure in the pacific northwest following earthquake-driven subsidence and sea-level rise. PNAS, 122(18), e2424659122. (www)

  @article{ , abstract = {Climate-driven sea-level rise is increasing the frequency of coastal flooding worldwide, exacerbated locally by factors like land subsidence from groundwater and resource extraction. However, a process rarely considered in future sea-level rise scenarios is sudden (over minutes) land subsidence associated with great (>M8) earthquakes, which can exceed 1 m. Along the Washington, Oregon, and northern California coasts, the next great Cascadia subduction zone earthquake could cause up to 2 m of sudden coastal subsidence, dramatically raising sea level, expanding floodplains, and increasing the flood risk to local communities. Here, we quantify the potential expansion of the 1% floodplain (i.e., the area with an annual flood risk of 1%) under low (~0.5 m), medium (~1 m), and high (~2 m) earthquake-driven subsidence scenarios at 24 Cascadia estuaries. If a great earthquake occurred today, floodplains could expand by 90 km 2 (low), 160 km 2 (medium), or 300 km 2 (high subsidence), more than doubling the flooding exposure of residents, structures, and roads under the high subsidence scenario. By 2100, when climate-driven sea-level rise will compound the hazard, a great earthquake could expand floodplains by 170 km 2 (low), 240 km 2 (medium), or 370 km 2 (high subsidence), more than tripling the flooding exposure of residents, structures, and roads under the high subsidence scenario compared to the 2023 floodplain. Our findings can support decision-makers and coastal communities along the Cascadia subduction zone as they prepare for compound hazards from the earthquake cycle and climate-driven sea-level rise and provide critical insights for tectonically active coastlines globally.}, archive = {J_PNAS}, author = {Dura, Tina and Chilton, William and Small, David and Garner, Andra J. and Hawkes, Andrea and Melgar, Diego and Engelhart, Simon E. and Staisch, Lydia M. and Witter, Robert C. and Nelson, Alan R. and Kelsey, Harvey M. and Allan, Jonathan C. and Bruce, David and DePaolis, Jessica and Priddy, Michael and Briggs, Richard W. and Weiss, Robert and La Selle, SeanPaul and Willis, Michael and Horton, Benjamin P.}, doi = {10.1073/pnas.2424659122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2424659122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Increased flood exposure in the pacific northwest following earthquake-driven subsidence and sea-level rise}, volume = {122}, year = {2025}, }
• (2025). Horizontal transfer of nuclear DNA in transmissible cancer. PNAS, 122(18), e2424634122. (www)

  @article{ , abstract = {Horizontal transfer of nuclear DNA between cells of host and cancer is a potential source of adaptive variation in cancer cells. An understanding of the frequency and significance of this process in naturally occurring tumors is, however, lacking. We screened for this phenomenon in the transmissible cancers of dogs and Tasmanian devils and found an instance in the canine transmissible venereal tumor (CTVT). This involved introduction of a 15-megabase dicentric genetic element, composed of 11 fragments of six chromosomes, to a CTVT sublineage occurring in Asia around 2,000 y ago. The element forms the short arm of a small submetacentric chromosome and derives from a dog with ancestry associated with the ancient Middle East. The introduced DNA fragment is transcriptionally active and has adopted the expression profile of CTVT. Its features suggest that it may derive from an engulfed apoptotic body. Our findings indicate that nuclear horizontal gene transfer, although likely a rare event in tumor evolution, provides a viable mechanism for the acquisition of genetic material in naturally occurring cancer genomes.}, archive = {J_PNAS}, author = {Gori, Kevin and Baez-Ortega, Adrian and Strakova, Andrea and Stammnitz, Maximilian R. and Wang, Jinhong and Chan, Jonathan and Hughes, Katherine and Belkhir, Sophia and Hammel, Maurine and Moralli, Daniela and Bancroft, James and Drydale, Edward and Allum, Karen M. and Brignone, María Verónica and Corrigan, Anne M. and de Castro, Karina F. and Donelan, Edward M. and Faramade, Ibikunle A. and Hayes, Alison and Ignatenko, Nataliia and Karmacharya, Rockson and Koenig, Debbie and Lanza-Perea, Marta and Lopez Quintana, Adriana M. and Meyer, Michael and Neunzig, Winifred and Pedraza-Ordoñez, Francisco and Phuentshok, Yoenten and Phuntsho, Karma and Ramirez-Ante, Juan C. and Reece, John F. and Schmeling, Sheila K. and Singh, Sanjay and Tapia Martinez, Lester J. and Taulescu, Marian and Thapa, Samir and Thapa, Sunil and van der Wel, Mirjam G. and Wehrle-Martinez, Alvaro S. and Stratton, Michael R. and Murchison, Elizabeth P.}, doi = {10.1073/pnas.2424634122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2424634122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Horizontal transfer of nuclear DNA in transmissible cancer}, volume = {122}, year = {2025}, }
• (2025). A responsive living material prepared by diffusion reveals extracellular enzyme activity of cyanobacteria. PNAS, 122(18), e2424405122. (www)

  @article{ , abstract = {Stimuli-responsive engineered living materials (ELMs) can respond to environmental or biochemical cues and have broad utility in biological sensors and machines, but have traditionally been limited to biocompatible scaffolds. This is because they are typically made by mixing cells into a precursor solution before crosslinking. Here, we demonstrate a diffusion mechanism for incorporating cells of the cyanobacterium Synechococcus elongatus sp. PCC 7942 ( S. elongatus ) into nanoclay-poly-N-isopropylacrylamide (NC-PNIPAm), a hydrogel with a cytotoxic precursor, by exploiting its temperature-dependent shape-morphing behavior. Subsequent growth of S. elongatus caused a decrease in the bending curvature and stiffness (local Young’s modulus) of NC-PNIPAm due to partial degradation by an unannotated enzyme. Creation and observation of this cyanobacteria-hydrogel ELM showcases a method for diffusing cells into a hydrogel as well as characterizing an extracellular enzyme.}, archive = {J_PNAS}, author = {Tang, Lisa and Soulier, Nathan T. and Wheeler, Rebecca and Pokorski, Jonathan K. and Golden, James W. and Golden, Susan S. and Bae, Jinhye}, doi = {10.1073/pnas.2424405122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2424405122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A responsive living material prepared by diffusion reveals extracellular enzyme activity of cyanobacteria}, volume = {122}, year = {2025}, }
• (2025). Diane e. griffin, physician–scientist extraordinaire. PNAS, 122(18), e2424274122. (www)

  @article{ , abstract = {In October 2024, the scientific world lost Diane E. Griffin, a highly accomplished physician–scientist who greatly heightened our understanding of viral pathogenesis. Apart from being a leading virologist in her time, she was unusual in working tirelessly to maintain the fabric of science through her service to journals, scientific societies, and the academies. She leaves a rich scientific legacy in explaining many facets of the pathogenesis of neurotropic viruses, including measles, and in a large network of trainees and colleagues who benefitted from her wisdom and care. In remembering Diane, we celebrate a great life in science and note with admiration how she leaves us with a shining example to emulate.}, archive = {J_PNAS}, author = {Casadevall, Arturo and Hardwick, J. Marie}, doi = {10.1073/pnas.2424274122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2424274122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Diane e. griffin, physician–scientist extraordinaire}, volume = {122}, year = {2025}, }
• (2025). Long-term tree population growth can predict woody encroachment patterns. PNAS, 122(18), e2424096122. (www)

  @article{ , abstract = {Recent increases in woody plant density in dryland ecosystems—or “woody encroachment”—around the world are often attributed to land-use changes such as increased livestock grazing and wildfire suppression or to global environmental trends (e.g., increasing atmospheric carbon dioxide). While such changes have undoubtedly impacted ecosystem structure and function, the evidence linking them to woody encroachment is mixed, and the underlying processes are not fully understood. To clarify the role of demographic processes in changing woody plant abundance, we conducted a meta-analysis of tree age structures from 29 woodland populations across the interior western United States, estimating per-capita tree establishment rates over the last several hundred years using demographic models. We found only limited evidence of increases in per-capita tree establishment rates following 19th-century Euro-American settlement. On the contrary, our results showed that observed age structures dominated by young trees, often cited as evidence of woody encroachment driven by anthropogenic processes, can be largely predicted by a null model based only on steady, multiplicative tree population growth. Moreover, we demonstrated that tree establishment rates in the last century have mostly declined rather than increased, and they are currently at their lowest rates since at least 1600 CE. Our results suggest that a large part of modern increases in woodland tree establishment and density may in fact be a result of long-term population increases, and failing to consider the demographic processes underlying population growth can lead to an overestimation of settlement effects on stand structure.}, archive = {J_PNAS}, author = {Shriver, Robert K. and Pletcher, Elise and Biondi, Franco and Urza, Alexandra K. and Weisberg, Peter J.}, doi = {10.1073/pnas.2424096122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2424096122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Long-term tree population growth can predict woody encroachment patterns}, volume = {122}, year = {2025}, }
• (2025). Next-generation rifamycins for the treatment of mycobacterial infections. PNAS, 122(18), e2423842122. (www)

  @article{ , abstract = {Mycobacterium abscessus is a rapidly growing nontuberculous Mycobacterium causing severe pulmonary infections, especially in immunocompromised individuals and patients with underlying lung conditions like cystic fibrosis (CF). While rifamycins are the pillar of tuberculosis treatment, their efficacy against M. abscessus lung disease is severely compromised by intrabacterial ADP-ribosylation. Additionally, rifamycins induce cytochrome P450 3A4 (CYP3A4), a major human drug-metabolizing enzyme, further limiting their use in patients with comorbidities that require treatment with CYP3A4 substrates such as CF and HIV coinfection. We chemically reengineered rifabutin to enhance its potency against M. abscessus by blocking intrabacterial inactivation and eliminate drug–drug interactions by removing induction of CYP3A4 gene expression. We have designed and profiled a series of C25-substituted derivatives resistant to intracellular inactivation and lacking CYP3A4 induction, while retaining excellent pharmacological properties. Against Mycobacterium tuberculosis , devoid of ADP-ribosyltransferase, the frontrunners are equipotent to rifabutin, suggesting superior clinical utility since they no longer come with the drug interaction liability typical of rifamycins. Prioritized compounds demonstrated superior antibacterial activity against a panel of M. abscessus clinical isolates, were highly bactericidal against replicating and drug-tolerant nonreplicating bacteria in caseum surrogate and were active against intracellular bacteria. As single agents, these rifamycins were as effective as a standard-of-care four-drug combination in a murine model of M. abscessus lung infection.}, archive = {J_PNAS}, author = {Dartois, Véronique and Lan, Tian and Ganapathy, Uday S. and Wong, Chui Fann and Sarathy, Jickky P. and Jimenez, Diana C. and Alshiraihi, Ilham M. and Lam, Ha and Rodriguez, Suyapa and Xie, Min and Soto-Ojeda, Maritza and Jackson, Mary and Wheat, William and Dillman, Nathan C. and Kostenkova, Kateryna and Schmitt, Jake and Mann, Lea and Richter, Adrian and Imming, Peter and Sarathy, Jansy and Kaya, Firat and Paruchuri, Sindhuja and Tatek, Betelhem and Folvar, Camilla and Proietto, Julianna and Zimmerman, Matthew and Gonzalez-Juarrero, Mercedes and Aldrich, Courtney C. and Dick, Thomas}, doi = {10.1073/pnas.2423842122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2423842122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Next-generation rifamycins for the treatment of mycobacterial infections}, volume = {122}, year = {2025}, }
• (2025). Multiscale biased chemical space remodeling for developing APLNR agonists with anti-HFpEF efficacy. PNAS, 122(18), e2423432122. (www)

  @article{ , abstract = {Heart failure with preserved ejection fraction (HFpEF) represents a significant global health burden, yet effective pharmacotherapies remain elusive. The angiotensin-like 1 receptor, also known as the apelin receptor (APLNR), is a promising target for treating HFpEF due to its role in modulating cardiovascular function. Despite the cardioprotective effects of endogenous ligand, apelin, achieving G-protein-biased agonism for therapeutic benefit poses a significant challenge. In this study, we unravel the biased signal transduction pathway mediated by a reported partial G i -protein-biased APLNR agonist CMF-019 and developed a biased chemical space remodeling approach to identify exclusive G-protein-biased agonists targeting APLNR. These agonists exhibited enhanced Gi-protein-biased function and protective effects in both in vitro and in vivo. Our findings not only enhance comprehension of APLNR-biased agonism but also establish drug design strategies for modifying and reshaping biased chemical landscapes in other G-protein-coupled receptors (GPCRs).}, archive = {J_PNAS}, author = {Sun, Qiu and Tian, Xiaowen and Tan, Lun and Deng, Yan and Liu, Sicen and Xiong, Yixiao and Feng, Yuying and Wang, Yujia and Zhang, Lele and Zhu, Jiayi and Xiao, Huan and Shao, Zhenhua and Guo, Yingqiang and Yan, Wei and Li, Tao and Ouyang, Liang}, doi = {10.1073/pnas.2423432122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2423432122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multiscale biased chemical space remodeling for developing APLNR agonists with anti-HFpEF efficacy}, volume = {122}, year = {2025}, }
• (2025). Persistent inequalities in global air quality monitoring should not delay pollution mitigation. PNAS, 122(18), e2423259122. (www)

  @article{ , abstract = {Air pollution is a global health crisis that disproportionately affects lower- and middle-income countries. We examine global air quality monitoring data, highlighting persistent inequalities in high-exposure regions, and assess the potential of emerging technologies to improve data utility for mitigation. Improving air quality, however, does not need to wait for more data, nor will monitoring alone drive action. Immediate mitigation measures with broad cobenefits are needed now to reduce pollution, even in data-scarce settings.}, archive = {J_PNAS}, author = {Smith, E. Keith and Fournier de Lauriere, Camille and Henninger, Ella}, doi = {10.1073/pnas.2423259122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2423259122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Persistent inequalities in global air quality monitoring should not delay pollution mitigation}, volume = {122}, year = {2025}, }
• (2025). Understanding TAK1 deficiency in microglia: Dual mechanisms for photoreceptor protection in a mouse model of retinitis pigmentosa. PNAS, 122(18), e2423134122. (www)

  @article{ , abstract = {Retinitis pigmentosa (RP) is a group of inherited retinal diseases characterized by the progressive loss of photoreceptors. Neuroinflammation has been implicated in the pathophysiology of RP and its progression. Previous studies have suggested that the transforming growth factor-beta-activated kinase 1 (TAK1) plays a pivotal role in regulating acute and chronic neuroinflammation. However, the functional role of TAK1 in neuroinflammation remains unclear in RP. Here, we observed TAK1 upregulation in activated microglia of the rd10 mouse model of RP. To create the conditional deletion of TAK1 in microglia, we backcrossed Cx3cr1 CreER/CreER mice and Tak1 fl/fl mice onto rd10 background. We found that both heterozygous (rd10;Cx3cr1 CreER/+ ;Tak1 fl/+ ) and homozygous (rd10;Cx3cr1 CreER/+ ;Tak1 fl/fl ) deletion of microglial TAK1 slowed down photoreceptor degeneration but with distinct mechanisms. The heterozygous TAK1 deficiency resulted in a reduction in the activation and proliferation of microglia and the release of proinflammatory cytokines by inhibiting STAT3 signaling. In contrast, the homozygous TAK1 deficiency induced apoptosis in microglia via the TNF/RIPK1/CASP3 signaling pathway, contributing to the reduction of microglia-mediated neurotoxicity and subsequent preservation of photoreceptors in RP. Overall, our findings highlight the crucial role of TAK1 in the survival and activation of microglia. We propose that targeting microglial TAK1, considering its expression levels and subsequent signal transduction, could offer a promising personalized therapeutic strategy for individuals with RP regardless of underlying genetic causes.}, archive = {J_PNAS}, author = {Zhang, Jing and Yang, Wei and Wu, Jiangmei and Lin, Bin}, doi = {10.1073/pnas.2423134122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2423134122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Understanding TAK1 deficiency in microglia: Dual mechanisms for photoreceptor protection in a mouse model of retinitis pigmentosa}, volume = {122}, year = {2025}, }
• (2025). Stiffness-gradient adhesive structure with mushroom-shaped morphology via electrically activated one-step growth. PNAS, 122(18), e2423039122. (www)

  @article{ , abstract = {Reptiles in nature have evolved excellent adhesion systems to adapt to complex natural environments, inspired by which high-performance bioinspired dry adhesives have been consistently created by precisely replicating the natural structures. Stiffness gradient, as a special feature evolved in reptilian adhesion systems, offers significant advantages in enhancing adhesion adaptation and stability. However, it remains a challenge to accurately replicate the geometrical morphology and soft-rigid composite properties of stiffness gradient structures, which limits the engineering applications of bioinspired adhesives. Here, a stiffness gradient adhesive structure with mushroom-shaped morphology via electrically activated one-step growth is proposed. Under the action of electric field, the liquid-phase polymer grows rheologically to realize the mushroom-shaped structural morphology, and the nanoparticles inside the polymer are aggregated toward the top by dielectrophoresis to realize the stiffness gradient distribution of rigid top and soft bottom. Due to the adaptation of the soft part to the interfacial contact and the effective inhibition of peeling by the rigid part, the proposed stiffness gradient structure improves the adhesion strength by 3 times in the parallel state and by 5 times in the nonparallel state compared to the conventional homogeneous structure. In addition, the application of adhesive structures in wall-climbing robots was demonstrated, opening an avenue for the development of dry adhesive-based devices and systems.}, archive = {J_PNAS}, author = {Wang, Duorui and Liu, Tianci and Tian, Hongmiao and Zhang, Jinyu and He, Qiguang and Li, Xiangming and Wang, Chunhui and Chen, Xiaoliang and Shao, Jinyou}, doi = {10.1073/pnas.2423039122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2423039122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stiffness-gradient adhesive structure with mushroom-shaped morphology via electrically activated one-step growth}, volume = {122}, year = {2025}, }
• (2025). A symbiotic gene stimulates aggressive behavior favoring the survival of parasitized caterpillars. PNAS, 122(18), e2422935122. (www)

  @article{ , abstract = {Animals often exhibit increased aggression in response to starvation, while parasites often manipulate host behavior. In contrast, underlying molecular mechanisms for these behavioral changes are mostly unknown. The diamondback moth, Plutella xylostella , is an agricultural pest that feeds on cruciferous plants as larvae, while Cotesia vestalis is a parasitoid wasp that parasitizes diamondback moth larvae. In this study, we determined that unparasitized diamondback moth larvae exhibit increased aggression and cannibalism when starved, while starved larvae parasitized by C. vestalis were more aggressive than unparasitized larvae. C. vestalis harbors a domesticated endogenized virus named Cotesia vestalis bracovirus (CvBV) that wasps inject into parasitized hosts. Starvation increased octopamine (OA) levels in the central nervous system (CNS) of diamondback moth larvae while a series of experiments identified a CvBV-encoded gene product named Assailant that further increased aggression in starved diamondback moth larvae. We determined that Assailant increases OA levels by activating tyramine beta-hydroxylase ( PxTβh ), which is a key enzyme in the OA biosynthesis pathway. Ectopic expression of assailant in Drosophila melanogaster likewise upregulated expression of DmTβh and OA, which increased aggressive behavior in male flies as measured by a well-established assay. While parasitized hosts are often thought to be at a competitive disadvantage to nonparasitized individuals, our results uncover how a parasitoid uses an endogenized virus to increase host aggression and enhance survival of offspring when competing against unparasitized hosts.}, archive = {J_PNAS}, author = {Wu, Zhiwei and Wu, Xiaotong and Wang, Zhizhi and Ye, Xiqian and Pang, Lan and Wang, Yanping and Zhou, Yuenan and Chen, Ting and Zhou, Sicong and Wang, Zehua and Sheng, Yifeng and Zhang, Qichao and Chen, Jiani and Tang, Pu and Shen, Xingxing and Huang, Jianhua and Drezen, Jean-Michel and Strand, Michael R. and Chen, Xuexin}, doi = {10.1073/pnas.2422935122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2422935122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A symbiotic gene stimulates aggressive behavior favoring the survival of parasitized caterpillars}, volume = {122}, year = {2025}, }
• (2025). Scattering diagrams, tight gradings, and generalized positivity. PNAS, 122(18), e2422893122. (www)

  @article{ , abstract = {In 2013, Lee, Li, and Zelevinsky introduced combinatorial objects called compatible pairs to construct the greedy bases for rank-2 cluster algebras, consisting of indecomposable positive elements including the cluster monomials. Subsequently, Rupel extended this construction to the setting of generalized rank-2 cluster algebras by defining compatible gradings. We find a class of combinatorial objects which we call tight gradings. Using this, we give a directly computable, manifestly positive, and elementary but highly nontrivial formula describing rank-2 consistent scattering diagrams. This allows us to show that the coefficients of the wall-functions on a generalized cluster scattering diagram of any rank are positive, which implies the Laurent positivity for generalized cluster algebras and the strong positivity of their theta bases.}, archive = {J_PNAS}, author = {Burcroff, Amanda and Lee, Kyungyong and Mou, Lang}, doi = {10.1073/pnas.2422893122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2422893122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Scattering diagrams, tight gradings, and generalized positivity}, volume = {122}, year = {2025}, }
• (2025). Possible evidence of excitonic condensation in a topological insulator. PNAS, 122(18), e2422667122. (www)

  @article{ , abstract = {The transient excitonic condensate is a nonequilibrium electron–hole Bardeen–Cooper–Schrieffer state in a photoexcited semiconductor and semimetal, where electron–hole pairs undergo a phase transition and condense into a single coherent quantum state. Despite numerous experimental works to realize the predicted excitonic condensation phase, experimental evidence still remains elusive. This is largely due to the absence of direct measurements of a material’s transient momentum-dependent electronic structure and the excitonic state in the condensation regime. Here, using time and angle-resolved photoemission spectroscopy, we find direct evidence of a transient excitonic condensate in the spin-polarized spatially indirect excitonic topological states in Bi 2 Te 3 . Accompanying the formation of the excitonic topological states by photoexcitation, we reveal a splitting of the hole’s and electron’s quasi-equilibrium chemical potential followed by the band flattening and backbending of the transient topological surface state. Moreover, within the same momentum range, we report a reshaping of the bulk valence band in the form of a Mexican-hat-like Bogoliubov dispersion—hallmarks of the excitonic condensation, followed by the opening of an energy gap at the Fermi level. The fluence and temperature dependence of these renormalization effects are reminiscent of excitonic condensation within Bardeen–Cooper–Schrieffer (BCS)-like behavior. These results, together with theoretical simulation, point to the possible formation of a transient excitonic condensate and provide opportunities to manipulate topologically protected Bose condensates with light.}, archive = {J_PNAS}, author = {Mori, Ryo and Takasan, Kazuaki and Ai, Ping and Ciocys, Samuel and Kawaguchi, Kaishu and Kondo, Takeshi and Morimoto, Takahiro and Lanzara, Alessandra}, doi = {10.1073/pnas.2422667122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2422667122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Possible evidence of excitonic condensation in a topological insulator}, volume = {122}, year = {2025}, }
• (2025). Quantification and potential functional relevance of binding cooperativity of adjacent transcription factors on DNA. PNAS, 122(18), e2422555122. (www)

  @article{ , abstract = {In eukaryotes, the expression of specific genes is regulated by a combination of transcription factors (TFs) bound on regulatory regions of the genomic DNA (promoters and enhancers). Recent advances in genomic sequencing technology have enabled the measurements of TFs’ footprints and binding affinities on DNA at the single-molecule level, facilitating the probing of binding cooperativity among adjacent TFs. This necessitates quantitative descriptions of TFs’ binding cooperativity and understanding of its potential functional relevance. In this study, we show that the binding cooperativities between two adjacent TFs can be quantified by the γ coefficient, which can be experimentally determined. Under thermodynamic equilibrium, the binding affinities of two TFs can either increase together (positive cooperativity) or decrease together (negative cooperativity), but not in opposing directions (one increases while the other decreases). Within the framework of thermodynamics, we investigate the functional relevance of cooperativity. The functional relevance of positive cooperativity, which has been extensively discussed in the literature, is the sigmoidal binding curve around a TF concentration threshold (analogous to oxygen binding to hemoglobin), whereas the functional relevance of negative cooperativity is twofold. First, mutual exclusion of the two TFs enables bidirectional gene switching, akin to the CI-Cro system in phage λ . Second, while TFs often exhibit intranuclear concentration fluctuations, negative binding cooperativity assures fast TF dissociation from DNA and hence rapid response for gene expression regulation. Furthermore, the nonequilibrium steady states of living cells can lead to either positive or negative cooperativity, which can also be quantified by the γ coefficient.}, archive = {J_PNAS}, author = {Wang, Xinyao and Xie, Chen and Shen, Ke and Li, Dubai and Xie, Xiaoliang Sunney}, doi = {10.1073/pnas.2422555122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2422555122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantification and potential functional relevance of binding cooperativity of adjacent transcription factors on DNA}, volume = {122}, year = {2025}, }
• (2025). Detecting DNA translocation through a nanopore using a van der waals heterojunction diode. PNAS, 122(18), e2422135122. (www)

  @article{ , abstract = {A long-unrealized goal in solid-state nanopore sensing is to achieve out-of-plane electrical sensing and control of DNA during translocation, which is a prerequisite for base-by-base ratcheting that enables DNA sequencing in biological nanopores. Two-dimensional (2D) heterostructures, with their capability to construct out-of-plane electronics with atomic layer precision, are ideal yet unexplored candidates for use as electrical sensing membranes. Here, we demonstrate a nanopore architecture using a vertical 2D heterojunction diode consisting of p-type WSe 2 on n-type MoS 2 . This diode exhibits rectified interlayer tunneling currents modulated by ionic potential, while the heterojunction potential reciprocally rectifies ionic transport through the nanopore. We achieve concurrent detection of DNA translocation using both ionic and diode currents and demonstrate a 2.3-fold electrostatic slowing of average translocation speed. Encapsulation layers enhance chemical and mechanical stability and durability while preserving the spatial resolution of atomically sharp 2D heterointerface for sensing. These results establish a paradigm for out-of-plane electrical sensing of single biomolecules.}, archive = {J_PNAS}, author = {Chen, Sihan and Huang, Siyuan and Son, Jangyup and Han, Edmund and Watanabe, Kenji and Taniguchi, Takashi and Huang, Pinshane Y. and King, William P. and van der Zande, Arend M. and Bashir, Rashid}, doi = {10.1073/pnas.2422135122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2422135122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Detecting DNA translocation through a nanopore using a van der waals heterojunction diode}, volume = {122}, year = {2025}, }
• (2025). Inhaled DNAI1 mRNA therapy for treatment of primary ciliary dyskinesia. PNAS, 122(18), e2421915122. (www)

  @article{ , abstract = {Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder caused by mutations in one of at least 50 different genes that encode proteins involved in the biogenesis, structure, or function of motile cilia. Genetically inherited defects in motile cilia cause PCD, a debilitating respiratory disease for which there is no approved therapy. The dynein axonemal intermediate chain 1 (DNAI1) protein is a key structural element of the ciliary outer dynein arm (ODA) critical for normal ciliary activity and subsequent clearance of mucus from the conducting airways in humans. Loss-of-function mutations in DNAI1 account for up to 10% of all PCD cases, with functional abnormalities in patients presenting at or near birth and leading to a life-long course of disability, including progressive loss of lung function and bronchiectasis by adulthood. This underscores the significant unmet need for disease-modifying treatments that restore ciliary activity and mucociliary clearance in PCD patients. In this work, we demonstrate that lipid nanoparticle (LNP)-formulated human DNAI1 mRNA can be delivered as an aerosol to primary human bronchial epithelial cell models and to nonhuman primate (NHP) lungs. Additionally, we show that delivery of aerosolized LNP- DNAI1 mRNA to NHPs leads to detectable levels of newly translated human DNAI1 protein, at doses that overlap with exposures in an in vitro cell-based PCD model enabling rescue of ciliary function. Therefore, these data support further development of the inhaled DNAI1 mRNA therapy in clinical studies as a potential disease-modifying treatment for PCD.}, archive = {J_PNAS}, author = {Hennig, Mirko and Bhattacharjee, Rumpa B. and Agarwal, Ishita and Alfaifi, Ali and Casillas, Jade E. and Chavez, Sofia and Ishimaru, Daniella and Liston, David and Mohapatra, Sakya and Molla, Touhidul and Pathare, Suyog and Sidhu, Maninder S. and Wang, Peng and Wang, Zechen and Lombana, T. Noelle and Kharitonov, Vladimir G. and Couch, Jessica A. and Lockhart, David J. and Wustman, Brandon A.}, doi = {10.1073/pnas.2421915122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2421915122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inhaled DNAI1 mRNA therapy for treatment of primary ciliary dyskinesia}, volume = {122}, year = {2025}, }
• (2025). Calcium-activated chloride channel TMEM16A opens via pi-helical transition in transmembrane segment 4. PNAS, 122(18), e2421900122. (www)

  @article{ , abstract = {TMEM16A is a Ca 2+ -activated Cl − channel that has crucial roles in various physiological and pathological processes. However, the structure of the open state of the channel and the mechanism of Ca 2+ -induced pore opening have remained elusive. Using extensive molecular dynamics simulations, protein structure prediction, and patch-clamp electrophysiology, we demonstrate that TMEM16A opens a hydrated Cl − -conductive pore via a pi-helical transition in transmembrane segment 4 (TM4). We also describe a coupling mechanism that links pi-helical transition and pore opening to the Ca 2+ -induced conformational changes in TMEM16A. Furthermore, we designed a pi-helix-stabilizing mutation (I551P) that facilitates TMEM16A activation, revealing atomistic details of the ion-conduction mechanism. Finally, AlphaFold2 structure predictions revealed the importance of the pi helix in TM4 to structure–function relations in TMEM16 and the related OSCA/TMEM63 family, further highlighting the relevance of dynamic pi helices for gating in various ion channels.}, archive = {J_PNAS}, author = {Kostritskii, Andrei Y. and Kostritskaia, Yulia and Dmitrieva, Natalia and Stauber, Tobias and Machtens, Jan-Philipp}, doi = {10.1073/pnas.2421900122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2421900122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Calcium-activated chloride channel TMEM16A opens via pi-helical transition in transmembrane segment 4}, volume = {122}, year = {2025}, }
• (2025). Dysregulation of MYBL2 impairs extravillous trophoblast lineage development and function, contributing to recurrent spontaneous abortion. PNAS, 122(18), e2421653122. (www)

  @article{ , abstract = {Recurrent spontaneous abortion (RSA) is a pregnancy-related condition characterized by a complex etiology. While placental trophoblast dysfunction is strongly associated with the development and progression of RSA, the underlying molecular mechanisms remain poorly understood. In this study, we observed a significant decrease in the expression of MYB Proto-Oncogene Like 2 (MYBL2) in the villous tissue of patients with RSA and the placentas of abortion-prone (AP) mice. Utilizing human trophoblast stem cells (hTSCs), we identified MYBL2 as a critical regulator of hTSCs stemness maintenance, promoting the expression of the stemness-associated genes Tumor protein p63 (TP63) and TEA Domain Transcription Factor 4 (TEAD4). Furthermore, MYBL2 facilitates the differentiation of hTSCs into extravillous trophoblast (EVT) by positively regulating Ajuba LIM Protein (AJUBA) expression. Using HTR-8/SVneo cell line, an immortalized EVT-like model, we found that MYBL2 positively regulates AJUBA expression by binding to the distal region of the AJUBA promoter. Additionally, the MYBL2–AJUBA axis enhances the migration and invasion of HTR-8/SVneo cells by suppressing the Hippo signaling pathway. Our study indicates that the dysregulation of MYBL2 expression in placental trophoblasts is associated with the pathogenesis of RSA, highlighting its potential as a therapeutic target for this condition.}, archive = {J_PNAS}, author = {Wu, Zhi-Hong and Yi, Cen and Chen, En-Xiang and Xu, Jia-Qi and Li, Cong and Yao, Lu and Li, Fang-Fang and Fu, Li-Juan and Ge, Lu-Xing and Wang, Ying-Xiong and Xie, You-Long and Ding, Yu-Bin and Tang, Jing}, doi = {10.1073/pnas.2421653122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2421653122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dysregulation of MYBL2 impairs extravillous trophoblast lineage development and function, contributing to recurrent spontaneous abortion}, volume = {122}, year = {2025}, }
• (2025). Water-directed pinning is key to tau prion formation. PNAS, 122(18), e2421391122. (www)

  @article{ , abstract = {Tau forms fibrillar aggregates that are pathological hallmarks of a family of neurodegenerative diseases known as tauopathies. The synthetic replication of disease-specific fibril structures is a critical gap for developing diagnostic and therapeutic tools. This study debuts a strategy of identifying a critical and minimal folding motif in fibrils characteristic of tauopathies and generating seeding-competent fibrils from the isolated tau peptides. The 19-residue jR2R3 peptide (295 to 313) which spans the R2/R3 splice junction of tau, and includes the P301L mutation, is one such peptide that forms prion-competent fibrils. This tau fragment contains the hydrophobic VQIVYK hexapeptide that is part of the core of all known pathological tau fibril structures and an intramolecular counterstrand that stabilizes the strand–loop–strand (SLS) motif observed in 4R tauopathy fibrils. This study shows that P301L exhibits a duality of effects: it lowers the barrier for the peptide to adopt aggregation-prone conformations and enhances the local structuring of water around the mutation site to facilitate site-directed pinning and dewetting around sites 300-301 to achieve in-register stacking of tau to cross β-sheets. We solved a 3 Å cryo-EM structure of jR2R3-P301L fibrils in which each protofilament layer contains two jR2R3-P301L copies, of which one adopts a SLS fold found in 4R tauopathies and the other wraps around the SLS fold to stabilize it, reminiscent of the three- and fourfold structures observed in 4R tauopathies. These jR2R3-P301L fibrils are competent to template full-length 4R tau in a prion-like manner.}, archive = {J_PNAS}, author = {Vigers, Michael P. and Lobo, Samuel and Najafi, Saeed and Dubose, Austin and Tsay, Karen and Ganguly, Pritam and Longhini, Andrew P. and Jin, Yingying and Buratto, Steven K. and Kosik, Kenneth S. and Shell, M. Scott and Shea, Joan-Emma and Han, Songi}, doi = {10.1073/pnas.2421391122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2421391122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Water-directed pinning is key to tau prion formation}, volume = {122}, year = {2025}, }
• (2025). Behavioral resilience via dynamic circuit firing homeostasis. PNAS, 122(18), e2421386122. (www)

  @article{ , abstract = {Homeostatic regulation ensures stable neural circuit output under changing conditions. We find that in Drosophila larvae, either presynaptic weakening due to perturbation of transmitter release or postsynaptic weakening due to perturbation of glutamate receptors at synapses between motor neuron (MN) and muscle has little impact on locomotion, suggesting a nonsynaptic compensatory mechanism. In vivo imaging shows that five different forms of synaptic weakening increase the duration of activity bouts in type I MNs. Strikingly, this compensation is input selective: occurring only in the tonic type Ib MN, not the phasic type Is MN that innervates the same muscle. Moreover, an inhibitory class of central pre-MNs that innervates the tonic—but not phasic—input decreases in activity. The adjustment in activity occurs remarkably quickly: within minutes of synapse perturbation. We propose that MN firing is dynamically regulated by two coordinated mechanisms: a cell-autonomous adjustment of MN excitability and a circuit adjustment of inhibitory central drive. The input selectivity of this process suggests homeostatic adjustment to maintain tonic drive but hold constant the phasic drive that organizes locomotory wave patterns.}, archive = {J_PNAS}, author = {Hoagland, Adam and Schultz, Ryan and Cai, Zerong and Newman, Zachary L. and Isacoff, Ehud Y.}, doi = {10.1073/pnas.2421386122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2421386122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Behavioral resilience via dynamic circuit firing homeostasis}, volume = {122}, year = {2025}, }
• (2025). Thermodynamic consistency of autocatalytic cycles. PNAS, 122(18), e2421274122. (www)

  @article{ , abstract = {Autocatalysis is seen as a potential key player in the origin of life, and perhaps more generally in the emergence of Darwinian dynamics. Building on recent formalizations of this phenomenon, we tackle the computational challenge of exhaustively detecting minimal autocatalytic cycles (autocatalytic cores) in reaction networks and further evaluate the impact of thermodynamic constraints on their realization under mass action kinetics. We first characterize the complexity of the detection problem by proving its NP-completeness. This justifies the use of constraint solvers to list all cores in a given reaction network, and also to group them into compatible sets, composed of cores whose stoichiometric requirements are not contradictory. Crucially, we show that the introduction of thermodynamic realism does constrain the composition of these sets. Compatibility relationships among autocatalytic cores can indeed be disrupted when the reaction kinetics obey thermodynamic consistency throughout the network. On the contrary, these constraints have no impact on the realizability of isolated cores, unless upper or lower bounds are imposed on the concentrations of the reactants. Overall, by better characterizing the conditions of autocatalysis in complex reaction systems, this work brings us a step closer to assessing the contribution of this collective chemical behavior to the emergence of natural selection in the primordial soup.}, archive = {J_PNAS}, author = {Kosc, Thomas and Kuperberg, Denis and Rajon, Etienne and Charlat, Sylvain}, doi = {10.1073/pnas.2421274122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2421274122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Thermodynamic consistency of autocatalytic cycles}, volume = {122}, year = {2025}, }
• (2025). Anatomy of the magmatic–hydrothermal system beneath uturuncu volcano, bolivia, by joint seismological and petrophysical analysis. PNAS, 122(18), e2420996122. (www)

  @article{ , abstract = {For a volcanic system, evaluating potential eruption probability requires understanding the extent of melt and gas accumulation in the upper crustal reservoir, which is challenging to resolve. Here, we jointly use geophysical imaging and petrophysical analysis to unravel the current state and pathway of gas or supercritical fluids in the upper crust beneath Uturuncu volcano in Bolivia. Although it last erupted 250 ± 5 ka ago, Uturuncu remains active with observable deformation and seismicity. To assess its current state, we have determined high-resolution isotropic and anisotropic seismic velocity structures of the volcanic system in the upper crust using local seismic networks. Combining our seismic analysis with previous geophysical imaging results and rock physics modeling, we delineate pathways of migrating fluids traveling toward the surface and a shallow gas accumulation zone beneath the crater. This fluid migration and accumulation explains why Uturuncu volcano still shows signs of activity. Our study exemplifies how seismology combined with rock physics models and petrological analysis can resolve the detailed structure and composition of a volcanic system, critical for assessing eruption hazard.}, archive = {J_PNAS}, author = {Liu, Ying and Kendall, John Michael and Zhang, Haijiang and Blundy, Jonathan D. and Pritchard, Matthew E. and Hudson, Thomas and MacQueen, Patricia}, doi = {10.1073/pnas.2420996122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2420996122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Anatomy of the magmatic–hydrothermal system beneath uturuncu volcano, bolivia, by joint seismological and petrophysical analysis}, volume = {122}, year = {2025}, }
• (2025). Micromechanical modeling of triphasic granular media. PNAS, 122(18), e2420314122. (www)

  @article{ , abstract = {This paper presents pore unit assembly-discrete element model (PUA-DEM), a pore-scale hydromechanical framework that resolves interactions between mobile granular particles and multiphase fluids in unsaturated granular media. The framework uniquely integrates DEM with pore-scale hydrodynamic models to capture unsaturated flow dynamics, while leveraging a two-way coupling mechanism to ensure bidirectional fluid–grain feedback through stabilized domain partitioning. Further innovations include a dynamic pore-merging and retriangulation algorithm that enhances computational efficiency for large-scale systems. Validated against experimental data for glass beads and Ottawa sand, PUA-DEM accurately reproduces critical hydromechanical phenomena-including capillary/viscous fingering, wetting-induced granular swelling/collapse, and quasi-static deformation-under diverse saturation and loading regimes. Numerical case studies reveal how capillary forces and wetting fluid saturation collectively govern granular response, from pore-scale meniscus evolution to macroscale flow instabilities. By bridging pore- and particle-scale physics, PUA-DEM advances predictive modeling of partially saturated granular systems, offering transformative insights for geohazard mitigation, sustainable agriculture, pharmaceutical manufacturing, and energy-related engineering applications.}, archive = {J_PNAS}, author = {Das, Amiya Prakash and Zhao, Jidong and Sweijen, Thomas}, doi = {10.1073/pnas.2420314122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2420314122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Micromechanical modeling of triphasic granular media}, volume = {122}, year = {2025}, }
• (2025). Intelligent self-correcting growth of uniform bernal-stacked bi-/trilayer graphene. PNAS, 122(18), e2419968122. (www)

  @article{ , abstract = {State-of-the-art synthesis strategies of two-dimensional (2D) materials have been designed following the nucleation-dominant pattern for structure control. However, this classical methodology fails to achieve the precise layer- and stacking-resolved growth of wafer-scale few-layer 2D materials due to its intrinsically low energy resolution. Here, we present an intelligent self-correcting method for the high-resolution growth of uniform few-layer graphene. We demonstrate the layer-resolved growth of wafer-scale bilayer and trilayer graphene (BLG and TLG) with selective Bernal stacking through spontaneous correction of the single-layer graphene film with disordered multilayer graphene islands. Theoretical calculations reveal that the self-correcting growth is driven by the stepwise energy minimization of the closed system and kinetically activated by forming a low-barrier pathway for the carbon detachment-diffusion-attachment. Such uniform Bernal-stacked BLG and TLG films show high quality with distinct quantum Hall effect being observed. Our work opens an avenue for developing an intelligent methodology to realize the precise synthesis of diverse 2D materials.}, archive = {J_PNAS}, author = {Ma, Wei and Ma, Lai-Peng and Kong, Xiao and Yan, Han and Liu, Zhibo and Han, Tiannan and Zhu, Chao and Cheng, Hui-Ming and Liu, Zheng and Ding, Feng and Ren, Wencai}, doi = {10.1073/pnas.2419968122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2419968122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intelligent self-correcting growth of uniform bernal-stacked bi-/trilayer graphene}, volume = {122}, year = {2025}, }
• (2025). Multiple sclerosis and gut microbiota: Lachnospiraceae from the ileum of MS twins trigger MS-like disease in germfree transgenic mice—An unbiased functional study. PNAS, 122(18), e2419689122. (www)

  @article{ , abstract = {We developed a two-tiered strategy aiming to identify gut bacteria functionally linked to the development of multiple sclerosis (MS). First, we compared gut microbial profiles in a cohort of 81 monozygotic twins discordant for MS. This approach allowed to minimize confounding effects by genetic and early environmental factors and identified over 50 differently abundant taxa with the majority of increased taxa within the Firmicutes . These included taxa previously described to be associated with MS ( Anaerotruncus colihominis and Eisenbergiella tayi ), along with newly identified taxa, such as Copromonas and Acutalibacter . Second, we interrogated the intestinal habitat and functional impact of individual taxa on the development of MS-like disease. In an exploratory approach, we enteroscopically sampled microbiota from different gut segments of selected twin pairs and compared their compositional profiles. To assess their functional potential, samples were orally transferred into germfree transgenic mice prone to develop spontaneous MS-like experimental autoimmune encephalomyelitis (EAE) upon bacterial colonization. We found that MS-derived ileal microbiota induced EAE at substantially higher rates than analogous material from healthy twin donors. Furthermore, female mice were more susceptible to disease development than males. The likely active organisms were identified as Eisenbergiella tayi and Lachnoclostridium, members of the Lachnospiraceae family. Our results identify potentially disease-facilitating bacteria sampled from the ileum of MS affected twins. The experimental strategy may pave the way to functionally understand the role of gut microbiota in initiation of MS.}, archive = {J_PNAS}, author = {Yoon, Hongsup and Gerdes, Lisa Ann and Beigel, Florian and Sun, Yihui and Kövilein, Janine and Wang, Jiancheng and Kuhlmann, Tanja and Flierl-Hecht, Andrea and Haller, Dirk and Hohlfeld, Reinhard and Baranzini, Sergio E. and Wekerle, Hartmut and Peters, Anneli}, doi = {10.1073/pnas.2419689122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2419689122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multiple sclerosis and gut microbiota: Lachnospiraceae from the ileum of MS twins trigger MS-like disease in germfree transgenic mice—An unbiased functional study}, volume = {122}, year = {2025}, }
• (2025). A universal strategy for multicolor organic circularly polarized afterglow materials with high dissymmetry factors. PNAS, 122(18), e2419481122. (www)

  @article{ , abstract = {Materials with pure organic circularly polarized afterglow (CPA) have attracted significant attention due to their spatiotemporal-resolved optical properties, yet achieving simultaneous high dissymmetry factor (glum) and multicolor ultralong emission remains a challenge. Here, we establish a universal energy transfer-photon coupling strategy to realize CPA spanning from blue to red with record-high glum (up to 1.90) and ultralong lifetimes (>6 s). Systematic characterization of nonchiral donor–acceptor systems (TP-BPEA, TP-Fluo, etc.) reveals the absence of ground-state chiral centers ( g CD ≈ 0) and orientation artifacts ( LD < 10 −7 ), confirming the key role of cholesteric liquid crystal polymer in chirality induction. This spatiotemporal synergy between energy transfer (wavelength modulation) and photonic engineering (polarization control) provides a framework for chiral photonic materials, with potential implications for multidimensional information encryption.}, archive = {J_PNAS}, author = {Yin, Chenjia and Sun, Siyu and Yan, Zi-Ang and Hu, Honglong and Jiang, Ping and Xu, Zhuoran and Tian, He and Ma, Xiang}, doi = {10.1073/pnas.2419481122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2419481122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A universal strategy for multicolor organic circularly polarized afterglow materials with high dissymmetry factors}, volume = {122}, year = {2025}, }
• (2025). Toward quantitative X-ray elastography of coronary arteries using flexural pulse waves. PNAS, 122(18), e2419060122. (www)

  @article{ , abstract = {Dynamic elastography uses an imaging system to visualize the propagation of elastic waves, the speed of which is directly related to the elasticity felt by palpation. Very few studies have focused on X-ray elastography because of the technical challenges it poses: a planar image of an integration volume at a very slow sampling rate. We demonstrate that tracking a slow elastic wave guided along a one-dimensional structure could provide a possible solution. The recently discovered flexural pulse wave, which is naturally generated by heartbeats and propagates along arteries, is the perfect candidate for X-ray elastography. As it reflects the cardiovascular health of patients, arterial elasticity is a biomarker of high clinical interest. We first validate the method by measuring the elasticity in artery phantoms using X-ray. We then move on to data obtained in vivo on coronary arteries during a routine angiography examination. During coronary angiography, a catheter is used to inject an X-ray contrast dye into the patient’s aorta. X-rays are then taken as the dye spreads through the coronary arteries. It shows the movement of the coronary arteries for a few seconds and provides an opportunity to follow the natural flexural pulse waves. The obtained Young’s moduli for two patients are E = 38 ± 30 kPa and E = 38 ± 28 kPa, respectively. These preliminary results are expected to pave the way for X-ray elastography.}, archive = {J_PNAS}, author = {Gregoire, Sibylle and Laloy-Borgna, Gabrielle and Rouviere, Olivier and Giammarinaro, Bruno and Catheline, Stefan}, doi = {10.1073/pnas.2419060122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2419060122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Toward quantitative X-ray elastography of coronary arteries using flexural pulse waves}, volume = {122}, year = {2025}, }
• (2025). Ultrasound-activated cilia for biofilm control in indwelling medical devices. PNAS, 122(18), e2418938122. (www)

  @article{ , abstract = {Biofilm formation and encrustation are major issues in indwelling medical devices, such as urinary stents and catheters, as they lead to blockages and infections. Currently, to limit these effects, frequent replacements of these devices are necessary, resulting in a significant reduction in patients’ quality of life and an increase in healthcare costs. To address these challenges, by leveraging recent advancements in robotics and microfluidic technologies, we envision a self-cleaning system for indwelling medical devices equipped with bioinspired ultrasound-activated cilia. These cilia could be regularly activated transcutaneously by ultrasound, generating steady streaming, which can be used to remove encrusted deposits. In this study, we tested the hypothesis that the generated streaming can efficiently remove encrustations and biofilm from surfaces. To this end, we developed a microfluidic model featuring ultrasound-activated cilia on its wall. We showed that upon ultrasound activation, the cilia generated intense, steady streaming, reaching fluid velocity up to 10 mm/s. In all our experiments, this mechanism was able to efficiently clean typical encrustation (calcium carbonate and oxalate) and biofilm found in urological devices. The generated shear forces released, broke apart, and flushed away encrusted deposits. These findings suggest a broad potential for ultrasound-activated cilia in the maintenance of various medical devices. Compared to existing methods, our approach could reduce the need for invasive procedures, potentially lowering infection risks and enhancing patient comfort.}, archive = {J_PNAS}, author = {Amado, Pedro and Dillinger, Cornel and Bahou, Chaimae and Hashemi Gheinani, Ali and Obrist, Dominik and Burkhard, Fiona and Ahmed, Daniel and Clavica, Francesco}, doi = {10.1073/pnas.2418938122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2418938122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ultrasound-activated cilia for biofilm control in indwelling medical devices}, volume = {122}, year = {2025}, }
• (2025). Four-million-year marinoan snowball shows multiple routes to deglaciation. PNAS, 122(18), e2418281122. (www)

  @article{ , abstract = {Twice during the Neoproterozoic Era, Earth experienced runaway ice-albedo catastrophes that resulted in multimillion year, low-latitude glaciations: the Sturtian and Marinoan snowball Earths. In the snowball climate state, CO 2 consumption through silicate weathering collapses, and atmospheric CO 2 accumulates via volcanic outgassing until a sufficiently strong greenhouse causes deglaciation. The duration and extent of ice cover are critical for planetary habitability, both on exoplanets and on Earth where animals emerged between the two glaciations. Radioisotopic ages have defined the duration of the Sturtian glaciation to 56 Myr, but the duration of the Marinoan glaciation (4 to 15 Myr) currently has 11 Myr of uncertainty. Here, we show that the Marinoan glaciation in Namibia lasted ca. 4 Myr with less than 10 m of vertical ice grounding line motion through glacial advance-retreat cycles. The stability of a low-latitude ice grounding line is consistent with the strong hysteresis of a hard snowball state. The disparity in durations demonstrates different routes to deglaciation, through slower CO 2 accumulation for the longer Sturtian and radiative perturbation for the Marinoan. The short duration of the Marinoan glaciation may have been essential for the survival and evolution of animals and illustrates an additional path toward habitability on exoplanets.}, archive = {J_PNAS}, author = {Tasistro-Hart, Adrian R. and Macdonald, Francis A. and Crowley, James L. and Schmitz, Mark D.}, doi = {10.1073/pnas.2418281122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2418281122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Four-million-year marinoan snowball shows multiple routes to deglaciation}, volume = {122}, year = {2025}, }
• (2025). Differentiated planetesimals record differing sources of sulfur in inner and outer solar system materials. PNAS, 122(18), e2418198122. (www)

  @article{ , abstract = {The isotope anomalies of noncarbonaceous (NC) and carbonaceous (CC) extraterrestrial materials provide a framework for tracing the distribution and accretion of matter in the early solar system. Here, we extend this framework to sulfur (S)—one of six “life-essential” volatile elements [T C ~ 664 K]—via the mass-independent S-isotope compositions of differentiated meteorites. We observe that on average, NC and CC iron meteorites are characterized by distinct Δ 33 S (Δ 33 S NC = 0.013 ± 0.003‰; Δ 33 S CC = −0.021 ± 0.009‰; 2 SE). The average Δ 36 S of NC and CC irons are less well resolved (Δ 36 S NC = −0.006 ± 0.039‰; Δ 36 S CC = −0.101 ± 0.114‰; 2 SE), but the Δ 36 S values of the CC irons are concentrated in the lower half of the range of those observed for iron meteorites. A lack of CC achondrite S-isotope analyses prevents direct comparison of the Δ 33 S and Δ 36 S of NC and CC achondrites, but the average Δ 33 S and Δ 36 S of NC achondrites (Δ 33 S = 0.02 ± 0.008; Δ 36 S = −0.019 ± 0.064‰; 2 SE) overlap with those of the NC irons. The average Δ 33 S values of NC achondrite groups also correlate with nucleosynthetic anomalies of other elements (e.g., Cr) previously used to define isotopic heterogeneity within the NC reservoir. The position of the Earth in Δ 33 S-Δ 36 S composition space implies that ~24% of terrestrial S derives from CC materials, while the majority (~76%) was delivered by NC materials.}, archive = {J_PNAS}, author = {Heiny, Elizabeth A. and Stolper, Edward M. and Eiler, John M.}, doi = {10.1073/pnas.2418198122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2418198122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Differentiated planetesimals record differing sources of sulfur in inner and outer solar system materials}, volume = {122}, year = {2025}, }
• (2025). Accurate identification and mechanistic evaluation of pathogenic missense variants with rhapsody-2. PNAS, 122(18), e2418100122. (www)

  @article{ , abstract = {Understanding the effects of missense mutations or single amino acid variants (SAVs) on protein function is crucial for elucidating the molecular basis of diseases/disorders and designing rational therapies. We introduce here Rhapsody-2 , a machine learning tool for discriminating pathogenic and neutral SAVs, significantly expanding on a precursor limited by the availability of structural data. With the advent of AlphaFold2 as a powerful tool for structure prediction, Rhapsody-2 is trained on a significantly expanded dataset of 117,525 SAVs corresponding to 12,094 human proteins reported in the ClinVar database. Adopting a broad set of descriptors composed of sequence evolutionary, structural, dynamic, and energetics features in the training algorithm, Rhapsody-2 achieved an AUROC of 0.94 in 10-fold cross-validation when all SAVs of a particular test protein (mutant) were excluded from the training set. Benchmarking against a variety of testing datasets demonstrated the high performance of Rhapsody-2 . While sequence evolutionary descriptors play a dominant role in pathogenicity prediction, those based on structural dynamics provide a mechanistic interpretation. Notably, residues involved in allosteric communication and those distinguished by pronounced fluctuations in the high-frequency modes of motion or subject to spatial constraints in soft modes usually give rise to pathogenicity when mutated. Overall, Rhapsody-2 provides an efficient and transparent tool for accurately predicting the pathogenicity of SAVs and unraveling the mechanistic basis of the observed behavior, thus advancing our understanding of genotype-to-phenotype relations.}, archive = {J_PNAS}, author = {Banerjee, Anupam and Bogetti, Anthony T. and Bahar, Ivet}, doi = {10.1073/pnas.2418100122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2418100122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Accurate identification and mechanistic evaluation of pathogenic missense variants with rhapsody-2}, volume = {122}, year = {2025}, }
• (2025). Bacterial extracellular vesicles target different bacterial species, impairing cell division and diminishing their pathogenicity. PNAS, 122(18), e2416652122. (www)

  @article{ , abstract = {Extracellular vesicles (EVs) produced by bacteria contain many bacterial-derived molecules, which play an important role in host interactions and as mediators of bacterial communication. However, the role of EVs in interspecies interactions and their physiological and ecological significance are not well understood. In this study, we found that Escherichia coli EVs inhibit the growth of group A Streptococcus (GAS; Streptococcus pyogenes ) by inducing defective cell division via the following processes. E. coli EVs first attach to the cell surface of GAS. In EV-attached GAS cells, multiple septa and Z-rings form in close proximity, which clearly differs from the typical cell division process. This is due to inhibition of peptidoglycan (PG) remodeling in the process after septum formation, in which the next cell division is initiated without completion of peripheral PG synthesis. Therefore, cell division proceeds while inducing cell elongation and cell separation failure, leading to growth inhibition. Furthermore, EV alters the expression of approximately 10% of all genes encoded on the GAS genome, and the diverse functions of these gene sets, which include replication, division, and metabolism, suggest that EVs have a variety of biological effects on the targeted bacterial cells. Notably, E. coli EVs significantly decreased the expression of genes involved in representative GAS virulence, such as slo , nga , and hasA , and also markedly attenuated the pathogenicity of GAS in mice. Our findings provide insight into the competitive functions of EVs between different bacterial species, expanding current knowledge on EV-mediated interspecies interactions.}, archive = {J_PNAS}, author = {Kawagishi, Yu and Murase, Kazunori and Grebenshchikova, Anna and Iibushi, Junpei and Ma, Chang and Kimeu, Teresia M. and Minowa-Nozawa, Atsuko and Nozawa, Takashi and Nakagawa, Ichiro}, doi = {10.1073/pnas.2416652122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2416652122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bacterial extracellular vesicles target different bacterial species, impairing cell division and diminishing their pathogenicity}, volume = {122}, year = {2025}, }
• (2025). Integrating single-cell data with biological variables. PNAS, 122(18), e2416516122. (www)

  @article{ , abstract = {Constructing single-cell atlases requires preserving differences attributable to biological variables, such as cell types, tissue origins, and disease states, while eliminating batch effects. However, existing methods are inadequate in explicitly modeling these biological variables. Here, we introduce SIGNAL, a general framework that leverages biological variables to disentangle biological and technical effects, thereby linking these metadata to data integration. SIGNAL employs a variant of principal component analysis to align multiple batches, enabling the integration of 1 million cells in approximately 2 min. SIGNAL, despite its computational simplicity, surpasses state-of-the-art methods across multiple integration scenarios: 1) heterogeneous datasets, 2) cross-species datasets, 3) simulated datasets, 4) integration on low-quality cell annotations, and 5) reference-based integration. Furthermore, we demonstrate that SIGNAL accurately transfers knowledge from reference to query datasets. Notably, we propose a self-adjustment strategy to restore annotated cell labels potentially distorted during integration. Finally, we apply SIGNAL to multiple large-scale atlases, including a human heart cell atlas containing 2.7 million cells, identifying tissue- and developmental stage-specific subtypes, as well as condition-specific cell states. This underscores SIGNAL’s exceptional capability in multiscale analysis.}, archive = {J_PNAS}, author = {Zhou, Yang and Sheng, Qiongyu and Jin, Shuilin}, doi = {10.1073/pnas.2416516122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2416516122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Integrating single-cell data with biological variables}, volume = {122}, year = {2025}, }
• (2025). A twist grain boundary phase in aqueous solutions of the nucleic acid tetramer GTAC. PNAS, 122(18), e2416142122. (www)

  @article{ , abstract = {At high concentration, long Watson/Crick (WC) double-helixed DNA forms columnar crystal or liquid crystal phases of linear, parallel duplex chains packed on periodic lattices. This can also be a structural motif of short NA oligomers such as the 5’-GTAC-3’ studied here, which makes four-base WC duplexes having hydrophobic blunt ends. End-to-end aggregation then assembles these duplexes into columns and columnar phases are stabilized, in spite of breaks in the double helix every four bases. But the new degrees of freedom introduced by such breaks also enable opportunities for a more diverse palette of self-assembly modes, producing striking self-assemblies of DNA that would not be achievable with contiguous polymers. These include recently reported three-dimensional (3D) periodic low-density nanoscale networks of GCCG, and the twist grain boundary (TGB) phase presented here. In the TGB, columns of GTAC pairs assemble into monolayer sheets in which the duplex columns are mutually parallel. However, unlike in the columnar crystals, these sheets stack in helical fashion into lamellar arrays in which the column axis of each layer is rotated through a 60° angle with respect to the columns in neighboring layers. This assembly of DNA is unique in that it the fills a 3D volume wherein the major grooves of columns in each layer mutually enter and interlock with the major grooves of columns in neighboring layers. This locking is optimized by small adjustments in structure enabled by the breaks in the duplex backbones.}, archive = {J_PNAS}, author = {Smith, Gregory P. and Zhu, Chenhui and Zernenkov, Mikail and Frechet, Guillaume and Clark, Noel A.}, doi = {10.1073/pnas.2416142122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2416142122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A twist grain boundary phase in aqueous solutions of the nucleic acid tetramer GTAC}, volume = {122}, year = {2025}, }
• (2025). Massive mutagenesis reveals an incomplete amyloid motif in bri2 that turns amyloidogenic upon C-terminal extension. PNAS, 122(18), e2415521122. (www)

  @article{ , abstract = {Stop-loss mutations cause over twenty different diseases. The effects of stop-loss mutations can have multiple consequences that are, however, hard to predict. Stop-loss in ITM2B/BRI2 results in C-terminal extension of the encoded protein and, upon furin cleavage, in the production of two 34 amino acid long peptides, ADan and ABri, that accumulate as amyloids in the brains of patients affected by familial Danish and British Dementia. To systematically explore the consequences of Bri2 C-terminal extension, here, we use a yeast-based massively parallel assay to measure amyloid formation for 676 ADan substitutions and identify the region that forms the putative amyloid core of ADan fibrils, located between positions 20 and 26, where stop-loss occurs. Moreover, we measure amyloid formation for ~18,000 random C-terminal extensions of Bri2 and find that ~32% of these sequences can nucleate amyloids. We find that the amino acid composition of these nucleating sequences varies with peptide length and that short extensions of two specific amino acids (Aliphatics, Aromatics, and Cysteines) are sufficient to generate de novo amyloid cores. Overall, our results show that the C-terminus of Bri2 contains an incomplete amyloid motif that can turn amyloidogenic upon extension. C-terminal extension with de novo formation of amyloid motifs may thus be a widespread pathogenic mechanism resulting from stop-loss, highlighting the importance of determining the impact of these mutations for other sequences across the genome.}, archive = {J_PNAS}, author = {Martín, Mariano and Bolognesi, Benedetta}, doi = {10.1073/pnas.2415521122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2415521122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Massive mutagenesis reveals an incomplete amyloid motif in bri2 that turns amyloidogenic upon C-terminal extension}, volume = {122}, year = {2025}, }
• (2025). Challenges to sustainable large-scale shale gas development in china. PNAS, 122(18), e2415192122. (www)

  @article{ , abstract = {China’s shale gas production has grown annually by 21% since 2017 with long-term national energy strategy calling for continued expansion. This large-scale shale gas development is challenged by constraints on water supply. It requires over 6,000 new wells to be drilled within the Yangtze River Basin in South China—one of China’s most populated regions with sensitive ecological and geological conditions, posing significant environmental threats to the hydrosphere, atmosphere, and biosphere. Hydraulic fracturing-induced seismicity also adds to the existing earthquake risk for the Sichuan/Chongqing region. These potential negative impacts challenge both China’s and the United Nations’ sustainable development goals. We explore China’s current shale gas operations in the Yangtze River Basin and their interaction with the environment from these multiple perspectives. We then suggest future improvements to practice that will promote sustainable development to jointly satisfy China’s burgeoning energy needs. We conclude that China’s shale gas industry would benefit from an innovation ecosystem that involves companies and research institutions, and that there is an urgent need to implement environmental regulations for shale gas extraction.}, archive = {J_PNAS}, author = {Wu, Jian and Tan, Jingqiang and Xu, Jinqi and Li, Lei and Beroza, Gregory C. and Mumford, Kevin G. and Van De Ven, Cole and Chen, Baixi and Elsworth, Derek}, doi = {10.1073/pnas.2415192122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2415192122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Challenges to sustainable large-scale shale gas development in china}, volume = {122}, year = {2025}, }
• (2025). Using pledges to improve the effectiveness of environmental information campaigns: The case of biowaste recycling. PNAS, 122(18), e2414578122. (www)

  @article{ , abstract = {Through a field study (N = 1,519) that uses a technology to record real-time data on waste sorting, we find that offering the opportunity to sign a pledge increases the effectiveness of an environmental campaign. With a timespan of over four years, the pledge increased waste sorting participation by 4.55 to 5.10 percentage points (SD = 0.1997). The effect is greater immediately after the campaign (around 9 to 10 pp during the first 15 wk), but it remains sizable and statistically significant 150 to 210 wk after signing (3.11 to 4.45 pp).}, archive = {J_PNAS}, author = {Alonso-Paulí, Eduard and Balart, Pau and Ezquerra, Lara and Hernandez-Arenaz, Iñigo}, doi = {10.1073/pnas.2414578122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2414578122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Using pledges to improve the effectiveness of environmental information campaigns: The case of biowaste recycling}, volume = {122}, year = {2025}, }
• (2025). Decreased likelihood of schooling as a consequence of tropical cyclones: Evidence from 13 low- and middle-income countries. PNAS, 122(18), e2413962122. (www)

  @article{ , abstract = {Increasing educational attainment is one of the most important and effective strategies for health and economic improvements. The extent to which extreme climate events disrupt education, resulting in reduced educational attainment, remains understudied. Children in low- and middle-income countries (LMICs) may be uniquely vulnerable to losing schooling after disasters due to the poor physical condition of schools and the lack of resources to mitigate unexpected household shocks. Our analysis assesses this overlooked social cost of tropical cyclones on schooling attainment. We study the education records of nearly 5.4 million individuals living in 13 LMICs that experienced tropical cyclones between 1954 and 2010. By comparing individuals living in the same locations but with different exposure levels, we estimate the change in the likelihood that a preschool-age child exposed to tropical cyclone received no schooling. We find that exposure during preschool age is associated with a 0.5 percentage point increase in the likelihood of never attending schooling (2.5% above baseline), with larger effects (up to 8.8% increase) from stronger storms. These effects are more pronounced among girls and are greater in areas less adapted to tropical cyclones. Between 2000 and 2020, we estimate that 79,000 children in the 13 study countries did not start school due to tropical cyclones, and, across all affected students, tropical cyclones resulted in a total loss of 1.1 My of school. These impacts, identified among some of the world’s poorest populations, may grow in importance as exposure to severe tropical cyclones is projected to increase with climate change.}, archive = {J_PNAS}, author = {Jing, Renzhi and Heft-Neal, Sam and Wang, Zetianyu and Chen, Jie and Qiu, Minghao and Opper, Isaac M. and Wagner, Zachary and Bendavid, Eran}, doi = {10.1073/pnas.2413962122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2413962122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Decreased likelihood of schooling as a consequence of tropical cyclones: Evidence from 13 low- and middle-income countries}, volume = {122}, year = {2025}, }
• (2025). Copy-cat evolution: Divergence and convergence within and between cat and dog breeds. PNAS, 122(18), e2413780122. (www)

  @article{ , abstract = {Many domesticated species exhibit remarkable phenotypic diversity. In nature, selection produces not only divergence but also convergence when organisms experience similar selective pressures. Whether artificial selection during domestication also produces convergence has received little attention. Three-dimensional shape analysis of domestic cat and dog skulls demonstrated convergence at multiple levels. Most broadly, cats and dogs have both diversified greatly: equaling or exceeding the morphological disparity among all modern-day species of their respective families. Moreover, as a result of artificial selection, some breeds of these two phenotypically distinct species, evolutionarily separated for 50 My, have converged to such an extreme extent that they are more similar to each other than they are to many members of their own species or their ancestors, a phenomenon never previously observed in domesticated species. Remarkably, this convergence evolved not only between dogs and cats but also multiple times within each taxon.}, archive = {J_PNAS}, author = {Drake, Abby Grace and Revell, Liam J. and Klingenberg, Christian Peter and Lattimer, Jimmy C. and Nelson, Nathan C. and Schmidt, Martin J. and Zwingenberger, Allison L. and Moyer, Joshua K. and Losos, Jonathan B.}, doi = {10.1073/pnas.2413780122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2413780122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Copy-cat evolution: Divergence and convergence within and between cat and dog breeds}, volume = {122}, year = {2025}, }
• (2025). Testing theories of political persuasion using AI. PNAS, 122(18), e2412815122. (www)

  @article{ , abstract = {Despite its importance to society and many decades of research, key questions about the social and psychological processes of political persuasion remain unanswered, often due to data limitations. We propose that AI tools, specifically generative large language models (LLMs), can be used to address these limitations, offering important advantages in the study of political persuasion. In two preregistered online survey experiments, we demonstrate the potential of generative AI as a tool to study persuasion and provide important insights about the psychological and communicative processes that lead to increased persuasion. Specifically, we test the effects of four AI-generated counterattitudinal persuasive strategies, designed to test the effectiveness of messages that include customization (writing messages based on a receiver’s personal traits and beliefs), and elaboration (increased psychological engagement with the argument through interaction). We find that all four types of persuasive AI produce significant attitude change relative to the control and shift vote support for candidates espousing views consistent with the treatments. However, we do not find evidence that message customization via microtargeting or cognitive elaboration through interaction with the AI have much more persuasive effect than a single generic message. These findings have implications for different theories of persuasion, which we discuss. Finally, we find that although persuasive messages are able to moderate some people’s attitudes, they have inconsistent and weaker effects on the democratic reciprocity people grant to their political opponents. This suggests that attitude moderation (ideological depolarization) does not necessarily lead to increased democratic tolerance or decreased affective polarization.}, archive = {J_PNAS}, author = {Argyle, Lisa P. and Busby, Ethan C. and Gubler, Joshua R. and Lyman, Alex and Olcott, Justin and Pond, Jackson and Wingate, David}, doi = {10.1073/pnas.2412815122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2412815122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Testing theories of political persuasion using AI}, volume = {122}, year = {2025}, }
• (2025). A hierarchy of processing complexity and timescales for natural sounds in the human auditory cortex. PNAS, 122(18), e2412243122. (www)

  @article{ , abstract = {Efficient behavior is supported by humans’ ability to rapidly recognize acoustically distinct sounds as members of a common category. Within the auditory cortex, critical unanswered questions remain regarding the organization and dynamics of sound categorization. We performed intracerebral recordings during epilepsy surgery evaluation as 20 patient-participants listened to natural sounds. We then built encoding models to predict neural responses using sound representations extracted from different layers within a deep neural network (DNN) pretrained to categorize sounds from acoustics. This approach yielded accurate models of neural responses throughout the auditory cortex. The complexity of a cortical site’s representation (measured by the depth of the DNN layer that produced the best model) was closely related to its anatomical location, with shallow, middle, and deep layers associated with core (primary auditory cortex), lateral belt, and parabelt regions, respectively. Smoothly varying gradients of representational complexity existed within these regions, with complexity increasing along a posteromedial-to-anterolateral direction in core and lateral belt and along posterior-to-anterior and dorsal-to-ventral dimensions in parabelt. We then characterized the time (relative to sound onset) when feature representations emerged; this measure of temporal dynamics increased across the auditory hierarchy. Finally, we found separable effects of region and temporal dynamics on representational complexity: sites that took longer to begin encoding stimulus features had higher representational complexity independent of region, and downstream regions encoded more complex features independent of temporal dynamics. These findings suggest that hierarchies of timescales and complexity represent a functional organizational principle of the auditory stream underlying our ability to rapidly categorize sounds.}, archive = {J_PNAS}, author = {Rupp, Kyle M. and Hect, Jasmine L. and Harford, Emily E. and Holt, Lori L. and Ghuman, Avniel Singh and Abel, Taylor J.}, doi = {10.1073/pnas.2412243122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2412243122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A hierarchy of processing complexity and timescales for natural sounds in the human auditory cortex}, volume = {122}, year = {2025}, }
• (2025). Gag proteins encoded by endogenous retroviruses are required for zebrafish development. PNAS, 122(18), e2411446122. (www)

  @article{ , abstract = {Transposable elements (TEs) make up the bulk of eukaryotic genomes and examples abound of TE-derived sequences repurposed for organismal function. The process by which TEs become coopted remains obscure because most cases involve ancient, transpositionally inactive elements. Reports of active TEs serving beneficial functions are scarce and often contentious due to difficulties in manipulating repetitive sequences. Here, we show that recently active TEs in zebrafish encode products critical for embryonic development. Knockdown and rescue experiments demonstrate that the endogenous retrovirus family BHIKHARI-1 (Bik-1) encodes a Gag protein essential for mesoderm development. Mechanistically, Bik-1 Gag associates with the cell membrane, and its ectopic expression in chicken embryos alters cell migration. Similarly, depletion of BHIKHARI-2 Gag, a relative of Bik-1, causes defects in neural crest development in zebrafish. We propose an “addiction” model to explain how active TEs can be integrated into conserved developmental processes.}, archive = {J_PNAS}, author = {Chang, Ni-Chen and Wells, Jonathan N. and Wang, Andrew Y. and Schofield, Phillip and Huang, Yi-Chia and Truong, Vinh H. and Simoes-Costa, Marcos and Feschotte, Cédric}, doi = {10.1073/pnas.2411446122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2411446122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Gag proteins encoded by endogenous retroviruses are required for zebrafish development}, volume = {122}, year = {2025}, }
• (2025). Genomic analysis of progenitors in viral infection implicates glucocorticoids as suppressors of plasmacytoid dendritic cell generation. PNAS, 122(18), e2410092122. (www)

  @article{ , abstract = {Plasmacytoid Dendritic cells (pDCs) are the most potent producers of interferons, which are critical antiviral cytokines. pDC development is, however, compromised following a viral infection, and this phenomenon, as well as its relationship to conventional (c)DC development is still incompletely understood. By using lymphocytic choriomeningitis virus (LCMV) infection in mice as a model system, we observed that DC progenitors skewed away from pDC and toward cDC development during in vivo viral infection. Subsequent characterization of the transcriptional and epigenetic landscape of fms-like tyrosine kinase 3 + (Flt3 + ) DC progenitors and follow-up studies revealed increased apoptosis and reduced proliferation in different individual DC-progenitors as well as a profound type I interferon (IFN-I)-dependent ablation of pre-pDCs, but not pre-DC precursors, after both acute and chronic LCMV infections. In addition, integrated genomic analysis identified altered activity of 34 transcription factors in Flt3 + DC progenitors from infected mice, including two regulators of Glucocorticoid (GC) responses. Subsequent studies demonstrated that addition of GCs to DC progenitors led to downregulated pDC-primed-genes while upregulating cDC-primed-genes, and that endogenous GCs selectively decreased pDC, but not cDC, numbers upon in vivo LCMV infection. These findings demonstrate a significant ablation of pre-pDCs in infected mice and identify GCs as suppressors of pDC generation from early progenitors. This provides a potential explanation for the impaired pDC development following viral infection and links pDC numbers to the hypothalamic–pituitary–adrenal axis.}, archive = {J_PNAS}, author = {Jo, Yeara and Greene, Trever T. and Chiale, Carolina and Zhang, Kai and Fang, Ziyan and Dallari, Simone and Marooki, Nuha and Wang, Wei and Zuniga, Elina I.}, doi = {10.1073/pnas.2410092122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2410092122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genomic analysis of progenitors in viral infection implicates glucocorticoids as suppressors of plasmacytoid dendritic cell generation}, volume = {122}, year = {2025}, }
• (2025). Psychological reactance to system-level policies before and after their implementation. PNAS, 122(18), e2409907122. (www)

  @article{ , abstract = {Governments need to develop and implement effective policies to address pressing societal problems of our time, such as climate change and global pandemics. While some policies focus on changing individual thoughts and behaviors (e.g., informational interventions, behavioral nudges), others involve systemic changes (e.g., car bans, vaccination mandates). Policymakers may use system-level policies to achieve socially desirable outcomes, yet often refrain from doing so because they anticipate public opposition. In this article, we propose that people’s psychological reactance driving this opposition is a transient phenomenon that dissipates once system-level policies are in place. Using secondary survey data ( N = 49,674) and experimental data (six studies; N = 4,629; all preregistered), we document that psychological reactance to system-level policies is greater when they are planned (ex ante implementation) than when they are already implemented (ex post implementation). We further demonstrate that this effect can be observed across various intervention contexts and provide insights into its underlying psychological mechanisms. Specifically, ex ante vs. ex post the system-level policy’s implementation, individuals focus more on the transition-induced personal losses than on the prospective societal outcome gains. In line with this perspective, we show that the decline in reactance to system-level policies after their implementation is mediated and moderated by the salience of personal losses, and that the initial reactance to such policies is mitigated by the salience of societal gains. These findings suggest that the public’s negative reactions to system-level policies are more transient than previously thought and can help policymakers design effective interventions.}, archive = {J_PNAS}, author = {Granulo, Armin and Fuchs, Christoph and Böhm, Robert}, doi = {10.1073/pnas.2409907122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2409907122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Psychological reactance to system-level policies before and after their implementation}, volume = {122}, year = {2025}, }
• (2025). Sexism in teams: Exposure to sexist comments increases emotional synchrony but eliminates its benefits for team performance. PNAS, 122(18), e2409708122. (www)

  @article{ , abstract = {In a world where teams serve as the backbone of collaboration and innovation, women must feel safe when contributing to teamwork. Unfortunately, an increasing number of women report experiencing sexual harassment in workplaces and other collective settings. This research included an examination of how exposure to sexist insults affects collaborative efforts. We argue that in addition to its well-documented effects on individuals, sexism within teams undermines team performance. Hence, emotional synchrony—temporally coordinated emotional facial expressions between individuals—loses its ability to enhance collaboration when team members are exposed to sexism. Under the threat of sexist comments, emotional synchrony signals social bonding rather than focusing team members on performance goals. To test this theory, 177 woman dyads interacting on a video-conferencing platform received instructions for a cooperative task with/without sexist comments from an actor-experimenter in sexism/control conditions. Emotional synchrony was assessed through temporal alignment in facial expressions between dyad members and was correlated with team performance. Our findings revealed a significant increase in facial expressive synchrony among teams in the sexism condition. Whereas facial expressive synchrony predicted better performance in the control condition, its classic positive effects on team performance vanished under sexism. These results suggest that exposure to sexism, while enhancing social cohesion, eliminates the benefits of emotional synchrony, which is considered the social glue of collective action. These findings suggest that zero-tolerance policies for sexual harassment are not only more ethical but can also promote effective teamwork.}, archive = {J_PNAS}, author = {Burns, Alon and Toker, Sharon and Berson, Yair and Gordon, Ilanit}, doi = {10.1073/pnas.2409708122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2409708122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sexism in teams: Exposure to sexist comments increases emotional synchrony but eliminates its benefits for team performance}, volume = {122}, year = {2025}, }
• (2025). A complete and dynamic tree of birds. PNAS, 122(18), e2409658122. (www)

  @article{ , abstract = {We present a complete, time-scaled, evolutionary tree of the world’s bird species. This tree unites phylogenetic estimates for 9,239 species from 262 studies published between 1990 and 2024, using the Open Tree synthesis algorithm. The remaining species are placed in the tree based on curated taxonomic information. The tips of this complete tree are aligned to the species in the Clements Taxonomy used by eBird and other resources, and cross-mapped to other taxonomic systems including the Open Tree of Life (Open Tree), National Center for Biotechnology Information, and Global Biodiversity Information Facility. The total number of named bird species varies between 10,824 and 11,017 across the taxonomy versions we applied (v2021, v2022, and v2023). We share complete trees for each taxonomy version. The procedure, software, and data stores we used to generate this tree are public and reproducible. The tree presented here is Aves 1.3 and can be easily updated with new phylogenetic information as new estimates are published. We demonstrate the types of large-scale analyses this data resource enables by linking geographic data with the phylogeny to calculate the regional phylogenetic diversity of birds across the world. We will release updated versions of the phylogenetic synthesis and taxonomic translation tables annually. The procedure we describe here can be applied to developing complete phylogenetic estimates for any taxonomic group of interest.}, archive = {J_PNAS}, author = {McTavish, Emily Jane and Gerbracht, Jeff A. and Holder, Mark T. and Iliff, Marshall J. and Lepage, Denis and Rasmussen, Pamela C. and Redelings, Benjamin D. and Sánchez Reyes, Luna L. and Miller, Eliot T.}, doi = {10.1073/pnas.2409658122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2409658122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A complete and dynamic tree of birds}, volume = {122}, year = {2025}, }
• (2025). Measuring global migration flows using online data. PNAS, 122(18), e2409418122. (www)

  @article{ , abstract = {Existing estimates of human migration are limited in their scope, reliability, and timeliness, prompting the United Nations and the Global Compact on Migration to call for improved data collection. Using privacy protected records from three billion Facebook users, we estimate country-to-country migration flows at monthly granularity for 181 countries, accounting for selection into Facebook usage. Our estimates closely match high-quality measures of migration where available but can be produced nearly worldwide and with less delay than alternative methods. We estimate that 39.1 million people migrated internationally in 2022 (0.63% of the population of the countries in our sample). Migration flows significantly changed during the COVID-19 pandemic, decreasing by 64% before rebounding in 2022 to a pace 24% above the precrisis rate. We also find that migration from Ukraine increased tenfold in the wake of the Russian invasion. To support research and policy interventions, we release these estimates publicly through the Humanitarian Data Exchange.}, archive = {J_PNAS}, author = {Chi, Guanghua and Abel, Guy J. and Johnston, Drew and Giraudy, Eugenia and Bailey, Mike}, doi = {10.1073/pnas.2409418122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2409418122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Measuring global migration flows using online data}, volume = {122}, year = {2025}, }
• (2025). Unbalanced social–ecological acceleration led to state formation failure in early medieval poland. PNAS, 122(18), e2409056122. (www)

  @article{ , abstract = {Rapid social–ecological intensification is a recurrent feature of human history. It occurred in different forms and contexts; its outcomes may have been sustainable or transient. Until recently, such intensifications usually accompanied state formation: Consolidation of political power was often coupled with exponential increase in human exploitation of the environment of a given area. Here, we study one such case, uniquely well-documented through our rich paleoecological, archaeological, numismatic, and literary data. Triggered by the Eurasian slave trade, the first “Polish” polity was founded in Central Europe c. 900 common era. It undertook unprecedented ecological intensification in its core territory, connected with large construction projects, and engaged in rapid territorial expansion. We provide new crucial evidence on this process by publishing here a high-resolution pollen profile from a location close to the polity’s capital and by an application of social network analysis to numismatic data. This state collapsed within a few generations after its foundation. The collapse of the political elites, however, did not produce a complete social and ecological disintegration of the polity’s former core region. We thus show how collapse and continuity can remain closely intertwined. Last but not least, the rich evidence on the mechanism of the collapse reveals that successful maintenance of social–ecological intensification requires reliance on a number of cultural, economic, religious, and social networks underlying the political expansion. The polity’s elite lacked access to or failed to mobilize such networks, which led to its demise.}, archive = {J_PNAS}, author = {Izdebski, Adam and Czerwiński, Sambor and Jankowiak, Marek and Danielewski, Marcin and Fiołna, Sabina and Gromig, Raphael and Guzowski, Piotr and Haghipour, Negar and Hajdas, Irka and Kołaczek, Piotr and Lamentowicz, Mariusz and Marcisz, Katarzyna and Niebieszczański, Jakub and Sankiewicz, Paweł and Wagner, Bernd}, doi = {10.1073/pnas.2409056122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2409056122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unbalanced social–ecological acceleration led to state formation failure in early medieval poland}, volume = {122}, year = {2025}, }
• (2025). Divergence in children’s gender stereotypes and motivation across STEM fields. PNAS, 122(18), e2408657122. (www)

  @article{ , abstract = {STEM disciplines are traditionally stereotyped as being for men and boys. However, in two preregistered studies of Grades 1 to 12 students in the United States ( N = 2,765), we find a significant divergence in students’ gender stereotypes about different STEM fields. Gender stereotypes about computer science and engineering more strongly favored boys than did gender stereotypes about math and science. These patterns hold across genders, intersections of gender and race/ethnicity, and two geographical regions. This divergence between different STEM fields was evident, although smaller, for children in elementary school compared to adolescents (students in middle school and high school). The divergence in stereotypes predicted students’ divergence in motivation for entering these fields. Gender stereotypes on average slightly favored girls in math and were egalitarian or slightly favored girls in science, while boys remained strongly favored for computer science and engineering, with implications for educational equity and targeted interventions.}, archive = {J_PNAS}, author = {Master, Allison and Meltzoff, Andrew N. and Tang, Daijiazi and Cheryan, Sapna}, doi = {10.1073/pnas.2408657122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2408657122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Divergence in children’s gender stereotypes and motivation across STEM fields}, volume = {122}, year = {2025}, }
• (2025). Exposure and health risks of livestock air resistomes. PNAS, 122(18), e2403866122. (www)

  @article{ , abstract = {Most of the global antibiotic consumption is by the livestock industry, making livestock farms a hotspot of antibiotic resistance genes (ARGs). Farm air poses direct ARG exposure to workers, but the health risks of air resistomes remain unclear. We evaluated the human exposure and health risks of air resistomes in pig and chicken farms and compared air resistomes in Chinese farms to those in European farms given their long-term restrictions on use of antibiotics in livestock. We found that livestock air was highly enriched in ARGs, with each cell harboring seven times more ARGs than urban air. The daily ARG inhalation of farm workers was equivalent to several years of ARG inhalation by urban residents. ARGs encoding resistance to last-resort antibiotics such as mcr-1 and tetX were detected in farm air, and tetX variants were prevalent in both Chinese and European farms. ARGs in livestock air were highly associated with mobile genetic elements, and conjugation experiments confirmed their cross-phyla transferability. The projected resistome risk of farm air was significantly higher than well-recognized ARG hotspots like air from hospitals, sewage treatment plants, and from animal manures. The diversity, abundance, and risk score of air resistomes in Chinese farms were significantly higher than those in European farms, suggesting that long-term restriction of antibiotic use mitigates antibiotic resistance in the livestock environment. Our results underscore the high exposure of farm workers to ARGs via farm air and highlight its role in ARG dissemination, supporting the importance of antibiotic stewardship practices in combating antibiotic resistance.}, archive = {J_PNAS}, author = {Sun, Wei and Wang, Jun and Wang, Guangdong and Jiang, Lan and Feng, Wenlu and Dang, Shuangsuo and Li, Mei and Jiao, Shuo and Wei, Gehong and Gu, Jie and Tiedje, James M. and Qian, Xun}, doi = {10.1073/pnas.2403866122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2403866122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exposure and health risks of livestock air resistomes}, volume = {122}, year = {2025}, }
• (2025). NEUROD1 efficiently converts peripheral blood cells into neurons with partial reprogramming by pluripotency factors. PNAS, 122(18), e2401387122. (www)

  @article{ , abstract = {The direct reprogramming of cells has tremendous potential in in vitro neurological studies. Previous attempts to convert blood cells into induced neurons have presented several challenges, necessitating a less invasive, efficient, rapid, and convenient approach. The current study introduces an optimized method for converting somatic cells into neurons using a nonsurgical approach that employs peripheral blood cells as an alternative source to fibroblasts. We have demonstrated the efficacy of a unique combination of transcription factors, including NEUROD1, and four Yamanaka reprogramming factors (OCT3/4, SOX2, KLF4, and c-MYC), in generating glutamatergic neurons within 3 wk. This approach, which requires only five pivotal factors (NEUROD1, OCT3/4, SOX2, KLF4, and c-MYC), has the potential to create functional neurons and circumvents the need for induced pluripotent stem cell (iPSC) intermediates, as evidenced by single-cell RNA sequencing and whole-genome bisulfite sequencing, along with lineage-tracing experiments using Cre-LoxP system. While fibroblasts have been widely used for neuronal reprogramming, our findings suggest that peripheral blood cells offer a potential alternative, particularly in contexts where minimally invasive sampling and procedures convenient for patients are emphasized. This method provides a rapid strategy for modeling neuronal diseases and contributes to advancements in drug discovery and personalized medicine.}, archive = {J_PNAS}, author = {Saito, Yoichi and Ishikawa, Mitsuru and Ohkuma, Mahito and Moody, Jonathan and Mabuchi, Yo and Sanosaka, Tsukasa and Ando, Yoshinari and Yamashita, Takayuki and Hon, Chung Chau and Shin, Jay W. and Akamatsu, Wado and Okano, Hideyuki}, doi = {10.1073/pnas.2401387122}, journal = {Proceedings of the National Academy of Sciences}, month = {5}, number = {18}, pages = {e2401387122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {NEUROD1 efficiently converts peripheral blood cells into neurons with partial reprogramming by pluripotency factors}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(17), eiti1725122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti1725122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {eiti1725122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Correction for mukhi et al., perception of structurally distinct effectors by the integrated WRKY domain of a plant immune receptor. PNAS, 122(17), e2508043122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2508043122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2508043122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for mukhi et al., perception of structurally distinct effectors by the integrated WRKY domain of a plant immune receptor}, volume = {122}, year = {2025}, }
• (2025). Correction for piacentino et al., temporal changes in plasma membrane lipid content induce endocytosis to regulate developmental epithelial-to-mesenchymal transition. PNAS, 122(17), e2507940122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2507940122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2507940122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for piacentino et al., temporal changes in plasma membrane lipid content induce endocytosis to regulate developmental epithelial-to-mesenchymal transition}, volume = {122}, year = {2025}, }
• (2025). Correction for zhou et al., tRNA selectivity during ribosome-associated quality control regulates the critical sterility-inducing temperature in two-line hybrid rice. PNAS, 122(17), e2507697122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2507697122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2507697122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for zhou et al., tRNA selectivity during ribosome-associated quality control regulates the critical sterility-inducing temperature in two-line hybrid rice}, volume = {122}, year = {2025}, }
• (2025). Correction for wang et al., unusual magnetotransport in twisted bilayer graphene from strain-induced open fermi surfaces. PNAS, 122(17), e2507349122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2507349122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2507349122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for wang et al., unusual magnetotransport in twisted bilayer graphene from strain-induced open fermi surfaces}, volume = {122}, year = {2025}, }
• (2025). An algorithmic constraint at the transition to complex life. PNAS, 122(17), e2505484122. (www)

  @article{ , archive = {J_PNAS}, author = {Ferrada, Evandro}, doi = {10.1073/pnas.2505484122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2505484122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An algorithmic constraint at the transition to complex life}, volume = {122}, year = {2025}, }
• (2025). Start your engines: How migratory fibroblasts respond to and remember mechanical stretch. PNAS, 122(17), e2504936122. (www)

  @article{ , archive = {J_PNAS}, author = {Weihs, Daphne}, doi = {10.1073/pnas.2504936122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2504936122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Start your engines: How migratory fibroblasts respond to and remember mechanical stretch}, volume = {122}, year = {2025}, }
• (2025). The ins and outs of plant specialized metabolite gene organization. PNAS, 122(17), e2504934122. (www)

  @article{ , archive = {J_PNAS}, author = {Dixon, Richard A.}, doi = {10.1073/pnas.2504934122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2504934122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The ins and outs of plant specialized metabolite gene organization}, volume = {122}, year = {2025}, }
• (2025). PEARLs of wisdom for ribosome-independent peptide bond synthesis. PNAS, 122(17), e2504930122. (www)

  @article{ , archive = {J_PNAS}, author = {Weeks, Amy M.}, doi = {10.1073/pnas.2504930122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2504930122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PEARLs of wisdom for ribosome-independent peptide bond synthesis}, volume = {122}, year = {2025}, }
• (2025). Elevated UDP-glucuronic acid levels mend drug resistance and stress responses via a protease and a transporter in cryptococcus gattii. PNAS, 122(17), e2503960122. (www)

  @article{ , abstract = {UDP-glucuronic acid (UDP-GlcUA) is a nucleotide sugar essential for various biological processes in many organisms, and its excess within the cell can disrupt cellular functions. In Cryptococcus , mutations in the UXS1 gene which encodes an enzyme responsible for converting UDP-GlcUA into UDP-xylose, result in excessive accumulation of UDP-GlcUA and confer resistance to the antifungal drug 5-fluorocytosine. Here, we demonstrate that elevation of UDP-GlcUA affects several cellular processes in Cryptococcus gattii , including growth rate, ability to grow under various stress conditions and resistance to fluorinated pyrimidine analogs. RNA-seq analyses of the uxs1Δ mutant identify three acid protease genes, notably PEP401 , that are differentially expressed. The absence of PEP401 in the uxs1Δ background significantly reduces UDP-GlcUA levels and reverts all the phenotypes of the uxs1Δ mutant to the wild-type characteristics. High levels of UDP-GlcUA not only regulate expression of PEP401 at RNA and protein levels but also enhance the proteolytic activity of total protein extracts in a PEP401 -dependent manner, establishing a functional link between nucleotide sugar metabolism and proteolytic regulation. Moreover, the UDP-GlcUA transporter gene, UUT1 , can further modulate the levels of UDP-GlcUA in the uxs1Δ pep401Δ double mutant and manifests drug resistance phenotypes observed in the uxs1Δ mutant. Collectively, these findings reveal a previously unrecognized regulatory network that links UDP-GlcUA metabolism to protease-mediated cellular processes and the transport of UDP-GlcUA. This interaction provides a foundation for targeting nucleotide sugar metabolism and protease regulation in the development of enhanced therapeutic strategies against cryptococcosis.}, archive = {J_PNAS}, author = {Pharkjaksu, Sujiraphong and Cai, Hongyi and Walter, Peter J. and Chang, Yun C. and Kwon-Chung, Kyung J.}, doi = {10.1073/pnas.2503960122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2503960122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Elevated UDP-glucuronic acid levels mend drug resistance and stress responses via a protease and a transporter in cryptococcus gattii}, volume = {122}, year = {2025}, }
• (2025). A simple method for mapping the location of cross-β-forming regions within protein domains of low sequence complexity. PNAS, 122(17), e2503382122. (www)

  @article{ , abstract = {Protein domains of low sequence complexity are unable to fold into stable, three-dimensional structures. In test tube studies, these unusual polypeptide regions can self-associate in a manner causing phase separation from aqueous solution. This form of protein:protein interaction has been implicated in numerous examples of dynamic morphological organization within eukaryotic cells. In several cases, the basis for low complexity domain (LCD) self-association and phase separation has been traced to the formation of labile cross-β structures. The primary energetic force favoring formation of these transient and reversible structures is enabled by polypeptide backbone interactions. Short, contiguous networks of peptide backbone amino groups and carbonyl oxygens are zippered together intermolecularly by hydrogen bonding as described by Linus Pauling seven decades ago. Here, we describe a simple, molecular biological method useful for the identification of localized, self-associating regions within larger protein domains of low sequence complexity.}, archive = {J_PNAS}, author = {Gu, Jinge and Zhou, Xiaoming and Sutherland, Lillian and Liszczak, Glen and McKnight, Steven L.}, doi = {10.1073/pnas.2503382122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2503382122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A simple method for mapping the location of cross-β-forming regions within protein domains of low sequence complexity}, volume = {122}, year = {2025}, }
• (2025). Phase transitions and dimensional cross-over in layered confined solids. PNAS, 122(17), e2502980122. (www)

  @article{ , abstract = {The nature of solid phases and cross-over of order–disorder phase transitions from two-dimensional (2D) layers to three-dimensional (3D) bulk in confined atomic systems remain largely unexplained. To this end, we consider noble gases and aluminum confined between graphene sheets at different pressures and temperatures. Using crystal structure search methods and molecular dynamics based on machine-learned potentials with quantum-mechanical accuracy, we identify structures of multilayer confined solids that deviate from simple close packing. Upon heating, we find that confined 2D monolayers melt according to the two-step continuous Kosterlitz–Thouless–Halperin–Nelson–Young theory. However, multilayer solids transition continuously into an intermediate layered-hexatic phase before melting discontinuously into an isotropic liquid. This intermediate phase persists at least up to 12 layers studied here. This change can be qualitatively understood based on the cross-over from 2D topological defects toward 3D ones during melting as the number of layers increases.}, archive = {J_PNAS}, author = {Wang, Yong and Wang, Junjie and Yao, Ge and Fan, Zheyong and Granato, Enzo and Kosterlitz, Michael and Ala-Nissila, Tapio and Car, Roberto and Sun, Jian}, doi = {10.1073/pnas.2502980122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2502980122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phase transitions and dimensional cross-over in layered confined solids}, volume = {122}, year = {2025}, }
• (2025). Rab32 regulates golgi structure and cell migration through protein kinase a–mediated phosphorylation of optineurin. PNAS, 122(17), e2502971122. (www)

  @article{ , abstract = {Rab32 is a small GTPase and molecular switch implicated in vesicular trafficking. Rab32 is also an A-Kinase Anchoring Protein (AKAP), which anchors cAMP-dependent Protein Kinase (PKA) to specific subcellular locations and specifies PKA phosphorylation of nearby substrates. Surprisingly, we found that a form of Rab32 deficient in PKA binding (Rab32 L188P) relocalized away from the Golgi apparatus and induced a marked disruption in Golgi organization, assembly, and dynamics. Although Rab32 L188P did not cause a global defect in PKA activity, our data indicate that Rab32 facilitates the phosphorylation of a specific PKA substrate. We uncovered a direct interaction between Rab32 and the adaptor protein optineurin (OPTN), which regulates Golgi dynamics. Further, our data indicate that optineurin is phosphorylated by PKA at Ser342 in a Rab32-dependent manner. Critically, blocking phosphorylation at OPTN Ser342 leads to Golgi fragmentation, and a phospho-mimetic version of OPTN rescues Golgi defects induced by Rab32 L188P. Finally, Rab32 AKAP function and OPTN phosphorylation are required for Golgi repositioning during cell migration, contributing to tumor cell invasion. Together, these data reveal a role for Rab32 in regulating Golgi dynamics through PKA-mediated phosphorylation of OPTN.}, archive = {J_PNAS}, author = {Johnson, Katherine M. and Marley, Maxwell G. and Drizyte-Miller, Kristina and Chen, Jing and Cao, Hong and Mostafa, Nourhan and Schott, Micah B. and McNiven, Mark A. and Razidlo, Gina L.}, doi = {10.1073/pnas.2502971122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2502971122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rab32 regulates golgi structure and cell migration through protein kinase a–mediated phosphorylation of optineurin}, volume = {122}, year = {2025}, }
• (2025). Bounded dissipation law and profiles of turbulent velocity moments in wall flows. PNAS, 122(17), e2502265122. (www)

  @article{ , abstract = {Understanding the effects of solid boundaries on turbulent fluctuations remains a long-standing challenge. Available data on mean-square fluctuations in these flows show apparent contradiction with classical scaling. We had earlier proposed an alternative model based on the principle of bounded dissipation. Despite its putative success, a conclusive outcome requires much higher Reynolds numbers than are available at present, or can be expected to be available in the near future. However, the model can be validated satisfactorily even within the Reynolds number range already available by considering high-order moments and their distributions in the wall-normal direction. Expressions for high-order moments of streamwise velocity fluctuation u are derived in the form ⟨ u + 2 q ⟩ 1 / q = α q − β q y ∗ 1 / 4 , where the superscript + indicates the wall unit normalization, and brackets stand for averages over time and the homogeneous plane normal to the wall, q is an integer, α q and β q are constants independent of the friction Reynolds number R e τ , and y ∗ = y / δ is the distance away from the wall, normalized by the flow thickness δ . In particular, α q = μ + σ q according to the “linear q-norm Gaussian” process, where μ and σ are flow-independent constants. Excellent agreement is found between this formula and the available data in boundary layers, pipes, and channels for 1 ≤ q ≤ 5 . For fixed y + = y ∗ R e τ , the present formulation leads to the bounded state ⟨ u + 2 q ⟩ 1 / q = α q as R e τ → ∞ . This work demonstrates the success of the present model in describing the behavior of fluctuations in wall flows.}, archive = {J_PNAS}, author = {Chen, Xi and Sreenivasan, Katepalli R.}, doi = {10.1073/pnas.2502265122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2502265122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bounded dissipation law and profiles of turbulent velocity moments in wall flows}, volume = {122}, year = {2025}, }
• (2025). Bridging life satisfaction data and neurobiological measures would elucidate human well-being. PNAS, 122(17), e2502095122. (www)

  @article{ , archive = {J_PNAS}, author = {Brandt, Anthony and Jaya Lesmana, Cokorda Bagus and Goldberg, Elkhonon}, doi = {10.1073/pnas.2502095122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2502095122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bridging life satisfaction data and neurobiological measures would elucidate human well-being}, volume = {122}, year = {2025}, }
• (2025). B cell–derived acetylcholine mitigates skin inflammation in mice through α9 nicotinic acetylcholine receptor–mediated signaling. PNAS, 122(17), e2501960122. (www)

  @article{ , abstract = {Chronic inflammatory skin disorders are characterized by keratinocyte hyperproliferation and hyperactivation as well as immune cell infiltration. We investigated whether immune cell–derived acetylcholine (ACh) is a modulator of skin inflammation in mice. Here, we identify skin epithelial B cells as a key source of ACh that damps down inflammation. We used imiquimod (IMQ) to induce inflammatory skin disease (ISD) in mice lacking ACh production specifically in B cells (ChAT fl/fl;Mb1-Cre mice). Increased keratinocyte proliferation, epidermal thickening, and elevated levels of proinflammatory cytokines resulted. ACh binding to α9 nicotinic ACh receptor (encoded by Chrna9 ) expressed on wild-type mouse keratinocytes reduced their proliferation. Chrna9 -deficient mice exhibited the same exacerbated ISD phenotype as ChAT fl/fl;Mb1-Cre mice following IMQ induction. Our data suggest that B cell–derived ACh maintains skin homeostasis by modulating keratinocyte turnover and controlling immune-related inflammation. Therapeutic manipulation of this cholinergic pathway might mitigate both keratinocyte dysfunction and immune dysregulation in human patients, potentially pointing to treatments for ISDs such as psoriasis and related disorders.}, archive = {J_PNAS}, author = {Foffi, Erica and Rugolo, Francesco and Ramamurthy, Nisha and Haight, Jillian and Helke, Simone and You-Ten, Annick and Tobin, Chantal and Jafari, Soode Moghadas and Elia, Andrew J. and Berger, Thorsten and Candi, Eleonora and Melino, Gerry and Mak, Tak W.}, doi = {10.1073/pnas.2501960122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2501960122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {B cell–derived acetylcholine mitigates skin inflammation in mice through α9 nicotinic acetylcholine receptor–mediated signaling}, volume = {122}, year = {2025}, }
• (2025). Abiotic origin of the citric acid cycle intermediates. PNAS, 122(17), e2501839122. (www)

  @article{ , abstract = {The molecular framework for protometabolism—chemical reactions in a prebiotic environment preceding modern metabolism—has remained unknown in evolutionary biology. Mono-, di-, and tricarboxylic acids that comprise contemporary metabolism, such as the Krebs cycle, are of particular prebiotic relevance and are theorized to predate life on Earth. Researchers have struggled to unravel the molecular origins of respiration, with theories pointing toward abiotic origins later co-opted by the earliest living organisms; however, the molecular network of these molecules has remained elusive. Recent detections of carboxylic acids linked to the Krebs cycle on the Ryugu asteroid and Murchison meteorite rekindled interest in their extraterrestrial origins. Replicating conditions analogous to the environment of dense molecular clouds in laboratory simulation experiments, our work provides compelling evidence on the abiotic synthesis of the complete suite of biorelevant molecules central to the Krebs cycle. The opportunity for these biomolecules forming in deep space could provide molecular origins of protometabolism on early Earth and also provide the molecular feedstock to worlds beyond our own.}, archive = {J_PNAS}, author = {McAnally, Mason and Bocková, Jana and Turner, Andrew M. and Hara, Nana and Mikhnova, Daria and Meinert, Cornelia and Kaiser, Ralf I.}, doi = {10.1073/pnas.2501839122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2501839122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Abiotic origin of the citric acid cycle intermediates}, volume = {122}, year = {2025}, }
• (2025). Disrupted sensorimotor predictions in high autistic characteristics. PNAS, 122(17), e2501624122. (www)

  @article{ , abstract = {Humans maintain a stable view of the world by omitting self-generated motion during rapid eye movements, or saccades. An efferent copy of the saccade motor command informs visual processing about the self-produced motion. However, efference copy information has been demonstrated to be disrupted in individuals with high autistic traits. Here, we investigated saccadic omission in participants with high vs. low autistic traits. Participants made saccades to peripheral targets and reported the location of drifting gratings that became visible during saccade execution. Sensitivity to motion was also assessed in a fixation condition, where retinal velocities matched those experienced during saccades. Our findings reveal that individuals with heightened autistic traits exhibit significantly reduced sensitivity to motion during saccades compared to those with low autistic traits, while no Autistic Quotient-dependent differences were observed in the fixation condition. These results suggest that impairments in sensorimotor processing affect the ability of individuals with high autistic traits to predict how their own movements affect the sensory input. The lack of sensorimotor integration might explain the sensory overload that autistics frequently experience.}, archive = {J_PNAS}, author = {Pomè, Antonella and Zimmermann, Eckart}, doi = {10.1073/pnas.2501624122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2501624122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Disrupted sensorimotor predictions in high autistic characteristics}, volume = {122}, year = {2025}, }
• (2025). Ecologically informed solar enables a sustainable energy transition in US croplands. PNAS, 122(17), e2501605122. (www)

  @article{ , abstract = {United States (US) croplands are ideal recipient environments for solar photovoltaic (PV) energy because they are flat and have a high solar resource. Perceived threats of solar to agriculture have led some stakeholders to suggest that croplands be exclusively used to produce food. However, 12 million hectares of US croplands, an area about the size of New York State, are already dedicated to corn grown for ethanol (i.e., biofuel), an energy product that requires significantly more land than solar PV per unit energy. Ecosystem service benefits of an ecologically informed approach to solar development (i.e., ecovoltaics), coupled with significant land-use advantages over corn ethanol, make solar an attractive solution for a sustainable energy transition in croplands. Here, we evaluated how the conversion of a small fraction of corn-ethanol croplands into ecovoltaic solar facilities might improve land-use efficiency of energy generation, enhance ecosystem services, and provide landscape diversification. Through spatial analyses, we determined that converting just 3.2% of land currently used for corn ethanol would increase the share of utility-scale solar energy in the US from 3.9 to 13%. We also identified target locations where strategic conversion of corn ethanol to solar PV colocated with perennial vegetation could filter excess nutrients transported from adjacent farm runoff, diversify and connect agricultural landscapes, and provide local wildlife habitat. In contrast to the common perception of land-use competition and land scarcity in the energy transition, our findings highlight benefits of colocated energy landscapes that integrate fundamental principles of energy development and sustainable agroecosystems.}, archive = {J_PNAS}, author = {Sturchio, Matthew A. and Gallaher, Adam and Grodsky, Steven M.}, doi = {10.1073/pnas.2501605122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2501605122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ecologically informed solar enables a sustainable energy transition in US croplands}, volume = {122}, year = {2025}, }
• (2025). Disentangling conduction pathways at the ionic–electronic interface in EMI-TFSI-covered graphene transistors. PNAS, 122(17), e2426506122. (www)

  @article{ , abstract = {Transport of electrons and ions at carbon surfaces immersed in electrolytes is instrumental for a wide variety of membrane processes as well as energy storage in batteries and supercapacitors. Ion transport in a nanoporous electrode strongly depends on its electronic conductance and on the interfacial capacitance with the electrolyte. In this study, we use in-plane impedance spectroscopy to disentangle in-plane ionic and electronic transport on a single crystal graphene transistor covered by an ionic liquid droplet (1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, EMI-TFSI). droplet. Due to the atomic thickness of graphene combined to the strong affinity of EMI+ for carbon, this transistor maximizes ion–electron couplings. Using gate- and temperature-dependent in-plane spectroscopy, we extract both the electronic and ionic conductance of the transistor on a wide range of charge carrier density and over several decades of electrolyte conductivity. We show that despite an exceptionally high capacitive coupling at the carbon–EMI-TFSI interface, the ionic and electronic transport pathways are decoupled at the micrometric scale, in agreement with predicted lengthscales involved in the electronic-ionic interfacial transport.}, archive = {J_PNAS}, author = {Lizée, Mathieu and Esfandiar, Ali and Panoni, Eva and Mischenko, Artem and Taberna, Pierre-Louis and Simon, Patrice and Bocquet, Lydéric}, doi = {10.1073/pnas.2426506122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2426506122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Disentangling conduction pathways at the ionic–electronic interface in EMI-TFSI-covered graphene transistors}, volume = {122}, year = {2025}, }
• (2025). PPARα regulates ER–lipid droplet protein calsyntenin-3β to promote ketogenesis in hepatocytes. PNAS, 122(17), e2426338122. (www)

  @article{ , abstract = {Ketogenesis requires fatty acid flux from intracellular (lipid droplets) and extrahepatic (adipose tissue) lipid stores to hepatocyte mitochondria. However, whether interorganelle contact sites regulate this process is unknown. Recent studies have revealed a role for Calsyntenin-3β (CLSTN3β), an endoplasmic reticulum–lipid droplet contact site protein, in the control of lipid utilization in adipose tissue. Here, we show that Clstn3b expression is induced in the liver by the nuclear receptor PPARα in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte-specific loss of CLSTN3β in mice impairs ketogenesis independent of changes in PPARα activation. Conversely, hepatic overexpression of CLSTN3β promotes ketogenesis in mice. Mechanistically, CLSTN3β affects LD–mitochondria crosstalk, as evidenced by changes in fatty acid oxidation, lipid-dependent mitochondrial respiration, and the mitochondrial integrated stress response. These findings define a function for CLSTN3β-dependent membrane contacts in hepatic lipid utilization and ketogenesis.}, archive = {J_PNAS}, author = {Uchiyama, Lauren F. and Nguyen, Alexander and Qian, Kevin and Cui, Liujuan and Pham, Khoi T. and Xiao, Xu and Gao, Yajing and Shimanaka, Yuta and Tol, Marcus J. and Vergnes, Laurent and Reue, Karen and Tontonoz, Peter}, doi = {10.1073/pnas.2426338122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2426338122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PPARα regulates ER–lipid droplet protein calsyntenin-3β to promote ketogenesis in hepatocytes}, volume = {122}, year = {2025}, }
• (2025). Subunit specialization in AAA+ proteins and substrate unfolding during transcription complex remodeling. PNAS, 122(17), e2425868122. (www)

  @article{ , abstract = {Bacterial RNA polymerase (RNAP) is a multisubunit enzyme that copies DNA into RNA in a process known as transcription. Bacteria use σ factors to recruit RNAP to promoter regions of genes that need to be transcribed, with 60% bacteria containing at least one specialized σ factor, σ 54 . σ 54 recruits RNAP to promoters of genes associated with stress responses and forms a stable closed complex that does not spontaneously isomerize to the open state where promoter DNA is melted out and competent for transcription. The σ 54 -mediated open complex formation requires specific AAA+ proteins ( A TPases A ssociated with diverse cellular A ctivities) known as bacterial enhancer-binding proteins (bEBPs). We have now obtained structures of new intermediate states of bEBP-bound complexes during transcription initiation, which elucidate the mechanism of DNA melting driven by ATPase activity of bEBPs and suggest a mechanistic model that couples the Adenosine triphosphate (ATP) hydrolysis cycle within the bEBP hexamer with σ 54 unfolding. Our data reveal that bEBP forms a nonplanar hexamer with the hydrolysis-ready subunit located at the furthest/highest point of the spiral hexamer relative to the RNAP. ATP hydrolysis induces conformational changes in bEBP that drives a vectoral transiting of the regulatory N terminus of σ 54 into the bEBP hexamer central pore causing the partial unfolding of σ 54 , while forming specific bEBP contacts with promoter DNA. Furthermore, our data suggest a mechanism of the bEBP AAA+ protein that is distinct from the hand-over-hand mechanism proposed for many other AAA+ proteins, highlighting the versatile mechanisms utilized by the large protein family.}, archive = {J_PNAS}, author = {Gao, Forson and Ye, Fuzhou and Buck, Martin and Zhang, Xiaodong}, doi = {10.1073/pnas.2425868122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2425868122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Subunit specialization in AAA+ proteins and substrate unfolding during transcription complex remodeling}, volume = {122}, year = {2025}, }
• (2025). Lab earthquakes reveal a wide range of rupture behaviors controlled by fault bends. PNAS, 122(17), e2425471122. (www)

  @article{ , abstract = {Natural faults are typically nonplanar and exhibit multiple bends, which deviate from the general fault orientation at different angles. However, while such deviations are considered a key factor controlling earthquake propagation and, hence, its intensity and magnitude, direct experimental evidence of how bends affect earthquake ruptures is nearly nonexistent. Here, we present direct experimental observations of the interaction of dynamic frictional ruptures with fault (double-) bends of different angles. Using ultrahigh-speed photography, we capture highly detailed full-field images of the complex rupture dynamics that evolve as lab earthquakes in an analog material [poly(methylmethacrylate)] propagate through fault bends, as well as the resulting near-field ground motions. Releasing bends, which extend as the fault slips, intensify the rupture by promoting a transition to supershear propagation speeds (i.e., above the medium shear wave velocities) and a crack-like rupture style with spread-out slip, while restraining bends, which contract as the fault slips, slow or arrest the rupture. Surprisingly, we find that secondary back-propagating supershear ruptures are spontaneously triggered at intermediate-angle restraining bends. These constraints on the effect of natural fault geometry on the behavior and extent of earthquake ruptures have significant implications for earthquake source physics, seismic hazards, and the interpretation of seismic data.}, archive = {J_PNAS}, author = {Gabrieli, Tom and Tal, Yuval}, doi = {10.1073/pnas.2425471122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2425471122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lab earthquakes reveal a wide range of rupture behaviors controlled by fault bends}, volume = {122}, year = {2025}, }
• (2025). Identifying air quality monitoring deserts in the united states. PNAS, 122(17), e2425310122. (www)

  @article{ , abstract = {Air quality is associated with adverse health outcomes and mortality risk. While most research has focused on the association between air quality estimates and these outcomes, little is known about the presence of air quality monitoring sites across the United States or the place-level characteristics associated with such placements. We classify counties without a monitoring station as air quality monitoring deserts. Using the Environmental Protection Agency’s AirData active sites directory, we determine the number and location of monitoring deserts. We then study whether demographic and socioeconomic characteristics are associated with the likelihood of a county being a monitoring desert. Our results indicate that 1,848 or 58.8% of US counties are an air quality monitoring desert, covering about 40% of the nation’s land area. Our estimates suggest that more than 50 million people or 15.3% of the population live in air quality monitoring deserts. Rural and counties with higher proportions of historically minoritized groups have higher odds of being a monitoring desert. Regionally speaking, air quality monitoring deserts are highly concentrated within the Midwest and the South. These findings highlight gaps in air quality monitoring in the United States. Identifying and addressing air quality monitoring deserts across the United States will allow us to better understand air quality across the nation and expand current knowledge of its impact on national health and well-being.}, archive = {J_PNAS}, author = {Roque, Nelson A. and Andrews, Hailey and Santos-Lozada, Alexis R.}, doi = {10.1073/pnas.2425310122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2425310122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identifying air quality monitoring deserts in the united states}, volume = {122}, year = {2025}, }
• (2025). Nonnative tree invaders lead to declines in native tree species richness. PNAS, 122(17), e2424908122. (www)

  @article{ , abstract = {Biological invasions are profoundly altering Earth’s ecosystems, but generalities about the effects of nonnative species on the diversity and productivity of native communities have been elusive. This lack of generality may reflect the limited spatial and temporal extents of most previous studies. Using >5 million tree measurements across eastern US forests from 1995 to 2023, we quantified temporal trends in tree diversity and biomass. We then analyzed community-level changes in native tree diversity and biomass in relation to nonnative tree invasion and native species colonization. Across the entire eastern United States, native tree species richness decreased over time in plots where nonnatives occurred, whereas nonnative species richness and the biomass of both natives and nonnatives increased over time. At the community scale, native richness tended to decline following nonnative invasion, whereas native biomass and richness-independent measures of trait and phylogenetic diversity tended to remain stable. These patterns can be explained by the rarity of the displaced native species and their functional and phylogenetic similarity to native species that survived nonnative invasions. In contrast, native survivors tended to be functionally distinct from nonnative invaders, suggesting an important role for niche partitioning in community dynamics. Colonization by previously absent native species was associated with an increase in native richness (beyond the addition of native colonizers), which contrasts with declines in native richness that tended to follow nonnative invasion. These results suggest a causal role for nonnative species in the native richness decline of invaded communities.}, archive = {J_PNAS}, author = {Liu, Yunpeng and Scheiner, Samuel M. and Hogan, J. Aaron and Thomas, Matthew B. and Soltis, Pamela S. and Guralnick, Robert P. and Soltis, Douglas E. and Lichstein, Jeremy W.}, doi = {10.1073/pnas.2424908122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2424908122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nonnative tree invaders lead to declines in native tree species richness}, volume = {122}, year = {2025}, }
• (2025). MOB1 deletion in murine mature adipocytes ameliorates obesity and diabetes. PNAS, 122(17), e2424741122. (www)

  @article{ , abstract = {There is currently a global epidemic of obesity and obesity-related diseases such as type 2 diabetes due to decreased physical activity, excessive food intake, and/or genetic predisposition. The Hippo-YAP1 pathway has attracted attention as a potential therapeutic target because YAP1/TAZ activation in murine immature adipocytes in vitro suppresses their differentiation by inhibiting PPARγ activity. However, the role of YAP1 activation in mature adipocytes in vivo remains unclear. MOB1, whose expression is increased in obesity, is the hub of the Hippo core molecule complex and negatively regulates YAP1/TAZ activation. Therefore, we generated aMob1DKO mutant mice, which feature deficiency of Mob1a/b specifically in mature adipocytes. Compared to controls, aMob1DKO mice subjected to a high-fat diet showed beneficial changes consistent with resistance to diet-induced obesity. The mutants exhibited increases in basal lipolysis, “beiging,” and energy expenditure, as well as suppression of ROS production and inflammation in white adipose tissue. Insulin sensitivity and glucose tolerance were improved, and ectopic fat accumulation was reduced. Most of these changes were dependent on the YAP1 activation observed in mature white adipose tissue of aMob1DKO mice. FGF21, which improves lipid metabolism, was upregulated directly via YAP1 activation, and many of the phenotypes seen in aMob1DKO mice were also dependent on FGF21. Thus, the aMob1DKO mouse is an interesting model for the study of the metabolic effects of diet-induced obesity and protection against diabetes. Our work suggests that a YAP1-FGF21 axis exists in adipocytes that may be a potential therapeutic target for obesity.}, archive = {J_PNAS}, author = {Nishio, Miki and Yamaguchi, Keiko and Otani, Junji and Yuguchi, Katsuya and Kohno, Daisuke and Sasaki, Tsutomu and Kitamura, Tadahiro and Shinohara, Masakazu and Soga, Tomoyoshi and Kawamura, Koichi and Sasaki, Atsuo T. and Oshima, Masashi and Hikasa, Hiroki and Woo, Minna and Sasaki, Takehiko and Nishina, Hiroshi and Nakao, Kazuwa and Maehama, Tomohiko and Suzuki, Akira}, doi = {10.1073/pnas.2424741122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2424741122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MOB1 deletion in murine mature adipocytes ameliorates obesity and diabetes}, volume = {122}, year = {2025}, }
• (2025). Extreme weather variability on hot rocky exoplanet 55 cancri e explained by magma temperature–cloud feedback. PNAS, 122(17), e2423473122. (www)

  @article{ , abstract = {Observations of the hot rocky exoplanet 55 Cancri e report significant but unexplained variability in brightness across visible and infrared bands, e.g., on subweekly timescales, its mid-infrared brightness temperature fluctuates by approximately 1,400 K (with hundreds of Kelvin uncertainty). We propose a magma temperature–cloud feedback as a potential explanation that relies on the planet’s atmosphere and surface. In this feedback, under cloud-free conditions, stellar radiation heats surface magma, releasing silicate vapor that condenses into clouds. Once formed, these clouds attenuate stellar insolation, thereby cooling the surface, reducing vapor supply, and decreasing cloudiness. A time lag between surface temperature increase and cloud formation, likely due to lagged atmospheric transport of cloud-forming vapor, enables self-sustained oscillations in surface temperature and cloudiness. These oscillations manifest as variations in both the planet’s thermal emission and reflected starlight, causing variability in secondary eclipse depths across wavelengths without significantly affecting the transit depth. Using a simple model, we find that diverse planetary parameters can reproduce the observed infrared brightness variability. We also demonstrate that brightness at different wavelengths can oscillate out of phase, consistent with recent observations by the James Webb Space Telescope. Additionally, we propose that time-varying and spatially nonuniform cloud cover can result in changing amplitude and phase offset of the planet’s phase curve, potentially explaining observations. Finally, we discuss observational strategies to test this proposed mechanism on 55 Cancri e. If confirmed, these observable ocean–atmosphere dynamics on exoplanets would provide valuable insights into the composition, evolution, and long-term fate of rocky planet volatiles.}, archive = {J_PNAS}, author = {Loftus, Kaitlyn and Luo, Yangcheng and Fan, Bowen and Kite, Edwin S.}, doi = {10.1073/pnas.2423473122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2423473122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Extreme weather variability on hot rocky exoplanet 55 cancri e explained by magma temperature–cloud feedback}, volume = {122}, year = {2025}, }
• (2025). Distinct oxytocin signaling pathways synergistically mediate rescue-like behavior in mice. PNAS, 122(17), e2423374122. (www)

  @article{ , abstract = {Spontaneous rescue behavior enhances the well-being and survival of social animals, yet the neural mechanisms underlying the recognition and response to conspecifics in need remain unclear. Here, we report that observer mice experience distress when encountering anesthetized conspecifics, prompting spontaneous rescue-like behavior toward the unconscious mice. This behavior facilitates the earlier awakening of anesthetized mice while simultaneously alleviating stress in the helper mice. Our findings reveal that endogenous oxytocin (OXT) release from the hypothalamic paraventricular nucleus (PVN) to the oxytocin receptor (OXTR) in the central nucleus of the amygdala (CeA) regulates the emotional component of rescue-like behavior. In contrast, OXT release from the PVN to OXTR in the dorsal bed nucleus of the stria terminalis (dBNST) mediates the motor component of the behavior. Furthermore, we demonstrate that these two pathways exhibited distinct temporal dynamics and functional roles. The OXT PVN -OXTR CeA pathway is activated in a transient and intense manner, acting as a trigger for rescue-like behavior, whereas the OXT PVN -OXTR dBNST pathway responds in a sustained manner, ensuring the continuation of the behavior. These findings highlight the remarkable ability of rodents to engage in targeted helping behavior and suggest that distinct subcortical oxytocinergic pathways selectively and synergistically regulate the motor and emotional aspects of rescue-like behavior.}, archive = {J_PNAS}, author = {Zhang, Feng-Rui and Liu, Juan and Wen, Jieqi and Zhang, Zi-Yan and Li, Yijia and Song, Eric and Hu, Li and Chen, Zhou-Feng}, doi = {10.1073/pnas.2423374122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2423374122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Distinct oxytocin signaling pathways synergistically mediate rescue-like behavior in mice}, volume = {122}, year = {2025}, }
• (2025). LACE-UP: An ensemble machine-learning method for health subtype classification on multidimensional binary data. PNAS, 122(17), e2423341122. (www)

  @article{ , abstract = {Disease and behavior subtype identification is of significant interest in biomedical research. However, in many settings, subtype discovery is limited by a lack of robust statistical clustering methods appropriate for binary data. Here, we introduce LACE-UP [latent class analysis ensembled with UMAP (uniform manifold approximation and projection) and PCA (principal components analysis)], an ensemble machine-learning method for clustering multidimensional binary data that does not require prespecifying the number of clusters and is robust to realistic data settings, such as the correlation of variables observed from the same individual and the inclusion of variables unrelated to the underlying subtype. The method ensembles latent class analysis, a model-based clustering method; principal components analysis, a spectral signal processing method; and UMAP, a cutting-edge model-free dimensionality reduction algorithm. In simulations, LACE-UP outperforms gold-standard techniques across a variety of realistic scenarios, including in the presence of correlated and extraneous data. We apply LACE-UP to dietary behavior data from the UK Biobank to demonstrate its power to uncover interpretable dietary subtypes that are associated with lipids and cardiovascular risk.}, archive = {J_PNAS}, author = {Danning, Rebecca and Hu, Frank B. and Lin, Xihong}, doi = {10.1073/pnas.2423341122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2423341122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {LACE-UP: An ensemble machine-learning method for health subtype classification on multidimensional binary data}, volume = {122}, year = {2025}, }
• (2025). Morphogenesis of spin cycloids in a noncollinear antiferromagnet. PNAS, 122(17), e2423298122. (www)

  @article{ , abstract = {Pattern formation in spin systems with continuous-rotational symmetry (CRS) provides a powerful platform to study emergent complex magnetic phases and topological defects in condensed-matter physics. However, its understanding and correlation with unconventional magnetic order along with high-resolution nanoscale imaging are challenging. Here, we employ scanning nitrogen vacancy (NV) magnetometry to unveil the morphogenesis of spin cycloids at both the local and global scales within a single ferroelectric domain of (111)-oriented BiFeO 3 , which is a noncollinear antiferromagnet, resulting in formation of a glassy labyrinthine pattern. We find that the domains of locally oriented cycloids are interconnected by an array of topological defects and exhibit isotropic energy landscape predicted by first-principles calculations. We propose that the CRS of spin-cycloid propagation directions within the (111) drives the formation of the labyrinthine pattern and the associated topological defects such as antiferromagnetic skyrmions. Unexpectedly, reversing the as-grown ferroelectric polarization from [ 1 ¯ 1 ¯ 1 ¯ ] to [111] produces a noncycloidal NV image contrast which could be attributed to either the emergence of a uniformly magnetized state or a reversal of the cycloid polarity. These findings highlight that (111)-oriented BiFeO 3 is not only important for studying the fascinating subject of pattern formation but could also be utilized as an ideal platform for integrating novel topological defects in the field of antiferromagnetic spintronics.}, archive = {J_PNAS}, author = {Ojha, Shashank Kumar and Pal, Pratap and Prokhorenko, Sergei and Husain, Sajid and Ramesh, Maya and Li, Xinyan and Kang, Deokyoung and Meisenheimer, Peter and Schlom, Darrell G. and Stevenson, Paul and Caretta, Lucas and Nahas, Yousra and Han, Yimo and Martin, Lane W. and Bellaiche, Laurent and Eom, Chang-Beom and Ramesh, Ramamoorthy}, doi = {10.1073/pnas.2423298122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2423298122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Morphogenesis of spin cycloids in a noncollinear antiferromagnet}, volume = {122}, year = {2025}, }
• (2025). Fungal argonaute proteins act in bidirectional cross-kingdom RNA interference during plant infection. PNAS, 122(17), e2422756122. (www)

  @article{ , abstract = {Argonaute (AGO) proteins bind to small RNAs to induce RNA interference (RNAi), a conserved gene regulatory mechanism in animal, plant, and fungal kingdoms. Small RNAs of the fungal plant pathogen Botrytis cinerea were previously shown to translocate into plant cells and to bind to the host AGO, which induced cross-kingdom RNAi to promote infection. However, the role of pathogen AGOs during host infection stayed elusive. In this study, we revealed that members of fungal plant pathogen B. cinerea BcAGO family contribute to plant infection. BcAGO1 binds to both fungal and plant small RNAs during infection and acts in bidirectional cross-kingdom RNAi, from fungus to plant and vice versa. BcAGO2 also binds fungal and plant small RNAs but acts independent from BcAGO1 by regulating distinct genes. Nevertheless, BcAGO2 is important for infection, as it is required for effective pathogen small RNA delivery into host cells and fungal induced cross-kingdom RNAi. Providing these mechanistic insights of pathogen AGOs promises to improve RNAi-based crop protection strategies.}, archive = {J_PNAS}, author = {Cheng, An-Po and Huang, Lihong and Oberkofler, Lorenz and Johnson, Nathan R. and Glodeanu, Adrian-Stefan and Stillman, Kyra and Weiberg, Arne}, doi = {10.1073/pnas.2422756122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2422756122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fungal argonaute proteins act in bidirectional cross-kingdom RNA interference during plant infection}, volume = {122}, year = {2025}, }
• (2025). Linking energetic instability to compositional changes in biological communities. PNAS, 122(17), e2422701122. (www)

  @article{ , abstract = {The resilience of an ecological community informs us how it will respond to future environmental disturbances. However, the concept is rarely tested in the context of predicting biodiversity change, particularly at broad spatial and taxonomic scales. Here, we show that measures of instability derived from the resilience of the current state of community compositions greatly improve the predictability of biodiversity change. We applied energy landscape analysis (ELA) to community compositions of both simulated and natural ecosystems of distinctive regions and taxa (birds, fishes, mollusks, and phytoplankton) and estimated the resilience of those systems. We found that a metric of local instability, which represents how current community states are inflated from local optima, explained well the magnitude of species turnover and energy changes from the current to future states for both simulated and real communities. A metric of global instability, which represents a community’s tendency to cross-over ridges of local basins of attraction to alternate stable states, also served as a weaker yet significant index of such changes. Our ELA results suggest that quantifying the resilience of real ecosystems is essential for understanding the mechanisms of community dynamics in an effort to improve the prediction of biodiversity change.}, archive = {J_PNAS}, author = {Kadoya, Taku and Suzuki, Kenta and Terui, Akira}, doi = {10.1073/pnas.2422701122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2422701122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Linking energetic instability to compositional changes in biological communities}, volume = {122}, year = {2025}, }
• (2025). A unified framework for hydromechanical signaling can explain transmission of local and long-distance signals in plants. PNAS, 122(17), e2422692122. (www)

  @article{ , abstract = {Local wounding in plants triggers signals that travel locally within the wounded leaf or systemically through the vasculature to distant leaves. Our understanding of the mechanisms of initiation and propagation of this ubiquitous class of signals remains incomplete. Here, we develop a unifying framework based on poroelastic dynamics to study two coupled biophysical processes—propagation of pressure changes and transmission of chemical elicitors via mass flows driven by these pressure changes—as potential mechanisms for the initiation and propagation of wound-induced signals. We show that rapid pressure changes in the xylem can transmit mechanical information across the plant, while their coupling with neighboring nonvascular tissue drives swelling and mass flow that can transport chemical elicitors to distant leaves. We confront predictions from our model with measurements of signaling dynamics in several species to show that i) the poroelastic model can capture the observed dynamics of purely mechanical changes (swelling of distant leaves) induced by wounding; ii) advection and diffusion of hypothetical elicitors with mass flows induced by poroelastic relaxations can explain distant cellular responses observed with gene-encoded reporters of cytosolic calcium concentration and electrical signals; and iii) poroelastic diffusion of pressure changes around local wounds in nonvascular tissue matches the observed cytosolic calcium signals and represents an alternative hypothesis relative to molecular diffusion of chemical elicitors. This framework provides a valuable foundation for assessing mechanisms of signal transmission and for designing future experiments to elucidate factors involved in signal initiation, propagation, and target elicitation.}, archive = {J_PNAS}, author = {Bacheva, Vesna and Rockwell, Fulton E. and Salmon, Jean-Baptiste and Woodson, Jesse D. and Frank, Margaret H. and Stroock, Abraham D.}, doi = {10.1073/pnas.2422692122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2422692122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A unified framework for hydromechanical signaling can explain transmission of local and long-distance signals in plants}, volume = {122}, year = {2025}, }
• (2025). Ligand-binding pockets in RNA and where to find them. PNAS, 122(17), e2422346122. (www)

  @article{ , abstract = {RNAs are critical regulators of gene expression, and their functions are often mediated by complex secondary and tertiary structures. Structured regions in RNA can selectively interact with small molecules—via well-defined ligand-binding pockets—to modulate the regulatory repertoire of an RNA. The broad potential to modulate biological function intentionally via RNA–ligand interactions remains unrealized, however, due to challenges in identifying compact RNA motifs with the ability to bind ligands with good physicochemical properties (often termed drug-like). Here, we devise fpocketR , a computational strategy that accurately detects pockets capable of binding drug-like ligands in RNA structures. Remarkably few, roughly 50, of such pockets have ever been visualized. We experimentally confirmed the ligandability of novel pockets detected with fpocketR using a fragment-based approach introduced here, Frag-MaP, that detects ligand-binding sites in cells. Analysis of pockets detected by fpocketR and validated by Frag-MaP reveals dozens of sites able to bind drug-like ligands, supports a model for RNA secondary structural motifs able to bind quality ligands, and creates a broad framework for understanding the RNA ligand-ome.}, archive = {J_PNAS}, author = {Veenbaas, Seth D. and Koehn, Jordan T. and Irving, Patrick S. and Lama, Nicole N. and Weeks, Kevin M.}, doi = {10.1073/pnas.2422346122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2422346122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ligand-binding pockets in RNA and where to find them}, volume = {122}, year = {2025}, }
• (2025). Molecular organization of central cholinergic synapses. PNAS, 122(17), e2422173122. (www)

  @article{ , abstract = {Synapses have undergone significant diversification and adaptation, contributing to the complexity of the central nervous system. Understanding their molecular architecture is essential for deciphering the brain’s functional evolution. While nicotinic acetylcholine receptors (nAchRs) are widely distributed across metazoan brains, their associated protein networks remain poorly characterized. Using in vivo proximity labeling, we generated proteomic maps of subunit-specific nAchR interactomes in developing and mature Drosophila brains. Our findings reveal a developmental expansion and reconfiguration of the nAchR interactome. Proteome profiling with genetic perturbations showed that removing individual nAchR subunits consistently triggers compensatory shifts in receptor subtypes, highlighting mechanisms of synaptic plasticity. We also identified the Rho-GTPase regulator Still life (Sif) as a key organizer of cholinergic synapses, with loss of Sif disrupting their molecular composition and structural integrity. These results provide molecular insights into the development and plasticity of central cholinergic synapses, advancing our understanding of synaptic identity conservation and divergence.}, archive = {J_PNAS}, author = {Rosenthal, Justin S. and Zhang, Dean and Yin, Jun and Long, Caixia and Yang, George and Li, Yan and Lu, Zhiyuan and Li, Wei-Ping and Yu, Zhiheng and Li, Jiefu and Yuan, Quan}, doi = {10.1073/pnas.2422173122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2422173122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular organization of central cholinergic synapses}, volume = {122}, year = {2025}, }
• (2025). Infrared light stimulates the cochlea through a mechanical displacement detected and amplified by hair cells. PNAS, 122(17), e2422076122. (www)

  @article{ , abstract = {Although cochlear implants (CI) are the standard of care for profound sensorineural hearing loss they are technically constrained by the tendency of electrical current to spread within the fluid-filled chambers of the cochlea. This limits the resolution of individual electrodes and patients’ perceptions of complex sounds. Infrared irradiation has been proposed as an alternative to electrical stimulation because it can elicit auditory responses while being spatially constrained, theoretically promising higher-fidelity hearing for the deaf. However, conflicting reports locate the site of infrared excitation at spiral ganglia neurons or hair cells. We use a combination of genetic, pharmacological, optical, and electrophysiological tools to determine the site of action of infrared irradiation. Infrared-evoked cochlear potentials are composed of two peaks: one driven by hair cells (the microphonic) and a second driven by spiral ganglion neurons (the neural response). Manipulations that prevented hair cell synaptic activity abolished the neural component, while manipulations blocking hair cell mechanotransduction abolished all responses, suggesting a mechanical component to the infrared response. Optical coherence tomography (OCT) confirmed that infrared irradiation creates a mechanical stimulus that is both amplified and detected by hair cells. Because infrared irradiation does not stimulate spiral ganglion neurons directly, it is unlikely to replace the electrical CI.}, archive = {J_PNAS}, author = {Azimzadeh, Julien B. and Quiñones, Patricia M. and Oghalai, John S. and Ricci, Anthony J.}, doi = {10.1073/pnas.2422076122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2422076122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Infrared light stimulates the cochlea through a mechanical displacement detected and amplified by hair cells}, volume = {122}, year = {2025}, }
• (2025). FlgY, PflA, and PflB form a spoke–ring network in the high-torque flagellar motor of helicobacter pylori. PNAS, 122(17), e2421632122. (www)

  @article{ , abstract = {Helicobacter pylori has evolved distinct flagellar motility to colonize the human stomach. Rotation of the H. pylori flagella is driven by one of the largest known bacterial flagellar motors. In addition to the core motor components found in Escherichia coli and Salmonella enterica , the flagellar motor in H. pylori possesses many accessories that enable the bacteria to penetrate the gastric mucus layer. Here, we utilize cryoelectron tomography with molecular genetics and biochemical approaches to characterize three accessory proteins, FlgY, PflA, and PflB, and their roles in H. pylori flagellar assembly and motility. Comparative analyses of in situ flagellar motor structures from pflA , pflB , and flgY mutants and wild-type H. pylori reveal that FlgY forms a 13-fold proximal spoke–ring around the MS-ring and that PflA and PflB form an 18-fold distal spoke–ring enclosing 18 torque-generating stator complexes. We build a pseudoatomic model of the H. pylori motor by leveraging AlphaFold-predicted structures, protein–protein interactions, and in situ motor structures. Our model suggests that the FlgY spoke–ring functions as a bearing around the rotating MS-ring and as a template for stabilizing the PflA–PflB spoke–ring, thus enabling the recruitment of 18 stator complexes for high-torque generation. Overall, our study sheds light on how this spoke–ring network between the MS-ring and stator complexes enables the unique motility of H. pylori . As these accessory proteins are conserved in the phylum Campylobacterota, our findings apply broadly to a better understanding of how polar flagella help bacteria thrive in gastric and enteric niches.}, archive = {J_PNAS}, author = {Tachiyama, Shoichi and Rosinke, Kyle and Khan, Mohammad F. and Zhou, Xiaotian and Xin, Yue and Botting, Jack M. and Yue, Jian and Roujeinikova, Anna and Hoover, Timothy R. and Liu, Jun}, doi = {10.1073/pnas.2421632122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2421632122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {FlgY, PflA, and PflB form a spoke–ring network in the high-torque flagellar motor of helicobacter pylori}, volume = {122}, year = {2025}, }
• (2025). Prevalence of simplex compression in adversarial deep neural networks. PNAS, 122(17), e2421593122. (www)

  @article{ , abstract = {Neural collapse (NC) reveals that the last layer of the network can capture data representations, leading to similar outputs for examples within the same class, while outputs for examples from different classes form a simplex equiangular tight frame (ETF) structure. This phenomenon has garnered significant attention due to its implications on the intrinsic properties of neural networks. Interestingly, we observe a simplex compression phenomenon in NC, where the geometric size of the simplex ETF reduces under adversarial training, with the degree of compression increasing as the perturbation radius grows. We provide empirical evidence supporting the existence of simplex compression across a wide range of models and datasets. Furthermore, we establish a rigorous theoretical framework that explains our experimental observations, offering insights into NC under adversarial conditions.}, archive = {J_PNAS}, author = {Cao, Yang and Chen, Yanbo and Liu, Weiwei}, doi = {10.1073/pnas.2421593122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2421593122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prevalence of simplex compression in adversarial deep neural networks}, volume = {122}, year = {2025}, }
• (2025). The tilt illusion arises from an efficient reallocation of neural coding resources at the contextual boundary. PNAS, 122(17), e2421565122. (www)

  @article{ , abstract = {The tilt illusion—a bias in the perceived orientation of a center stimulus induced by an oriented surround—illustrates how context shapes visual perception. Although extensively studied for decades, we still lack a comprehensive account of the illusion that connects its behavioral and neural characteristics. Here, we demonstrate that the tilt illusion originates from dynamic changes in neural coding precision induced by the surround context. We simultaneously obtained psychophysical and functional MRI responses from human subjects while they viewed gratings in the absence and presence of an oriented surround and independently extracted sensory encoding precision from their behavioral and neural data. Both measures show that in the absence of an oriented surround, encoding reflects the natural scene statistics of orientation. However, with an oriented surround, encoding precision is significantly increased for stimuli similar to the surround orientation. This local change in encoding is sufficient to predict the behavioral characteristics of the tilt illusion using a Bayesian observer model. The effect of surround modulation increases along the ventral stream and is localized to the portion of the visual cortex with receptive fields at the center-surround boundary. The pattern of change in coding accuracy reflects the surround-conditioned orientation statistics in natural scenes, but cannot be explained by local stimulus configuration. Our results suggest that the tilt illusion naturally emerges from an adaptive coding strategy that efficiently reallocates neural coding resources based on the current stimulus context.}, archive = {J_PNAS}, author = {Zhang, Ling-Qi and Mao, Jiang and Aguirre, Geoffrey K. and Stocker, Alan A.}, doi = {10.1073/pnas.2421565122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2421565122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The tilt illusion arises from an efficient reallocation of neural coding resources at the contextual boundary}, volume = {122}, year = {2025}, }
• (2025). Reducing the effects of radiation damage in cryo-EM using liquid helium temperatures. PNAS, 122(17), e2421538122. (www)

  @article{ , abstract = {The physical limit in determining the atomic structure of biological molecules is radiation damage. In electron cryomicroscopy, there have been numerous attempts to reduce the effects of radiation damage by cooling the specimen beyond liquid-nitrogen temperatures, yet all failed to realize the potential improvement for single-particle structure determination. We have identified the physical causes of information loss at liquid-helium temperatures, and overcome them using a combination of nanoscale electron beam illumination and a gold specimen support with 100 nm diameter holes. This combination allowed structure determination where every frame in the exposure contained more information than was available with cryomicroscopy at liquid-nitrogen temperatures, matching expectations from crystal diffraction. Since a 100 nm hole is smaller than the field of view of a typical micrograph, the edges of the foil are directly visible in each micrograph. Protein molecules that are degraded tend to aggregate at the edges of foil holes and can constitute a significant fraction of the micrograph. This and the need for minimal water-foil irradiation will both be important to consider as new cryomicroscopes and specimen supports are developed for imaging molecules at extremely low temperatures where the effects of radiation damage are reduced.}, archive = {J_PNAS}, author = {Dickerson, Joshua L. and Naydenova, Katerina and Peet, Mathew J. and Wilson, Hugh and Nandy, Biplob and McMullan, Greg and Morrison, Robert and Russo, Christopher J.}, doi = {10.1073/pnas.2421538122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2421538122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reducing the effects of radiation damage in cryo-EM using liquid helium temperatures}, volume = {122}, year = {2025}, }
• (2025). A selfish supergene causes meiotic drive through both sexes in drosophila. PNAS, 122(17), e2421185122. (www)

  @article{ , abstract = {Meiotic drivers are selfish genetic elements that bias their own transmission during meiosis or gamete formation. Due to the fundamental differences between male and female meiosis in animals and plants, meiotic drivers operate through distinct mechanisms in the two sexes: In females, they exploit the asymmetry of meiosis to ensure their inclusion in the egg, whereas in males, they eliminate competing gametes after symmetric meiosis. Meiotic drive is commonly reported in males, where it strongly influences the evolution of spermatogenesis, while the few known cases in females have highlighted its crucial role in centromere evolution. Despite a growing number of examples in a wide range of organisms, meiotic drive has so far only been observed in one sex or the other since its discovery nearly 100 y ago. Here, we show that a selfish X chromosome known to cause meiotic drive in male Drosophila testacea flies also causes meiotic drive in females. We find that this X chromosome has supergene architecture, harboring extensive structural rearrangements that suppress recombination between the two X chromosomes. This has contributed to a substantial expansion of its size compared to the wild-type chromosome, partly due to the accumulation of species-specific repetitive elements. Our findings suggest that female meiotic drive may play an important role in the evolutionary dynamics of polymorphic structural variants that suppress recombination, including inversions, translocations, and supergenes.}, archive = {J_PNAS}, author = {Keais, Graeme L. and Saad-Roy, Chadi M. and Gonzalez-Sqalli, Emmanuel and Powell, Candice N. and Rieseberg, Loren H. and Gawryluk, Ryan M. R. and van den Driessche, P. and Wei, Kevin H.-C. and Loppin, Benjamin and Perlman, Steve J.}, doi = {10.1073/pnas.2421185122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2421185122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A selfish supergene causes meiotic drive through both sexes in drosophila}, volume = {122}, year = {2025}, }
• (2025). Patulin and xestoquinol are inhibitors of DNA topoisomerase 1. PNAS, 122(17), e2421167122. (www)

  @article{ , abstract = {DNA topoisomerase 1 (TOP1) is essential for transcription, replication, and repair. Its function relies on two catalytic steps, DNA breakage and rejoining. Inhibitors of the second step prevent DNA rejoining and lead to persistent DNA breaks, acting as topoisomerase poisons, used as anticancer drugs. However, reliable inhibitors of the first step are not available. Here, we provide genetic and molecular evidence supporting that Patulin and, to a lesser extent, Xestoquinol inhibit the first catalytic step of TOP1 in vitro, in yeast and in human cells. Particularly, Patulin prevents the accumulation of TOP1 cleavage complexes caused by the TOP1 poison camptothecin (CPT) in human cells. Moreover, Patulin pretreatment of human or yeast cells reduces DNA damage and the accumulation of DNA breaks upon CPT exposure. Consistent with the protective role of TOP1 against harmful R-loops, Patulin treatment increases R-loops and R-loop-associated cytotoxicity, mimicking the effect of TOP1 silencing. Altogether our findings indicate that Patulin and Xestoquinol are nonpoisoning inhibitors of TOP1, which should potentiate new research approaches in molecular biology and medicine.}, archive = {J_PNAS}, author = {Tumini, Emanuela and Wellinger, Ralf E. and Herrera-Moyano, Emilia and Navarro-Cansino, Patricia and García-Rubio, María and Salas-Lloret, Daniel and Losada, Alejandro and Muñoz-Alonso, María J. and Gaillard, Hélène and Luna, Rosa and Aguilera, Andrés}, doi = {10.1073/pnas.2421167122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2421167122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Patulin and xestoquinol are inhibitors of DNA topoisomerase 1}, volume = {122}, year = {2025}, }
• (2025). Opioid receptors reveal a discrete cellular mechanism of endosomal g protein activation. PNAS, 122(17), e2420623122. (www)

  @article{ , abstract = {Many GPCRs initiate a second phase of G protein-mediated signaling from endosomes. This inherently requires the GPCR to increase cognate G protein activity on the endosome surface. G s -coupled GPCRs are thought to achieve this by internalizing and mediating a second round of allosteric coupling to G proteins on the endosome membrane. Here, we provide evidence that the μ-opioid receptor (MOR), a G i -coupled GPCR, is able to increase endosomal G protein activity in a different way. Leveraging conformational biosensors, we show that MOR activation triggers a transient increase of active-state G i/o on the plasma membrane that is followed by a prolonged increase on endosomes. Contrary to the G s -coupled GPCR paradigm, however, we show that the MOR-induced increase of active-state G i/o on endosomes requires neither internalization of MOR nor the presence of activated MOR in the endosome membrane. We propose a distinct and additional cellular mechanism of endosomal signaling by G i/o that is communicated through trafficking of the activated G protein rather than its activating GPCR.}, archive = {J_PNAS}, author = {Fisher, Nicole M. and von Zastrow, Mark}, doi = {10.1073/pnas.2420623122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2420623122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Opioid receptors reveal a discrete cellular mechanism of endosomal g protein activation}, volume = {122}, year = {2025}, }
• (2025). Phospholipid flippase ATP11A brokers uterine epithelial integrity and function. PNAS, 122(17), e2420617122. (www)

  @article{ , abstract = {Uterine adaptations driven by the steroid hormones estrogen and progesterone are pivotal for embryo implantation and, ultimately, for a successful pregnancy. Here, we show in mice that genetic ablation of the membrane lipid flippase Atp11a causes severe deficits in this hormonal response and profound defects in the morphological organization and transcriptional profile of the uterine epithelial compartment where Atp11a is expressed. Atp11a -null uterine epithelial cells lack tight junctions, and the luminal epithelium exhibits profound disruptions to cellular morphology. Interestingly, the specification of luminal epithelial cells remains incomplete as they maintain expression of the normally gland-restricted marker FOXA2. The uterine glands of Atp11a -null females are depleted for progenitor cells marked by SOX9, PAX8, LGR5, and PROM1. Collectively, these findings point to a uterine receptivity deficit that underpins the frequent failure of Atp11a -depleted females to establish a successful pregnancy. Most intriguingly, however, loss of only a single functional Atp11a allele causes a higher frequency of abnormal placental trophoblast differentiation as well as a higher incidence of developmental heart defects in wild-type embryos. These data emphasize the far-reaching impact of uterine dysfunction on reproductive outcome and highlight the importance of the maternal genotype in the etiology of developmental disorders.}, archive = {J_PNAS}, author = {Krala, Alexa and Tsolova, Aleksandra O. and Radford, Bethany N. and Jadli, Anshul S. and Zhao, Xiang and Blackwell, Danielle and Narang, Ankita and Dean, Wendy and Hemberger, Myriam}, doi = {10.1073/pnas.2420617122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2420617122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phospholipid flippase ATP11A brokers uterine epithelial integrity and function}, volume = {122}, year = {2025}, }
• (2025). Dynamical-generative downscaling of climate model ensembles. PNAS, 122(17), e2420288122. (www)

  @article{ , abstract = {Regional high-resolution climate projections are crucial for many applications, such as agriculture, hydrology, and natural hazard risk assessment. Dynamical downscaling, the state-of-the-art method to produce localized future climate information, involves running a regional climate model (RCM) driven by an Earth System Model (ESM), but it is too computationally expensive to apply to large climate projection ensembles. We propose an approach combining dynamical downscaling with generative AI to reduce the cost and improve the uncertainty estimates of downscaled climate projections. In our framework, an RCM dynamically downscales ESM output to an intermediate resolution, followed by a generative diffusion model that further refines the resolution to the target scale. This approach leverages the generalizability of physics-based models and the sampling efficiency of diffusion models, enabling the downscaling of large multimodel ensembles. We evaluate our method against dynamically downscaled climate projections from the Coupled Model Intercomparison Project 6 (CMIP6) ensemble. Our results demonstrate its ability to provide more accurate uncertainty bounds on future regional climate than alternatives such as dynamical downscaling of smaller ensembles, or traditional empirical statistical downscaling methods. We also show that dynamical-generative downscaling results in significantly lower errors than popular statistical downscaling techniques, and captures more accurately the spectra, tail dependence, and multivariate correlations of meteorological fields. These characteristics make the dynamical-generative framework a flexible, accurate, and efficient way to downscale large ensembles of climate projections, currently out of reach for pure dynamical downscaling.}, archive = {J_PNAS}, author = {Lopez-Gomez, Ignacio and Wan, Zhong Yi and Zepeda-Núñez, Leonardo and Schneider, Tapio and Anderson, John and Sha, Fei}, doi = {10.1073/pnas.2420288122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2420288122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamical-generative downscaling of climate model ensembles}, volume = {122}, year = {2025}, }
• (2025). Mechanism of read-through enhancement by aminoglycosides and mefloquine. PNAS, 122(17), e2420261122. (www)

  @article{ , abstract = {Nonsense mutations are associated with numerous and diverse pathologies, yet effective treatment strategies remain elusive. A promising approach to combat these conditions involves the use of aminoglycosides, particularly in combination with stop-codon read-through enhancers, for developing drugs that can rescue the production of full-length proteins. Using X-ray crystallography and single-particle cryo-EM, we obtained structures of the eukaryotic ribosome in complexes with several aminoglycosides (geneticin G418, paromomycin, and hygromycin B) and the antimalarial drug mefloquine (MFQ), which has also been identified as a read-through enhancer. Our study reveals a binding site of MFQ, which holds significant promise for the development of therapies targeting premature termination codon-related genetic and oncological diseases. The results underscore the crucial role of the bridge B7b/c in mediating the effects of MFQ on subunit rotation dynamics. Through a comprehensive analysis of the interactions between the drugs and the eukaryotic ribosome, we propose a unifying hypothesis for read-through enhancement by small molecules, highlighting the role of decoding center rearrangements and intersubunit rotation dynamics.}, archive = {J_PNAS}, author = {Kolosova, Olga and Zgadzay, Yury and Stetsenko, Artem and Sukhinina, Anastasia P. and Atamas, Anastasia and Validov, Shamil and Rogachev, Andrey and Usachev, Konstantin and Jenner, Lasse and Dmitriev, Sergey E. and Yusupova, Gulnara and Guskov, Albert and Yusupov, Marat}, doi = {10.1073/pnas.2420261122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2420261122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mechanism of read-through enhancement by aminoglycosides and mefloquine}, volume = {122}, year = {2025}, }
• (2025). Host use drives convergent evolution in clownfish. PNAS, 122(17), e2419716122. (www)

  @article{ , abstract = {Clownfishes (Amphiprioninae) are a fascinating example of a marine radiation. From a central Pacific ancestor, they quickly colonized the coral reefs of the Indo-Pacific and diversified independently on each side of the Indo-Australian Archipelago. Their association with sea anemones has been proposed to be a key innovation that enabled the clownfish radiation. However, this intuition has little empirical or theoretical support given our current knowledge of the group. To date, no ecological variable has been identified to explain clownfish niche partitioning, phenotypic evolution, species co-occurrence, and thus, the adaptive aspect of the group’s radiation. Our study solves this long-standing mystery by testing the influence of sea anemone host use on phenotypic divergence. We provide a major revision of the known clownfish-sea anemone host associations, accounting for the biologically relevant aspects of host associations. We gathered whole-genome data for all 28 clownfish species and reconstructed a fully supported species tree for the Amphiprioninae. Integrating this data into comparative genomic approaches, we demonstrate that the host sea anemones are the drivers of convergent evolution in clownfish color pattern and morphology. During the diversification of this group, clownfishes in different regions that associate with the same hosts have evolved similar phenotypes. Comparative genomics also reveals several genes under convergent positive selection linked to host specialization events. Our findings reveal that the sea anemone host plays a crucial role in driving clownfish diversification. This highlights how a strong mutualistic interaction can promote the diversification of entire clades by influencing their phenotypes, defining their geographic distribution, and ultimately contributing to their evolutionary and ecological success.}, archive = {J_PNAS}, author = {Gaboriau, Théo and Marcionetti, Anna and Garcia-Jimenez, Alberto and Schmid, Sarah and Fitzgerald, Lucy M. and Micheli, Baptiste and Titus, Benjamin and Salamin, Nicolas}, doi = {10.1073/pnas.2419716122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2419716122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Host use drives convergent evolution in clownfish}, volume = {122}, year = {2025}, }
• (2025). 40 hz sensory stimulation enhances CA3–CA1 coordination and prospective coding during navigation in a mouse model of alzheimer’s disease. PNAS, 122(17), e2419364122. (www)

  @article{ , abstract = {40 Hz sensory stimulation (“flicker”) has emerged as a new technique to potentially mitigate pathology and improve cognition in mouse models of Alzheimer’s disease (AD) pathology. However, it remains unknown how 40 Hz flicker affects neural codes essential for memory. Accordingly, we investigate the effects of 40 Hz flicker on neural representations of experience in the hippocampus of the 5XFAD mouse model of AD by recording 1,000s of neurons during a goal-directed spatial navigation task. We find that an hour of daily exposure to 40 Hz audio-visual stimulation over 8 d leads to higher coordination between hippocampal subregions CA3 and CA1 during navigation. Consistent with CA3’s role in generating sequential activity that represents future positions, 40 Hz flicker exposure increased prospective coding of future positions. In turn, prospective coding was more prominent during efficient navigation behavior. Our findings show how 40 Hz flicker enhances key hippocampal activity during behavior that is important for memory.}, archive = {J_PNAS}, author = {Paulson, Abigail L. and Zhang, Lu and Prichard, Ashley M. and Singer, Annabelle C.}, doi = {10.1073/pnas.2419364122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2419364122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {40 hz sensory stimulation enhances CA3–CA1 coordination and prospective coding during navigation in a mouse model of alzheimer’s disease}, volume = {122}, year = {2025}, }
• (2025). Evolutionary feedbacks for drosophila aggression revealed through experimental evolution. PNAS, 122(17), e2419068122. (www)

  @article{ , abstract = {Evolutionary feedbacks occur when evolution in one generation alters the environment experienced by subsequent generations and are an expected result of indirect genetic effects (IGEs). Hypotheses abound for the role of evolutionary feedbacks in climate change, agriculture, community dynamics, population persistence, social interactions, the genetic basis of evolution, and more, but evolutionary feedbacks have rarely been directly measured experimentally, leaving open questions about how feedbacks influence evolution. Using experimental evolution, we manipulated the social environment in which aggression was expressed and selected in fruit fly ( Drosophila melanogaster ) populations to allow or limit feedbacks. We selected for increased male–male aggression while allowing either positive, negative, or no feedbacks, alongside unselected controls. We show that populations undergoing negative feedbacks had the weakest evolutionary changes in aggression, while populations undergoing positive evolutionary feedbacks evolved supernormal aggression. Further, the underlying social dynamics evolved only in the negative feedbacks treatment. Our results demonstrate that IGE-mediated evolutionary feedbacks can alter the rate and pattern of behavioral evolution.}, archive = {J_PNAS}, author = {Girardeau, Anna R. and Enochs, Grace E. and Saltz, Julia B.}, doi = {10.1073/pnas.2419068122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2419068122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolutionary feedbacks for drosophila aggression revealed through experimental evolution}, volume = {122}, year = {2025}, }
• (2025). NAT10 exacerbates acute renal inflammation by enhancing n4-acetylcytidine modification of the CCL2/CXCL1 axis. PNAS, 122(17), e2418409122. (www)

  @article{ , abstract = {Inflammation plays an essential role in eliminating microbial pathogens and repairing tissues, while sustained inflammation accelerates kidney damage and disease progression. Therefore, understanding the mechanisms of the inflammatory response is vital for developing therapies for inflammatory kidney diseases like acute kidney injury (AKI), which currently lacks effective treatment. Here, we identified N-acetyltransferase 10 ( NAT10 ) as an important regulator for acute inflammation. NAT10 , the only known “writer” protein for N4-acetylcytidine (ac4C) acetylation, is elevated in renal tubules across various AKI models, human biopsies, and cultured tubular epithelial cells (TECs). Conditional knockout (cKO) of NAT10 in mouse kidneys attenuates renal dysfunction, inflammation, and infiltration of macrophages and neutrophils, whereas its conditional knock-in (cKI) exacerbates these effects. Mechanistically, our findings from ac4C-RIP-seq and RNA-seq analyses revealed that NAT10-mediated ac4C acetylation enhances the mRNA stability of a range of key chemokines, including C-C motif chemokine ligand 2 ( CCL2 ) and C-X-C motif chemokine ligand 1( CXCL1 ), promoting macrophage and neutrophil recruitment and accelerating renal inflammation. Additionally, CCL2 and CXCL1 neutralizing antibodies or their receptor inhibitors, abrogated renal inflammation in NAT10 -overexpression TECs or NAT10 -cKI mice. Importantly, inhibiting NAT10 , either through Adeno-associated virus 9 (AAV9)-mediated silencing or pharmacologically with our found inhibitor Cpd-155, significantly reduces renal inflammation and injury. Thus, targeting the NAT10/CCL2/CXCL1 axis presents a promising therapeutic strategy for treating inflammatory kidney diseases.}, archive = {J_PNAS}, author = {Wang, Jia-nan and Suo, Xiao-guo and Yu, Ju-tao and Luo, Qi-chao and Ji, Ming-lu and Zhang, Meng-meng and Zhu, Qi and Cheng, Xin-ran and Hou, Chao and Chen, Xin and Wang, Fang and Xu, Chuan-hui and Li, Chao and Xie, Shuai-shuai and Wei, Jie and Zhang, Dan-feng and Zhang, Xin-ru and Wang, Zhi-juan and Dong, Yu-hang and Zhu, Sai and Peng, Li-jin and Li, Xiang-yu and Chen, Hai-yong and Xu, Tao and Jin, Juan and Chen, Fei Xavier and Meng, Xiao-ming}, doi = {10.1073/pnas.2418409122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2418409122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {NAT10 exacerbates acute renal inflammation by enhancing n4-acetylcytidine modification of the CCL2/CXCL1 axis}, volume = {122}, year = {2025}, }
• (2025). Proteostasis landscapes of cystic fibrosis variants reveal drug response vulnerability. PNAS, 122(17), e2418407122. (www)

  @article{ , abstract = {Cystic fibrosis (CF) is a lethal genetic disorder caused by variants in CF transmembrane conductance regulator (CFTR). Many variants are treatable with correctors, which enhance the folding and trafficking of CFTR. However, approximately 3% of persons with CF harbor poorly responsive variants. Here, we used affinity purification mass spectrometry proteomics to profile the protein homeostasis (proteostasis) changes of CFTR variants during correction to assess modulated interactions with protein folding and maturation pathways. Responsive variant interactions converged on similar proteostasis pathways during correction. In contrast, poorly responsive variants subtly diverged, revealing a partial restoration of protein quality control surveillance and partial correction. Computational structural modeling showed that corrector VX-445 failed to confer enough NBD1 stability to poor responders. NBD1 secondary stabilizing mutations rescued poorly responsive variants, revealing structural vulnerabilities in NBD1 required for treating poor responders. Our study provides a framework for discerning the underlying protein quality control and structural defects of CFTR variants not reached with existing drugs to expand therapeutics to all susceptible CFTR variants.}, archive = {J_PNAS}, author = {McDonald, Eli Fritz and Kim, Minsoo and Olson, John A. and Meiler, Jens and Plate, Lars}, doi = {10.1073/pnas.2418407122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2418407122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Proteostasis landscapes of cystic fibrosis variants reveal drug response vulnerability}, volume = {122}, year = {2025}, }
• (2025). Relaxation to universal non-maxwellian equilibria in a collisionless plasma. PNAS, 122(17), e2417813122. (www)

  @article{ , abstract = {Generic equilibria are derived for turbulent relaxing plasmas via an entropy-maximization procedure that accounts for the short-time conservation of certain collisionless invariants. The conservation of these collisionless invariants endows the system with a partial “memory” of its prior conditions but is imperfect on long time scales due to the development of a turbulent cascade to small scales, which breaks the precise conservation of phase volume, making this memory imprecise. The equilibria are still determined by the short-time collisionless invariants, but the invariants themselves are driven to a universal form by the nature of the turbulence. This is numerically confirmed for the case of beam instabilities in one-dimensional electrostatic plasmas, where sufficiently strong turbulence appears to cause the distribution function of particle energies to develop a universal power-law tail, with exponent −2.}, archive = {J_PNAS}, author = {Ewart, Robert J. and Nastac, Michael L. and Bilbao, Pablo J. and Silva, Thales and Silva, Luís O. and Schekochihin, Alexander A.}, doi = {10.1073/pnas.2417813122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2417813122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Relaxation to universal non-maxwellian equilibria in a collisionless plasma}, volume = {122}, year = {2025}, }
• (2025). Biofilm architecture determines the dissemination of conjugative plasmids. PNAS, 122(17), e2417452122. (www)

  @article{ , abstract = {Plasmid conjugation is a contact-dependent horizontal gene transfer mechanism that significantly contributes to the dissemination of antibiotic resistance among bacteria. While the molecular mechanisms of conjugation have been extensively studied, our understanding of plasmid transfer dynamics within spatially structured bacterial communities and the influence of community architecture on plasmid dissemination remains limited. In this study, we use live-cell fluorescence microscopy to investigate the propagation of the broad host range RP4 conjugative plasmid in Escherichia coli populations exhibiting varying levels of spatial organization. In high-density, two-dimensional cell monolayers, direct and tight contact between donors and recipients is not only necessary but also sufficient to trigger RP4 plasmid transfer, ensuring optimal plasmid propagation. In three-dimensional mature biofilms, the emergent community architecture limits the ability of donor cells to enter regions with high cell density, which hinders the establishment of direct contacts with recipients and impedes plasmid transfer in biofilms. In contrast, microcolonies, early-stage biofilms, and biofilms with a lower surface coverage leave open access points for donor cells in regions that later emerge as high-cell-density regions in mature biofilms, which facilitates plasmid transfer. These findings reveal the crucial role of bacterial community architecture in determining the efficiency of plasmid dissemination.}, archive = {J_PNAS}, author = {Djermoun, Sarah and Rode, Daniel K. H. and Jiménez-Siebert, Eva and Netter, Niklas and Lesterlin, Christian and Drescher, Knut and Bigot, Sarah}, doi = {10.1073/pnas.2417452122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2417452122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biofilm architecture determines the dissemination of conjugative plasmids}, volume = {122}, year = {2025}, }
• (2025). Comparative analysis of STP6 and STP10 unravels molecular selectivity in sugar transport proteins. PNAS, 122(17), e2417370122. (www)

  @article{ , abstract = {The distribution of sugars is crucial for plant energy, signaling, and defense mechanisms. Sugar Transport Proteins (STPs) are Sugar Porters (SPs) that mediate proton-driven cellular uptake of glucose. Some STPs also transport fructose, while others remain highly selective for only glucose. What determines this selectivity, allowing STPs to distinguish between compounds with highly similar chemical composition, remains unknown. Here, we present the structure of Arabidopsis thaliana STP6 in an inward-occluded conformational state with glucose bound and demonstrate its role as both a glucose and fructose transporter. We perform a comparative analysis of STP6 with the glucose-selective STP10 using in vivo and in vitro systems, demonstrating how different experimental setups strongly influence kinetic transport properties. We analyze the properties of the monosaccharide binding site and show that the position of a single methyl group in the binding site is sufficient to shuffle glucose and fructose specificity, providing detailed insights into the fine-tuned dynamics of affinity-induced specificity for sugar uptake. Altogether, these findings enhance our understanding of sugar selectivity in STPs and more broadly SP proteins.}, archive = {J_PNAS}, author = {Andersen, Camilla Gottlieb and Bavnhøj, Laust and Brag, Søren and Bohush, Anastasiia and Chrenková, Adriana and Driller, Jan Heiner and Pedersen, Bjørn Panyella}, doi = {10.1073/pnas.2417370122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2417370122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Comparative analysis of STP6 and STP10 unravels molecular selectivity in sugar transport proteins}, volume = {122}, year = {2025}, }
• (2025). Mapping the developmental profile of ventricular zone–derived neurons in the human cerebellum. PNAS, 122(17), e2415425122. (www)

  @article{ , abstract = {The cerebellar ventricular zone (VZ) is the primary source of progenitors that generate cerebellar GABAergic neurons, including Purkinje cells (PCs) and interneurons (INs). This study provides detailed characterization of human cerebellar GABAergic neurogenesis using transcriptomic and histopathological analyses and reveals conserved and unique features compared to rodents. We show that the sequential progression of neurogenesis is conserved and occurs before 8 postconception weeks. Notably, PC differentiation occurs in the outer subventricular zone (SVZ), a region absent in the mouse cerebellum. Human PCs are generated during a compact two-week period before the onset of cerebral cortex histogenesis. A subset of human PCs retain proliferative marker expression weeks after leaving the VZ, another feature not observed in rodents. Human PC maturation is protracted with an extensive migration and reorganization throughout development with dendritic arborization developing in late gestation. We define a continuous transcriptional cascade of PC development from neuroepithelial cells to mature PCs. In contrast, while human interneuronal progenitors are born beginning in early fetal development, they exhibit an even more protracted differentiation across late gestation and into postnatal ages. These findings show dynamic developmental process for human cerebellar GABAergic neurons and underscore the importance of the embryonic environment, with early disruptions having potentially significant impacts.}, archive = {J_PNAS}, author = {Erickson, Anders W. and Tan, Henry and Hendrikse, Liam D. and Millman, Jake and Thomson, Zachary and Golser, Joseph and Khan, Omar and He, Guanyi and Bach, Kathleen and Mishra, Arpit Suresh and Kopic, Janja and Krsnik, Zeljka and Encha-Razavi, Ferechte and Petrilli, Giulia and Guimiot, Fabien and Silvestri, Evelina and Aldinger, Kimberly A. and Taylor, Michael D. and Millen, Kathleen J. and Haldipur, Parthiv}, doi = {10.1073/pnas.2415425122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2415425122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mapping the developmental profile of ventricular zone–derived neurons in the human cerebellum}, volume = {122}, year = {2025}, }
• (2025). Thermal homogenization of boreal communities in response to climate warming. PNAS, 122(17), e2415260122. (www)

  @article{ , abstract = {Globally, rising temperatures are increasingly favoring warm-affiliated species. Although changes in community composition are typically measured by the mean temperature affinity of species (the community temperature index, CTI), they may be driven by different processes and accompanied by shifts in the diversity of temperature affinities and breadth of species thermal niches. To resolve the pathways to community warming in Finnish flora and fauna, we examined multidecadal changes in the dominance and diversity of temperature affinities among understory forest plant, freshwater phytoplankton, butterfly, moth, and bird communities. CTI increased for all animal communities, with no change observed for plants or phytoplankton. In addition, the diversity of temperature affinities declined for all groups except butterflies, and this loss was more pronounced for the fastest-warming communities. These changes were driven in animals mainly by a decrease in cold-affiliated species and an increase in warm-affiliated species. In plants and phytoplankton the decline of thermal diversity was driven by declines of both cold- and warm-affiliated species. Plant and moth communities were increasingly dominated by thermal specialist species, and birds by thermal generalists. In general, climate warming outpaced changes in both the mean and diversity of temperature affinities of communities. Our results highlight the complex dynamics underpinning the thermal reorganization of communities across a large spatiotemporal gradient, revealing that extinctions of cold-affiliated species and colonization by warm-affiliated species lag behind changes in ambient temperature, while communities become less thermally diverse. Such changes can have important implications for community structure and ecosystem functioning under accelerating rates of climate change.}, archive = {J_PNAS}, author = {Mäkinen, Jussi and Ellis, Emilie E. and Antão, Laura H. and Davrinche, Andréa and Laine, Anna-Liisa and Saastamoinen, Marjo and Conenna, Irene and Hällfors, Maria and Santangeli, Andrea and Kaarlejärvi, Elina and Heliölä, Janne and Huikkonen, Ida-Maria and Kuussaari, Mikko and Leinonen, Reima and Lehikoinen, Aleksi and Pöyry, Juha and Suuronen, Anna and Salemaa, Maija and Tonteri, Tiina and Vuorio, Kristiina M. and Skjelbred, Birger and Järvinen, Marko and Drakare, Stina and Carvalho, Laurence and Welk, Erik and Seidler, Gunnar and Vangansbeke, Pieter and Máliš, František and Hédl, Radim and Auffret, Alistair G. and Plue, Jan and De Frenne, Pieter and Kalwij, Jesse M. and Vanhatalo, Jarno and Roslin, Tomas}, doi = {10.1073/pnas.2415260122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2415260122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Thermal homogenization of boreal communities in response to climate warming}, volume = {122}, year = {2025}, }
• (2025). Conserved c143 forms a branched intermediate in hedgehog autoprocessing: A cancer drug discovery target against hedgehog signaling. PNAS, 122(17), e2415144122. (www)

  @article{ , abstract = {Hedgehog (Hh) signaling plays fundamental roles in embryonic development while its abnormal activation in adults is associated with cancer. Hh targeting drugs have gained FDA approval but resistance emerged quickly, underlining the need for novel types of Hh inhibitors. Hh signaling is initiated by the Hh ligand, generated from the autoprocessing of Hh precursor. However, the catalytic role of a highly conserved Hedgehog residue C143 is still poorly understood. Here, we confirmed that C143 is required for Hh autoprocessing in mammalian cells. NMR titration showed that C143 has an extremely low pK a of 4.5, befitting a highly reactive catalytic residue. We further established that Hh autoprocessing involves a branched intermediate (BI) with two N-termini, formed as a thioester on the C143 sidechain. BI migrates slower than the linear Hh precursor on SDS-PAGE and disappears with DTT treatment. With trypsin digestion and LC–MS/MS, we detected the N-terminal fragment from BI, which is absent from the linear Hh precursor. Therefore, C143 mediates the formation of a BI thioester in Hh autoprocessing, with a catalytic role equivalent to C + 1 in intein splicing. These findings bring us closer to a full mechanistic understanding of Hh autoprocessing while unifying the first two catalytic steps of Hh autoprocessing with intein splicing, its likely evolutionary predecessor. C143 can also serve as a target for covalent drugs for inhibiting Hh signaling in cancer.}, archive = {J_PNAS}, author = {Faris, Shannon and Xia, Ke and Wagner, Andrew G. and Xu, Zihan and Smith, Nathan and Giner, José-Luis and Callahan, Brian and Xie, Jian and Wang, Chunyu}, doi = {10.1073/pnas.2415144122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2415144122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Conserved c143 forms a branched intermediate in hedgehog autoprocessing: A cancer drug discovery target against hedgehog signaling}, volume = {122}, year = {2025}, }
• (2025). Mixing individual and collective behaviors to predict out-of-routine mobility. PNAS, 122(17), e2414848122. (www)

  @article{ , abstract = {Predicting human displacements is crucial for addressing various societal challenges, including urban design, traffic congestion, epidemic management, and migration dynamics. While predictive models like deep learning and Markov models offer insights into individual mobility, they often struggle with out-of-routine behaviors. Our study introduces an approach that dynamically integrates individual and collective mobility behaviors, leveraging collective intelligence to enhance prediction accuracy. Evaluating the model on millions of privacy-preserving trajectories across five US cities, we demonstrate its superior performance in predicting out-of-routine mobility, surpassing even advanced deep learning methods. The spatial analysis highlights the model’s effectiveness near urban areas with a high density of points of interest, where collective behaviors strongly influence mobility. During disruptive events like the COVID-19 pandemic, our model retains predictive capabilities, unlike individual-based models. By bridging the gap between individual and collective behaviors, our approach offers transparent and accurate predictions, which are crucial for addressing contemporary mobility challenges.}, archive = {J_PNAS}, author = {Bontorin, Sebastiano and Centellegher, Simone and Gallotti, Riccardo and Pappalardo, Luca and Lepri, Bruno and Luca, Massimiliano}, doi = {10.1073/pnas.2414848122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2414848122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mixing individual and collective behaviors to predict out-of-routine mobility}, volume = {122}, year = {2025}, }
• (2025). A diverse single-stranded DNA–annealing protein library enables efficient genome editing across bacterial phyla. PNAS, 122(17), e2414342122. (www)

  @article{ , abstract = {Genome modification is essential for studying and engineering bacteria, yet making efficient modifications to most species remains challenging. Bacteriophage-encoded single-stranded DNA–annealing proteins (SSAPs) can facilitate efficient genome editing by homologous recombination, but their typically narrow host range limits broad application. Here, we demonstrate that a single library of 227 SSAPs enables efficient genome-editing across six diverse bacteria from three divergent classes: Actinomycetia ( Mycobacterium smegmatis and Corynebacterium glutamicum ), Alphaproteobacteria ( Agrobacterium tumefaciens and Caulobacter crescentus ), and Bacilli ( Lactococcus lactis and Staphylococcus aureus ). Surprisingly, the most effective SSAPs frequently originated from phyla distinct from their bacterial hosts, challenging the assumption that phylogenetic relatedness is necessary for recombination efficiency, and supporting the value of a large unbiased library. Across these hosts, the identified SSAPs enable genome modifications requiring efficient homologous recombination, demonstrated through three examples. First, we use SSAPs with Cas9 in C. crescentus to introduce single amino acid mutations with >70% efficiency. Second, we adapt SSAPs for dsDNA editing in C. glutamicum and S. aureus , enabling one-step gene knockouts using PCR products. Finally, we apply SSAPs for multiplexed editing in S. aureus to precisely map the interaction between a conserved protein and a small-molecule inhibitor. Overall, this library-based SSAP screen expands engineering capabilities across diverse, previously recalcitrant microbes, enabling efficient genetic manipulation for both fundamental research and biotechnological applications.}, archive = {J_PNAS}, author = {Filsinger, Gabriel T. and Mychack, Aaron and Lyerly, Evan and Henriksen, Camilla and Bartlett, Thomas M. and Kuchwara, Helene and Eitzinger, Simon and Bernhardt, Thomas G. and Walker, Suzanne and Church, George M. and Wannier, Timothy M.}, doi = {10.1073/pnas.2414342122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2414342122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A diverse single-stranded DNA–annealing protein library enables efficient genome editing across bacterial phyla}, volume = {122}, year = {2025}, }
• (2025). Annihilation-limited long-range exciton transport in high-mobility conjugated copolymer films. PNAS, 122(17), e2413850122. (www)

  @article{ , abstract = {A combination of ultrafast, long-range, and low-loss excitation energy transfer from the photoreceptor location to a functionally active site is essential for cost-effective polymeric semiconductors. Delocalized electronic wavefunctions along π-conjugated polymer (CP) backbone can enable efficient intrachain transport, while interchain transport is generally thought slow and lossy due to weak chain–chain interactions. In contrast to the conventional strategy of mitigating structural disorder, amorphous layers of rigid CPs, exemplified by highly planar poly(indacenodithiophene-co-benzothiadiazole) (IDT-BT) donor-accepter copolymer, exhibit trap-free transistor performance and charge-carrier mobilities similar to amorphous silicon. Here, we report long-range exciton transport in HJ -aggregated IDTBT thin-film, in which the competing exciton transport and exciton–exciton annihilation (EEA) dynamics are spectroscopically separated using a phase-cycling-based scheme and shown to depart from the classical diffusion-limited and strong-coupling regime. In the thin film, we find an annihilation-limited mechanism with ≪100% per-encounter annihilation probability, facilitating the minimization of EEA-induced excitation losses. In contrast, excitons on isolated IDTBT chains diffuse over 350 nm with 0.56 cm 2 s −1 diffusivity, before eventually annihilating with unit probability on first contact. We complement the pump–probe studies with temperature-dependent photocurrent and EEA measurements from 295 K to 77 K and find a remarkable correspondence of annihilation rate and photocurrent activation energies in the 140 K to 295 K temperature range.}, archive = {J_PNAS}, author = {Shi, Yuping and Roy, Partha P. and Higashitarumizu, Naoki and Lee, Tsung-Yen and Li, Quanwei and Javey, Ali and Landfester, Katharina and McCulloch, Iain and Fleming, Graham R.}, doi = {10.1073/pnas.2413850122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2413850122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Annihilation-limited long-range exciton transport in high-mobility conjugated copolymer films}, volume = {122}, year = {2025}, }
• (2025). Neuronal autophagy controls excitability via ryanodine receptor–mediated regulation of calcium-activated potassium channel function. PNAS, 122(17), e2413651122. (www)

  @article{ , abstract = {Glutamate-mediated neuronal hyperexcitation plays a causative role in eliciting seizures and promoting epileptogenesis. Recent data suggest that altered autophagy can contribute to the occurrence of epilepsy. We examined the role of autophagy in neuronal physiology by generating knockout mice conditionally lacking the essential autophagy protein ATG5 in glutamatergic neurons. We demonstrate that conditional genetic blockade of neuronal autophagy results in action potential narrowing, axonal hyperexcitability, and an increase in kainate-induced epileptiform bursts ex vivo, indicative of a lower threshold for the induction of epileptic seizures. Neuronal hyperexcitability in hippocampal slices from conditional ATG5 knockout mice is due to elevated activity of the large conductance calcium-activated potassium channel BKCa downstream of calcium influx via the endoplasmic reticulum (ER)-localized calcium channel ryanodine receptor (RYR). Consistently, pharmacological blockade of RYR or BKCa function rescued hyperexcitability and reduced the frequency of kainate-induced epileptiform bursts in ATG5 cKO brain slices. Our findings reveal a physiological role for neuronal autophagy in the regulation of neuronal excitability via the control of RYR-mediated calcium release, and thereby, calcium-activated potassium channel function in the mammalian brain.}, archive = {J_PNAS}, author = {Kochlamazashvili, Gaga and Swaminathan, Aarti and Stumpf, Alexander and Kumar, Amit and Posor, York and Schmitz, Dietmar and Haucke, Volker and Kuijpers, Marijn}, doi = {10.1073/pnas.2413651122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2413651122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neuronal autophagy controls excitability via ryanodine receptor–mediated regulation of calcium-activated potassium channel function}, volume = {122}, year = {2025}, }
• (2025). Pathogen growth and virulence dynamics drive the host evolution against coinfections. PNAS, 122(17), e2412124122. (www)

  @article{ , abstract = {The occurrence of coinfections, where hosts are simultaneously infected by multiple pathogens, is widespread in nature and has significant negative impacts on global health. In humans, over one-sixth of the world’s population is affected by coinfections, contributing to several diseases. However, despite the broad ecological relevance and impact on global health, most biomedical research has focused on understanding interactions between a single host and a single pathogen. The extent to which coinfections could impact host adaptation and immune system evolution, particularly in comparison to infections by single pathogens, thus remains largely unknown. Also, what roles do individual pathogen species play in this evolutionary process? To address these questions, in this study, we combined theoretical modeling and experimental validation in a model insect Tribolium castaneum evolving against two coinfecting bacterial pathogens with contrasting growth (e.g., fast- vs slow-growing) and virulence (fast- vs slow-killing) dynamics. Our findings show that fast-growing pathogens causing rapid mortality surges (i.e., fast-acting) can effectively limit the host’s adaptive success against coinfections. While hosts rapidly evolved better survival against slow-growing bacteria causing long-lasting infections, adaptation against coinfections was significantly delayed and resembled the slow rate of adaptation against fast-acting pathogens. Finally, RNAseq analyses revealed that the observed delay in adaptation was associated with the limited scopes for suitable immune modulations against fast-acting pathogens. They might also be costly and pleiotropic (e.g., phenoloxidase activity), posing challenges for further immunomodulation and slowing adaptation. Our study thus highlights how individual pathogens’ growth and virulence dynamics critically regulate adaptive responses against coinfections.}, archive = {J_PNAS}, author = {Seal, Srijan and Basu, Dipendra Nath and Ghosh, Kripanjali and Ramachandran, Aryan and Kutum, Rintu and Shelke, Triveni and Gupta, Ishaan and Khan, Imroze}, doi = {10.1073/pnas.2412124122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2412124122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pathogen growth and virulence dynamics drive the host evolution against coinfections}, volume = {122}, year = {2025}, }
• (2025). Mitigation justice. PNAS, 122(17), e2411231122. (www)

  @article{ , abstract = {Mitigating climate change and social injustice are critical, interwoven challenges. Climate change is driven by grossly unequal contributions to elevated greenhouse gas emissions among individuals, socioeconomic groups, and nations. Yet, its deleterious impacts disproportionately affect poor and less powerful nations, and the poor and the less powerful within each nation. This climate injustice prompts a call for mitigation strategies that buffer the poorest and the most vulnerable against climate change impacts. Unfortunately, all emissions mitigation strategies also reshape social, economic, political, and ecological processes in ways that may create climate change mitigation injustices—i.e., a unique set of injustices not caused by climate change, but by the strategies designed to stem it. Failing to stop climate change is not an answer—this will swamp all adverse impacts of even unjust mitigation in terms of the scope and scale of disastrous consequences. However, mitigation without justice will create uniquely negative consequences for the more vulnerable. The ensuing analysis systematically assesses how climate change mitigation strategies can generate or ameliorate injustices. We first examine how climate science and social justice interact within and among countries. We then ask what there is to learn from the available evidence on how emissions reductions, well-being, and equity have unfolded in a set of countries. Finally, we discuss the intersection between emissions reduction and mitigation justice through actions in important domains including energy, technology, transport, and food systems; nature-based solutions; and policy and governance.}, archive = {J_PNAS}, author = {Reich, Peter B. and Grace, Kathryn and Agrawal, Arun and Nagendra, Harini}, doi = {10.1073/pnas.2411231122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2411231122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mitigation justice}, volume = {122}, year = {2025}, }
• (2025). Computational analysis of 100 k choice dilemmas: Decision attributes, trade-off structures, and model-based prediction. PNAS, 122(17), e2406489122. (www)

  @article{ , abstract = {We present a dataset of over 100 K textual descriptions of real-life choice dilemmas, obtained from social media posts and large-scale survey data. Using large language models (LLMs), we extract hundreds of choice attributes at play in these dilemmas and map them onto a common representational space. This representation allows us to quantify the broader themes and specific trade-offs inherent in life choices and analyze how they vary across different contexts. We also present our dilemmas to human participants and find that our LLM pipeline, when combined with established decision models, accurately predicts people’s choices, outperforming models based on unstructured textual content, demographics, and personality. In this way, our research provides insights into the attributes, outcomes, and goals that underpin life choices, and shows how large-scale LLM-based structure extraction can be used in combination with existing scientific theory to study complex real-world human behavior.}, archive = {J_PNAS}, author = {Bhatia, Sudeep and van Baal, Simon T. and Wang, Feiyi and Walasek, Lukasz}, doi = {10.1073/pnas.2406489122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2406489122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Computational analysis of 100 k choice dilemmas: Decision attributes, trade-off structures, and model-based prediction}, volume = {122}, year = {2025}, }
• (2025). Trophic convergence of marine vertebrate communities worldwide. PNAS, 122(17), e2403754122. (www)

  @article{ , abstract = {Biogeographic regions arise due to constraints on species ranges, fostering lineage divergence as a result. Yet, convergent evolution means that evolutionary distinct lineages can share similar characteristics when subjected to similar environmental conditions. The ecological convergence of distinct regions has been demonstrated in terrestrial communities, but it remains uncertain if marine systems exhibit similar patterns, given the greater ease of dispersal in the ocean. Using information on the dietary preferences of marine vertebrates, we develop an ocean regionalization that groups regions with similar trophic communities, describing how species are organized into trophic guilds and how guilds overlap with one another. Six types of trophic communities emerge globally, largely explained by temperature, productivity, and depth. Regions with analogous environments support similar numbers of species with analogous feeding strategies, even if the species do not share the same evolutionary origins. These findings support the notion that independently evolving sets of marine species can converge into functionally analogous trophic communities when exposed to similar environmental conditions. They also provide a benchmark for studying the functional consequences of global environmental change.}, archive = {J_PNAS}, author = {González-Trujillo, Juan David and Assis, Jorge and Serrão, Ester and Costello, Mark John and Fragkopoulou, Eliza and Mendoza, Manuel and Araújo, Miguel B.}, doi = {10.1073/pnas.2403754122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2403754122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Trophic convergence of marine vertebrate communities worldwide}, volume = {122}, year = {2025}, }
• (2025). Structure in conversation: Evidence for the vocabulary, semantics, and syntax of prosody. PNAS, 122(17), e2403262122. (www)

  @article{ , abstract = {Prosody, the musical facet of speech, is pivotal in human communication, and its structure and meaning remain subjects of ongoing research. In this study, we introduce a data-driven model for English prosody, based on large-scale analysis of spontaneous conversations. As a first step, we identify approximately 200 discernible prosodic patterns—which we view as building blocks of the prosodic vocabulary—and outline their properties and range of meanings. Next, we reveal a Markovian logic, akin to a syntax, for concatenating these elementary building blocks into coherent utterances. We identify distinct compound functions associated with pairs of consecutive patterns and show that the Markovian syntax is more prevalent in spontaneous prosody, as compared to scripted speech. These findings offer invaluable insights into the underlying mechanisms of conversational prosody: They empirically inform and refine existing theoretical concepts. The methodology we present, combining unsupervised analysis of large datasets of spontaneous speech with manual sampling of the results, could guide future research aimed at refining our model and expanding it to other languages.}, archive = {J_PNAS}, author = {Matalon, Nadav and Weinreb, Eyal and Freche, Dominik and Volk, Erez and Biron, Tirza and Moses, Elisha and Biron, David}, doi = {10.1073/pnas.2403262122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {17}, pages = {e2403262122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure in conversation: Evidence for the vocabulary, semantics, and syntax of prosody}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(16), eiti1625122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti1625122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {eiti1625122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Correction for gasparin et al., combining exchangeable P-values. PNAS, 122(16), e2507343122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2507343122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2507343122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for gasparin et al., combining exchangeable P-values}, volume = {122}, year = {2025}, }
• (2025). QnAs with nora newcombe. PNAS, 122(16), e2507333122. (www)

  @article{ , archive = {J_PNAS}, author = {Ravindran, Sandeep}, doi = {10.1073/pnas.2507333122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2507333122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {QnAs with nora newcombe}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for li et al., primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia. PNAS, 122(16), e2507216122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2507216122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2507216122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for li et al., primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia}, volume = {122}, year = {2025}, }
• (2025). Is killing animals an effective way to regulate populations?. PNAS, 122(16), e2506919122. (www)

  @article{ , archive = {J_PNAS}, author = {McDermott, Amy}, doi = {10.1073/pnas.2506919122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2506919122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Is killing animals an effective way to regulate populations?}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for nishiguchi et al., vortex reversal is a precursor of confined bacterial turbulence. PNAS, 122(16), e2506387122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2506387122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2506387122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for nishiguchi et al., vortex reversal is a precursor of confined bacterial turbulence}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for moreno-spiegelberg et al., how spatiotemporal dynamics can enhance ecosystem resilience. PNAS, 122(16), e2506282122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2506282122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2506282122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for moreno-spiegelberg et al., how spatiotemporal dynamics can enhance ecosystem resilience}, volume = {122}, year = {2025}, }
• (2025). Tearing down the house of mosquito-transmitted viruses. PNAS, 122(16), e2504932122. (www)

  @article{ , archive = {J_PNAS}, author = {Pandey, Shanti and Gack, Michaela U.}, doi = {10.1073/pnas.2504932122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2504932122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tearing down the house of mosquito-transmitted viruses}, volume = {122}, year = {2025}, }
• (2025). In the flow, how fluid dynamics shapes amyloid formation. PNAS, 122(16), e2504573122. (www)

  @article{ , archive = {J_PNAS}, author = {Willis, Leon F. and Brockwell, David J. and Radford, Sheena E.}, doi = {10.1073/pnas.2504573122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2504573122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In the flow, how fluid dynamics shapes amyloid formation}, volume = {122}, year = {2025}, }
• (2025). European neolithic farmers interbred their domestic pigs with wild boar. PNAS, 122(16), e2504472122. (www)

  @article{ , archive = {J_PNAS}, author = {Rowley-Conwy, Peter}, doi = {10.1073/pnas.2504472122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2504472122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {European neolithic farmers interbred their domestic pigs with wild boar}, volume = {122}, year = {2025}, }
• (2025). Design principles for self-organization of mitotic spindle bipolarity. PNAS, 122(16), e2504470122. (www)

  @article{ , archive = {J_PNAS}, author = {Mitchison, Timothy J.}, doi = {10.1073/pnas.2504470122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2504470122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Design principles for self-organization of mitotic spindle bipolarity}, volume = {122}, year = {2025}, }
• (2025). Correction for sahi and craig, network of general and specialty j protein chaperones of the yeast cytosol. PNAS, 122(16), e2504093122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504093122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2504093122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for sahi and craig, network of general and specialty j protein chaperones of the yeast cytosol}, volume = {122}, year = {2025}, }
• (2025). Correction for yardeni et al., mitochondrial DNA lineages determine tumor progression through t cell reactive oxygen signaling. PNAS, 122(16), e2503874122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2503874122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2503874122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for yardeni et al., mitochondrial DNA lineages determine tumor progression through t cell reactive oxygen signaling}, volume = {122}, year = {2025}, }
• (2025). Functional redundancy in the toxic pathway of bt protein Cry1Ab, but not Cry1Fa, against the asian corn borer. PNAS, 122(16), e2503674122. (www)

  @article{ , abstract = {Crops genetically engineered to produce insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) have been used extensively to control some major crop pests, but their benefits decrease when pests evolve resistance. Better understanding of the genetic basis of resistance is needed to effectively monitor, manage, and counter pest resistance to Bt crops. Resistance to Bt proteins in at least 11 species of Lepidoptera, including many important crop pests, is associated with naturally occurring mutations that disrupt one or more of three larval midgut proteins: cadherin and ATP-binding cassette proteins ABCC2 and ABCC3. Here, we determined how CRISPR/Cas9-mediated mutations disrupting cadherin, ABCC2, and ABCC3 singly and in pairs affect resistance to Bt proteins Cry1Ab and Cry1Fa in the Asian corn borer ( Ostrinia furnacalis ), which is the most damaging pest of corn in Asia and is closely related to the European corn borer ( Ostrinia nubilalis ), a major pest in Europe and North America. The results from bioassays of six knockout strains and their parent susceptible strain support a model in which Cry1Ab can kill larvae via one path requiring ABCC2 or another path requiring cadherin and ABCC3, whereas Cry1Fa uses only the first path. The model’s predictions are generally supported by results from genetic linkage analyses and responses to Cry1Ab and Cry1Fa of Sf9 cells and Xenopus oocytes modified to produce cadherin, ABCC2, and ABCC3 singly or in pairs. The functional redundancy identified here for Cry1Ab could sustain its efficacy against O. furnacalis and may exemplify a widespread natural strategy for delaying resistance.}, archive = {J_PNAS}, author = {Wang, Xingliang and Yue, Yujin and Zhai, Yuqian and Wang, Falong and Zhuang, Xuna and Wu, Shuwen and Yang, Yihua and Tabashnik, Bruce E. and Wu, Yidong}, doi = {10.1073/pnas.2503674122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2503674122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Functional redundancy in the toxic pathway of bt protein Cry1Ab, but not Cry1Fa, against the asian corn borer}, volume = {122}, year = {2025}, }
• (2025). RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis. PNAS, 122(16), e2503531122. (www)

  @article{ , abstract = {Mitochondrial DNA (mtDNA) replication requires a steady supply of deoxyribonucleotides (dNTPs), synthesized de novo by ribonucleotide reductase (RNR). In nondividing cells, RNR consists of RRM1 and RRM2B subunits. Mutations in RRM2B cause mtDNA depletion syndrome, linked to muscle weakness, neurological decline, and early mortality. The impact of RRM2B deficiency on dNTP pools in nondividing tissues remains unclear. Using a mouse knockout model, we demonstrate that RRM2B deficiency selectively depletes dATP and dGTP, while dCTP and dTTP levels remain stable or increase. This depletion pattern resembles the effects of hydroxyurea, an inhibitor that reduces overall RNR activity. Mechanistically, we propose that the depletion of dATP and dGTP arises from their preferred degradation by the dNTPase SAMHD1 and the lower production rate of dATP by RNR. Identifying dATP and dGTP depletion as a hallmark of RRM2B deficiency provides insights for developing nucleoside bypass therapies to alleviate the effects of RRM2B mutations.}, archive = {J_PNAS}, author = {Awoyomi, Ololade Folajimi and Gorospe, Choco Michael and Das, Biswajit and Mishra, Pradeep and Sharma, Sushma and Diachenko, Olena and Nilsson, Anna Karin and Tran, Phong and Wanrooij, Paulina H. and Chabes, Andrei}, doi = {10.1073/pnas.2503531122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2503531122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis}, volume = {122}, year = {2025}, }
• (2025). The evolution of robustness and fragility during long-term bacterial adaptation. PNAS, 122(16), e2501901122. (www)

  @article{ , abstract = {Theory predicts that well-adapted populations may evolve mechanisms to counteract the inevitable influx of deleterious mutations. While mutational robustness can be directly selected in the laboratory, evidence for its spontaneous evolution during general adaptation is mixed. Moreover, whether robustness evolves to include pleiotropic effects remains largely unexplored. Here, we studied the effects of point mutations in the RNA polymerase of Escherichia coli over a 15,000-generation adaptive trajectory. Fitness effects of both beneficial and deleterious mutations were attenuated in fitter backgrounds. In contrast, pleiotropic effects became more severe and widespread with greater adaptation. These results show that trade-offs between robustness and fragility can evolve in regulatory networks, regardless of whether driven by adaptive or nonadaptive processes. More broadly, they illustrate how adaptation can generate hidden variability, with unpredictable evolutionary consequences in new environments.}, archive = {J_PNAS}, author = {Chihoub, Doha and Pintard, Coralie and Lenski, Richard E. and Tenaillon, Olivier and Couce, Alejandro}, doi = {10.1073/pnas.2501901122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2501901122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The evolution of robustness and fragility during long-term bacterial adaptation}, volume = {122}, year = {2025}, }
• (2025). Development of DPP-4-resistant CXCL9-fc and CXCL10-fc chemokines for effective cancer immunotherapy. PNAS, 122(16), e2501791122. (www)

  @article{ , abstract = {CXCR3 is a chemokine receptor for three ligands: CXCL9, CXCL10, and CXCL11. Accumulating evidence, including data presented here, suggests that the interaction between CXCL9/CXCL10 and CXCR3 not only attracts CXCR3+ T cells but also promotes the induction of IFNγ- high effector/cytotoxic CD4+ and CD8+ T cells, establishing a CXCL9/10-CXCR3-IFNγ self-amplifying cycle that promotes efficient cancer cell killing. One of the homeostatic mechanisms that may limit this cycle is the cleavage of the two N-terminal amino acids of these chemokines by Dipeptidyl Peptidase IV (DPP-4). The modified chemokines retain their ability to bind CXCR3 but no longer activate it, becoming competitive antagonists to native CXCL9/CXCL10. To develop a DPP-4-resistant variant, we combined biochemical analysis with computational modeling, demonstrating that the addition of N-terminal glutamine (Q) to CXCL9-Fc and CXCL10-Fc rendered them fully active CXCR3 agonists, yet resistant to DPP-4 cleavage. Preclinical evaluations imply that they offer significant therapeutic potential in cancer immunotherapy.}, archive = {J_PNAS}, author = {Lugassy, Jennie and Abdala-Saleh, Noor and Jarrous, Ghada and Turky, Abeer and Saidemberg, Daniel and Ridner-Bahar, Gabriela and Berger, Nir and Bar-On, Dana and Taura, Tetsuya and Wilson, David and Karin, Nathan}, doi = {10.1073/pnas.2501791122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2501791122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Development of DPP-4-resistant CXCL9-fc and CXCL10-fc chemokines for effective cancer immunotherapy}, volume = {122}, year = {2025}, }
• (2025). Structural basis of excitatory amino acid transporter 3 substrate recognition. PNAS, 122(16), e2501627122. (www)

  @article{ , abstract = {Excitatory amino acid transporters (EAATs) reside on cell surfaces and uptake substrates, including L-glutamate, L-aspartate, and D-aspartate, using ion gradients. Among five EAATs, EAAT3 is the only isoform that can efficiently transport L-cysteine, a substrate for glutathione synthesis. Recent studies suggest that EAAT3 also transports the oncometabolite R-2-hydroxyglutarate (R-2HG). Here, we examined the structural basis of substrate recognition by determining the cryogenic electron microscopy (cryo-EM) structures of EAAT3 bound to different substrates. We found that L-cysteine binds to EAAT3 in thiolate form, and EAAT3 recognizes different substrates by fine-tuning local conformations of the coordinating residues. However, using purified human EAAT3, we could not observe R-2HG binding or transport. Imaging of EAAT3 bound to L-cysteine revealed several conformational states, including an outward-facing state with a semi-open gate and a disrupted sodium-binding site. These structures demonstrate that the full gate closure, coupled with the binding of the last sodium ion, occurs after substrate binding. Furthermore, we observed that different substrates affect how the transporter distributes between a fully outward-facing conformation and intermediate occluded states on a path to the inward-facing conformation, suggesting that translocation rates are substrate-dependent.}, archive = {J_PNAS}, author = {Qiu, Biao and Boudker, Olga}, doi = {10.1073/pnas.2501627122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2501627122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis of excitatory amino acid transporter 3 substrate recognition}, volume = {122}, year = {2025}, }
• (2025). Protein phosphatase 1 regulatory subunit 3C integrates cholesterol metabolism and isocitrate dehydrogenase in chondrocytes and neoplasia. PNAS, 122(16), e2501519122. (www)

  @article{ , abstract = {Enchondromas are common bone tumors composed of chondrocytes originating from growth plate cells which can progress to malignant chondrosarcoma. Mutations in the genes encoding isocitrate dehydrogenase (IDH1 and IDH2) are identified in a large proportion of these tumors. IDH enzymes convert isocitrate to alpha-ketoglutarate (α-KG), an essential component of the citric acid cycle. While mutant IDH enzymes produce 2-hydroxyglutarate, which has epigenetic effects important in tumor initiation, cell maintenance and growth rely on additional factors. Prior work shows that intracellular cholesterol and glycogen are upregulated in mutant IDH chondrocytes. Here, we show that Protein Phosphatase 1 Regulatory Subunit 3C (PPP1R3C, previously termed Protein Targeting to Glycogen or PTG) is highly expressed in chondrocytes harboring a mutant IDH. Furthermore, Sterol Regulatory Element-Binding Proteins (SREBPs), transcriptional regulators of sterol biosynthesis, regulate PPP1R3C expression. We found that PPP1R3C regulates glycolysis and glycolytic capacity in chondrocytes. Depletion of PPP1R3C in mouse chondrocytes in vivo suppresses the neoplastic phenotype. The growth plate phenotype associated with the genetic inhibition of cholesterol biosynthesis is partially rescued by PPP1R3C overexpression. Taken together, our data show that PPP1R3C integrates cholesterol metabolism and isocitrate dehydrogenase in growth plate and neoplastic chondrocyte metabolism by regulating intracellular glycogen levels.}, archive = {J_PNAS}, author = {Nakagawa, Makoto and Shimada, Eijiro and Guardino, Nicholas and Miyamoto, Ryo and Puviindran, Vijitha and Peairs, Emily and Matarangas, Ariana and Ishikawa, Koji and Nguyen, Tuyet and Browne, Makenna and Marius, Choiselle and Wallace, Asjah and Hirata, Makoto and Nadesan, Puviindran and Alman, Benjamin A.}, doi = {10.1073/pnas.2501519122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2501519122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Protein phosphatase 1 regulatory subunit 3C integrates cholesterol metabolism and isocitrate dehydrogenase in chondrocytes and neoplasia}, volume = {122}, year = {2025}, }
• (2025). Generating the polymorph landscapes of amyloid fibrils using AI: RibbonFold. PNAS, 122(16), e2501321122. (www)

  @article{ , abstract = {The concept that proteins are selected to fold into a well-defined native state has been effectively addressed within the framework of energy landscapes, underpinning the recent successes of structure prediction tools like AlphaFold. The amyloid fold, however, does not represent a unique minimum for a given single sequence. While the cross- β hydrogen-bonding pattern is common to all amyloids, other aspects of amyloid fiber structures are sensitive not only to the sequence of the aggregating peptides but also to the experimental conditions. This polymorphic nature of amyloid structures challenges structure predictions. In this paper, we use AI to explore the landscape of possible amyloid protofilament structures composed of a single stack of peptides aligned in a parallel, in-register manner. This perspective enables a practical method for predicting protofilament structures of arbitrary sequences: RibbonFold. RibbonFold is adapted from AlphaFold2, incorporating parallel in-register constraints within AlphaFold2’s template module, along with an appropriate polymorphism loss function to address the structural diversity of folds. RibbonFold outperforms AlphaFold2/3 on independent test sets, achieving a mean TM-score of 0.5. RibbonFold proves well-suited to study the polymorphic landscapes of widely studied sequences with documented polymorphisms. The resulting landscapes capture these observed polymorphisms effectively. We show that while well-known amyloid-forming sequences exhibit a limited number of plausible polymorphs on their “solubility” landscape, randomly shuffled sequences with the same composition appear to be negatively selected in terms of their relative solubility. RibbonFold is a valuable framework for structurally characterizing amyloid polymorphism landscapes.}, archive = {J_PNAS}, author = {Guo, Liangyue and Yu, Qilin and Wang, Di and Wu, Xiaoyu and Wolynes, Peter G. and Chen, Mingchen}, doi = {10.1073/pnas.2501321122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2501321122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Generating the polymorph landscapes of amyloid fibrils using AI: RibbonFold}, volume = {122}, year = {2025}, }
• (2025). Steeper social discounting after human basolateral amygdala damage. PNAS, 122(16), e2500692122. (www)

  @article{ , abstract = {Translational research suggests that the basolateral part of the amygdala (BLA) computes some of the core processes underlying social preferences, but its precise role in prosocial choice remains unclear. We hypothesize that the human BLA is not necessary for prosocial behavior per se, but fine-tunes the degree of prosociality as a function of the social distance between actor and recipient of a prosocial act. We tested five participants with Urbach–Wiethe disease (UWD) who had isolated, bilateral damage to BLA and compared their behavior in a modified dictator game to that of 16 healthy control participants matched for (neuro-) psychological traits and cultural and socioeconomic background. In this game, participants selected eight people from their social environment and assigned them to variable social distance levels ranging from 1 (emotionally closest person) to 100 (random stranger on the street). They decided how much of a monetary endowment they would share with each person at each social distance. Compared to controls, UWD participants were less generous overall and showed steeper social discounting, that is, their willingness to share declined more sharply with increasing social distance. This difference in social discounting could not be explained by empathy, personality, or social network size. Our data suggest that BLA is critical for resolving the conflict between selfish and altruistic motives during social discounting. This finding underlines the BLA’s role in model-based social cognition, calibrating prosocial behavior based on the social-emotional distance between individuals.}, archive = {J_PNAS}, author = {Kalenscher, Tobias and Lüpken, Luca M. and Stoop, Ron and Terburg, David and van Honk, Jack}, doi = {10.1073/pnas.2500692122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2500692122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Steeper social discounting after human basolateral amygdala damage}, volume = {122}, year = {2025}, }
• (2025). A single mutation in an enteric virus alters tropism and sensitivity to microbiota. PNAS, 122(16), e2500612122. (www)

  @article{ , abstract = {Many enteric viruses benefit from the microbiota. In mice, microbiota depletion reduces infection by noroviruses and picornaviruses. However, Reovirales viruses are outliers among enteric viruses. Rotavirus infection is inhibited by bacteria, and we determined that several reovirus strains have enhanced replication following microbiota depletion. Here, we focused on an isogenic pair of reoviruses that have opposing infection outcomes after microbiota depletion. Microbiota depletion reduces infection by reovirus strain T3SA+ but increases infection by strain T3SA−. These strains differ by a single amino acid polymorphism in the σ1 attachment protein, which confers sialic acid binding to T3SA+. Sialic acid binding facilitates T3SA+ infection of intestinal endothelial cells, while T3SA− inefficiently infects intestinal epithelial cells due to restriction by microbiota-driven, host-derived type III interferon responses. This study enhances an understanding of the interactions of enteric viruses, the microbiota, intestinal tropism, and antiviral responses.}, archive = {J_PNAS}, author = {Erickson, Andrea K. and Sutherland, Danica M. and Welsh, Olivia L. and Maples, Robert W. and Dermody, Terence S. and Pfeiffer, Julie K.}, doi = {10.1073/pnas.2500612122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2500612122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A single mutation in an enteric virus alters tropism and sensitivity to microbiota}, volume = {122}, year = {2025}, }
• (2025). Cleavage cascade of the sigma regulator FecR orchestrates TonB-dependent signal transduction. PNAS, 122(16), e2500366122. (www)

  @article{ , abstract = {TonB-dependent signal transduction is a versatile mechanism observed in gram-negative bacteria that integrates energy-dependent substrate transport with signal relay. In Escherichia coli , the TonB–ExbBD motor complex energizes the TonB-dependent outer membrane transporter FecA, facilitating ferric citrate import. FecA also acts as a sensor, transmitting signals to the cytoplasmic membrane protein FecR, which eventually activates the cytoplasmic sigma factor FecI, driving transcription of the fec operon. Building on our previous finding that FecR undergoes functional maturation through a three-step cleavage process [T. Yokoyama et al., J. Biol. Chem. 296 , 100673 (2021)], we here describe the complete mechanism of FecR-mediated ferric citrate signaling involving FecA and TonB. The cleavage cascade begins with FecR autoproteolysis prior to membrane integration. The soluble C-terminal domain (CTD) fragment of FecR is cotranslocated with the N-terminal domain (NTD) fragment through a twin-arginine translocation (Tat) system–mediated process. In the periplasm, the interaction between the CTD and NTD fragments prevents further cleavage. Binding of ferric citrate induces a conformational change in FecA, exposing its TonB box to the periplasmic space. This structural alteration is transmitted to the interacting FecR CTD via the motor function of TonB, resulting in the release of the CTD blockage from the NTD. Consequently, the successive cleavage of FecR’s NTD is initiated, culminating in the ferric citrate signal–induced activation of fec gene expression. Our findings reveal that the regulation of FecR cleavage, controlled by the TonB–FecA axis, plays a central role in the bacterial response to ferric citrate signals.}, archive = {J_PNAS}, author = {Yokoyama, Tatsuhiko and Miyazaki, Ryoji and Suzuki, Takehiro and Dohmae, Naoshi and Nagai, Hiroki and Tsukazaki, Tomoya and Kubori, Tomoko and Akiyama, Yoshinori}, doi = {10.1073/pnas.2500366122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2500366122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cleavage cascade of the sigma regulator FecR orchestrates TonB-dependent signal transduction}, volume = {122}, year = {2025}, }
• (2025). An integrated mechanism of gq regulation of PLCβ enzymes. PNAS, 122(16), e2500318122. (www)

  @article{ , abstract = {Phospholipase Cβ (PLCβ) enzymes are the principal effectors activated by G q heterotrimers. Both Gα q and Gβγ subunits can activate PLCβ, which requires precise positioning of PLCβ at the plasma membrane to relieve structural autoinhibition and give the active site access to the phosphatidylinositol 4,5-bisphosphate (PIP2) substrate. PLCβ enzymes possess a unique distal C-terminal domain (dCTD) that is critical for activation by Gα q , but the reason for this is unclear. It is also not known how G protein activation affects the subcellular localization of PLCβ enzymes, some of which are found primarily in the cytosol despite needing to act at the plasma membrane. Here, we use bioluminescence spectroscopy, imaging, and gene editing to study the membrane disposition of PLCβ enzymes in living cells and to define the functional roles of the dCTD. We find that PLCβ translocates to the plasma membrane upon G q activation, primarily by binding to Gα q subunits. This is rapidly counteracted by PIP2 hydrolysis, which promotes PLCβ translocation back into the cytosol. PLCβ translocation and activation require binding of Gα q to the catalytic domain and the dCTD at two distinct interfaces. Gα q binding to the dCTD is required for activation even when PLCβ is artificially tethered to the plasma membrane, suggesting that this domain has functions beyond simply recruiting the enzyme to the PIP2 substrate. We propose that in addition to associating PLCβ with the plasma membrane, the dCTD reorders the αN helix of active Gα q and thus participates directly in the precise positioning of the catalytic domain.}, archive = {J_PNAS}, author = {Senarath, Kanishka and Fisher, Isaac J. and Jang, Wonjo and Lu, Sumin and Inoue, Asuka and Kostenis, Evi and Lyon, Angeline M. and Lambert, Nevin A.}, doi = {10.1073/pnas.2500318122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2500318122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An integrated mechanism of gq regulation of PLCβ enzymes}, volume = {122}, year = {2025}, }
• (2025). Regulatory mimicry of cyclin-dependent kinases by a conserved herpesvirus protein kinase. PNAS, 122(16), e2500264122. (www)

  @article{ , abstract = {Herpesviruses encode conserved protein kinases (CHPKs) that target cellular cyclin-dependent kinase (CDK) phosphorylation sites; thus, they are termed viral CDK-like kinases. Tyrosine 15 in the GxGxxG motifs of CDK1 and CDK2, whose phosphorylation down-regulates their catalytic activities, is conserved in the corresponding motifs of CHPKs. We found that CHPK UL13, the corresponding Tyr-162 in herpes simplex virus 2 (HSV-2), was phosphorylated in HSV-2-infected cells. Mutational analyses of HSV-2 UL13 Tyr-162 suggested that phosphorylation of UL13 Tyr-162 reduced the phosphorylation of all UL13 substrates tested in HSV-2-infected cells. These findings suggested that HSV-2 UL13 mimicked the regulatory mechanism of CDKs and that this CHPK has regulatory and functional mimicry with CDKs. Furthermore, phosphorylation of HSV-2 UL13 Tyr-162 was suggested to be required for the downregulation of viral replication and pathogenicity, specifically in the brains of mice, and for efficient viral recurrence in guinea pigs. These findings highlight the dual impact of the regulatory mimicry of CDKs by CHPK on the fine-tuned regulation of lytic and latent HSV-2 infections in vivo.}, archive = {J_PNAS}, author = {Koyanagi, Naoto and Hengphasatporn, Kowit and Kato, Akihisa and Nobe, Moeka and Takeshima, Kosuke and Maruzuru, Yuhei and Maenaka, Katsumi and Shigeta, Yasuteru and Kawaguchi, Yasushi}, doi = {10.1073/pnas.2500264122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2500264122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Regulatory mimicry of cyclin-dependent kinases by a conserved herpesvirus protein kinase}, volume = {122}, year = {2025}, }
• (2025). Cryo-EM structure of the conjugation H-pilus reveals the cyclic nature of the TrhA pilin. PNAS, 122(16), e2427228122. (www)

  @article{ , abstract = {Conjugation, the major driver of the spread of antimicrobial resistance genes, relies on a conjugation pilus for DNA transfer. Conjugative pili, such as the F-pilus, are dynamic tubular structures, composed of a polymerized pilin, that mediate the initial donor–recipient interactions, a process known as mating pair formation (MPF). IncH are low-copy-number plasmids, traditionally considered broad host range, which are found in bacteria infecting both humans and animals. The reference IncHI1 plasmid R27, isolated from Salmonella enterica serovar Typhi, encodes the conjugative H-pilus subunit TrhA containing 74 residues after cleavage of the signal sequence. Here, we show that the H-pilus forms long filamentous structures that mediate MPF and describe its cryoelectron-microscopic (cryo-EM) structure at 2.2 Å resolution. Like the F pilus, the H-pilin subunits form helical assemblies with phospholipid molecules at a stoichiometric ratio of 1:1. While there were previous reports that the T-pilus from Agrobacterium tumefaciens was composed of cyclic subunits, three recent cryo-EM structures of the T-pilus found no such cyclization. Here, we report that the H-pilin is cyclic, with a covalent bond connecting the peptide backbone between the N and C termini. Both the cryo-EM map and mass spectrometry revealed cleavage of the last five residues of the pilin, followed by cyclization via condensation of the amine and carboxyl residues. Mutagenesis experiments revealed that loss of cyclization abolished pilus biogenesis and efficient plasmid transfer. The cyclic nature of the pilin could stabilize the pilus and may explain the high incidence of IncH plasmid dissemination.}, archive = {J_PNAS}, author = {Ishimoto, Naito and Wong, Joshua L. C. and He, Shan and Shirran, Sally and Wright-Paramio, Olivia and Seddon, Chloe and Singh, Nanki and Balsalobre, Carlos and Sonani, Ravi R. and Clements, Abigail and Egelmane, Edward H. and Frankel, Gad and Beis, Konstantinos}, doi = {10.1073/pnas.2427228122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2427228122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryo-EM structure of the conjugation H-pilus reveals the cyclic nature of the TrhA pilin}, volume = {122}, year = {2025}, }
• (2025). Quantifying the impact of biobanks and cohort studies. PNAS, 122(16), e2427157122. (www)

  @article{ , abstract = {Biobanks advance biomedical and clinical research by collecting and offering data and biological samples for numerous studies. However, the impact of these repositories varies greatly due to differences in their purpose, scope, governance, and data collected. Here, we computationally identified 2,663 biobanks and their textual mentions in 228,761 scientific articles, 16,210 grants, 15,469 patents, 1,769 clinical trials, and 9,468 public policy documents, helping characterize the academic communities that utilize and support them. We found a strong concentration of biobank-related research on a few diseases, including obesity, Alzheimer’s disease, breast cancer, and diabetes. Moreover, collaboration, rather than citation count, shapes the community’s recognition of a biobank. We show that, on average, 41.1% of articles fail to reference any of the biobank’s reference papers, but 59.6% include a biobank member as a coauthor. Using a generalized linear model, we identified the key factors that contribute to the impact of a biobank, finding that an impactful biobank tends to be more open to external researchers and that quality data—especially linked medical records—as opposed to large data, correlates with a higher impact in science, innovation, and disease. The collected data and findings are accessible through an open-access web application intended to inform strategies to expand access and maximize the value of these resources.}, archive = {J_PNAS}, author = {Dorantes-Gilardi, Rodrigo and Ivey, Kerry L. and Costa, Lauren and Matty, Rachael and Cho, Kelly and Gaziano, John Michael and Barabási, Albert-László}, doi = {10.1073/pnas.2427157122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2427157122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantifying the impact of biobanks and cohort studies}, volume = {122}, year = {2025}, }
• (2025). Verapamil and its metabolite norverapamil inhibit the mycobacterium tuberculosis MmpS5L5 efflux pump to increase bedaquiline activity. PNAS, 122(16), e2426827122. (www)

  @article{ , abstract = {Bedaquiline is the cornerstone of a new regimen for the treatment of drug-resistant tuberculosis. However, its clinical use is threatened by the emergence of bedaquiline-resistant strains of Mycobacterium tuberculosis . Bedaquiline targets mycobacterial ATP synthase but the predominant route to clinical bedaquiline resistance is via upregulation of the MmpS5L5 efflux pump due to mutations that inactivate the transcriptional repressor Rv0678 . Here, we show that the MmpS5L5 efflux pump reduces susceptibility to bedaquiline as well as its new, more potent derivative TBAJ-876 and other antimicrobial substrates, including clofazimine and the DprE1 inhibitors PBTZ-169 and OPC-167832. Furthermore, the increased resistance of Rv0678 mutants stems entirely from increased MmpS5L5 expression. These results highlight the potential of a pharmacological MmpS5L5 inhibitor to increase drug efficacy. Verapamil, primarily used as a calcium channel inhibitor, is known to inhibit diverse efflux pumps and to potentiate bedaquiline and clofazimine activity in M. tuberculosis . Here, we show that verapamil potentiates the activity of multiple diverse MmpS5L5 substrates. Using biochemical approaches, we demonstrate that verapamil does not exert this effect by acting as a disruptor of the protonmotive force used to power MmpS5L5, as previously proposed, suggesting that verapamil inhibits the function of the MmpS5L5 pump. Finally, norverapamil, the major verapamil metabolite, which has greatly reduced calcium channel activity, has equal potency in reducing resistance to MmpS5L5 substrates. Our findings highlight verapamil’s potential for enhancing bedaquiline TB treatment, for preventing acquired resistance to bedaquiline and other MmpS5L5 substrates, while also providing the impetus to identify additional MmpS5L5 inhibitors.}, archive = {J_PNAS}, author = {Fountain, Adam J. and Waller, Natalie J. E. and Cheung, Chen-Yi and Jowsey, William and Chrisp, Michael T. and Troll, Mark and Edelstein, Paul H. and Cook, Gregory M. and McNeil, Matthew B. and Ramakrishnan, Lalita}, doi = {10.1073/pnas.2426827122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2426827122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Verapamil and its metabolite norverapamil inhibit the mycobacterium tuberculosis MmpS5L5 efflux pump to increase bedaquiline activity}, volume = {122}, year = {2025}, }
• (2025). Virion-associated influenza hemagglutinin clusters upon sialic acid binding visualized by cryoelectron tomography. PNAS, 122(16), e2426427122. (www)

  @article{ , abstract = {Influenza viruses are enveloped, negative-sense single-stranded RNA viruses covered in a dense layer of glycoproteins. Hemagglutinin (HA) accounts for 80 to 90% of influenza glycoprotein and plays a role in host cell binding and membrane fusion. While previous studies have characterized structures of purified receptor-free and receptor-bound HA, the effect of receptor binding on HA organization and structure on virions remains unknown. Here, we used cryoelectron tomography to visualize influenza virions bound to a sialic acid receptor mimic. Overall, receptor binding did not result in significant changes in viral morphology; however, we observed rearrangements of HA trimer organization and orientation. Compared to the even interglycoprotein spacing of unliganded HA trimers, receptor binding promotes HA trimer clustering and the formation of a triplet of trimers. Subtomogram averaging and refinement yielded 8 to 10 Å reconstructions that allowed us to visualize specific contacts between HAs from neighboring trimers and identify molecular features that mediate clustering. Taken together, we present structural evidence that receptor binding triggers clustering of HA trimers, revealing an additional layer of HA dynamics and plasticity.}, archive = {J_PNAS}, author = {Huang, Qiuyu J. and Kim, Ryan and Song, Kangkang and Grigorieff, Nikolaus and Munro, James B. and Schiffer, Celia A. and Somasundaran, Mohan}, doi = {10.1073/pnas.2426427122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2426427122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Virion-associated influenza hemagglutinin clusters upon sialic acid binding visualized by cryoelectron tomography}, volume = {122}, year = {2025}, }
• (2025). The multifaceted roles of the transcriptional coactivator TAZ in extravillous trophoblast development of the human placenta. PNAS, 122(16), e2426385122. (www)

  @article{ , abstract = {Insights into the molecular processes that drive early development of the human placenta is crucial for our understanding of pregnancy complications such as preeclampsia and fetal growth restriction, since defects in maturation of its epithelial cell, the trophoblast, have been detected in the severe forms of these diseases. However, key regulators specifying the differentiated trophoblast subtypes of the placenta are only slowly emerging. By using diverse trophoblast cell models, we herein show that the transcriptional coactivator of HIPPO signaling, TAZ, plays a pivotal role in the development of invasive extravillous trophoblasts (EVTs), cells that are essential for decidual vessel remodeling and adaption of maternal blood flow to the placenta. Ribonucleic acid sequencing (RNA-seq) or protein analyses upon TAZ gene silencing or CRISPR-Cas9-mediated knockout in differentiating trophoblast stem cells, organoids, primary EVTs, choriocarcinoma cells, or villous explant cultures unraveled that the coactivator promoted expression of genes associated with EVT identity, motility, and survival. Accordingly, depletion or chemical inhibition of TAZ, interacting with TEA domain family member 1 (TEAD1), impaired EVT differentiation, invasion, and migration and triggered apoptosis in the different trophoblast models. Notably, the coactivator also suppressed cell cycle genes and regulators of trophoblast self-renewal and prevented EVTs from cell fusion in organoids and primary cultures. Moreover, TAZ promoted human leukocyte antigen G (HLA-G) surface expression and increased NUAK1 kinase in EVTs thereby maintaining its own expression. In summary, the transcriptional coactivator TAZ plays a multifaceted role in the development of the EVT cell lineage by controlling different biological processes that initiate and preserve differentiation.}, archive = {J_PNAS}, author = {Meinhardt, Gudrun and Waldhäusl, Hanna and Lackner, Andreas I. and Wächter, Jasmin and Maxian, Theresa and Höbler, Anna-Lena and Vondra, Sigrid and Kunihs, Victoria and Saleh, Leila and Haslinger, Peter and Kiraly, Peter and Szilagyi, Andras and Than, Nandor G. and Pollheimer, Jürgen and Haider, Sandra and Knöfler, Martin}, doi = {10.1073/pnas.2426385122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2426385122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The multifaceted roles of the transcriptional coactivator TAZ in extravillous trophoblast development of the human placenta}, volume = {122}, year = {2025}, }
• (2025). St3gal5-mediated sialylation of glyco-CD177 on neutrophils restricts neuroinflammation following CNS injury. PNAS, 122(16), e2426187122. (www)

  @article{ , abstract = {Neutrophils are the most abundant circulating leukocyte population that play critical roles in neuroinflammation following central nervous system (CNS) injury. CD177, a glycoprotein on neutrophils, is emerging as an important immune regulator which can fundamentally affect multiple human inflammatory diseases. However, the role and regulatory mechanism of CD177 glycobiology of neutrophils in neuroinflammation remain elusive. Here, we show that CD177 + neutrophils expand significantly and infiltrate the injured brain following CNS injury both in the human and mouse. Using single-cell RNA sequencing and genetic approaches, we find CD177 + neutrophils as an anti-inflammatory subset that is critical for modulating neuroinflammation after CNS injury. We further identify St3gal5, a sialyltransferase (ST), that can mediate the sialylation and cell surface presentation of glyco-CD177 on neutrophils. Glycoproteomics reveal downregulated sialylation levels in St3gal5-deficient neutrophils. Neutrophil-specific depletion of St3gal5 prevents the cell surface presentation of CD177 on brain-infiltrated neutrophils and exacerbates neuroinflammation. Administration of the FDA-approved anticonvulsant valproic acid (VPA), an St3gal5 upregulator, promotes the glycosylation of neutrophils and attenuates neuroinflammation following CNS injury. Our study reveals a glycoimmuno-regulatory effect of neutrophils and suggests VPA as a neutrophil glycobiology targeting approach to combat neuroinflammation following CNS injury.}, archive = {J_PNAS}, author = {Huang, Tingting and Xie, Wanqing and Guo, Yunlu and Li, Yan and Yin, Jiemin and Jin, Xia and Ma, Yezhi and Zhang, Yueman and Huang, Dan and Chen, Caiyang and Wang, Xin and Zhu, Ziyu and Gan, Yu and Liesz, Arthur and Yu, Weifeng and Yuan, Junying and Li, Peiying}, doi = {10.1073/pnas.2426187122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2426187122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {St3gal5-mediated sialylation of glyco-CD177 on neutrophils restricts neuroinflammation following CNS injury}, volume = {122}, year = {2025}, }
• (2025). MFRP is a molecular hub that organizes the apical membrane of RPE cells by engaging in interactions with specific proteins and lipids. PNAS, 122(16), e2425523122. (www)

  @article{ , abstract = {Membrane frizzled-related protein (MFRP), present in the retinal pigment epithelium (RPE), is an integral membrane protein essential for ocular development and the normal physiology of the retina. Mutations in MFRP are associated with autosomal recessive nonsyndromic nanophthalmos, leading to severe hyperopia and early-onset retinitis pigmentosa. While several preclinical gene-augmentation and gene-editing trials hold promise for future therapies aimed at stopping degeneration and restoring retinal function, the molecular mechanisms involved in MFRP biology are still not well understood. Here, we studied the biochemical properties of MFRP and the molecular consequences of its loss of function in the retinal degeneration 6 (rd6) mouse model. Using transcriptomic and lipidomic approaches, we observed that accumulation of docosahexaenoic acid (DHA) constitutes a primary defect in the MFRP-deficient RPE. In biochemical assays, we showed that MFRP undergoes extensive glycosylation, and it preferentially binds lipids of several classes, including phosphatidylserine and phosphatidylinositol-4-phosphate; as well as binding to several transmembrane proteins, notably adiponectin receptor 1 (ADIPOR1) and inward rectifier potassium channel 13 (KCNJ13). Moreover, MFRP determines the subcellular localization of ADIPOR1 and KCNJ13 in the RPE in vivo. This feature is altered by MFRP deficiency and can be restored by gene-therapy approaches. Overall, our observations suggest that MFRP constitutes an important interaction hub within the apical membrane of RPE cells, coordinating protein trafficking and subcellular localization within the RPE, and lipid homeostasis within the entire retina.}, archive = {J_PNAS}, author = {Tworak, Aleksander and Smidak, Roman and Rodrigues Menezes, Carolline and Du, Samuel W. and Suh, Susie and Choi, Elliot H. and Imanishi, Sanae S. and Dong, Zhiqian and Lewandowski, Dominik and Fong, Kristen E. and Grigorean, Gabriela and Pinto, Antonio F. M. and Xu, Qianlan and Skowronska-Krawczyk, Dorota and Blackshaw, Seth and Imanishi, Yoshikazu and Palczewski, Krzysztof}, doi = {10.1073/pnas.2425523122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2425523122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MFRP is a molecular hub that organizes the apical membrane of RPE cells by engaging in interactions with specific proteins and lipids}, volume = {122}, year = {2025}, }
• (2025). The emergence and loss of cyclic peptides in nicotiana illuminate dynamics and mechanisms of plant metabolic evolution. PNAS, 122(16), e2425055122. (www)

  @article{ , abstract = {Specialized metabolism plays a central role in how plants cope with both biotic and abiotic stresses in order to survive and reproduce within dynamic and challenging environments. One recently described class of plant-specific, ribosomally synthesized, and posttranslationally modified peptides are the burpitides, which are characterized by the installation of distinct sidechain macrocycles by enzymes known as burpitide cyclases. While they are found across many plant families and exhibit diverse bioactivities, little is known about their evolution or how new variants arise. Here, we present the identification of a burpitide cyclase, resurrected from a defunct pseudogene from the model organism Nicotiana attenuata , the coyote tobacco. By repairing the pseudogene ΨNatBURP2 and expressing it heterologously in Nicotiana benthamiana , we successfully reconstituted its original enzymatic activity. As an autocatalytic peptide cyclase, it installs a unique C–C bond between the tyrosine side chain and a specific backbone α-carbon of a heptapeptide core motif, resulting in burpitides dubbed “nanamins.” Despite its pseudogenization in N. attenuata , we found that the closely related species, Nicotiana clevelandii , retains the wild-type gene and produces nanamins. Phylogenetic analyses and targeted mutagenesis experiments reveal that this chemotype must have evolved from the duplication and neofunctionalization of a more promiscuous ancestral gene. This work highlights how novel peptide chemotypes may rapidly emerge and disappear in plants, while expanding the molecular toolkit for engineering novel peptides with applications in agriculture and drug discovery.}, archive = {J_PNAS}, author = {Suh, Elliot M. and Reinhardt, Jakob K. and Weng, Jing-Ke}, doi = {10.1073/pnas.2425055122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2425055122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The emergence and loss of cyclic peptides in nicotiana illuminate dynamics and mechanisms of plant metabolic evolution}, volume = {122}, year = {2025}, }
• (2025). Sex chromosome evolution in haploid plants: Microchromosomes, disappearing chromosomes, and giant chromosomes. PNAS, 122(16), e2425050122. (www)

  @article{ , abstract = {As in many diploid organisms with genetic sex determination, haploid-dominant organisms have also evolved sex chromosomes or extensive genomic regions that lack genetic recombination. An understanding of sex chromosome evolution should explain the causes and consequences of such regions in both diploids and haploids. However, haploids have been little studied, even though differences from sex chromosomes in diploids carry implications concerning the evolution of suppressed recombination in diploid organisms, and make predictions about genome evolution in the sex-linked regions of haploids that can now be tested by approaches using genome sequences. I review these ideas, and the current empirical evidence concerning them, in more detail than recent reviews focusing on progress in understanding the mechanisms involved in sex determination. I also discuss evidence that one specific prediction, that genetic degeneration should be minor in haploids, is not upheld. I suggest that this prediction does not take account of all processes leading to gene loss from sex-linked regions and that profound degeneration may evolve if sex-linked genes become duplicated to autosomes, a process that also appears to occur in diploids. I emphasize types of data that are needed to make progress in testing several of the ideas described.}, archive = {J_PNAS}, author = {Charlesworth, Deborah}, doi = {10.1073/pnas.2425050122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2425050122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sex chromosome evolution in haploid plants: Microchromosomes, disappearing chromosomes, and giant chromosomes}, volume = {122}, year = {2025}, }
• (2025). Thermotropic reentrant isotropic symmetry and induced smectic antiferroelectricity in the ferroelectric nematic material RM734. PNAS, 122(16), e2424917122. (www)

  @article{ , abstract = {We report a transition from the ferroelectric nematic liquid crystal (N F ) phase to a lower-temperature, apolar fluid phase having reentrant isotropic symmetry (I R ), in the liquid crystal compound RM734 doped with small concentrations of the ionic liquids 1-Butyl-3-methylimidazolium hexafluorophosphate (BMIM-PF 6 ) or 1-Ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EMIM-TFSI). Even a trace amount of ionic liquid dopant facilitates the kinetic pathway for the transition from the N F to the I R , enabling simple cooling to produce this isotropic fluid phase rather than resulting in immediate crystallization. The I R was also obtained in the absence of specific ionic liquid doping by appropriate temperature cycling in three distinct, as-synthesized-and-purified batches of RM734, two commercial and one from our laboratory. Ionic liquid doping also stabilizes the smectic Z A , an additional birefringent antiferroelectric phase having the director parallel to fluid smectic layers, significantly increasing its temperature range between the paraelectric and ferroelectric nematic phases with increasing BMIM concentration.}, archive = {J_PNAS}, author = {Chen, Xi and Shuai, Min and Zhong, Bingchen and Martinez, Vikina and Korblova, Eva and Glaser, Matthew A. and Maclennan, Joseph E. and Walba, David M. and Clark, Noel A.}, doi = {10.1073/pnas.2424917122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2424917122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Thermotropic reentrant isotropic symmetry and induced smectic antiferroelectricity in the ferroelectric nematic material RM734}, volume = {122}, year = {2025}, }
• (2025). Targeting the complement lectin pathway with a highly specific MASP-2 inhibitor protects against renal ischemia–reperfusion injury. PNAS, 122(16), e2424754122. (www)

  @article{ , abstract = {Renal ischemia–reperfusion injury (IRI) is a common complication in several clinical scenarios including kidney transplantation. Mannan-binding lectin-associated serine proteinase (MASP)-2 is essential for activation of the complement lectin pathway, which has been implicated in the pathogenesis of renal IRI and therefore represents a potential therapeutic target. We developed a new, affinity-enhanced MASP-2 inhibitor, EVO24, by directed evolution of the D2 domain of human tissue factor pathway inhibitor. EVO24 was fused with a human IgG1-Fc to create the homodimer EVO24L, which potently and selectively inhibited the lectin pathway in human and mouse serum in vitro. EVO24L was tested in a mouse model of unilateral warm renal IRI. EVO24L administered before and after ischemia significantly protected against IRI, with improved renal function as well as reduced tubular injury and inflammatory cell infiltration at 24 h compared to vehicle-treated mice. Immunofluorescence analyses showed reduced deposition of complement components (C3d, C4d, and C9) and reduced expression of VCAM-1, indicating a decrease in complement activation and endothelial cell activation. Additionally, EVO24L treatment lowered plasma levels of complement C5a, hyaluronan (a marker of endothelial glycocalyx shedding), and the proinflammatory cytokines IL-6 and TNF-α. Our findings indicate that EVO24L inhibits acute inflammatory responses in renal IRI by blocking the lectin pathway, confirming the important role of this pathway in acute ischemic kidney injury and warranting further investigation of EVO24L in clinical settings.}, archive = {J_PNAS}, author = {Bongoni, Anjan K. and Kiss, Bence and McRae, Jennifer L. and Salvaris, Evelyn J. and Fisicaro, Nella and Muntz, Fenella and Németh, Bálint Zoltán and Nagy, Zoltán Attila and Kocsis, Andrea and Gál, Péter and Cowan, Peter J. and Pál, Gábor}, doi = {10.1073/pnas.2424754122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2424754122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Targeting the complement lectin pathway with a highly specific MASP-2 inhibitor protects against renal ischemia–reperfusion injury}, volume = {122}, year = {2025}, }
• (2025). The pentameric chloride channel BEST1 is activated by extracellular GABA. PNAS, 122(16), e2424474122. (www)

  @article{ , abstract = {Bestrophin-1 (BEST1) is a chloride channel expressed in the eye and other tissues of the body. A link between BEST1 and the principal inhibitory neurotransmitter γ -aminobutyric acid (GABA) has been proposed. The most appreciated receptors for extracellular GABA are the GABA B G-protein-coupled receptors and the pentameric GABA A chloride channels, both of which have fundamental roles in the central nervous system. Here, we demonstrate that BEST1 is directly activated by GABA. Through functional studies and atomic-resolution structures of human and chicken BEST1, we identify a GABA binding site on the channel’s extracellular side and determine the mechanism by which GABA binding stabilizes opening of the channel’s central gate. This same gate, “the neck,” is activated by intracellular [Ca 2+ ], indicating that BEST1 is controlled by ligands from both sides of the membrane. The studies demonstrate that BEST1, which shares no structural homology with GABA A receptors, is a GABA-activated chloride channel. The physiological implications of this finding remain to be studied.}, archive = {J_PNAS}, author = {Pant, Swati and Tam, Stephanie W. and Long, Stephen B.}, doi = {10.1073/pnas.2424474122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2424474122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The pentameric chloride channel BEST1 is activated by extracellular GABA}, volume = {122}, year = {2025}, }
• (2025). Rolling two-dimensional covalent organic framework (COF) sheets into one-dimensional electronic and proton-conductive nanotubes. PNAS, 122(16), e2424314122. (www)

  @article{ , abstract = {Mimicking the interconvertible carbon allotropes of 2-dimensional (2D) graphene and 1-dimensional (1D) carbon nanotubes (CNTs), herein we report the in situ transformation of 2D π-conjugated covalent organic frameworks (COFs) sheet into 1D nanotubular structures via self-assembly the sheets at solvent interfaces. The facile “roll-sheets” self-assembly resulted in coaxial nanotubes with uniform cross-sectional diameter, which was realized for diazapyrene-based COFs but not for the corresponding pyrene COF, although both possess similar chemical structures. Upon replacing the carbon atoms at 2,7-positions of pyrene with nitrogen, contrasting optical and electronic properties were realized, reflecting the rolled structure of the conjugated 2D sheets. The nanotubes exhibited concerted electronic- and proton-conducting nature with stable conducting pathways at ambient conditions. The nitrogen centers act simultaneously as the site for charge carrier doping and proton acceptors, as evidenced by the high photo- and electrical conductivity, as well as the record proton conductivity (σ = 1.98 S cm −1 ) results. The present diazapyrene-based 1D nanotubular COF serves as a unique materials platform with electronic conduction in the wall and proton conduction in the core, respectively.}, archive = {J_PNAS}, author = {Li, Zhuowei and Paitandi, Rajendra Prasad and Tsutsui, Yusuke and Matsuda, Wakana and Nobuoka, Masaki and Chen, Bin and Ghosh, Samrat and Tanaka, Takayuki and Suda, Masayuki and Zhu, Tong and Kageyama, Hiroshi and Miyake, Yoshihiro and Shinokubo, Hiroshi and Takagi, Makito and Shimazaki, Tomomi and Tachikawa, Masanori and Suzuki, Katsuaki and Kaji, Hironori and Ando, Yasunobu and Ezaki, Takahiro and Seki, Shu}, doi = {10.1073/pnas.2424314122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2424314122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rolling two-dimensional covalent organic framework (COF) sheets into one-dimensional electronic and proton-conductive nanotubes}, volume = {122}, year = {2025}, }
• (2025). Unified molecular approach for spatial epigenome, transcriptome, and cell lineages. PNAS, 122(16), e2424070122. (www)

  @article{ , abstract = {Spatial epigenomics and multiomics can provide fine-grained insights into cellular states but their widespread adoption is limited by the requirement for bespoke slides and capture chemistries for each data modality. Here, we present SPatial assay for Accessible chromatin, Cell lineages, and gene Expression with sequencing (SPACE-seq), a method that utilizes polyadenine-tailed epigenomic libraries to enable facile spatial multiomics using standard whole transcriptome reagents. Applying SPACE-seq to a human glioblastoma specimen, we reveal the state of the tumor microenvironment, extrachromosomal DNA copy numbers, and identify putative mitochondrial DNA variants.}, archive = {J_PNAS}, author = {Huang, Yung-Hsin and Belk, Julia A. and Zhang, Ruochi and Weiser, Natasha E. and Chiang, Zachary and Jones, Matthew G. and Mischel, Paul S. and Buenrostro, Jason D. and Chang, Howard Y.}, doi = {10.1073/pnas.2424070122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2424070122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unified molecular approach for spatial epigenome, transcriptome, and cell lineages}, volume = {122}, year = {2025}, }
• (2025). Intussusceptive angiogenesis-on-a-chip: Evidence for transluminal vascular bridging by endothelial delamination. PNAS, 122(16), e2423700122. (www)

  @article{ , abstract = {Intussusceptive angiogenesis is an increasingly recognized vessel duplication process that generates and reshapes microvascular beds. However, the mechanism by which a vessel splits into two is poorly understood. Particularly vexing is formation of the hallmark transluminal endothelial cell bridge. How an endothelial cell comes to cross a flowing lumen rather than line it is enigmatic. To elucidate this, we used a microvessel-on-a-chip strategy, creating a microconduit coherently lined with flow-sensitive endothelial cells but in which transluminal bridges also formed. Bridge morphologies ranged from filamentous strand to multicellular columns with a central extracellular matrix-containing core. These bridge architectures were found to recapitulate those in microvessels in embryos, tumors, diseased organs, and the dermis of patients with limb-threatening ischemia. Time-lapse, multiplane, three-dimensional (3D) microscopy of the microphysiologic conduit revealed that bridges arose from endothelial cells oriented orthogonal to flow that partially released from the wall while retaining attachments at the ends. This delamination process was blocked by hyperactivation of Rho and augmented by interventions that weaken cell–substrate interactions, including inhibiting nonmuscle myosin II and blocking α5ß1 integrin. Thus, endothelial cells can leave their monolayer and transect a flowing lumen through controlled delamination. This previously unrecognized lumen entry program could explain the launch of intussusceptive angiogenesis and opens a framework for intervening.}, archive = {J_PNAS}, author = {Staples, Sabrina C. R. and Yin, Hao and Sutherland, Frances S. K. and Prescott, Emma K. and Tinney, Dylan and Hamilton, Douglas W. and Goldman, Daniel and Poepping, Tamie L. and Ellis, Christopher G. and Pickering, J. Geoffrey}, doi = {10.1073/pnas.2423700122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2423700122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intussusceptive angiogenesis-on-a-chip: Evidence for transluminal vascular bridging by endothelial delamination}, volume = {122}, year = {2025}, }
• (2025). Semaphorin 6A phase separation sustains a histone lactylation–dependent lactate buildup in pathological angiogenesis. PNAS, 122(16), e2423677122. (www)

  @article{ , abstract = {Ischemic retinal diseases are major causes of blindness worldwide and are characterized by pathological angiogenesis. Epigenetic alterations in response to metabolic shifts in endothelial cells (ECs) suffice to underlie excessive angiogenesis. Lactate accumulation and its subsequent histone lactylation in ECs contribute to vascular disorders. However, the regulatory mechanism of establishing and sustaining lactylation modification remains elusive. Here, we showed that lactate accumulation induced histone lactylations on H3K9 and H3K18 in neovascular ECs in the proliferative stage of oxygen-induced retinopathy. Joint CUT&Tag and scRNA-seq analyses identified Prmt5 as a target of H3K9la and H3K18la in isolated retinal ECs. EC-specific deletion of Prmt5 since the early stage of revascularization suppressed a positive feedback loop of lactate production and histone lactylation, thus inhibiting neovascular tuft formation. Mechanistically, the C-terminal intrinsically disorder region (IDR) of the transmembrane semaphorin 6A (SEMA6A) forms liquid–liquid phase separation condensates to recruit RHOA and P300, facilitating P300 phosphorylation and histone lactylation cycle. Deletion of endothelial Sema6A reduced H3K9la and H3K18la at the promoter of PRMT5 and diminished its expression. The induction of histone lactylation by SEMA6A-IDR and its pro-angiogenic effect were abrogated by deletion of Prmt5 . Our study illustrates a sustainable histone lactylation machinery driven by phase separation-dependent lactyltransferase activation in dysregulated vascularization.}, archive = {J_PNAS}, author = {Ma, Ya and Zhang, Zhuyi and Cao, Xiaolian and Guo, Dianlei and Huang, Shuting and Xie, Lijing and Wu, Mingjuan and Li, Junru and Li, Chenxin and Chu, Yu and Jiang, Shuxin and Hao, Yu and Wang, Can and Zhong, Xiali and Ju, Rong and Zhang, Feng and Liu, Chunqiao and Wei, Yanhong}, doi = {10.1073/pnas.2423677122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2423677122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Semaphorin 6A phase separation sustains a histone lactylation–dependent lactate buildup in pathological angiogenesis}, volume = {122}, year = {2025}, }
• (2025). Elevated brain manganese induces motor disease by upregulating the kynurenine pathway of tryptophan metabolism. PNAS, 122(16), e2423628122. (www)

  @article{ , abstract = {Elevated brain levels of the essential metals manganese (Mn), copper, or iron induce motor disease. However, mechanisms of metal-induced motor disease are unclear and treatments are lacking. Elucidating the mechanisms of Mn-induced motor disease is particularly important because occupational and environmental Mn overexposure is a global public health problem. To address this, here we combined unbiased transcriptomics and metabolomics with functional studies in a mouse model of human environmental Mn exposure. Transcriptomics unexpectedly revealed that Mn exposure up-regulated expression of metabolic pathways in the brain and liver. Notably, genes in the kynurenine pathway of tryptophan metabolism, which produces neuroactive metabolites that impact neurological function, were up-regulated by Mn. Subsequent unbiased metabolomics revealed that Mn treatment altered kynurenine pathway metabolites in the brain and liver. Functional experiments then demonstrated that pharmacological inhibition of the first and rate-limiting step of the kynurenine pathway fully rescued Mn-induced motor deficits. Finally, elevated Mn directly activates hypoxia-inducible factor (HIF) transcription factors, and additional mechanistic assays identified a role for HIF1, but not HIF2, in regulating expression of hepatic kynurenine pathway genes under physiological or Mn exposure conditions, suggesting that Mn-induced HIF1 activation may contribute to the dysregulation of the kynurenine pathway in Mn toxicity. These findings (1) identify the upregulation of the kynurenine pathway by elevated Mn as a fundamental mechanism of Mn-induced motor deficits; (2) provide a pharmacological approach to treat Mn-induced motor disease; and (3) should broadly advance understanding of the general principles underlying neuromotor deficits caused by metal toxicity.}, archive = {J_PNAS}, author = {Warden, Anna S. and Sharma, Nishant and Hutchens, Steven and Liu, Chunyi and Haggerty, Noah R. and Gurol, Kerem C. and Jursa, Thomas and Smith, Donald R. and Dayne Mayfield, Roy and Mukhopadhyay, Somshuvra}, doi = {10.1073/pnas.2423628122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2423628122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Elevated brain manganese induces motor disease by upregulating the kynurenine pathway of tryptophan metabolism}, volume = {122}, year = {2025}, }
• (2025). Exotic mechanical properties enabled by countersnapping instabilities. PNAS, 122(16), e2423301122. (www)

  @article{ , abstract = {Mechanical snapping instabilities are leveraged by natural systems, metamaterials, and devices for rapid sensing, actuation, and shape changes, as well as to absorb impact. In all current forms of snapping, shapes deform in the same direction as the exerted forces, even though there is no physical law that dictates this. Here, we realize countersnapping mechanical structures that respond in the opposite way. In contrast to regular snapping, countersnapping manifests itself in a sudden shortening transition under increasing tension or a sudden increase in tensile force under increasing extension. We design these structures by combining basic flexible building blocks that leverage geometric nonlinearities. We demonstrate experimentally that countersnapping can be employed to obtain new exotic properties, such as unidirectional stick–slip motion, switchable stiffness that does not otherwise affect the state of the system, and passive resonance avoidance. Moreover, we demonstrate that combining multiple countersnapping elements allows sequential stiffness switching for elements coupled in parallel, or instantaneous collective switching for elements in series. By expanding the repertoire of realizable elastic instabilities, our work opens routes to principles for mechanical sensing, computation, and actuation.}, archive = {J_PNAS}, author = {Ducarme, Paul and Weber, Bart and van Hecke, Martin and Overvelde, Johannes T. B.}, doi = {10.1073/pnas.2423301122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2423301122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exotic mechanical properties enabled by countersnapping instabilities}, volume = {122}, year = {2025}, }
• (2025). Bidirectional disruption of GNAS transcripts causes broad methylation defects in pseudohypoparathyroidism type 1B. PNAS, 122(16), e2423271122. (www)

  @article{ , abstract = {Pseudohypoparathyroidism type 1B (PHP1B) is a multihormone resistance disorder caused by aberrant GNAS methylation. Characteristic epigenetic changes at GNAS differentially methylated regions (DMRs), i.e., NESP, AS1, AS2, XL, and A/B, are associated with specific structural defects in different autosomal dominant PHP1B (AD-PHP1B) subtypes. However, mechanisms underlying abnormal GNAS methylation remain incompletely defined, largely because viable PHP1B mouse models are lacking. Using lymphoblastoid cells and induced pluripotent stem cells, we show that various GNAS methylation patterns in PHP1B reflect differential disruption of sense and antisense GNAS transcripts. In cases with broad GNAS methylation changes, loss of the maternal, sense-transcribed exon H/AS region impairs methylation of the AS1 DMR, which results in biallelic expression of an antisense transcript, GNAS-AS1 , and NESP hypermethylation. In contrast, cases with normal AS1 methylation, including STX16 deletions, show monoallelic GNAS-AS1 expression and normal NESP methylation. The roles of these GNAS transcripts were confirmed by a retrotransposon in GNAS-AS1 intron 1, identified in an AD-PHP1B family. This insertion impaired exon H/AS transcription when located on the maternal allele, thus preventing the complete establishment of methylation at all maternal GNAS DMRs, leading to biallelic GNAS-AS1 transcription. However, maternal GNAS-AS1 transcription was profoundly attenuated, thus allowing only a small gain-of-methylation at NESP. Likewise, on the paternal allele, the retrotransposon attenuated GNAS-AS1 transcription, thus preventing complete NESP methylation. Our findings support a model of bidirectional transcription-mediated regulation of methylation at GNAS DMRs and will help to refine systematic approaches for establishing molecular defects underlying different PHP1B subtypes.}, archive = {J_PNAS}, author = {Iwasaki, Yorihiro and Reyes, Monica and Ryabets-Lienhard, Anna and Gales, Barbara and Linglart, Agnès and Miller, Danny E. and Salusky, Isidro B. and Bastepe, Murat and Jüppner, Harald}, doi = {10.1073/pnas.2423271122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2423271122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bidirectional disruption of GNAS transcripts causes broad methylation defects in pseudohypoparathyroidism type 1B}, volume = {122}, year = {2025}, }
• (2025). Profile of john hopfield and geoffrey hinton: 2024 nobel laureates in physics. PNAS, 122(16), e2423094122. (www)

  @article{ , abstract = {The 2024 Nobel Prize in Physics recognizes breakthroughs contributing to the emergence of a new understanding of the computations that underlie human intelligence, with profound implications for artificially intelligent systems. John Hopfield and Geoffrey Hinton played seminal roles in these breakthroughs. I begin by characterizing the scientific context in which the new understanding of intelligence began to arise. I then consider Hopfield’s and Hinton’s ideas and their centrality in the sciences of natural and artificial intelligence, while mentioning others who made major contributions. I conclude with a brief consideration of the current state of the fields these ideas have influenced and of the importance of governmental and scientific organizations in the past and future of these sciences.}, archive = {J_PNAS}, author = {McClelland, James L.}, doi = {10.1073/pnas.2423094122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2423094122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profile of john hopfield and geoffrey hinton: 2024 nobel laureates in physics}, volume = {122}, year = {2025}, }
• (2025). ATM priming and end resection–coupled phosphorylation of MRE11 is important for fork protection and replication restart. PNAS, 122(16), e2422720122. (www)

  @article{ , abstract = {The MRE11/RAD50/NBS1 (MRN) complex plays multiple roles in the maintenance of genome stability. MRN is associated with replication forks to preserve fork integrity and is also required for end resection at double-strand breaks (DSBs) to facilitate homologous recombination (HR). The critical need for proper control of the MRE11 nuclease activity is highlighted by the extensive nascent strand DNA degradation driven by MRE11 in BRCA-deficient cells, leading to genome instability and increased sensitivity to chemotherapeutics. In this study, we identified a tightly controlled mechanism, elicited by sequential phosphorylation of MRE11 by ATM and ATR to regulate MRE11 nuclease activities through its DNA binding. Specifically, at DSBs, MRE11 phosphorylation by ATM at the C-terminal S676/S678 primes it for subsequent phosphorylation by ATR, whose activation is triggered by end resection which requires the MRE11 nuclease activity. This ATR-mediated phosphorylation in turn induces MRE11 dissociation from DNA, providing a feedback mechanism to regulate the extent of end resection. At stalled replication forks, however, without ATM priming, MRN is stably associated with forks despite ATR activation. Furthermore, the ATR phosphorylation–defective MRE11 mutants are retained at single-ended DSBs formed by fork reversal upon replication stress, leading to extensive degradation of nascent DNA strands. Importantly, this end resection–coupled MRE11 phosphorylation elicits another critical layer of fork protection of nascent DNA in addition to BRCA2, ensuring proper end resection that is sufficient for replication restart at reversed forks while maintaining fork stability.}, archive = {J_PNAS}, author = {Zhang, Huimin and Li, Youhang and Shah, Sameer Bikram and Li, Shibo and Li, Qingrong and Oaks, Joshua and Lv, Tinghong and Shi, Linda Z. and Wang, Hailong and Wang, Dong and Wu, Xiaohua}, doi = {10.1073/pnas.2422720122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2422720122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ATM priming and end resection–coupled phosphorylation of MRE11 is important for fork protection and replication restart}, volume = {122}, year = {2025}, }
• (2025). MiR-155 impairs ICOSL and MHC-I expression in DLBCL lymphomas. PNAS, 122(16), e2422615122. (www)

  @article{ , abstract = {Elevated miR-155 levels in B cell malignancies, such as CLL and DLBCL, correlate with increased aggressiveness of the disease. We recently reported that, in two different mouse models of miR-155 -driven B cell malignancy, miR-155 targets and down-regulates transcripts encoding ICOSL, the ligand for the Inducible T cell costimulator (ICOS), thereby impairing the capacity of T lymphocytes to recognize and eliminate malignant cells. In this report, we extend our previous findings to Human by showing that miR-155 levels negatively correlate with those of both ICOSL and MHC-I in samples from DLBCL patients. We present evidence of miR-155 reducing the levels of ICOSL transcripts in ABC, but not in GCB primary tumors (PTs) and cell lines (CLs). In contrast, there was no evidence of miR-155 targeting MHC-I transcript levels in both types of DLBCLs. Nevertheless, miR-155 and MHC-I levels inversely correlated in DLBCLs samples, suggesting the existence of indirect regulatory effects of miR-155 . There was also evidence of dose-dependent effects at low miR-155 levels. Altogether, our findings indicate that the deficiency of both ICOSL and MHC-I activity, driven by high levels of miR-155 , may be causative in the failure of the host immune system to recognize and eliminate malignant B cells.}, archive = {J_PNAS}, author = {Tili, Esmerina and Commisso, Teresa L. and Balatti, Veronica and Michaille, Jean-Jacques and Nuovo, Gerard J. and Croce, Carlo M.}, doi = {10.1073/pnas.2422615122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2422615122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MiR-155 impairs ICOSL and MHC-I expression in DLBCL lymphomas}, volume = {122}, year = {2025}, }
• (2025). Genomic signatures associated with the evolutionary loss of egg yolk in parasitoid wasps. PNAS, 122(16), e2422292122. (www)

  @article{ , abstract = {Trait regression and loss have occurred repeatedly in numerous lineages in response to environmental changes. In parasitoid wasps, a megadiverse group of hymenopteran insects, yolk protein reduction or loss has been observed in many species, likely linked to the transition from ectoparasitism to endoparasitism. However, the genetic basis of this trait and the impact of its loss on genome evolution remain poorly understood. Here, we performed a comparative genomic analysis of 64 hymenopteran insects. The conserved insect yolk protein gene vitellogenin ( Vg ) underwent five independent loss events in four families, involving 23 of the analyzed endoparasitoid species. Whole-genome alignment suggested that Vg loss occurred during genome rearrangement events. Analysis of Vg receptor gene ( VgR ) loss, selection, and structural variation in lineages lacking Vg demonstrated functional biases in the patterns of gene loss. The ectoparasitism to endoparasitism transition did not appear to be the primary driver of Vg loss or the subsequent VgR evolution. Together, these findings reveal the genomic changes underlying a unique trait loss in parasitoid wasps. More broadly, this study enhances our understanding of yolk protein loss evolution outside the class Mammalia, highlighting a potential evolutionary trend arising from the availability of an alternative nutrient source for embryonic development.}, archive = {J_PNAS}, author = {Zhao, Xianxin and Liu, Yuanyuan and Yuan, Bo and Cao, Zhichao and Yang, Yi and He, Chun and Chan, Kevin C. and Xiao, Shan and Lin, Haiwei and Fang, Qi and Ye, Gongyin and Ye, Xinhai}, doi = {10.1073/pnas.2422292122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2422292122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genomic signatures associated with the evolutionary loss of egg yolk in parasitoid wasps}, volume = {122}, year = {2025}, }
• (2025). A plant CLE peptide and its fungal mimic promote arbuscular mycorrhizal symbiosis via CRN-mediated ROS suppression. PNAS, 122(16), e2422215122. (www)

  @article{ , abstract = {CLAVATA3/EMBRYO SURROUNDING REGION-related (CLE) peptides have emerged as key regulators of plant–microbe interactions, including arbuscular mycorrhizal (AM) symbiosis. Here, we identify Medicago truncatula CLE16 as a positive regulator of AM symbiosis. MtCLE16 is expressed in root cells colonized by AM fungi (AMF) and its overexpression within colonized tissues increases arbuscule abundance by finetuning their growth and lifespan. Functional and transcriptomic analyses reveal that MtCLE16 acts via the M. truncatula pseudokinase CORYNE (MtCRN) and suppresses the accumulation of reactive oxygen species (ROS) in roots, thereby attenuating immune responses and promoting root colonization by mutualistic AM fungi. Notably, AMF also express MtCLE16-like peptides. We show that the Rhizophagus irregularis MtCLE16-like peptide, RiCLE1, also attenuates ROS and promotes AMF colonization via MtCRN. This finding suggests that RiCLE1 can interfere with the MtCLE16-MtCRN signaling module of host roots to benefit the fungus. Our research uncovers a functional mechanism underpinning cross-kingdom signaling and molecular mimicry in mutualistic plant–microbe interactions.}, archive = {J_PNAS}, author = {Bashyal, Sagar and Everett, Hasani and Matsuura, Suzanne and Müller, Lena Maria}, doi = {10.1073/pnas.2422215122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2422215122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A plant CLE peptide and its fungal mimic promote arbuscular mycorrhizal symbiosis via CRN-mediated ROS suppression}, volume = {122}, year = {2025}, }
• (2025). Dynamics of two distinct memory interactions during water seeking in drosophila. PNAS, 122(16), e2422028122. (www)

  @article{ , abstract = {Forming and forgetting memories shape our self-awareness and help us face future challenges. Therefore, understanding how memories are formed and how different memories interact in the brain is important. Previous studies have shown that thirsty flies sense humidity through ionotropic receptors, which help them locate water sources. Here, we showed that thirsty flies can be trained to associate specific odors with humidity to form a humidity memory that lasts for 30 min after association. Humidity memory formation requires the Ir93a and Ir40a ionotropic receptors, which are essential for environmental humidity sensing. Water memory takes precedence, leading to the forgetting of humidity memory by activating a small subset of dopaminergic neurons called protocerebral anterior medial (PAM)-γ4, that project to the restricted region of the mushroom body (MB) γ lobes. Adult-stage-specific silencing of Dop2R dopaminergic receptors in MB γ neurons prolongs humidity memory for 3 h. Live-brain calcium imaging and dopamine sensor studies revealed significantly increased PAM-γ4 neural activity after odor/humidity association, suggesting its role in forgetting the humidity memory. Our results suggest that overlapping neural circuits are responsible for the acquisition of water memory and forgetting humidity memory in thirsty flies.}, archive = {J_PNAS}, author = {Lee, Wang-Pao and Chiang, Meng-Hsuan and Chao, Yi-Ping and Wang, Ying-Fong and Chen, Yan-Lin and Lin, Yu-Chun and Jenq, Shan-Yun and Lu, Jun-Wei and Fu, Tsai-Feng and Liang, Jia-Yu and Yang, Kai-Cing and Chang, Li-Yun and Wu, Tony and Wu, Chia-Lin}, doi = {10.1073/pnas.2422028122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2422028122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamics of two distinct memory interactions during water seeking in drosophila}, volume = {122}, year = {2025}, }
• (2025). Active control of mitochondrial network morphology by metabolism-driven redox state. PNAS, 122(16), e2421953122. (www)

  @article{ , abstract = {Mitochondria are dynamic organelles that constantly change morphology. What controls mitochondrial morphology however remains unresolved. Using actively respiring yeast cells growing in distinct carbon sources, we find that mitochondrial morphology and activity are unrelated. Cells can exhibit fragmented or networked mitochondrial morphology in different nutrient environments independent of mitochondrial activity. Instead, mitochondrial morphology is controlled by the intracellular redox state, which itself depends on the nature of electron entry into the electron transport chain (ETC)—through complex I/II or directly to coenzyme Q/cytochrome c. In metabolic conditions where direct electron entry is high, reactive oxygen species (ROS) increase, resulting in an oxidized cytosolic environment and rapid mitochondrial fragmentation. Decreasing direct electron entry into the ETC by genetic or chemical means, or reducing the cytosolic environment rapidly restores networked morphologies. Using controlled disruptions of electron flow to alter ROS and redox state, we demonstrate minute-scale, reversible control between networked and fragmented forms in an activity-independent manner. Mechanistically, the fission machinery through Dnm1 responds in minute-scale to redox state changes, preceding the change in mitochondrial form. Thus, the metabolic state of the cell and its consequent cellular redox state actively control mitochondrial form.}, archive = {J_PNAS}, author = {Singh, Gaurav and Vengayil, Vineeth and Khanna, Aayushee and Adhikary, Swagata and Laxman, Sunil}, doi = {10.1073/pnas.2421953122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2421953122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Active control of mitochondrial network morphology by metabolism-driven redox state}, volume = {122}, year = {2025}, }
• (2025). Reconsidering indoor residual spraying coverage targets: A retrospective analysis of high-resolution programmatic malaria control data. PNAS, 122(16), e2421531122. (www)

  @article{ , abstract = {Indoor residual spraying (IRS) is one of the core vector control interventions available to malaria control programs. Normative and scientific guidance has long held that very high IRS coverage (at least 80 to 85% houses sprayed) is necessary to provide community protection, but there is little evidence backing these recommendations, in large part due to the operational and ethical concerns that conducting appropriate trials of differing IRS coverage levels would raise. The present study leverages data from four years of targeted IRS implementation on Bioko Island, Equatorial Guinea, to estimate a dose–response curve of IRS coverage. Due to the observational nature of the data, a double robust causal inference technique was utilized. The results suggest that at all spatial scales examined a threshold providing community protection was reached at much lower coverage levels than previously assumed (30 to 50%). Sensitivity analysis corroborated this result across multiple methods, but there was less agreement on whether extremely high coverage ( ≥ 85%) has additional benefit. A secondary analysis of the impact of changing operational coverage targets found that significantly reducing coverage targets (to 30 to 60%) could provide nearly the same protection as maintaining the existing 80% target in Bioko. While these findings are limited in strength by the observational nature of the data and may be specific to the context of Bioko Island, they raise important questions for further research on how IRS coverage impacts epidemiological outcomes and on how malaria control programs should set programmatic IRS coverage targets.}, archive = {J_PNAS}, author = {Galick, David S. and Vaz, Liberato Motobe and Ondo, Lucas and Iyanga, Marcos Mbulito and Bikie, Faustino Etoho Ebang and Avue, Restituto Mba Nguema and Donfack, Olivier Tresor and Eyono, Jeremías Nzamío Mba and Ondo Mifumu, Teresa Ayingono and Hergott, Dianna E. B. and Phiri, Wonder P. and Smith, David L. and Guerra, Carlos A. and García, Guillermo A.}, doi = {10.1073/pnas.2421531122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2421531122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reconsidering indoor residual spraying coverage targets: A retrospective analysis of high-resolution programmatic malaria control data}, volume = {122}, year = {2025}, }
• (2025). Diet-regulated transcriptional plasticity of plant parasites in plant–mutualist environments. PNAS, 122(16), e2421367122. (www)

  @article{ , abstract = {Crop pathogens often lack exclusive access to their host and must interact with plants concurrently engaged with numerous other symbionts. Here, we demonstrate that the colonization of hosts by plant–mutualistic mycorrhizal fungi can indirectly induce transcriptional responses of a major plant parasite, the nematode Globodera pallida , via a modified host resource profile. A shift in the resource profile of the root, where the parasite feeds, is perceived and responded to by the parasite through transcriptional changes, potentially to optimize resource intake. Specifically, G. pallida react to reduced host-photosynthate influx due to concurrent mycorrhizal-host symbiosis by upregulating the expression of a sugar transporter ( SWEET3 ) in the nematode intestine. We identify this gene’s role in parasite growth and development, regulated by the putative diet-responsive transcription factor Gp-HBL1. Overall, our data unveil a mechanism by which a parasitic animal responds to fluctuations in host plant quality that is induced by a plant–mutualistic fungus, to enhance parasitism and reproduction.}, archive = {J_PNAS}, author = {Maxwell, M. Willow H. and Causier, Barry E. and Chippendale, Jasper and Ault, James R. and Bell, Chris A.}, doi = {10.1073/pnas.2421367122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2421367122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Diet-regulated transcriptional plasticity of plant parasites in plant–mutualist environments}, volume = {122}, year = {2025}, }
• (2025). Flocking and giant fluctuations in epithelial active solids. PNAS, 122(16), e2421327122. (www)

  @article{ , abstract = {The collective motion of epithelial cells is a fundamental biological process which plays a significant role in embryogenesis, wound healing, and tumor metastasis. While it has been broadly investigated for over a decade both in vivo and in vitro, large-scale coherent flocking phases remain underexplored and have so far been mostly described as fluid. In this work, we report an additional mode of large-scale collective motion for different epithelial cell types in vitro with distinctive features. By tracking individual cells, we show that cells move over long time scales coherently not as a fluid, but as a polar elastic solid with negligible cell rearrangements. Our analysis reveals that this solid flocking phase exhibits signatures of long-range polar order, accompanying with scale-free correlations of the transverse component of velocity fluctuations, anomalously large density fluctuations, and shear waves. Based on a general theory of active polar solids, we argue that these features result from massless orientational Goldstone mode, which, in contrast to polar fluids where they are generic, require the decoupling of global rotations of the polarity and in-plane elastic deformations in polar solids. We theoretically show and consistently observe in experiments that the fluctuations of elastic deformations diverge for large system sizes in such polar active solid phases, leading eventually to rupture and thus potentially loss of tissue integrity at large scales.}, archive = {J_PNAS}, author = {Shen, Yuan and O’Byrne, Jérémy and Schoenit, Andreas and Maitra, Ananyo and Mège, René-Marc and Voituriez, Raphaël and Ladoux, Benoit}, doi = {10.1073/pnas.2421327122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2421327122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Flocking and giant fluctuations in epithelial active solids}, volume = {122}, year = {2025}, }
• (2025). The world through infant eyes: Evidence for the early emergence of the cardinal orientation bias. PNAS, 122(16), e2421277122. (www)

  @article{ , abstract = {The structure of the environment includes more horizontal and vertical (i.e. cardinal) orientations than oblique orientations, meaning that edges tend to be aligned with or perpendicular to the direction of gravity. This bias in the visual scene is associated with a bias in visual sensitivity in adults. Although infants must learn to function in this biased environment, their immature motor control prevents them from consistently orienting themselves, relative to gravity. This study therefore asked whether cardinal orientations dominate human visual experience from early infancy or only from later in development, as motor control improves. We analyze video clips from head-mounted cameras, showing the egocentric perspective of 75 infants (1 to 12 mo) in their home environments in two communities (Indiana, USA vs. Tamil Nadu, India). We measured the distribution of orientations in each frame of these videos and found that horizontal and vertical orientations were overrepresented in infants from both countries. A cardinal orientation bias was evident even in the egocentric view of the youngest infants (3 wk) and became more prominent during the subsequent weeks of development. The early presence of a cardinal orientation bias in infants’ visual input may serve as a consistent cue to gravity and ground planes, potentially influencing motor development and contributing to the formation of sensory, perceptual, and cognitive biases.}, archive = {J_PNAS}, author = {Petroff, Zachary J. and Jayaraman, Swapnaa and Smith, Linda B. and Candy, T. Rowan and Bonnen, Kathryn}, doi = {10.1073/pnas.2421277122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2421277122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The world through infant eyes: Evidence for the early emergence of the cardinal orientation bias}, volume = {122}, year = {2025}, }
• (2025). A hydrophobic photouncaging reaction to profile the lipid droplet interactome in tissues. PNAS, 122(16), e2420861122. (www)

  @article{ , abstract = {Most bioorthogonal photouncaging reactions preferentially occur in polar environments to accommodate biological applications in the aqueous cellular milieu. However, they are not precisely designed to chemically adapt to the diverse microenvironments of the cell. Herein, we report a hydrophobic photouncaging reaction with tailored photolytic kinetics toward solvent polarity. Structural modulations of the aminobenzoquinone-based photocage reveal the impact of cyclic ring size, steric substituent, and electronic substituent on the individual uncaging kinetics ( k H2O and k dioxane ) and polarity preference ( k dioxane / k H2O ). Rational incorporation of optimized moieties leads to up to 20.2-fold nonpolar kinetic selectivity ( k dioxane / k H2O ). Further photochemical spectroscopic characterizations and theoretical calculations together uncover the mechanism underlying the polarity-dependent uncaging kinetics. The uncaged ortho-quinone methide product bears covalent reactivity toward diverse nucleophiles of a protein revealed by tandem mass spectrometry. Finally, we demonstrate the application of such lipophilic photouncaging chemistry toward selective labeling and profiling of proteins in proximity to lipid droplets inside human fatty liver tissues. Together, this work studies the solvent polarity effects of a photouncaging reaction and chemically adapts it toward suborganelle-targeted protein proximity labeling and profiling.}, archive = {J_PNAS}, author = {Shen, Di and Zhao, Qun and Zhang, Huaiyue and Wu, Ci and Jin, Hao and Guo, Kun and Sun, Rui and Guo, Hengke and Zhao, Qi and Feng, Huan and Dong, Xuepeng and Gao, Zhenming and Zhang, Lihua and Liu, Yu}, doi = {10.1073/pnas.2420861122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2420861122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A hydrophobic photouncaging reaction to profile the lipid droplet interactome in tissues}, volume = {122}, year = {2025}, }
• (2025). Receptor kinase pathway signal tuning through a nontranscriptional incoherent feedforward loop. PNAS, 122(16), e2420575122. (www)

  @article{ , abstract = {Cellular signaling processes can elicit powerful responses and may need to be amplified to be efficient or dampened to prevent overstimulation. Therefore, they often involve autoregulatory feedbacks. Receptor kinase signaling pathways are abundant in plants, where they convey the presence of both exogenous and endogenous ligands. Among them, endogenous CLAVATA3/EMBRYO SURROUNDING REGION (CLE) peptide signaling acts in an inherently quantitative manner to determine the size of stem cell pools and direct tissue formation. The plant-specific MEMBRANE-ASSOCIATED KINASE REGULATOR (MAKR) family proteins act downstream of receptor kinases. Among the seven family members in Arabidopsis ( Arabidopsis thaliana ), MAKR5 conveys CLE45 signaling downstream of the receptor kinase BARELY ANY MERISTEM 3 (BAM3). Here, we show that the distinct MAKR5 mode of action can only be fully mimicked by MAKR3, suggesting functional diversification of MAKR proteins. Moreover, we find that CLE45-stimulated and BAM3-dependent MAKR5 recruitment to the plasma membrane can be triggered independent of receptor-like cytoplasmic kinases that act downstream of BAM3 and depends on membrane charge. The CLE45-BAM3-triggered enhancement of MAKR5 production and plasma membrane association is mediated by autoregulatory feedback on MAKR5 mRNA translation, for which the 5′ UTR is required. At the same time, this signal amplification is dampened through CLE45-stimulated MAKR5 phosphorylation, which inactivates MAKR5, enhances its turnover, and impinges on MAKR5 mRNA levels. In summary, our results reveal a nontranscriptional incoherent feedforward loop in which receptor kinase signaling is amplified via ligand-triggered translation of a signal enhancer’s mRNA yet also balanced via ligand-triggered inactivation of the signal enhancer protein.}, archive = {J_PNAS}, author = {Wang, Qian and Kang, Yeon Hee and Hardtke, Christian S.}, doi = {10.1073/pnas.2420575122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2420575122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Receptor kinase pathway signal tuning through a nontranscriptional incoherent feedforward loop}, volume = {122}, year = {2025}, }
• (2025). Mechanism of allosteric activation in human mitochondrial ClpP protease. PNAS, 122(16), e2419881122. (www)

  @article{ , abstract = {Human ClpP protease contributes to mitochondrial protein quality control by degrading misfolded proteins. ClpP is overexpressed in cancers such as acute myeloid leukemia (AML), where its inhibition leads to the accumulation of damaged respiratory chain subunits and cell death. Conversely, hyperactivating ClpP with small-molecule activators, such as the recently discovered ONC201, disrupts mitochondrial protein degradation and impairs respiration in cancer cells. Despite its critical role in human health, the mechanism underlying the structural and functional properties of human ClpP remains elusive. Notably, human ClpP is paradoxically activated by active-site inhibitors. All available structures of human ClpP published to date are in the inactive compact or compressed states, surprisingly even when ClpP is bound to an activator molecule such as ONC201. Here, we present structures of human mitochondrial ClpP in the active extended state, including a pair of structures where ClpP is bound to an active-site inhibitor. We demonstrate that amino acid substitutions in the handle region (A192E and E196R) recreate a conserved salt bridge found in bacterial ClpP, stabilizing the extended active state and significantly enhancing ClpP activity. We elucidate the ClpP activation mechanism, highlighting a hormetic effect where substoichiometric inhibitor binding triggers an allosteric transition that drives ClpP into its active extended state. Our findings link the conformational dynamics of ClpP to its catalytic function and provide high-resolution structures for the rational design of potent and specific ClpP inhibitors, with implications for targeting AML and other disorders with ClpP involvement.}, archive = {J_PNAS}, author = {Goncalves, Monica M. and Uday, Adwaith B. and Forrester, Taylor J. B. and Currie, S. Quinn W. and Kim, Angelina S. and Feng, Yue and Jitkova, Yulia and Velyvis, Algirdas and Harkness, Robert W. and Kimber, Matthew S. and Schimmer, Aaron D. and Zeytuni, Natalie and Vahidi, Siavash}, doi = {10.1073/pnas.2419881122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2419881122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mechanism of allosteric activation in human mitochondrial ClpP protease}, volume = {122}, year = {2025}, }
• (2025). The Q226L mutation can convert a highly pathogenic h5 2.3.4.4e virus to bind human-type receptors. PNAS, 122(16), e2419800122. (www)

  @article{ , abstract = {H5Nx viruses continue to wreak havoc in avian and mammalian species worldwide. The virus distinguishes itself by the ability to replicate to high titers and transmit efficiently in a wide variety of hosts in diverse climatic environments. Fortunately, transmission to and between humans is scarce. Yet, if such an event were to occur, it could spark a pandemic as humans are immunologically naïve to H5 viruses. A significant determinant of transmission to and between humans is the ability of the influenza A virus hemagglutinin (HA) protein to shift from an avian-type to a human-type receptor specificity. Here, we demonstrate that a 2016 2.3.4.4e virus HA can convert to human-type receptor binding via a single Q226L mutation, in contrast to a cleavage-modified 2016 2.3.4.4b virus HA. Using glycan arrays, X-ray structural analyses, tissue- and direct glycan binding, we show that L133a Δ and 227Q are vital for this phenotype. Thus, whereas the 2.3.4.4e virus HA only needs a single amino acid mutation, the modified 2016 2.3.4.4b HA was not easily converted to human-type receptor specificity.}, archive = {J_PNAS}, author = {Ríos Carrasco, María and Lin, Ting-Hui and Zhu, Xueyong and Gabarroca García, Alba and Uslu, Elif and Liang, Ruonan and Spruit, Cindy M. and Richard, Mathilde and Boons, Geert-Jan and Wilson, Ian A. and de Vries, Robert P.}, doi = {10.1073/pnas.2419800122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2419800122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The Q226L mutation can convert a highly pathogenic h5 2.3.4.4e virus to bind human-type receptors}, volume = {122}, year = {2025}, }
• (2025). Focusing a viral risk ranking tool on prediction. PNAS, 122(16), e2419337122. (www)

  @article{ , abstract = {Preparing to rapidly respond to emerging infectious diseases is critical. SpillOver: Viral Risk Ranking is an open-source tool developed to assess the risk of novel wildlife-origin viruses spilling over from animals to humans and spreading in human populations. Several risk factors used by the tool depend on evidence of previous zoonotic spillover itself or sustained transmission in humans. Therefore, we reanalyzed the Ranking Comparison after removing eight of the 31 risk factors that require postspillover knowledge and compared the adjusted risk rankings to the originals. The area under the receiver operating characteristic curve deteriorated from 0.94 for the original risk scores to 0.73 for the adjusted ones for predicting the classification as a human virus. We also compared the mean and SD of the risk scores for the human and non-human viruses at the risk factor level. Most excluded spillover-dependent risk factors had dissimilar means between the human and non-human virus classifications, but nonspillover-dependent risk factors frequently showed similar means between the two classifications. The original formulation of the tool depended on the inclusion of spillover-dependent risk factors to quantitatively assess the risk of zoonotic spillover for a novel virus. Future iterations of the tool should omit such risk factors and consider other nonspillover-dependent risk factors to ensure that the tool is fit for risk prediction of novel viruses.}, archive = {J_PNAS}, author = {Budeski, Katherine and Lipsitch, Marc}, doi = {10.1073/pnas.2419337122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2419337122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Focusing a viral risk ranking tool on prediction}, volume = {122}, year = {2025}, }
• (2025). Existential risk narratives about AI do not distract from its immediate harms. PNAS, 122(16), e2419055122. (www)

  @article{ , abstract = {There is broad consensus that AI presents risks, but considerable disagreement about the nature of those risks. These differing viewpoints can be understood as distinct narratives, each offering a specific interpretation of AI’s potential dangers. One narrative focuses on doomsday predictions of AI posing long-term existential risks for humanity. Another narrative prioritizes immediate concerns that AI brings to society today, such as the reproduction of biases embedded into AI systems. A significant point of contention is that the “existential risk” narrative, which is largely speculative, may distract from the less dramatic but real and present dangers of AI. We address this “distraction hypothesis” by examining whether a focus on existential threats diverts attention from the immediate risks AI poses today. In three preregistered, online survey experiments (N = 10,800), participants were exposed to news headlines that either depicted AI as a catastrophic risk, highlighted its immediate societal impacts, or emphasized its potential benefits. Results show that i) respondents are much more concerned with the immediate, rather than existential, risks of AI, and ii) existential risk narratives increase concerns for catastrophic risks without diminishing the significant worries respondents express for immediate harms. These findings provide important empirical evidence to inform ongoing scientific and political debates on the societal implications of AI.}, archive = {J_PNAS}, author = {Hoes, Emma and Gilardi, Fabrizio}, doi = {10.1073/pnas.2419055122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2419055122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Existential risk narratives about AI do not distract from its immediate harms}, volume = {122}, year = {2025}, }
• (2025). SNX10 deficiency impairs sensitivity to anti-HER2 antibody–drug conjugates via altering HER2 trafficking in HER2-positive breast cancer. PNAS, 122(16), e2417586122. (www)

  @article{ , abstract = {Antibody–drug conjugates (ADCs) are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable efficacy in breast cancer. Despite the promising efficacy of anti-HER2 ADCs, many patients are still experiencing disease progression under treatment. Here, by analyzing the transcriptome data from patient-derived organoid models, I-SPY2 trial, and resistant cell lines, we identified that SNX10 deficiency conferred anti-HER2 ADCs resistance in HER2-positive breast cancer. Low levels of SNX10 attenuated HER2 recycling and promoted HER2 trafficking into lysosomes. Furthermore, we found the underlying mechanism of SNX10 in HER2 traffic by regulating the endosomal RAB11A. We propose that SNX10 deficiency contributes to the inhibition of HER2 recycling as well as the decrease of cell-surface HER2 and causes anti-HER2 ADC resistance.}, archive = {J_PNAS}, author = {Chen, Yu-Fei and Zhang, Qing-Hua and Zhang, Zhong-Wei and Zhou, Yu-Jie and Liu, Cui-Cui and Shao, Zhi-Ming and Yu, Ke-Da}, doi = {10.1073/pnas.2417586122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2417586122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SNX10 deficiency impairs sensitivity to anti-HER2 antibody–drug conjugates via altering HER2 trafficking in HER2-positive breast cancer}, volume = {122}, year = {2025}, }
• (2025). The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability. PNAS, 122(16), e2417477122. (www)

  @article{ , abstract = {Mitochondrial DNA (mtDNA) stability, essential for cellular energy production, relies on DNA polymerase gamma (POLγ). Here, we show that the POLγ Y951N disease-causing mutation induces replication stalling and severe mtDNA depletion. However, unlike other POLγ disease-causing mutations, Y951N does not directly impair exonuclease activity and only mildly affects polymerase activity. Instead, we found that Y951N compromises the enzyme’s ability to efficiently toggle between DNA synthesis and degradation, and is thus a patient-derived mutation with impaired polymerase-exonuclease switching. These findings provide insights into the intramolecular switch when POLγ proofreads the newly synthesized DNA strand and reveal a new mechanism for causing mitochondrial DNA instability.}, archive = {J_PNAS}, author = {Forslund, Josefin M. E. and Nguyen, Tran V. H. and Parkash, Vimal and Berner, Andreas and Goffart, Steffi and Pohjoismäki, Jaakko L. O. and Wanrooij, Paulina H. and Johansson, Erik and Wanrooij, Sjoerd}, doi = {10.1073/pnas.2417477122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2417477122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability}, volume = {122}, year = {2025}, }
• (2025). Pulse timing dominates binaural hearing with cochlear implants. PNAS, 122(16), e2416697122. (www)

  @article{ , abstract = {Although cochlear implants (CIs) provide valuable auditory information to more than one million profoundly deaf patients, these devices remain inadequate in conveying fine timing cues. Early deaf patients in particular struggle to use interaural time differences (ITDs) for spatial hearing and auditory scene analysis. Why CI patients experience these limitations remains controversial. One possible explanation, which we investigate here, is that the stimulation by clinical CIs is inappropriate, as it encodes temporal features of sounds only in the envelope of electrical pulse trains, not the pulse timing. We have recently demonstrated that early deaf, adult implanted rats fitted with bilateral CIs that deliver carefully timed pulses routinely develop sensitivity to very small ITDs. Here we show that, while the early deafened mammalian auditory pathway can innately easily resolve pulse timing ITDs as small as 80 µs, it is many times less sensitive to the ITDs of pulse train envelopes. Our results indicate that the stimulation strategies in current clinical use do not present ITD cues in a manner that the inexperienced auditory pathway is highly sensitive to. This may deprive early deaf CI patients of the opportunity to hone their submillisecond temporal processing skills as they learn to hear through their prosthetic devices.}, archive = {J_PNAS}, author = {Schnupp, Jan W. H. and Buchholz, Sarah and Buck, Alexa N. and Budig, Henrike and Khurana, Lakshay and Rosskothen-Kuhl, Nicole}, doi = {10.1073/pnas.2416697122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2416697122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pulse timing dominates binaural hearing with cochlear implants}, volume = {122}, year = {2025}, }
• (2025). Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential. PNAS, 122(16), e2416106122. (www)

  @article{ , abstract = {Decreased dendritic spine density in the cortex is a key pathological feature of neuropsychiatric diseases including depression, addiction, and schizophrenia (SCZ). Psychedelics possess a remarkable ability to promote cortical neuron growth and increase spine density; however, these compounds are contraindicated for patients with SCZ or a family history of psychosis. Here, we report the molecular design and de novo total synthesis of (+)-JRT, a structural analogue of lysergic acid diethylamide (LSD) with lower hallucinogenic potential and potent neuroplasticity-promoting properties. In addition to promoting spinogenesis in the cortex, (+)-JRT produces therapeutic effects in behavioral assays relevant to depression and cognition without exacerbating behavioral and gene expression signatures relevant to psychosis. This work underscores the potential of nonhallucinogenic psychoplastogens for treating diseases where the use of psychedelics presents significant safety concerns.}, archive = {J_PNAS}, author = {Tuck, Jeremy R. and Dunlap, Lee E. and Khatib, Yara A. and Hatzipantelis, Cassandra J. and Weiser Novak, Sammy and Rahn, Rachel M. and Davis, Alexis R. and Mosswood, Adam and Vernier, Anna M. M. and Fenton, Ethan M. and Aarrestad, Isak K. and Tombari, Robert J. and Carter, Samuel J. and Deane, Zachary and Wang, Yuning and Sheridan, Arlo and Gonzalez, Monica A. and Avanes, Arabo A. and Powell, Noel A. and Chytil, Milan and Engel, Sharon and Fettinger, James C. and Jenkins, Amaya R. and Carlezon, William A. and Nord, Alex S. and Kangas, Brian D. and Rasmussen, Kurt and Liston, Conor and Manor, Uri and Olson, David E.}, doi = {10.1073/pnas.2416106122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2416106122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential}, volume = {122}, year = {2025}, }
• (2025). Sleep homeostasis in lizards and the role of the cortex. PNAS, 122(16), e2415929122. (www)

  @article{ , abstract = {Slow-wave sleep (SWS) and rapid eye movement sleep are the two primary components of electrophysiological sleep (e-sleep) in mammals and birds. Slow waves in the cortex not only characterize SWS but are also used as biological markers for sleep homeostasis, given their rebound after sleep deprivation (SD). Recently, it has been reported that the Australian dragon Pogona vitticeps exhibits a two-stage sleep pattern in the dorsal ventricular ridge (DVR), which includes a homologue of the mammalian claustrum (CLA). It remains unclear whether reptilian e-sleep, which has been characterized by activity outside the cortex, compensates for sleep loss, as observed in mammals. We here report a significant rebound in the local field potential (LFP) after 7 h of SD. Meanwhile, the mean bout length of each sleep state remained unaffected. We further investigated a possible role of the cortex in e-sleep regulation and homeostasis in Pogona and found that although a corticotomy had no obvious effect on the LFP features of baseline sleep, it abolished LFP power rebound in the CLA/DVR after SD. These findings suggest that e-sleep homeostasis is a common feature in amniotes and that the cortex is involved in regulating activity rebounds in reptiles and mammals.}, archive = {J_PNAS}, author = {Hatori, Sena and Yamaguchi, Sho T. and Kobayashi, Riho and Okamoto, Kazuki and Zhou, Zhiwen and Kotake, Koki T. and Matsui, Futaba and Hioki, Hiroyuki and Norimoto, Hiroaki}, doi = {10.1073/pnas.2415929122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2415929122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sleep homeostasis in lizards and the role of the cortex}, volume = {122}, year = {2025}, }
• (2025). Integratable all-solid-state thin-film microbatteries. PNAS, 122(16), e2415693122. (www)

  @article{ , abstract = {Large-scale integration of microbattery systems on chips has long been hindered by the technical barrier between electrochemistry and microelectronics, particularly in terms of the compatibility of microbattery cells and their collective manufacturability. In this work, a silicon-based all-solid-state thin-film microbattery cell is developed at low temperatures for on-chip integration applications. Stress management at the interfaces covering both the resistance to interfacial fracture and the stress dissipation through strain regulation enables microbattery cells to deliver a high-rate performance (34.4 mA cm −2 ), fast charge–discharge properties (1,000,000 cycles at 20 mA cm −2 ), and high-temperature tolerance (150 °C) under zero stack pressure. An intrinsic relationship among lithium utilization ratio, strain, stress, and interface manifestation is uncovered. A collective microfabrication protocol for on-chip microbattery packs is proposed, resulting in a prototype of series-connected microbattery packs. This work focuses on practically addressing the technologies and challenges in engineering on-chip microbattery systems for large-scale integration.}, archive = {J_PNAS}, author = {Ke, Bingyuan and Wang, Xinghui}, doi = {10.1073/pnas.2415693122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2415693122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Integratable all-solid-state thin-film microbatteries}, volume = {122}, year = {2025}, }
• (2025). Force spectroscopy reveals membrane fluctuations and surface adhesion of extracellular nanovesicles impact their elastic behavior. PNAS, 122(16), e2414174122. (www)

  @article{ , abstract = {The elastic properties of nanoscale extracellular vesicles (EVs) are believed to influence their cellular interactions, thus having a profound implication in intercellular communication. However, accurate quantification of their elastic modulus is challenging due to their nanoscale dimensions and their fluid-like lipid bilayer. We show that the previous attempts to develop atomic force microscopy-based protocol are flawed as they lack theoretical underpinning as well as ignore important contributions arising from the surface adhesion forces and membrane fluctuations. We develop a protocol comprising a theoretical framework, experimental technique, and statistical approach to accurately quantify the bending and elastic modulus of EVs. The method reveals that membrane fluctuations play a dominant role even for a single EV. The method is then applied to EVs derived from human embryonic kidney cells and their genetically engineered classes altering the tetraspanin expression. The data show a large spread; the area modulus is in the range of 4 to 19 mN/m and the bending modulus is in the range of 15 to 33 k B T , respectively. Surprisingly, data for a single EV, revealed by repeated measurements, also show a spread that is attributed to their compositionally heterogeneous fluid membrane and thermal effects. Our protocol uncovers the influence of membrane protein alterations on the elastic modulus of EVs.}, archive = {J_PNAS}, author = {Stridfeldt, Fredrik and Pandey, Vikash and Kylhammar, Hanna and Talebian Gevari, Moein and Metem, Prattakorn and Agrawal, Vipin and Görgens, André and Mamand, Doste R. and Gilbert, Jennifer and Palmgren, Lukas and Holme, Margaret N. and Gustafsson, Oskar and El Andaloussi, Samir and Mitra, Dhrubaditya and Dev, Apurba}, doi = {10.1073/pnas.2414174122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2414174122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Force spectroscopy reveals membrane fluctuations and surface adhesion of extracellular nanovesicles impact their elastic behavior}, volume = {122}, year = {2025}, }
• (2025). CD70 recruitment to the immunological synapse is dependent on CD20 in b cells. PNAS, 122(16), e2414002122. (www)

  @article{ , abstract = {CD20 is a four-transmembrane protein expressed at the surface of B cells from late pro-B cells to memory B cells, with the exception of plasma cells. Its expression pattern makes it an attractive therapeutic target for different B cell malignancies and autoimmune diseases. Despite the clinical success of CD20-targeting antibodies, the biology of the CD20 protein is still not well understood. We investigated CD20 binding partners in the membrane of human B cells using immunoprecipitation followed by mass spectrometry analysis. We identified a molecular interaction between CD70 and CD20, and confirmed this using proximity ligation assays. CD20–CD70 spatiotemporal colocalization was validated at the plasma membrane of B cells using high-resolution microscopy. Cell surface expression of CD70 was found to be enhanced upon CD20 overexpression, suggesting a role for CD20 in stabilizing CD70 at the B cell membrane. Moreover, we observed impaired B-T cell synapse formation and defective recruitment of CD70 to the immunological synapse in the absence of CD20. Impaired synapse formation was confirmed by deleting CD20 in primary B cells, and analysis of B cells from a CD20-deficient patient. Finally, CD20-deletion resulted in diminished T cell activation and cytokine secretion. Together, this study demonstrates that CD20 interacts with CD70 at the B cell membrane, and that CD20 is required for immune synapse formation between B and T cells and consequent T cell activation.}, archive = {J_PNAS}, author = {Arp, Abbey B. and Abel Gutierrez, Andrea and ter Beest, Martin and Franken, Guus A. and Warner, Harry and Rodgers Furones, Andrea and Kenyon, Angelique N. and Jäger, Franziska and Cabrera-Orefice, Alfredo and Kläsener, Kathrin and van Deventer, Sjoerd and Droesen, Lenny and Dunlock, Vera Marie E. and Classens, René and Staniek, Julian and Borst, Jannie and Reth, Michael and Brandt, Ulrich and Gros, Piet and Kuijpers, Taco W. and Heemskerk, Mirjam H. M. and Rizzi, Marta and Querol Cano, Laia and van Spriel, Annemiek B.}, doi = {10.1073/pnas.2414002122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2414002122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CD70 recruitment to the immunological synapse is dependent on CD20 in b cells}, volume = {122}, year = {2025}, }
• (2025). Temperature thresholds induce abrupt shifts in biodiversity and ecosystem services in montane ecosystems worldwide. PNAS, 122(16), e2413981122. (www)

  @article{ , abstract = {Montane ecosystems are crucial for maintaining global biodiversity and function that sustain life on our planet. Yet, these ecosystems are highly vulnerable to changing temperatures and may undergo critical transitions under ongoing climate change. What we do not know is to what extent montane biodiversity and ecosystem services will respond to local temperature variations in a gradual versus abrupt manner across global environments. To fill this knowledge gap, we conducted a global synthesis, including 4,462 observations from 290 elevation gradients, to investigate how biodiversity (spanning animals and plants) and ecosystem services (including plant production, soil carbon, and fertility) respond to local temperature variations along elevation gradients. We found that nearly one-third of these gradients exhibited abrupt shifts in multiple biodiversity and ecosystem services in response to local variations in temperature along elevation gradients. More specifically, we showed that once a particular local temperature level (~10 °C for mean annual temperature) was reached, even small increases in temperature resulted in dramatic variations in biodiversity and ecosystem services. We further showed that those abrupt shifts in response to local temperature increases were commonly positive for plant and animal diversity, as well as plant production, while soil carbon and fertility more commonly exhibit negative abrupt trends. Our work, based on the most comprehensive empirical evidence available so far, reveals the pervasive abrupt responses of biodiversity and ecosystem services to local temperature variations in montane ecosystems worldwide, highlighting the highly sensitive nature of montane ecosystems in the context of climate change.}, archive = {J_PNAS}, author = {Zeng, Xiao-Min and Berdugo, Miguel and Saez-Sandino, Tadeo and Tao, Dongxue and Ren, Tingting and Zhou, Guiyao and Liu, Yu-Rong and Terrer, Cesar and Reich, Peter B. and Delgado-Baquerizo, Manuel}, doi = {10.1073/pnas.2413981122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2413981122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Temperature thresholds induce abrupt shifts in biodiversity and ecosystem services in montane ecosystems worldwide}, volume = {122}, year = {2025}, }
• (2025). Intraflagellar transport trains can switch rails and move along multiple microtubules in intact primary cilia. PNAS, 122(16), e2413968122. (www)

  @article{ , abstract = {Structural homeostasis and proper distributions of signaling molecules in cilia require a constant flow of cargoes carried by intraflagellar transport (IFT) trains in both anterograde and retrograde directions within the thin, long ciliary shafts. In the motile cilium framework, the nine microtubule doublets of the same length serve as the transportation rails, and a preferential association to the two subtubules of the microtubule doublets prevents collisions among the IFT trains that move in opposite directions. However, this mechanism is incompatible with the primary cilia structure, where most of the nine microtubule doublets terminate in the ciliary shafts—only several of them reach the ciliary tip and only in a singlet form. Here, we demonstrate that anterograde and retrograde trains in primary cilia interact with both subtubules of the microtubule doublets without apparent preference. They can switch microtubules, and they may simultaneously interact with multiple microtubules to facilitate their movement. This architecture makes the collisions inevitable, and live-cell recordings reveal that anterograde and retrograde trains tend to pause when they come into direct contact. We also find that the velocity of the train’s movement often changes after the pause. Thus, the motion behaviors of IFT trains in primary cilia are distinctive from those of motile cilia, and our data offer an essential foundation for understanding proper signaling molecule distributions in primary cilia.}, archive = {J_PNAS}, author = {Sun, Shufeng and Liang, Biqing and Koplas, Adam and Tikhonenko, Irina and Nachury, Maxence and Khodjakov, Alexey and Sui, Haixin}, doi = {10.1073/pnas.2413968122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2413968122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intraflagellar transport trains can switch rails and move along multiple microtubules in intact primary cilia}, volume = {122}, year = {2025}, }
• (2025). Global warming drives a threefold increase in persistence and 1 °C rise in intensity of marine heatwaves. PNAS, 122(16), e2413505122. (www)

  @article{ , abstract = {Marine heatwaves are extreme climatic events consisting of persistent periods of warm ocean waters that have profound impacts on marine life. These episodes are becoming more intense, longer, and more frequent in response to anthropogenic global warming. Here, we provide a comprehensive and quantitative assessment on the role of global warming on marine heatwaves. To do so, we construct a counterfactual version of observed global sea surface temperatures since 1940, corresponding to a stationary climate without the effect of long-term increasing global temperatures, and use it to calculate the contribution of global air temperature rise on the intensity and persistence of marine heatwaves. We determine that global warming is responsible for nearly half of these extreme events and that, on a global average, it has led to a three-fold increase in the number of days per year that the oceans experience extreme surface heat conditions. We also show that global warming is responsible for an increase of 1 ° C in the maximum intensity of the events. Our findings highlight the detrimental role that human-induced global warming plays on marine heatwaves. This study supports the need for mitigation and adaptation strategies to address these threats to marine ecosystems.}, archive = {J_PNAS}, author = {Marcos, Marta and Amores, Angel and Agulles, Miguel and Robson, Jon and Feng, Xiangbo}, doi = {10.1073/pnas.2413505122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2413505122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global warming drives a threefold increase in persistence and 1 °C rise in intensity of marine heatwaves}, volume = {122}, year = {2025}, }
• (2025). Peripheral CD4+ t cells mediate the destructive effects of maternal separation on prefrontal myelination and cognitive functions. PNAS, 122(16), e2412995122. (www)

  @article{ , abstract = {Maternal separation (MS), a chronic stress event in early life, impairs myelination in the prefrontal cortex (PFC) and leads to PFC cognitive disorders. It remains largely unclear how such deficits are mediated. Here, we show that peripheral CD4 + T cells play an essential role in mediating the destructive effects of MS on medial prefrontal cortical (mPFC) myelination and cognitive functions in mice. Offspring mice with MS experience (MS mice) exhibited an increase in CD4 + T cells and xanthine levels in peripheral blood and a severe deficit in mPFC-dependent cognitive functions such as working memory, social interaction, and anxiety/depression emotion regulation, along with a decrease in oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs) in the mPFC. These phenotypes were rescued upon treatment with the antibody neutralizing peripheral CD4 + T cells. Rag1 −/− immunodeficient mice receiving transplantation of CD4 + T cells isolated from the peripheral blood of MS mice showed similar phenotypes as observed in MS mice. Immunofluorescence staining revealed a rich expression of adenosine receptor A1 (A1) in OPCs in the mPFC, and the A1-expressing OPCs decreased in the Rag1 −/− mice receiving CD4 + T cell transplantation. The present study demonstrates a causal link between peripheral CD4 + T cells and MS-induced prefrontal cortical hypomyelination and cognitive dysfunction, and such a link is probably mediated via xanthine–adenosine receptor A1 signaling in OPCs.}, archive = {J_PNAS}, author = {Xiong, Rui and Hu, Yinyin and Wang, Menghan and Han, Ting and Hu, Yuying and Ma, Chaolin and Li, Baoming}, doi = {10.1073/pnas.2412995122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2412995122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Peripheral CD4+ t cells mediate the destructive effects of maternal separation on prefrontal myelination and cognitive functions}, volume = {122}, year = {2025}, }
• (2025). The “don’t eat me” signal CD47 is associated with microglial phagocytosis defects and autism-like behaviors in 16p11.2 deletion mice. PNAS, 122(16), e2411080122. (www)

  @article{ , abstract = {Various pathological characteristics of autism spectrum disorder (ASD) stem from abnormalities in brain resident immune cells, specifically microglia, to prune unnecessary synapses or neural connections during early development. Animal models of ASD exhibit an abundance of synapses in different brain regions, which is strongly linked to the appearance of ASD behaviors. Overexpression of CD47 on neurons acts as a “don’t eat me” signal, safeguarding synapses from inappropriate pruning by microglia. Indeed, CD47 overexpression occurs in 16p11.2 deletion carriers, causing decreased synaptic phagocytosis and the manifestation of ASD characteristics. However, the role of CD47 in synaptic pruning impairment leading to ASD phenotypes in the 16p11.2 deletion mouse model is unclear. Moreover, whether blocking CD47 can alleviate ASD mice’s behavioral deficits remains unknown. Here, we demonstrate a strong link between increased CD47 expression, decreased microglia phagocytosis capacity, and increased impairment in social novelty preference in the 16p11.2 deletion mice. The reduction in microglia phagocytosis caused a rise in excitatory synapses and transmission in the prefrontal cortex of 16p11.2 deletion mice. Importantly, blocking CD47 using a specific CD47 antibody or reducing CD47 expression using a specific short hairpin RNA (shRNA) enhanced the microglia phagocytosis and reduced excitatory transmission. Reduction in CD47 expression improved social novelty preference deficits in 16p11.2 mice. These findings demonstrate that CD47 is associated with the ASD phenotypes in the 16p11.2 deletion mice and could be a promising target for the development of treatment for ASD.}, archive = {J_PNAS}, author = {Ju, Jun and Pan, Yifan and Yang, Xinyi and Li, Xuanyi and Chen, Jinghong and Wu, Shiyu and Hou, Sheng-Tao}, doi = {10.1073/pnas.2411080122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2411080122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The “don’t eat me” signal CD47 is associated with microglial phagocytosis defects and autism-like behaviors in 16p11.2 deletion mice}, volume = {122}, year = {2025}, }
• (2025). CB-1 receptor agonist drastically changes oscillatory activity, defining active sleep. PNAS, 122(16), e2411063122. (www)

  @article{ , abstract = {Brain oscillations in different behavioral states are essential for cognition, and oscillopathies contribute to cognitive dysfunction in neuropsychiatric diseases. Cannabis-1 receptor (CB1-R) activation was reported to suppress theta and fast gamma activities in rats during waking exploration, and here, we show that cannabis fundamentally alters network activity during sleep as well. Prominent theta rhythm is present in rapid eye movement sleep (REMS), whereas fast oscillations appear as regular sequences of sleep spindles during intermediate sleep (IS)—both implicated in dreaming and memory consolidation. The CB1-R agonist disrupted these mechanisms, restructuring IS-REMS episodes; IS lengthened sixfold and intruded REMS, where ongoing theta was drastically reduced. The spindle architecture was also affected; its amplitude increased, and its peak frequency downshifted into the theta range. Cannabis is known to induce psychotic-like conditions and cognitive deficits; thus, our results may help in understanding the dual effect of cannabis on cognitive states and the role of network oscillations in psychiatric pathology.}, archive = {J_PNAS}, author = {Topchiy, Irina and Kocsis, Bernat}, doi = {10.1073/pnas.2411063122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2411063122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CB-1 receptor agonist drastically changes oscillatory activity, defining active sleep}, volume = {122}, year = {2025}, }
• (2025). A 5-HT-mediated urethral defense against urinary tract infections. PNAS, 122(16), e2409754122. (www)

  @article{ , abstract = {The urethra is considered a passive conduit for urine. Here, we reveal a surprising multicellular signaling pathway guiding the urethra’s dynamic response to an invading pathogen. Using a genetic approach in female mice, we deposited uropathogenic Escherichia coli into the distal urethra to establish a model of ascending urinary tract infection that progresses to the bladder within 4 h. We show that urethral neuroendocrine cells (UNECs), and the serotonin they synthesize, protect the bladder from bacterial colonization. We tested the hypothesis that serotonin initiates urethral contraction to expel ascending bacteria. We identified transient receptor potential cation channel subfamily A member 1, a noncanonical lipopolysaccharide receptor, in human and mouse UNECs and localized the serotonin receptors (HTR) 2B and 3, as well as the calcium-activated chloride channel anoctamin 1 (ANO1) to the pacemaker cells of the human and mouse urethra, the interstitial cells of Cajal (ICCs). HTR2B or ANO1 activation is sufficient for urethral contraction and is required for serotonin-induced mouse urethral contraction. Our results support the hypothesis that the urethra actively surveils its environment and responds to an ascending pathogen by evoking UNECs and ICC to induce urethral contraction and pathogen expulsion.}, archive = {J_PNAS}, author = {Ambrogi, Marcela and Hernandez, Laura L. and Strand, Douglas W. and Kumar, Sathish and Romero, Michael F. and Barasch, Jonathan and Ridlon, Monica and Keil Stietz, Kimberly P. and Vezina, Chad M.}, doi = {10.1073/pnas.2409754122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2409754122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A 5-HT-mediated urethral defense against urinary tract infections}, volume = {122}, year = {2025}, }
• (2025). Evaluating interdisciplinary research: Disparate outcomes for topic and knowledge base. PNAS, 122(16), e2409752122. (www)

  @article{ , abstract = {Interdisciplinary research is essential for addressing complex global challenges, but there are concerns that scientific institutions like journals select against it. Prior work has focused largely on how interdisciplinarity relates to outcomes for published papers, but which papers get accepted for publication in the first place is unclear. Furthermore, journals may evaluate two key dimensions of interdisciplinarity,—topic and knowledge base,—differently. Topic interdisciplinarity (measured through title and abstract) may incur evaluation penalties by cutting across disciplinary evaluation standards and threatening symbolic boundaries, while knowledge-base interdisciplinarity (measured through references) may incur benefits by combining a large pool of nonredundant information. Evaluations may also depend on how well these dimensions align with each other and the intended audience. We test these arguments using data on 128,950 submissions to 62 journals across STEM disciplines, including both accepted and rejected manuscripts. We find that a 1SD increase in knowledge-base interdisciplinarity is associated with a 0.9 percentage-point higher acceptance probability, while a 1SD increase in topic interdisciplinarity corresponds to a 1.2 percentage-point lower acceptance probability. However, the penalty for high topic-interdisciplinarity diminishes when knowledge-base interdisciplinarity is also high, and when submitted to journals designated as “interdisciplinary.” These findings challenge the narrative of a uniform bias against interdisciplinary research and highlight the importance of distinguishing between its dimensions, as well as their alignment with each other and the intended audience.}, archive = {J_PNAS}, author = {Xiang, Sidney and Romero, Daniel M. and Teplitskiy, Misha}, doi = {10.1073/pnas.2409752122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2409752122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evaluating interdisciplinary research: Disparate outcomes for topic and knowledge base}, volume = {122}, year = {2025}, }
• (2025). Inhibitory control explains locomotor statistics in walking drosophila. PNAS, 122(16), e2407626122. (www)

  @article{ , abstract = {In order to forage for food, many animals regulate not only specific limb movements but the statistics of locomotor behavior, switching between long-range dispersal and local search depending on resource availability. How premotor circuits regulate locomotor statistics is not clear. Here, we analyze and model locomotor statistics and their modulation by attractive food odor in walking Drosophila . Food odor evokes three motor regimes in flies: baseline walking, upwind running during odor, and search behavior following odor loss. During search, we find that flies adopt higher angular velocities and slower ground speeds and turn for longer periods in the same direction. We further find that flies adopt periods of different mean ground speed and that these state changes influence the length of odor-evoked runs. We next developed a simple model of neural locomotor control that suggests that contralateral inhibition plays a key role in regulating the statistical features of locomotion. As the fly connectome predicts decussating inhibitory neurons in the premotor lateral accessory lobe (LAL), we gained genetic access to a subset of these neurons and tested their effects on behavior. We identified one population whose activation induces all three signature of local search and that regulates angular velocity at odor offset. We identified a second population, including a single LAL neuron pair, that bidirectionally regulates ground speed. Together, our work develops a biologically plausible computational architecture that captures the statistical features of fly locomotion across behavioral states and identifies neural substrates of these computations.}, archive = {J_PNAS}, author = {Gattuso, Hannah C. and van Hassel, Karin A. and Freed, Jacob D. and Nuñez, Kavin M. and de la Rea, Beatriz and May, Christina E. and Ermentrout, Bard and Victor, Jonathan D. and Nagel, Katherine I.}, doi = {10.1073/pnas.2407626122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2407626122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inhibitory control explains locomotor statistics in walking drosophila}, volume = {122}, year = {2025}, }
• (2025). Mapping global brain reconfigurations following local targeted manipulations. PNAS, 122(16), e2405706122. (www)

  @article{ , abstract = {Understanding how localized brain interventions influence whole-brain dynamics is essential for deciphering neural function and designing therapeutic strategies. Using longitudinal functional MRI datasets collected from mice, we investigated the effects of focal interventions, such as thalamic lesions and chemogenetic silencing of cortical hubs. We found that these local manipulations disrupted the brain’s ability to sustain network-wide activity, leading to global functional connectivity (FC) reconfigurations. Personalized mouse brain simulations based on experimental data revealed that alterations in local excitability modulate firing rates and frequency content across distributed brain regions, driving these FC changes. Notably, the topography of the affected brain regions depended on the intervention site, serving as distinctive signatures of localized perturbations. These findings suggest that focal interventions produce consistent yet region-specific patterns of global FC reorganization, providing an explanation for the seemingly paradoxical observations of hypo- and hyperconnectivity reported in the literature. This framework offers mechanistic insights into the systemic effects of localized neural modulation and holds potential for refining clinical diagnostics in focal brain disorders and advancing personalized neuromodulation strategies.}, archive = {J_PNAS}, author = {Rabuffo, Giovanni and Lokossou, Houefa-Armelle and Li, Zengmin and Ziaee-Mehr, Abolfazl and Hashemi, Meysam and Quilichini, Pascale P. and Ghestem, Antoine and Arab, Ouafae and Esclapez, Monique and Verma, Parul and Raj, Ashish and Gozzi, Alessandro and Sorrentino, Pierpaolo and Chuang, Kai-Hsiang and Perles-Barbacaru, Teodora-Adriana and Viola, Angèle and Jirsa, Viktor K. and Bernard, Christophe}, doi = {10.1073/pnas.2405706122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2405706122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mapping global brain reconfigurations following local targeted manipulations}, volume = {122}, year = {2025}, }
• (2025). Dynamic coexistence driven by physiological transitions in microbial communities. PNAS, 122(16), e2405527122. (www)

  @article{ , abstract = {Microbial ecosystems are commonly modeled by fixed interactions between species in steady exponential growth states. However, microbes in exponential growth often modify their environments so strongly that they are forced out of the growth state into stressed, nongrowing states. Such dynamics are typical of ecological succession in nature and serial-dilution cycles in the laboratory. Here, we introduce a phenomenological model, the Community State Model, to gain insight into the dynamic coexistence of microbes due to changes in their physiological states during cyclic succession. Our model specifies the growth preference of each species along a global ecological coordinate, taken to be the biomass density of the community, but is otherwise agnostic to specific interactions (e.g., nutrient starvation, stress, aggregation), in order to focus on self-consistency conditions on combinations of physiological states, “community states,” in a stable ecosystem. We identify three key features of such dynamical communities that contrast starkly with steady-state communities: enhanced community stability through staggered dominance of different species in different community states, increased tolerance of community diversity to fast growing species dominating distinct community states, and increased requirement of growth dominance by late-growing species. These features, derived explicitly for simplified models, are proposed here as principles aiding the understanding of complex dynamical communities. Our model shifts the focus of ecosystem dynamics from bottom–up studies based on fixed, idealized interspecies interaction to top–down studies based on accessible macroscopic observables such as growth rates and total biomass density, enabling quantitative examination of community-wide characteristics.}, archive = {J_PNAS}, author = {Narla, Avaneesh V. and Hwa, Terence and Murugan, Arvind}, doi = {10.1073/pnas.2405527122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2405527122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic coexistence driven by physiological transitions in microbial communities}, volume = {122}, year = {2025}, }
• (2025). A rare variant in GPR156 associated with depression in a mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice. PNAS, 122(16), e2404754122. (www)

  @article{ , abstract = {Major depressive disorder (MDD) is a leading cause of disability worldwide. Risk for MDD is heritable, and the genetic structure of founder populations enables investigation of rare susceptibility alleles with large effect. In an extended Old Order Mennonite family cohort, we identified a rare missense variant in GPR156 (c.1599G>T, p.Glu533Asp) associated with a two-fold increase in the relative risk of MDD. GPR156 is an orphan G protein–coupled receptor localized in the medial habenula, a region implicated in mood regulation. Insertion of a human sequence containing c.1599G>T into the murine Gpr156 locus induced medial habenula hyperactivity and abnormal stress-related behaviors. This work reveals a human variant that is associated with depression, implicates GPR156 as a target for mood regulation, and introduces informative murine models for investigating the pathophysiology and treatment of affective disorders.}, archive = {J_PNAS}, author = {Miller, Bradley R. and Gonzaga-Jauregui, Claudia and Brigatti, Karlla W. and de Jong, Job and Breese, Robert S. and Ko, Seung Yeon and Puffenberger, Erik G. and Van Hout, Cristopher and Young, Millie and Luna, Victor M. and Staples, Jeffrey and First, Michael B. and Gregoire, Hilledna J. and Dwork, Andrew J. and Pefanis, Evangelos and McCarthy, Shane and Brydges, Susannah and Rojas, Jose and Ye, Bin and Stahl, Eli and Di Gioia, Silvio Alessandro and Hen, René and Elwood, Kevin and Rosoklija, Gorazd and Li, Dadong and Mellis, Scott and Carey, David and Croll, Susan D. and Overton, John D. and Macdonald, Lynn E. and Economides, Aris N. and Shuldiner, Alan R. and Chuhma, Nao and Rayport, Stephen and Amin, Najaf and Kushner, Steven A. and Alessandri-Haber, Nicole and Markx, Sander and Strauss, Kevin A.}, doi = {10.1073/pnas.2404754122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2404754122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A rare variant in GPR156 associated with depression in a mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice}, volume = {122}, year = {2025}, }
• (2025). Introducing the special feature on housing differences and inequality over the very long term. PNAS, 122(16), e2401989122. (www)

  @article{ , archive = {J_PNAS}, author = {Kohler, Timothy A. and Bogaard, Amy and Ortman, Scott G.}, doi = {10.1073/pnas.2401989122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2401989122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Introducing the special feature on housing differences and inequality over the very long term}, volume = {122}, year = {2025}, }
• (2025). Iconicity as an organizing principle of the lexicon. PNAS, 122(16), e2401041122. (www)

  @article{ , abstract = {The view that words are arbitrary is a foundational assumption about language, used to set human languages apart from nonhuman communication. We present here a study of the alignment between the semantic and phonological structure (systematicity) of American Sign Language (ASL), and for comparison, two spoken languages—English and Spanish. Across all three languages, words that are semantically related are more likely to be phonologically related, highlighting systematic alignment between word form and word meaning. Critically, there is a significant effect of iconicity (a perceived physical resemblance between word form and word meaning) on this alignment: words are most likely to be phonologically related when they are semantically related and iconic. This phenomenon is particularly widespread in ASL: half of the signs in the ASL lexicon are iconically related to other signs, i.e., there is a nonarbitrary relationship between form and meaning that is shared across signs. Taken together, the results reveal that iconicity can act as a driving force behind the alignment between the semantic and phonological structure of spoken and signed languages, but languages may differ in the extent that iconicity structures the lexicon. Theories of language must account for iconicity as a possible organizing principle of the lexicon.}, archive = {J_PNAS}, author = {Campbell, Erin E. and Sehyr, Zed Sevcikova and Pontecorvo, Elana and Cohen-Goldberg, Ariel and Emmorey, Karen and Caselli, Naomi}, doi = {10.1073/pnas.2401041122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2401041122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Iconicity as an organizing principle of the lexicon}, volume = {122}, year = {2025}, }
• (2025). Toward multiscalar measures of inequality in archaeology. PNAS, 122(16), e2400700121. (www)

  @article{ , abstract = {The Gini coefficient is a statistical measure commonly used to characterize distributions of socioeconomic quantities. Archaeologists and social scientists have recently adopted this method to analyze ancient inequality by targeting specific proxy variables (e.g., residential unit size, burial data, etc.). Variations in the Gini are then examined in relation to key factors such as time, geography, and subsistence. Yet, Gini coefficients could be obtained across different scales of aggregation, from small neighborhoods within a larger settlement to an ensemble of multiple settlements that are part of the same polity. These different scales of aggregation represent considerable methodological and theoretical challenges, as larger scales might, for example, imply greater social and economic variation within groups and thus affect the Gini coefficients. Furthermore, these issues can also be exacerbated by the idiosyncrasies and limitations of historical and archaeological datasets. This paper discusses the potential and challenges of measuring Gini coefficients at and above the scale of individual archaeological sites, contrasting different approaches and discussing how each can reveal insights into different patterns of past wealth inequality, addressing methodological, empirical, and theoretical implications arising from the multiscalar nature of human interactions.}, archive = {J_PNAS}, author = {Crema, Enrico R. and Fochesato, Mattia and Mejía Ramón, Andrés G. and Munson, Jessica and Ortman, Scott G.}, doi = {10.1073/pnas.2400700121}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2400700121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Toward multiscalar measures of inequality in archaeology}, volume = {122}, year = {2025}, }
• (2025). Assessing neighborhoods, wealth differentials, and perceived inequality in preindustrial societies. PNAS, 122(16), e2400699121. (www)

  @article{ , abstract = {Humans often live in neighborhoods, nested socio-spatial clusters within settlements of varying size and population density. In today’s cities, neighborhoods are often characterized as relatively homogenous and may exhibit segregation along various socioeconomic dimensions. However, even within neighborhoods of similar social or economic status, there is often residential disparity, which in turn impacts perceived inequality. Drawing on the Global Dynamics of Inequality (GINI) project database, we study housing inequality within a sample of neighborhoods using the Gini coefficient of residential unit area and related measures of inequality. We examine patterns of intracommunity inequality within more than 80 settlements from diverse spatiotemporal contexts including some of the earliest cities in Mesopotamia, the Roman Empire, the Classic Maya region, the Central Andes, and the Indus River Basin. Residential disparity differs within and among sectors of these settlements; some neighborhoods exhibit more similarity in residence size, resulting in lower degrees of housing inequality, while other sectors display greater variations in residence size with higher degrees of housing inequality. We observe a meaningful relationship between neighborhood inequality and population size, but not date of foundation or longevity of occupation. The macro-level structural processes associated with varying forms of governance seem to trickle down to the scale of the neighborhood. These findings may help explain why more unequal systems are not necessarily more unstable, as the inequality people experienced in their neighborhoods may generally have been less than that present in the overall settlement.}, archive = {J_PNAS}, author = {Thompson, Amy E. and Munson, Jessica and Ortman, Scott G. and Mejía Ramón, Andrés G. and Feinman, Gary M. and Cervantes Quequezana, Gabriela and Cruz, Pablo and Green, Adam S. and Lawrence, Dan and Roscoe, Paul}, doi = {10.1073/pnas.2400699121}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2400699121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Assessing neighborhoods, wealth differentials, and perceived inequality in preindustrial societies}, volume = {122}, year = {2025}, }
• (2025). Assessing grand narratives of economic inequality across time. PNAS, 122(16), e2400698121. (www)

  @article{ , abstract = {Long-entrenched grand narratives have tied inequality in large human aggregations to generally linear trends, a direct outcome of domestication, then fostered by population growth and/or stepped scalar transitions in the hierarchical complexity of human institutions. This general pattern has been argued to short-circuit or reverse only in the context of cataclysmic disasters or societal breakdowns. Yet, for the most part, these universal deterministic frameworks have been constructed from historical or ethnographic snapshots in time and afford little systematic attention to human institutions or agency. Here, we leverage quantitative, temporally defined archaeological, and ethnographic data from a suite of global regions, most of which transitioned through the process of urbanism and complex hierarchy formation, to examine shifts in degrees of inequality over time. Although broad temporal patterns are evidenced, the regional trends in inequality are neither linear, uniform, nor triggered immediately or mechanically by Malthusian dynamics or scalar increases.}, archive = {J_PNAS}, author = {Feinman, Gary M. and Cervantes Quequezana, Gabriela and Green, Adam and Lawrence, Dan and Munson, Jessica and Ortman, Scott and Petrie, Cameron and Thompson, Amy and Nicholas, Linda M.}, doi = {10.1073/pnas.2400698121}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2400698121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Assessing grand narratives of economic inequality across time}, volume = {122}, year = {2025}, }
• (2025). 100 generations of wealth equality after the neolithic transitions. PNAS, 122(16), e2400697122. (www)

  @article{ , abstract = {From Rousseau onward, scholars have identified the transition to sedentary agriculture as crucial to the history of wealth inequality. Here, using the GINI project’s global database on disparities in residential size, we examine the effects of important innovations in plant cultivation, animal husbandry, and traction on wealth inequality. Over a series of regional case studies, we find no evidence of major changes in residential disparity before or after these technological innovations became widespread, and where the effects of systemic change are recognizable, they are ambiguous. The introduction of horticulture/farming is accompanied by a slight general increase in inequality, while subsequent innovations tend to have a leveling effect. Although increasing productivity and surplus are critical to generating wealth inequality, nothing in our data suggests that rising productivity alone led to greater wealth inequality.}, archive = {J_PNAS}, author = {Kerig, Tim and Crema, Enrico R. and Birch, Jennifer and Feinman, Gary M. and Green, Adam S. and Gronenborn, Detlef and Lawrence, Dan and Petrie, Cameron A. and Roscoe, Paul and Thompson, Amy E. and Kohler, Timothy A.}, doi = {10.1073/pnas.2400697122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2400697122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {100 generations of wealth equality after the neolithic transitions}, volume = {122}, year = {2025}, }
• (2025). Housing inequality and settlement persistence are associated across the archaeological record. PNAS, 122(16), e2400696122. (www)

  @article{ , abstract = {Definitions of sustainability commonly stress both systemic continuity and equality over time. However, the degree to which these two sides of sustainability might be related has not been systematically investigated. Recent theoretical and methodological insights have provided archaeologists with new tools for investigating sustainability in premodern societies. Here, we use Gini coefficients on residence size measurements as an estimate of material inequality and information on the persistence of settlements as a measure of continuity. Persistence is derived from the length of time a settlement endured in a particular state, and we assume that higher levels of persistence indicate greater adaptive capacity and resilience. We articulate an approach which allows us to combine these proxies to investigate the relationship between these two sides of sustainability and apply this to a global dataset of settlements from the last 10,000 y. We find that persistence is weakly correlated with material inequality, rather than equality, overall. We also find that this relationship grows stronger as settlement systems increase in scale and is strongest for larger sites in larger systems. This pattern may be the result of both increased functional diversity at a site level and network effects whereby residents of larger settlements were able to claim a larger share of the surplus produced by the settlement system.}, archive = {J_PNAS}, author = {Lawrence, Dan and Bogaard, Amy and Cervantes Quequezana, Gabriela and Chelazzi, Francesca and Feinman, Gary M. and Green, Adam S. and Hamerow, Helena and Munson, Jessica and Ortman, Scott G. and Thompson, Amy E.}, doi = {10.1073/pnas.2400696122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2400696122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Housing inequality and settlement persistence are associated across the archaeological record}, volume = {122}, year = {2025}, }
• (2025). War both reduced and increased inequality over the past ten thousand years. PNAS, 122(16), e2400695121. (www)

  @article{ , abstract = {Scholars are divided over the long-term effects that war has had on inequality. Some have argued that conflict grows the gap between rich and poor. Others counter that violence levels out wealth differences. The GINI Project Database is a large global sample of archaeological data on house sizes created to investigate what factors influenced economic inequality over long periods of time, including warfare. Over 39,000 individual residential units were coded as having fortifications present or absent, with about a third in fortified settlements (n = 13,372) and two-thirds in unfortified settlements (n = 25,897). We compared residential disparity (differences in residential unit sizes within a settlement) at sites around the world (n = 770) dating as far back as 10,000 y ago. We found strong support for the expectation that conflict was linked with increasing residential disparity (i.e., wealth inequality), specifically when governance was less collective and the main factor limiting agricultural production was available land. However, we also found long periods, especially in the earliest eras represented in the database, when fortified settlements had residential disparity less than or equal to unfortified settlements. These early societies tended to be more collective with available labor limiting agricultural production. We speculate that in these communities, the relative value of coalition building was higher, whereas in cases where conflict was associated with rising residential disparity, elites found a way to leverage their wealth to protect property. These contradictory models help explain why war co-occurs with increasing inequality in some cases and decreasing inequality in others.}, archive = {J_PNAS}, author = {McCoy, Mark D. and Birch, Jennifer and Chirikure, Shadreck and Cruz, Pablo and Green, Adam S. and Gronenborn, Detlef and Lawrence, Dan and Roscoe, Paul}, doi = {10.1073/pnas.2400695121}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2400695121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {War both reduced and increased inequality over the past ten thousand years}, volume = {122}, year = {2025}, }
• (2025). Labor, land, and the global dynamics of economic inequality. PNAS, 122(16), e2400694122. (www)

  @article{ , abstract = {Here, we assess the extent to which land use relating to food acquisition (farming, herding, foraging) and associated value regimes shaped past economic inequality. We consider the hypothesis that land-use systems in which production was limited by heritable material wealth (such as land) sustained higher levels of inequality than those limited by (free) human labor. We address this hypothesis using the Global Dynamics of InequalIty (GINI) project database, estimating economic inequalities based on disparities in residential unit area and storage capacity within sites in different world regions and through time. We find that inequality was significantly greater in land-limited than labor-limited regimes, whether based on residence area or storage capacity, though governance could moderate these differences. Increasing inequality with larger residence and/or site size is associated with underlying shifts from labor- to land-limited economies. Transitions from labor- to land-limited regimes also appear to underlie the development of extended political hierarchies. Increases in inequality after cultivation became common in each hemisphere similarly reflect shifts from labor- to land-limited systems. Land-limited systems in the eastern hemisphere, incorporating animal traction, exhibit an upward trend in inequality over time, while a downward trend in the western hemisphere reflects the lower persistence of land-limited regimes based solely on human labor.}, archive = {J_PNAS}, author = {Bogaard, Amy and Cruz, Pablo and Fochesato, Mattia and Birch, Jennifer and Cervantes Quequezana, Gabriela and Chirikure, Shadreck and Crema, Enrico R. and Feinman, Gary M. and Green, Adam S. and Hamerow, Helena and Jin, Guiyun and Kerig, Tim and Lawrence, Dan and McCoy, Mark D. and Munson, Jessica and Ortman, Scott G. and Petrie, Cameron A. and Roscoe, Paul}, doi = {10.1073/pnas.2400694122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2400694122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Labor, land, and the global dynamics of economic inequality}, volume = {122}, year = {2025}, }
• (2025). Changes in agglomeration and productivity are poor predictors of inequality across the archaeological record. PNAS, 122(16), e2400693122. (www)

  @article{ , abstract = {We address three basic issues regarding the long-term dynamics of inequality in society. First, we consider the interpretation of residence sizes in socioeconomic terms by comparing statistical patterns extracted from the Global Dynamics of Inequality (GINI) Project database with those from the 21st-century United States. Second, we examine the degree to which the size and productivity of human networks is systematically related to inequality. Finally, we investigate relationships between productivity and productivity growth distributions for patterns of inequality and development across preindustrial societies. We find that across preindustrial societies residence size distributions provide a reasonable proxy for the distribution of productivity (income, a flow of physical and social resources to the group) and a minimum estimator for the distribution of wealth (a stock of such resources accumulated over time); that scale and productivity affect levels of inequality but account for only a small fraction of the observed variance across societies; and that inequality growth is independent of productivity growth, on average and over time. These findings have important implications for efforts to promote more equitable economic development in the present.}, archive = {J_PNAS}, author = {Ortman, Scott G. and Bogaard, Amy and Munson, Jessica and Lawrence, Dan and Green, Adam S. and Feinman, Gary M. and Chirikure, Shadreck and Uhl, Johannes H. and Leyk, Stefan}, doi = {10.1073/pnas.2400693122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2400693122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Changes in agglomeration and productivity are poor predictors of inequality across the archaeological record}, volume = {122}, year = {2025}, }
• (2025). Economic inequality is fueled by population scale, land-limited production, and settlement hierarchies across the archaeological record. PNAS, 122(16), e2400691122. (www)

  @article{ , abstract = {Defining wealth broadly to include wealth in people, relational connections, and material possessions, we examine the prehistory of wealth inequality at the level of the residential units using the consistent proxy of Gini coefficients calculated across areas of contemporaneous residential units. In a sample of >1,100 sites and > 47,000 residential units spanning >10,000 y, persistent wealth inequality typically lags the onset of plant cultivation by more than a millennium. It accompanies landscape modifications and subsistence practices in which land (rather than labor) limits production, and growth of hierarchies of settlement size. Gini coefficients are markedly higher through time in settlements at or near the top of such hierarchies; settlements not enmeshed in these systems remain relatively egalitarian even long after plant and animal domestication. We infer that some households in top-ranked settlements were able to exploit the network effects, agglomeration opportunities, and (eventually) political leverage provided by these hierarchies more effectively than others, likely boosted by efficient intergenerational transmission of material resources after increased sedentism made that more common. Since population growth is associated with increased sedentism, more land-limited production, and the appearance and growth of settlement hierarchies, it is deeply implicated in the postdomestication rise of wealth inequality. Governance practices mediate the degree of wealth inequality, as do technical innovations such as the use of animals for portage, horseback riding, and the development of iron smelting.}, archive = {J_PNAS}, author = {Kohler, Timothy A. and Bogaard, Amy and Ortman, Scott G. and Crema, Enrico R. and Chirikure, Shadreck and Cruz, Pablo and Green, Adam and Kerig, Tim and McCoy, Mark D. and Munson, Jessica and Petrie, Cameron and Thompson, Amy E. and Birch, Jennifer and Cervantes Quequezana, Gabriela and Feinman, Gary M. and Fochesato, Mattia and Gronenborn, Detlef and Hamerow, Helena and Jin, Guiyun and Lawrence, Dan and Roscoe, Paul B. and Rosenstock, Eva and Erny, Grace K. and Kim, Habeom and Ohlrau, René and Hanson, J. W. and Fargher Navarro, Lane and Pailes, Matthew}, doi = {10.1073/pnas.2400691122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2400691122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Economic inequality is fueled by population scale, land-limited production, and settlement hierarchies across the archaeological record}, volume = {122}, year = {2025}, }
• (2025). Kuznets’ tides: An archaeological perspective on the long-term dynamics of sustainable development. PNAS, 122(16), e2400603121. (www)

  @article{ , abstract = {Understanding the relationship between inequality and economic growth is a critical science problem that hinders sustainable development. In 1955, Simon Kuznets hypothesized that rising economic growth raises inequality, which levels off as that growth continues. Kuznets’ “curve,” which is a cornerstone of development economics, was based on data from a small sample of rich capitalist economies. Here, we draw on the GINI database, which includes area measurements of 53,464 residences from 1,176 settlements dating from 21,000 BC to the present, and published data from the Spatial Analysis in Maya Studies (SAMS) group, to radically reevaluate Kuznets’ curve. We use Gini coefficients of residential disparity, a proxy of inequality, and mean residence area, a proxy of productivity, to investigate past sustainable development in the Bronze Age Interaction Zone (BAIZ), the Mundo Maya, and Britain prior to, over the course of, and after the Roman conquest. We interpolate spatial patterns across each zone to statistically evaluate changes in inequality and economic growth. We find a recurring pattern in which phases of sustainable development, a rise in productivity without a rise in inequality, gave way to increasing inequality. These patterns resemble those Branko Milanovic termed “Kuznets’ waves,” albeit at timescales better described as “tides,” which began after the introduction of weight metrology, an early form of economic governance associated with long-distance exchange. We posit that past sustainable development was predicated on balancing reciprocity from the bottom–up with mechanisms like early weight metrology but was repeatedly forestalled as inchoate elites co-opted these mechanisms.}, archive = {J_PNAS}, author = {Green, Adam S. and Feinman, Gary M. and Thompson, Amy E. and Cruz, Pablo and Chirikure, Shadreck and Kerig, Tim and Lawrence, Dan and Petrie, Cameron A. and Ortman, Scott G.}, doi = {10.1073/pnas.2400603121}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2400603121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Kuznets’ tides: An archaeological perspective on the long-term dynamics of sustainable development}, volume = {122}, year = {2025}, }
• (2025). Psychological impacts of climate change on US youth. PNAS, 122(16), e2311400122. (www)

  @article{ , abstract = {Awareness of the threats of climate change is causing distress in increasingly documented ways, with youth particularly affected. Experiences such as climate distress and eco-anxiety have implications for the health and well-being of societies and economies, including individuals’ mental health and future planning, as well as their agency beliefs. Here, we show in a large sample of US youth (n = 2,834, ages 16 to 24) that the majority of US youth experience moderate climate distress and some functional interference from climate-related thoughts and feelings and a neutral to slightly positive sense of agency. They feel concern, interest, disappointment, frustration, sadness, anxiousness, and anger as affective responses to the crisis, and a majority report that their climate awareness may influence their plans for education, travel, and family planning. The key takeaway of this study is that the psychological impacts of climate change in US youth can have either impairing or strengthening effects, especially in the face of increased perceived direct exposure. Results show that self-reported direct experience of climate-related events is associated with increased eco-anxiety, climate distress, and impact of climate change on future planning, but also fortifying responses such as psychological adaptation and agency. These findings highlight the need for health systems and communities to prepare to address increased climate distress and related concerns in US youth as perceived exposure to climate-related hazards increases, in ways that strengthen healthy coping and agency to act. These findings have implications for the mental health of populations, climate behaviors, and life choices of young people experiencing these threats.}, archive = {J_PNAS}, author = {Vercammen, Ans and Wray, Britt and Crider, Yoshika S. and Belkin, Gary and Lawrance, Emma L.}, doi = {10.1073/pnas.2311400122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {16}, pages = {e2311400122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Psychological impacts of climate change on US youth}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(15), eiti1525122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti1525122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {eiti1525122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Correction for zhang et al., HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis. PNAS, 122(15), e2506047122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2506047122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2506047122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for zhang et al., HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis}, volume = {122}, year = {2025}, }
• (2025). Correction for he et al., radiation-induced cellular plasticity primes glioblastoma for forskolin-mediated differentiation. PNAS, 122(15), e2506044122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2506044122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2506044122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for he et al., radiation-induced cellular plasticity primes glioblastoma for forskolin-mediated differentiation}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for karayel et al., impairment of DET1 causes neurological defects and lethality in mice and humans. PNAS, 122(15), e2505796122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2505796122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2505796122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for karayel et al., impairment of DET1 causes neurological defects and lethality in mice and humans}, volume = {122}, year = {2025}, }
• (2025). Correction for epstein-barash et al., prolonged duration local anesthesia with minimal toxicity. PNAS, 122(15), e2505793122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2505793122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2505793122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for epstein-barash et al., prolonged duration local anesthesia with minimal toxicity}, volume = {122}, year = {2025}, }
• (2025). Correction for du et al., the RNA-binding protein RBPMS inhibits smooth muscle cell–driven vascular remodeling in atherosclerosis and vascular injury. PNAS, 122(15), e2505618122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2505618122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2505618122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for du et al., the RNA-binding protein RBPMS inhibits smooth muscle cell–driven vascular remodeling in atherosclerosis and vascular injury}, volume = {122}, year = {2025}, }
• (2025). Correction for johnson et al., comparing integrative ventilatory and renal acid–base acclimatization in lowlanders and tibetan highlanders during ascent to 4,300 m. PNAS, 122(15), e2505576122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2505576122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2505576122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for johnson et al., comparing integrative ventilatory and renal acid–base acclimatization in lowlanders and tibetan highlanders during ascent to 4,300 m}, volume = {122}, year = {2025}, }
• (2025). Correction for wijnakker et al., integrin-activating yersinia protein invasin sustains long-term expansion of primary epithelial cells as 2D organoid sheets. PNAS, 122(15), e2505259122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2505259122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2505259122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for wijnakker et al., integrin-activating yersinia protein invasin sustains long-term expansion of primary epithelial cells as 2D organoid sheets}, volume = {122}, year = {2025}, }
• (2025). Correction for kumar et al., cluster dynamical mean-field study of intra-unit-cell charge nematicity in hole-doped cuprates. PNAS, 122(15), e2505231122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2505231122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2505231122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for kumar et al., cluster dynamical mean-field study of intra-unit-cell charge nematicity in hole-doped cuprates}, volume = {122}, year = {2025}, }
• (2025). Enhanced polymorph metastability drives glycine nucleation in aqueous salt solutions. PNAS, 122(15), e2503490122. (www)

  @article{ , archive = {J_PNAS}, author = {Wang, Ruiyu and Tiwary, Pratyush}, doi = {10.1073/pnas.2503490122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2503490122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Enhanced polymorph metastability drives glycine nucleation in aqueous salt solutions}, volume = {122}, year = {2025}, }
• (2025). Coupling between the lever arm and active site via an N-terminal extension tunes force sensitivity in the myosin-1 family. PNAS, 122(15), e2502977122. (www)

  @article{ , archive = {J_PNAS}, author = {Rathbone, Harry W. and Houdusse, Anne}, doi = {10.1073/pnas.2502977122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2502977122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Coupling between the lever arm and active site via an N-terminal extension tunes force sensitivity in the myosin-1 family}, volume = {122}, year = {2025}, }
• (2025). Degenerate domain walls in supersymmetric theories. PNAS, 122(15), e2502703122. (www)

  @article{ , abstract = {In supersymmetric Yang–Mills theories tension-degenerate domain walls are typical. Adding matter fields in fundamental representation, we arrive at supersymmetric quantum chromodynamics (SQCD) supporting similar walls. We demonstrate that the degenerate domain walls can belong to one of two classes: i) locally distinguishable, i.e. those which differ from each other locally (which could be detected in local measurements); and ii) those which have identical local structure and are differentiated only topologically, through a judicially chosen compactification of R 4 . Depending on the number of flavors F and the pattern of Higgsing, both classes can coexist among SQCD k walls interpolating between the vacua n and n + k . We prove that the overall multiplicity of the domain walls obtained after accounting for both classes is ν N , k walls = N ! / [ ( N − k ) ! k ! ] , as was discovered previously in limiting cases. (Here, N is the number of colors.) Thus, ν N , k walls is a peculiar index. For the locally distinguishable degenerate domain walls, we observe two-wall junctions, a phenomenon specific for supersymmetry with central extensions. This phenomenon does not exist for topological replicas.}, archive = {J_PNAS}, author = {Chen, Shi and Ievlev, Evgenii and Shifman, Mikhail}, doi = {10.1073/pnas.2502703122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2502703122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Degenerate domain walls in supersymmetric theories}, volume = {122}, year = {2025}, }
• (2025). A continental view of climate effects on lakes. PNAS, 122(15), e2502695122. (www)

  @article{ , archive = {J_PNAS}, author = {Carpenter, Stephen R.}, doi = {10.1073/pnas.2502695122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2502695122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A continental view of climate effects on lakes}, volume = {122}, year = {2025}, }
• (2025). Mixing microbiomes in vitro reveals rules of community assembly. PNAS, 122(15), e2502663122. (www)

  @article{ , archive = {J_PNAS}, author = {Mitchell, Alyssa H. and Lieberman, Tami D.}, doi = {10.1073/pnas.2502663122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2502663122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mixing microbiomes in vitro reveals rules of community assembly}, volume = {122}, year = {2025}, }
• (2025). Self-organized institutions in evolutionary dynamical-systems games. PNAS, 122(15), e2500960122. (www)

  @article{ , abstract = {Social institutions are systems of shared norms and rules that regulate people’s behaviors, often emerging without external enforcement. They provide criteria to distinguish cooperation from defection and establish rules to sustain cooperation, shaped through long-term trial and error. While principles for successful institutions have been proposed, the mechanisms underlying their emergence remain poorly understood. To address this, we introduce the evolutionary dynamical-systems game theory that couples game actions with environmental dynamics and explores the evolution of cognitive frameworks for decision-making. We analyze a minimal model of common-pool resource management, where resources grow naturally and are harvested. Players use decision-making functions to determine whether to harvest at each step, based on environmental and peer monitoring. After evolution, decision-making functions enable players to detect selfish harvesting and punish it by overharvesting, which degrades the environment. This process leads to the self-organization of norms that classify harvesting actions as cooperative, defective, or punitive. The emergent norms for “cooperativeness” and rules of punishment serve as institutions. The environmental and players’ states converge to distinct modes characterized by limit-cycle attractors, representing temporal regularities in socio-ecological systems. These modes remain stable despite slight variations in individual decision-making, illustrating the stability of institutions. We measure evolutionary robustness of decision-making functions, defined as the capacity to keep dominance against invasion. It is revealed that plasticity, the ability to adjust actions to cope with diverse opponents, allows for such robustness. This work introduces foundational concepts in evolutionary dynamical-systems games and elucidates the mechanisms underlying the self-organization of social institutions.}, archive = {J_PNAS}, author = {Itao, Kenji and Kaneko, Kunihiko}, doi = {10.1073/pnas.2500960122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2500960122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Self-organized institutions in evolutionary dynamical-systems games}, volume = {122}, year = {2025}, }
• (2025). Reply to vanunu and newell: The frequent-winner effect is necessary to explain experience-based decisions. PNAS, 122(15), e2500422122. (www)

  @article{ , archive = {J_PNAS}, author = {Olschewski, Sebastian and Spektor, Mikhail S. and Le Mens, Gaël}, doi = {10.1073/pnas.2500422122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2500422122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to vanunu and newell: The frequent-winner effect is necessary to explain experience-based decisions}, volume = {122}, year = {2025}, }
• (2025). The importance of playing the long game when it comes to pandemic surveillance. PNAS, 122(15), e2500328122. (www)

  @article{ , archive = {J_PNAS}, author = {Shearer, Freya M. and Lipsitch, Marc}, doi = {10.1073/pnas.2500328122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2500328122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The importance of playing the long game when it comes to pandemic surveillance}, volume = {122}, year = {2025}, }
• (2025). Unsupervised learning of structural relaxation in supercooled liquids from short-term fluctuations. PNAS, 122(15), e2427246122. (www)

  @article{ , abstract = {Unraveling the relationship between structural information and the dynamic properties of supercooled liquids is one of the great challenges of physics. Dynamic heterogeneity, characterized by the propensity of particles, is often used as a proxy for dynamic slowing. Over the years, significant efforts have been made to capture the structural variations linked to dynamic heterogeneity in supercooled liquids. In this work, we present an innovative unsupervised machine learning protocol based on time-lagged canonical correlation analysis or time-lagged autoencoder to autonomously identify a key order parameter (OP) for the amorphous structures of the Kob-Andersen glass former. The OP is constructed by integrating numerous classical structural descriptors and represents the component with the strongest short-term correlation on a timescale thousands of times shorter than the relaxation time. Strikingly, this OP demonstrates a remarkable correlation with the propensity at long times, significantly outperforming traditional unsupervised models and rivaling supervised models. This demonstrates that fluctuations of structural descriptors contain sufficient information about the long-time dynamic heterogeneity. The most important structural features are the density distributions at mid-range. As a consequence, the OP also exhibits excellent transferability in capturing dynamic heterogeneity across a wide temperature range and greatly facilitates the evaluation of descriptor importance, highlighting its potential for broader application to other glassy systems.}, archive = {J_PNAS}, author = {Qiu, Yunrui and Jang, Inhyuk and Huang, Xuhui and Yethiraj, Arun}, doi = {10.1073/pnas.2427246122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2427246122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unsupervised learning of structural relaxation in supercooled liquids from short-term fluctuations}, volume = {122}, year = {2025}, }
• (2025). Compositional and topological determinants of a physiological Ashwell–Morell receptor ligand. PNAS, 122(15), e2427129122. (www)

  @article{ , abstract = {The hepatocyte Ashwell–Morell receptor (AMR) is the prototypical mammalian lectin and the first cell receptor isolated. This recycling endocytic receptor of the plasma membrane determines the concentrations of hundreds of circulating glycoproteins in the blood and plays important roles in host responses to and outcomes of infection. The compositional and topological determinants of a physiological AMR ligand have remained unclear with contradictory findings reported. Previous studies established that the AMR binds multivalent galactose on desialylated triantennary or higher-branched N-glycans with little to no binding to galactose on biantennary forms. However, the vast majority of circulating blood glycoproteins are modified by biantennary N-glycans, rendering them unlikely to be ligands bound and eliminated by the AMR. Separately, other studies reported that AMR ligands include sialylated N-glycans, and specifically α2-6, but not α2-3, sialic acid linkages. Herein, we investigated the composition and topology of AMR ligands using a known physiological AMR ligand, intestinal alkaline phosphatase (IAP). Recombinant active IAP was produced in glycoengineered cells with either biantennary or higher valency triantennary and tetra-antennary N-glycan structures, and further with and without either α2-6 or α2-3 sialic acid linkages. These closely homogenous IAP monomer glycoforms assemble as dimers with similar enzymatic activity and were compared in AMR binding and clearance assays. Our results indicate that the AMR does not significantly bind IAP when its N-glycans are predominantly sialylated with either α2-6 or α2-3 sialic acid linkages. Multivalent desialylated AMR ligands may, however, appear when IAP monomers dimerize, resulting in the close proximation of biantennary N-glycans.}, archive = {J_PNAS}, author = {Hintze, John and Fraumeni, Robert and de Haan, Noortje and Miller, Rebecca L. and Saraswat, Mayank and Yang, Zhang and Clausen, Henrik and Marth, Jamey D.}, doi = {10.1073/pnas.2427129122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2427129122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Compositional and topological determinants of a physiological Ashwell–Morell receptor ligand}, volume = {122}, year = {2025}, }
• (2025). Evolutionary divergent kinetoplast genome structure and RNA editing patterns in the trypanosomatid vickermania. PNAS, 122(15), e2426887122. (www)

  @article{ , abstract = {The trypanosomatid flagellates possess in their single mitochondrion a highly complex kinetoplast (k)DNA, which is composed of interlocked circular molecules of two types. Dozens of maxicircles represent a classical mitochondrial genome, and thousands of minicircles encode guide (g)RNAs, which direct the processive and essential uridine insertion/deletion messenger RNA (mRNA) editing of maxicircle transcripts. While the details of kDNA structure and this type of RNA editing are well established, our knowledge mostly relies on a narrow foray of intensely studied human parasites of the genera Leishmania and Trypanosoma . Here, we analyzed kDNA, its expression, and RNA editing of two members of the poorly characterized genus Vickermania with very different cultivation histories. In both Vickermania species, the gRNA-containing heterogeneous large (HL)-circles are atypically large with multiple gRNAs each. Examination of Vickermania spadyakhi HL-circle loci revealed a massive redundancy of gRNAs relative to the editing needs. In comparison, the HL-circle repertoire of extensively cultivated Vickermania ingenoplastis is greatly reduced. It correlates with V. ingenoplastis -specific loss of productive editing of transcripts encoding subunits of respiratory chain complex I and corresponding lack of complex I activity. This loss in a parasite already lacking genes for subunits of complexes III and IV suggests an apparent requirement for its mitochondrial adenosine triphosphate (ATP) synthase to work in reverse to maintain membrane potential. In contrast, V. spadyakhi retains a functional complex I that allows ATP synthase to work in its standard direction.}, archive = {J_PNAS}, author = {Gerasimov, Evgeny S. and Afonin, Dmitry A. and Škodová-Sveráková, Ingrid and Saura, Andreu and Trusina, Natália and Gahura, Ondřej and Zakharova, Alexandra and Butenko, Anzhelika and Baráth, Peter and Horváth, Anton and Opperdoes, Fred R. and Pérez-Morga, David and Zimmer, Sara L. and Lukeš, Julius and Yurchenko, Vyacheslav}, doi = {10.1073/pnas.2426887122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2426887122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolutionary divergent kinetoplast genome structure and RNA editing patterns in the trypanosomatid vickermania}, volume = {122}, year = {2025}, }
• (2025). Bourbon and mycbp function with otu to promote sxl protein expression in the drosophila female germline. PNAS, 122(15), e2426524122. (www)

  @article{ , abstract = {In Drosophila ovaries, germ cells differentiate through several stages of cyst development before entering meiosis. This early differentiation program depends on both the stepwise deployment of specific regulatory mechanisms and on maintenance of germline sexual identity. The study of female sterile mutations that result in formation of germ cell tumors has been invaluable in identifying the mechanisms that control these developmental events. Here, we characterize the germ cell–enriched gene bourbon (bbn), null mutants of which cause the formation of a mixture of agametic ovarioles and cystic germ cell tumors. We performed proteomic analysis and found Bbn forms a complex with Ovarian tumor (Otu), a protein previously linked with regulation of the sex determination factor Sex lethal ( Sxl ), and the Drosophila ortholog of c-Myc binding protein (Mycbp). Loss of Mycbp also results in the formation of cystic germ cell tumors. Bbn promotes the stability of Otu and fosters interactions between Otu and Mycbp. Germ cells from bbn and Mycbp mutants display a loss of Sxl expression specifically in the germline. Transgenic rescue experiments show the bbn sterile phenotype is independent from Sxl splicing defects. Further evidence suggests Otu physically interacts with and promotes Sxl protein stability. This function does not depend on Otu’s deubiquitinase activity. Last, we find the human orthologs of Otu and Mycbp, OTUD4, and MYCBP, also physically interact, suggesting conservation of function. Together these data provide insights into how a conserved complex promotes the germline expression of Sxl protein and the differentiation of Drosophila germ cells.}, archive = {J_PNAS}, author = {Mercer, Marianne and Dasgupta, Anirban and Pawłowski, Krzysztof and Buszczak, Michael}, doi = {10.1073/pnas.2426524122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2426524122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bourbon and mycbp function with otu to promote sxl protein expression in the drosophila female germline}, volume = {122}, year = {2025}, }
• (2025). Uniform elementary fibrils in diverse plant cell walls. PNAS, 122(15), e2426467122. (www)

  @article{ , abstract = {Plant cell walls are composed of skeletal cellulose and a filling matrix of hemicelluloses and lignin. Cellulose has slender crystallite units referred to as microfibrils or elementary fibrils, and these crystallites form a dense network skeleton in the cell walls. In this study, we assessed the morphology and crystallinity of individually dispersed microfibrils isolated from the cell walls of wood, cotton, and ramie celluloses. It is well known that microfibrils in higher plants exhibit structural diversity, and these three plants, in particular, have distinct differences in the morphology and crystallinity of microfibrils. Our structural analyses combining atomic force microscopy (AFM), wide-angle X-ray diffraction (WAXD), small-angle X-ray scattering (SAXS), solid-state 13 C NMR spectroscopy, and all-atom molecular dynamics (MD) simulations revealed the uniformity in the cross-sectional dimensions and crystallinity of the dispersed microfibrils, irrespective of the plant species. The majority of the microfibrils were dispersed as structural units with widths of approximately 2 to 3 nm, and their crystallite sizes and crystallinity degrees were approximately 2 nm and 20%, respectively. These structural profiles were in agreement with the simulation results; here, the model assumed that a single microfibril consisted of 18 cellulose molecules. These results from the direct dimensional assessments support a recent hypothesis in biophysics that a single biosynthesis system of cellulose, referred to as the terminal complex (TC), consisted of 18 synthases. Some of the dispersed microfibrils had bundled sizes of two or three microfibrils. We also demonstrated that this bundling was stabilized by the fusion of several crystallites.}, archive = {J_PNAS}, author = {Daicho, Kazuho and Fujisawa, Shuji and Doi, Yoshinori and Suzuki, Michio and Shiomi, Junichiro and Saito, Tsuguyuki}, doi = {10.1073/pnas.2426467122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2426467122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Uniform elementary fibrils in diverse plant cell walls}, volume = {122}, year = {2025}, }
• (2025). The fruit fly, drosophila melanogaster, as a microrobotics platform. PNAS, 122(15), e2426180122. (www)

  @article{ , abstract = {Engineering small autonomous agents capable of operating in the microscale environment remains a key challenge, with current systems still evolving. Our study explores the fruit fly, Drosophila melanogaster , a classic model system in biology and a species adept at microscale interaction, as a biological platform for microrobotics. Initially, we focus on remotely directing the walking paths of fruit flies in an experimental arena. We accomplish this through two distinct approaches: harnessing the fruit flies’ optomotor response and optogenetic modulation of its olfactory system. These techniques facilitate reliable and repeated guidance of flies between arbitrary spatial locations. We guide flies along predetermined trajectories, enabling them to scribe patterns resembling textual characters through their locomotion. We enhance olfactory-guided navigation through additional optogenetic activation of attraction-inducing mushroom body output neurons. We extend this control to collective behaviors in shared spaces and navigation through constrained maze-like environments. We further use our guidance technique to enable flies to carry a load across designated points in space, establishing the upper bound on their weight-carrying capabilities. Additionally, we demonstrate that visual guidance can facilitate novel interactions between flies and objects, showing that flies can consistently relocate a small spherical object over significant distances. Last, we demonstrate multiagent formation control, with flies alternating between distinct spatial patterns. Beyond expanding tools available for microrobotics, these behavioral contexts can provide insights into the neurological basis of behavior in fruit flies.}, archive = {J_PNAS}, author = {Iwasaki, Kenichi and Neuhauser, Charles and Stokes, Chris and Rayshubskiy, Aleksandr}, doi = {10.1073/pnas.2426180122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2426180122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The fruit fly, drosophila melanogaster, as a microrobotics platform}, volume = {122}, year = {2025}, }
• (2025). Phosphatic stromatoporoid sponges formed reefs ~480 mya. PNAS, 122(15), e2426105122. (www)

  @article{ , abstract = {Stromatoporoid sponges were important reef-builders during the middle Paleozoic, yet their early history and integration into reef ecosystems remain poorly understood. Here, we report Lophiostroma leizunia Jeon sp. nov., the oldest known stromatoporoid from upper Tremadocian to lower Floian (~480 My-old) strata of South China. L. leizunia formed complex reef structures, playing crucial roles in framework construction and binding other components, including calcimicrobes, lithistid sponges, stalked echinoderms, and Calathium . This discovery pushes back the fossil record of stromatoporoids and the reefs that they formed by approximately 20 My, advancing the onset of the Great Ordovician Biodiversification Event in reef evolution. L. leizunia unusually constructed its skeleton using fluorapatite—a feature previously unknown in sponges. This establishes Porifera as the first metazoan phylum known to have utilized all three principal biominerals: silica, calcium carbonate, and calcium phosphate. The presence of phosphatic skeletons in this early stromatoporoid expands our understanding of biomineralization capabilities in early animals and suggests that the genetic toolkit for diverse biomineralization strategies may have been present in early sponges. The unique combination of the earliest known reef-building stromatoporoids and their phosphatic skeletal composition provides insights into the evolutionary dynamics of biomineralization and the rise of metazoan-dominated reef ecosystems during a critical period of Earth’s history.}, archive = {J_PNAS}, author = {Jeon, Juwan and Simonet Roda, Mar and Chen, Zhong-Yang and Luo, Cui and Kershaw, Stephen and Kim, Daeyeong and Ma, Jun-Ye and Lee, Jeong-Hyun and Zhang, Yuan-Dong}, doi = {10.1073/pnas.2426105122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2426105122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phosphatic stromatoporoid sponges formed reefs ~480 mya}, volume = {122}, year = {2025}, }
• (2025). Biallelic variants in the conserved ribosomal protein chaperone gene PDCD2 are associated with hydrops fetalis and early pregnancy loss. PNAS, 122(15), e2426078122. (www)

  @article{ , abstract = {Pregnancy loss is a major problem in clinical medicine with devastating consequences for families. Next generation sequencing has improved our ability to identify underlying molecular causes, though over half of all cases lack a clear etiology. Here, we began with clinical evaluation combined with exome sequencing across independent families to identify bi-allelic candidate genetic variants in the Programmed Cell Death 2 (PDCD2) gene in multiple fetuses with nonimmune hydrops fetalis (NIHF). PDCD2 is an evolutionarily conserved protein with no prior association with monogenic disorders. PDCD2 is known to act as a molecular chaperone for the ribosomal protein uS5, and this complex formation is important for incorporation of uS5 into the 40S subunit, a crucial step in ribosome biogenesis. Primary fibroblasts from an affected fetus and cell lines expressing PDCD2 patient variants demonstrated reduced levels of PDCD2, reduced PDCD2 binding to uS5, and altered ribosomal RNA processing. Xenopus tadpoles with Pdcd2 knockdown demonstrated developmental defects and edema, reminiscent of the NIHF seen in affected fetuses, and showed altered ribosomal RNA processing. Through genetic, biochemical, and in vivo approaches, we provide evidence that bi-allelic PDCD2 variants cause an autosomal recessive ribosomal biogenesis disorder resulting in pregnancy loss.}, archive = {J_PNAS}, author = {Landry-Voyer, Anne-Marie and Holling, Tess and Mis, Emily K. and Mir Hassani, Zabih and Alawi, Malik and Ji, Weizhen and Jeffries, Lauren and Kutsche, Kerstin and Bachand, François and Lakhani, Saquib A.}, doi = {10.1073/pnas.2426078122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2426078122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biallelic variants in the conserved ribosomal protein chaperone gene PDCD2 are associated with hydrops fetalis and early pregnancy loss}, volume = {122}, year = {2025}, }
• (2025). Structural basis of ZP2-targeted female nonhormonal contraception. PNAS, 122(15), e2426057122. (www)

  @article{ , abstract = {Monoclonal antibody IE-3 prevents mouse fertilization by binding ZP2, a major component of the oocyte-specific zona pellucida (ZP). We show that an IE-3-derived single-chain variable fragment (scFV) is sufficient for blocking fertilization in vitro and determine the structural basis of IE-3/ZP2 recognition. The high affinity of this interaction depends on induced fit of the epitope, offering insights for nonhormonal contraceptive design without off-target effects.}, archive = {J_PNAS}, author = {Dioguardi, Elisa and Stsiapanava, Alena and Fahrenkamp, Eileen and Han, Ling and de Sanctis, Daniele and Inzunza, José and Jovine, Luca}, doi = {10.1073/pnas.2426057122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2426057122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis of ZP2-targeted female nonhormonal contraception}, volume = {122}, year = {2025}, }
• (2025). Conformational signatures induced by ubiquitin modification in the amyloid-forming tau repeat domain. PNAS, 122(15), e2425831122. (www)

  @article{ , abstract = {Posttranslational modifications can critically affect conformational changes of amyloid-forming proteins. Ubiquitination of the microtubule-associated tau protein, an intrinsically disordered biomolecule, has been proposed to influence the formation of filamentous deposits in neurodegenerative conditions. Given the reported link between aggregation propensity and intrinsic structural preferences (e.g., transient extended structural motifs or tertiary contacts) in disordered proteins, we sought to explore the conformational landscape of ubiquitinated tau. Exploiting selective conjugation reactions, we produced single- and double-monoubiquitinated protein samples. Next, we examined the ubiquitinated species from different standpoints using NMR spectroscopy, small-angle X-ray scattering experiments, and native ion mobility–mass spectrometry (IM–MS). Moreover, we obtained atomistic representations of the conformational ensembles via scaled MD calculations, consistent with the experimental data. Modifying the repeat domain of tau with ubiquitin had a limited effect on secondary structure propensities and local mobility of distal regions. Instead, ubiquitination enhanced the compaction of the conformational ensemble, with the effect modulated by the site and the number of modifications. Native IM–MS patterns pinpointed similarities and differences between distinct tau proteoforms. It emerges that ubiquitination exerts a position-specific influence on the conformational distribution of tau molecules. This study reveals the unique conformational features of ubiquitinated forms of tau and points to their potential impact on aggregation and phase separation propensities, offering clues for a better understanding of disease-related structural alterations.}, archive = {J_PNAS}, author = {Viola, Giovanna and Trivellato, Daniele and Laitaoja, Mikko and Jänis, Janne and Felli, Isabella C. and D’Onofrio, Mariapina and Mollica, Luca and Giachin, Gabriele and Assfalg, Michael}, doi = {10.1073/pnas.2425831122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2425831122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Conformational signatures induced by ubiquitin modification in the amyloid-forming tau repeat domain}, volume = {122}, year = {2025}, }
• (2025). On the hidden transient interphase in metal anodes: Dynamic precipitation controls electrochemical interfaces in batteries. PNAS, 122(15), e2425752122. (www)

  @article{ , abstract = {The solid–electrolyte interphase (SEI) formed on a battery electrode has been a central area of research for decades. This structurally complex layer profoundly impacts the electrochemical deposition morphology and stability of metal anodes. Departing from conventional approaches, we investigate metal dissolution—the reverse reaction of deposition—in battery environments using a state-of-the-art electroanalytical system combining a rotating-disk electrode and operando visualization. Our key finding is the presence of a transient SEI (T-SEI) that forms during fast discharging at high dissolution rates. We attribute T-SEI formation to local supersaturation and resultant electrolyte salt deposition. The T-SEI fundamentally alters the dissolution kinetics at the electrochemical interface, yielding a flat, clean surface. Unlike a classical SEI formed due to electrolyte decomposition, the T-SEI is “relaxable” upon removal of the enforced dissolution current; that is, the T-SEI dissolves back into the electrolyte when rested. The formation of T-SEI plays an unexpected critical role in the subsequent electrodeposition. When the metal is redeposited on a fully relaxed T-SEI surface, the morphology is remarkably different from that deposited on pristine or low-rate-discharged metal electrodes. Electron backscatter diffraction analysis suggests that the deposition occurs via growth of the original grains; this is in stark contrast to the isolated, new nuclei seen on standard metal electrodes without T-SEI formation. Using 3D profilometry, we observe a 42% reduction in surface roughness due to T-SEI formation. Our findings provide important insights into the kinetics at ion-producing electrochemical interfaces, and suggest a new dimension for engineering next generation batteries.}, archive = {J_PNAS}, author = {Fuller, Stephen T. and Zheng, J.-X. Kent}, doi = {10.1073/pnas.2425752122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2425752122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {On the hidden transient interphase in metal anodes: Dynamic precipitation controls electrochemical interfaces in batteries}, volume = {122}, year = {2025}, }
• (2025). Exploring RNA destabilization mechanisms in biomolecular condensates through atomistic simulations. PNAS, 122(15), e2425261122. (www)

  @article{ , abstract = {Biomolecular condensates are currently recognized to play a key role in organizing cellular space and in orchestrating biochemical processes. Despite an increasing interest in characterizing their internal organization at the molecular scale, not much is known about how the densely crowded environment within these condensates affects the structural properties of recruited macromolecules. Here, we adopted explicit-solvent all-atom simulations based on a combination of enhanced sampling approaches to investigate how the conformational ensemble of an RNA hairpin is reshaped in a highly concentrated peptide solution that mimics the interior of a biomolecular condensate. Our simulations indicate that RNA structure is greatly perturbed by this distinctive physico-chemical environment, which weakens RNA secondary structure and promotes extended nonnative conformations. The resulting high-resolution picture reveals that RNA unfolding is driven by the effective solvation of nucleobases through hydrogen bonding and stacking interactions with surrounding peptides. This solvent effect can be modulated by the amino acid composition of the model condensate as proven by the differential RNA behavior observed in the case of arginine-rich and lysine-rich peptides.}, archive = {J_PNAS}, author = {Boccalini, Matteo and Berezovska, Yelyzaveta and Bussi, Giovanni and Paloni, Matteo and Barducci, Alessandro}, doi = {10.1073/pnas.2425261122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2425261122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Exploring RNA destabilization mechanisms in biomolecular condensates through atomistic simulations}, volume = {122}, year = {2025}, }
• (2025). An integrated AI knowledge graph framework of bacterial enzymology and metabolism. PNAS, 122(15), e2425048122. (www)

  @article{ , abstract = {The study of bacterial metabolism holds immense significance for improving human health and advancing agricultural practices. The prospective applications of genomically encoded bacterial metabolism present a compelling opportunity, particularly in the light of the rapid expansion of genomic sequencing data. Current metabolic inference tools face challenges in scaling with large datasets, leading to increased computational demands, and often exhibit limited inter-relatability and interoperability. Here, we introduce the Integrated Biosynthetic Inference Suite (IBIS), which employs deep learning models and a knowledge graph to facilitate rapid, scalable bacterial metabolic inference. This system leverages a series of Transformer based models to generate high quality, meaningful embeddings for individual enzymes, biosynthetic domains, and metabolic pathways. These embedded representations enable rapid, large-scale comparisons of metabolic proteins and pathways, surpassing the capabilities of conventional methodologies. The examination of evolutionary and functionally conserved metabolites across diverse bacterial species is facilitated by integrating the predictive capabilities of IBIS into a graph database enriched with comprehensive metadata. The consideration of both primary and specialized metabolism, combined with an embedding logic for enzyme discovery, uniquely positions IBIS to identify potential novel metabolic pathways. With the expansion of genomic data necessitating transformative approaches to advance molecular metabolism research, IBIS delivers an AI-driven holistic investigation of bacterial metabolism.}, archive = {J_PNAS}, author = {Spencer, Norman R. and Gunabalasingam, Mathusan and Dial, Keshav and Di, Xiaxia and Malcolm, Tonya and Magarvey, Nathan A.}, doi = {10.1073/pnas.2425048122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2425048122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An integrated AI knowledge graph framework of bacterial enzymology and metabolism}, volume = {122}, year = {2025}, }
• (2025). Proximity-activated DNA scanning encoded sequencing for massive access to membrane proteins nanoscale organization. PNAS, 122(15), e2425000122. (www)

  @article{ , abstract = {Cellular structure maintenance and function regulation critically depend on the composition and spatial distribution of numerous membrane proteins. However, current methods face limitations in spatial coverage and data scalability, hindering the comprehensive analysis of protein interactions in complex cellular nanoenvironment. Herein, we introduce p roximity- a ctivated D NA s canning e ncoded sequencing (PADSE-seq), an innovative technique that utilizes flexible DNA probes with adjustable lengths. These dynamic probes are anchored at a single end, enabling free swings within a nanoscale range to perform global scanning, recording, and accumulating of information on diverse proximal proteins in random directions along unrestricted paths. PADSE-seq leverages the autonomous cyclic cleavage of single-stranded DNA to sequentially activate encoded probes distributed throughout the local area. This process triggers strand displacement amplification and bidirectional extension reactions, linking proteins barcodes with molecular barcodes in tandem and further generating millions to billions of amplicons embedded with the combinatorial identifiers for next-generation sequencing analysis. As a proof of concept, we validated PADSE-seq for mapping the distribution of over a dozen kinds of proteins, including HER1, EpCAM, and PDL1, in proximity to HER2 in breast cancer cell lines, demonstrating its ability to decode multiplexed protein proximities at the nanoscale. Notably, we observed that the spatial distribution of proximal proteins around low-abundance target proteins exhibited greater diversity across regions with variable proximity ranges. This method offers a massive access for high-resolution and comprehensive mapping of cellular molecular interactions, paving the way for deeper insights into complex biological processes and advancing the field of precision medicine.}, archive = {J_PNAS}, author = {Zhao, Xueqi and Zhao, Yue and Li, Zhu and Liu, Huan and Fu, Wenhao and Chen, Feng and Sun, Ying and Song, Daqian and Fan, Chunhai and Zhao, Yongxi}, doi = {10.1073/pnas.2425000122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2425000122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Proximity-activated DNA scanning encoded sequencing for massive access to membrane proteins nanoscale organization}, volume = {122}, year = {2025}, }
• (2025). A monoclonal anti-hemagglutinin stem antibody modified with zanamivir protects against both influenza a and b viruses. PNAS, 122(15), e2424889122. (www)

  @article{ , abstract = {Influenza remains a significant public health threat. Both monoclonal antibodies and small-molecule inhibitors can target the influenza surface glycoproteins hemagglutinin (HA) or neuraminidase (NA) for prevention and treatment of influenza. Here, we combine the strengths of anti-influenza antibodies and small molecules by site-specific conjugation of the NA inhibitor zanamivir to MEDI8852, an HA-specific fully human monoclonal antibody. MEDI8852 targets the conserved stem region of HA and inhibits HA-mediated fusion of the viral and host cell membranes. Elimination of virus-infected cells involves Fcγ receptor–mediated effector functions. The efficacy of MEDI8852 is limited to influenza A viruses. Zanamivir, on the other hand, binds to the active site of NA in both influenza A and B viruses to inhibit NA activity and virus release. However, because of its small size, zanamivir has a short half-life and requires repeated dosing at high concentrations. We produced a MEDI8852–zanamivir antibody–drug conjugate (ADC) that engages Fc-mediated effector functions and benefits from neonatal Fc receptor (FcRn)-mediated recycling. The MEDI8852–zanamivir conjugate extends the circulatory half-life of zanamivir, targets both influenza HA and NA, and shows enhanced antibody-dependent cellular cytotoxicity (ADCC) compared to MEDI8852 alone. The MEDI8852–zanamivir conjugate protected mice from a lethal (10 × LD 50 ) challenge with influenza A and B viruses at a dose similar to that required for broadly neutralizing anti-NA antibodies, with the added advantage of simultaneously targeting NA (influenza A and B) and HA (influenza A).}, archive = {J_PNAS}, author = {Liu, Xin and Balligand, Thomas and Le Gall, Camille and Ploegh, Hidde L.}, doi = {10.1073/pnas.2424889122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2424889122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A monoclonal anti-hemagglutinin stem antibody modified with zanamivir protects against both influenza a and b viruses}, volume = {122}, year = {2025}, }
• (2025). Global subnational estimates of migration of scientists reveal large disparities in internal and international flows. PNAS, 122(15), e2424521122. (www)

  @article{ , abstract = {Researchers are key contributors to innovation. Their migration results in talent circulation and recombination of ideas. Due to data shortage, little is known about subnational mobility of scientists and the interrelationships between their internal and international migration patterns. We used data on 30+ million Scopus publications of 19+ million authors to infer migration from changes in affiliations. Our publicly shared database of global subnational estimates of migration reveals relevant disparities in the attractiveness of subnational regions. While, at the country level, some countries have acted as a global hub that attracts scholars from throughout the world, at the subnational level, some of their regions have negative net migration rates, with implications for scientific output and regional development, as well as the perpetuation of migration corridors. On average, subnational inequalities in attracting and sending scholars have increased for international but decreased for internal migration. In most countries, there is no single trend such that all subnational regions have been sending or receiving more scholars. Instead, a mix of patterns has been simultaneously at work, on the backdrop of globalization of migration, which is an asymmetric process where specific regions and subpopulations have higher access to international migration. For most subnational regions, when they are attractive for international migrants, they are also attractive for internal migrants, which is not always the case for emigration. Our results have implications for the global circulation of academic talent by adding the dimension of internal migration to “brain drain” and “brain circulation” in international migration.}, archive = {J_PNAS}, author = {Akbaritabar, Aliakbar and Dańko, Maciej J. and Zhao, Xinyi and Zagheni, Emilio}, doi = {10.1073/pnas.2424521122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2424521122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global subnational estimates of migration of scientists reveal large disparities in internal and international flows}, volume = {122}, year = {2025}, }
• (2025). Roquin exhibits opposing effects on RNA stem-loop stability through its two ROQ domain binding sites. PNAS, 122(15), e2424434122. (www)

  @article{ , abstract = {The interaction of mRNA and regulatory proteins is critical for posttranscriptional control. For proper function, these interactions, as well as the involved protein and RNA structures, are highly dynamic, and thus, mechanistic insights from structural biology are challenging to obtain. In this study, we employ a multifaceted approach combining single-molecule force spectroscopy (SMFS) with NMR spectroscopy to analyze the concerted interaction of the two RNA-binding interfaces (A-site and B-site) of the immunoregulatory protein Roquin’s ROQ domain with the 3’ untranslated region (UTR) of the Ox40 mRNA. This 3’UTR contains two specific hairpin structures termed constitutive and alternative decay elements (CDE, ADE), which mediate mRNA degradation through Roquin binding. Our single-molecule experiments reveal that the CDE folds cooperatively, while ADE folding involves at least three on-pathway and three off-pathway intermediates. Using an integrated microfluidics setup, we extract binding kinetics to Roquin in real time. Supported by NMR data, we find opposing effects of the two Roquin subdomains on distinct regions of the ADE: While the A-site interacts strongly with the folded apical stem-loop, we find that the B-site has a distinct destabilizing effect on the central stem of the ADE owed to single-strand RNA binding. We propose that RNA-motif nature and Roquin A- and B-sites jointly steer mRNA decay with context-encoded specificity, and we suggest plasticity of stem structures as key determinant for Roquin–RNA complex formation. The unique combination of NMR and SMFS uncovers a mechanism of a dual-function RNA-binding domain, offering a model for target RNA recognition by Roquin.}, archive = {J_PNAS}, author = {Tants, Jan-Niklas and Walbrun, Andreas and Kollwitz, Lucas and Friedrich, Katharina and Rief, Matthias and Schlundt, Andreas}, doi = {10.1073/pnas.2424434122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2424434122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Roquin exhibits opposing effects on RNA stem-loop stability through its two ROQ domain binding sites}, volume = {122}, year = {2025}, }
• (2025). Nat10-mediated n4-acetylcytidine modification enhances nfatc1 translation to exacerbate osteoclastogenesis in postmenopausal osteoporosis. PNAS, 122(15), e2423991122. (www)

  @article{ , abstract = {Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenopausal osteoporosis (PMOP). N4‐acetylcytidine (ac4C) modification, catalyzed by Nat10, is a novel posttranscriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10-mediated ac4C positively correlates with osteoclast differentiation of monocytes and low bone mass in PMOP. The specific knockout of Nat10 in monocytes and remodelin, a Nat10 inhibitor, alleviates ovariectomized (OVX)-induced bone loss by downregulating osteoclast differentiation. Mechanistically, epitranscriptomic analyses reveal that the nuclear factor of activated T cells cytoplasmic 1 (Nfatc1) is the key downstream target of ac4C modification during osteoclast differentiation. Subsequently, translatomic results demonstrate that Nat10-mediated ac4C enhances the translation efficiency (TE) of Nfatc1, thereby inducing Nfatc1 expression and consequent osteoclast maturation. Cumulatively, these findings reveal the promotive role of Nat10 in osteoclast differentiation and PMOP from a novel field of RNA modifications and suggest that Nat10 can be a target of epigenetic therapy for preventing bone loss in PMOP.}, archive = {J_PNAS}, author = {Mo, Xiaoyi and Meng, Keyu and Xu, Bohan and Li, Zehui and Lan, Shanwei and Ren, Zhengda and Xiang, Xin and Zou, Peiqian and Chen, Zesen and Lai, Zhongming and Ao, Xiang and Liu, Zhongyuan and Shang, Wanjing and Dai, Bingyang and Luo, Li and Xu, Jiajia and Wang, Zhizhang and Zhang, Zhongmin}, doi = {10.1073/pnas.2423991122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2423991122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nat10-mediated n4-acetylcytidine modification enhances nfatc1 translation to exacerbate osteoclastogenesis in postmenopausal osteoporosis}, volume = {122}, year = {2025}, }
• (2025). Maximizing underwater energy harvesting efficiency using flexible solar cells: A pathway to sustainable ocean power. PNAS, 122(15), e2423651122. (www)

  @article{ , abstract = {Photovoltaic technology has emerged as a key candidate for powering underwater devices. However, traditional solar cells face limitations in real marine environments. Flexible solar cells offer new possibilities for underwater energy harvesting. This study identifies the optimal bandgap and depth for flexible underwater solar cells through detailed balance calculations and experiments. We also established an optical model for underwater flexible solar cells, determining the ideal curvature through outdoor testing. The flexible a-Si solar cell achieves an impressive maximum efficiency of 59.7% at 2 m, generating up to 15.9% more energy throughout the day compared to planar solar cells. Theoretical results surpass the fundamental limits of seabed solar collection, outperforming all existing underwater photovoltaic solutions. Building on this foundation, we demonstrated their all-day capabilities in powering unmanned underwater vehicles (UUVs) and LED light beacons. Furthermore, we explored the global power generation potential of flexible solar cells at typical depths, identifying the optimal operating ranges during different seasons and analyzing the power generation costs for typical water bodies. This study highlights the immense potential of flexible solar cells in advancing marine energy generation.}, archive = {J_PNAS}, author = {Bai, Haoliang and Lu, Tonghui and Liu, Wenzhuo and Li, Xianglin and Lv, Wenhao and Lv, Song}, doi = {10.1073/pnas.2423651122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2423651122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Maximizing underwater energy harvesting efficiency using flexible solar cells: A pathway to sustainable ocean power}, volume = {122}, year = {2025}, }
• (2025). ID3 enhances PD-l1 expression by restructuring MYC to promote colorectal cancer immune evasion. PNAS, 122(15), e2423490122. (www)

  @article{ , abstract = {The inhibitor of DNA binding protein ID3 has been associated with the progression of colorectal cancer (CRC). Despite its significance, its specific role in the immune evasion strategies utilized by CRC remains unclear. RNA-seq analysis revealed that ID3 was positively associated with the PD-L1 immune checkpoint. We further demonstrated that tumor cell–expressed ID3 enhanced PD-L1 expression, suppressed the infiltration and activation of CD8 + T cells, and facilitated the immune evasion of CRC cells. Additionally, we found that knockdown of ID3 significantly enhanced the effectiveness of PD-L1 antibody blockade treatment in combating CRC, reduced the upregulation of PD-L1 induced by the antibody, and altered the immune microenvironment within CRC. Mechanistically, ID3 interacted with the transcription factor MYC and reconstructed the four-dimensional structure of MYC, thereby enhancing its binding affinity to the PD-L1 promoter and augmenting PD-L1 transcriptional activity. By integrating analysis of ChIP-seq, RNA-seq, and ImmPort gene sets, we found that ID3’s DNA-assisted binding function was widespread and could either enhance or suppress gene transcription, not only affecting tumor immune escape through immune checkpoints but also regulating various cytokines and immune cells involved in tumor immunity. In conclusion, our study uncovers a mechanism by which ID3 promotes immune evasion in CRC and implicates that targeting ID3 may improve the efficacy of anti-PD-1/PD-L1 immunotherapy.}, archive = {J_PNAS}, author = {Huang, Chuanzhong and Wang, Ling and Zhuo, Changhua and Chen, Wenxin and Fan, Hongmei and Hong, Yilin and Zhang, Yu and Zhou, Dongmei and Lin, Wansong and Zhang, Lingyu and Zhao, Jingjing and Chen, Shuping and Yu, Chundong and Ye, Yunbin}, doi = {10.1073/pnas.2423490122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2423490122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ID3 enhances PD-l1 expression by restructuring MYC to promote colorectal cancer immune evasion}, volume = {122}, year = {2025}, }
• (2025). Privacy for free in the overparameterized regime. PNAS, 122(15), e2423072122. (www)

  @article{ , abstract = {Differentially private gradient descent (DP-GD) is a popular algorithm to train deep learning models with provable guarantees on the privacy of the training data. In the last decade, the problem of understanding its performance cost with respect to standard GD has received remarkable attention from the research community, which has led to upper bounds on the excess population risk R P in different learning settings. However, such bounds typically degrade with overparameterization, i.e., as the number of parameters p gets larger than the number of training samples n —a regime which is ubiquitous in current deep-learning practice. As a result, the lack of theoretical insights leaves practitioners without clear guidance, leading some to reduce the effective number of trainable parameters to improve performance, while others use larger models to achieve better results through scale. In this work, we show that in the popular random features model with quadratic loss, for any sufficiently large p , privacy can be obtained for free, i.e., R P = o ( 1 ) , not only when the privacy parameter ε has constant order but also in the strongly private setting ε = o ( 1 ) . This challenges the common wisdom that overparameterization inherently hinders performance in private learning.}, archive = {J_PNAS}, author = {Bombari, Simone and Mondelli, Marco}, doi = {10.1073/pnas.2423072122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2423072122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Privacy for free in the overparameterized regime}, volume = {122}, year = {2025}, }
• (2025). Tetrathienylethene-based porous framework composites for boosting photocatalytic antibacterial activity. PNAS, 122(15), e2423052122. (www)

  @article{ , abstract = {In order to reduce the risk of high-threat pathogens, a photocatalytic antibacterial method with a reputation for high efficiency and sustainability has attracted widespread attention. Recently, metal-organic frameworks (MOFs) have emerged as desirable platforms for photocatalytic applications by virtue of their structural diversity and functional adjustability. Herein, we report that we have synthesized a stable and photosensitive zirconium-based MOF (Zr-MOF) with a photoactive tetrathienylethene-based organic linker, Zr-TSS-1. Compared with all-carbocyclic Zr-MOF counterparts, Zr-TSS-1 shows a substantial improvement in visible-light harvesting and free-carrier generation, enabling it to be a promising candidate for photocatalytic antibacterial applications. In order to validate the advantages of this framework as an antibacterial protective material, a composite was fabricated by incorporating robust Zr-TSS-1 onto sustainably accessible bacterial cellulose (BC) using an in situ growth method. This composite exhibits near-complete lethality toward typical Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus within 1 h under mild irradiation and preserves outstanding antibacterial capability after five cycles of reutilization. In addition, the high biocompatibility is confirmed by the low cytotoxicity toward human skin fibroblast, suggesting its potential for biomedical and healthcare applications. This research demonstrates the efficacious integration of a purposely designed photosensitive porous framework onto a sustainable substrate for synergistic functionality, paving a practical way for the development of the next-generation high-efficiency antimicrobial technology.}, archive = {J_PNAS}, author = {Ma, Si and Lam, Yintung and Shi, Le and Yang, Jian and Wang, Kun and Yu, Bo and Kan, Chiwai and Fei, Bin and Xin, John H. and Ma, Kaikai and Stoddart, J. Fraser and Chen, Zhijie}, doi = {10.1073/pnas.2423052122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2423052122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tetrathienylethene-based porous framework composites for boosting photocatalytic antibacterial activity}, volume = {122}, year = {2025}, }
• (2025). ZmGCT1/2 negatively regulate drought tolerance in maize by inhibiting ZmSLAC1 to maintain guard cell turgor. PNAS, 122(15), e2423037122. (www)

  @article{ , abstract = {Stomata, which are essential for the exchange of CO 2 and water vapor between plant leaves and the atmosphere, are regulated by a variety of environmental and internal factors. In this study, we identified and characterized two genes, Guard Cell Turgor Maintaining 1 ( GCT1 ) and its closest homolog GCT2 , which encode rapidly accelerated fibrosarcoma (RAF)-like protein kinases that play a critical role in maintaining guard cell turgor in Zea mays . We found that overexpression of ZmGCT1 and ZmGCT2 confers resistance to abscisic acid (ABA)-promoted stomatal closure, whereas the zmgct1 zmgct2 double loss-of-function mutants exhibit a loss of guard cell turgor, resulting in nearly closed stomata even under favorable growth conditions. A dominant mutation, zmgct1-9D , which lacks nine amino acids including T80, retains its kinase activity and plasma membrane localization but displays insensitive to ABA-, CO 2 -, Ca 2+ -, or H 2 O 2 -promoted stomatal closure. ABA-activated ZmSnRK2.8/9 phosphorylates ZmGCT1 at T80, reducing its plasma membrane localization. Intriguingly, the ZmSnRK2.10 or ZmSLAC1 mutant can suppress the reduced turgor phenotype in guard cells of the zmgct1 mutant. Furthermore, ZmGCT1 phosphorylates the penultimate threonine residue (T573) of ZmSLAC1, inhibiting both the constitutively active ZmSLAC1 and ZmSnRK2.8-activated ZmSLAC1 in Xenopus laevis oocytes, a process dependent on ZmGCT1 kinase activity. These findings suggest that ZmGCT1 and ZmGCT2 directly inhibit ZmSLAC1 to maintain guard cell turgor under favorable growth conditions, while ABA treatment alleviates this inhibition primarily by reducing ZmGCT1’s plasma membrane localization. This study provides mechanistic insights into the regulation of stomatal movement by ZmGCT1/2 kinases under both favorable and stress conditions.}, archive = {J_PNAS}, author = {Feng, Zhenkai and Li, Huiying and Sun, Zhihui and Cheng, Jinkui and Hua, Deping and Wang, Yu and Qi, Junsheng and Yang, Shuhua and Gong, Zhizhong}, doi = {10.1073/pnas.2423037122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2423037122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ZmGCT1/2 negatively regulate drought tolerance in maize by inhibiting ZmSLAC1 to maintain guard cell turgor}, volume = {122}, year = {2025}, }
• (2025). Two transcription factors play critical roles in mediating epigenetic regulation of fruit ripening in tomato. PNAS, 122(15), e2422798122. (www)

  @article{ , abstract = {DNA methylation regulates fruit ripening in tomato, and disruption of the DNA demethylase DEMETER-LIKE 2 (DML2) results in genome-wide DNA hypermethylation and impaired ripening. We report here that the transcription factors Ripening Inhibitor (RIN) and FRUITFULL 1 (FUL1) play critical roles in mediating the effect of DNA methylation on tomato fruit ripening. RIN and FUL1 are silenced in dml2 mutant plants, and the defective ripening phenotype of dml2 is mimicked by the rin/ful1 double mutant. Restoration of RIN expression in dml2 partially rescues its ripening defects. DNA methylation controls ripening not only by regulating the expression of RIN and FUL1 but also by interfering with the genomic binding of RIN. In dml2 mutant plants, RIN cannot bind to some of its targets in vivo even though DNA methylation does not interfere with RIN binding in vitro; this inhibited binding in vivo is correlated with increased DNA methylation and histone H3 enrichment within 100 bp of the binding site. Our work uncovers the molecular mechanisms underlying DNA methylation control of fruit ripening in tomato.}, archive = {J_PNAS}, author = {Niu, Qingfeng and Xu, Yaping and Huang, Huan and Li, Linzhu and Tang, Dengguo and Wu, Siqun and Liu, Ping and Liu, Ruie and Ma, Yu and Zhang, Bo and Zhu, Jian-Kang and Lang, Zhaobo}, doi = {10.1073/pnas.2422798122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2422798122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Two transcription factors play critical roles in mediating epigenetic regulation of fruit ripening in tomato}, volume = {122}, year = {2025}, }
• (2025). Epistasis-mediated compensatory evolution in a fitness landscape with adaptational tradeoffs. PNAS, 122(15), e2422520122. (www)

  @article{ , abstract = {The evolutionary adaptation of an organism to a stressful environment often comes at the cost of reduced fitness. For example, resistance to antimicrobial drugs frequently reduces growth rate in the drug-free environment. This cost can be compensated without loss in resistance by mutations at secondary sites when the organism evolves again in the stress-free environment. Here, we analytically and numerically study evolution on a simple model fitness landscape to show that compensatory evolution can occur even in the presence of the stress and without the need for mutations at secondary sites. Fitness in the model depends on two phenotypes—the null-fitness defined as the fitness in the absence of stress, and the resistance level to the stress. Mutations universally exhibit antagonistic pleiotropy between the two phenotypes, that is they increase resistance while decreasing the null-fitness. Initial adaptation in this model occurs in a smooth region of the landscape with a rapid accumulation of stress resistance mutations and a concurrent decrease in the null-fitness. This is followed by a second, slower phase exhibiting partial recovery of the null-fitness. The second phase occurs on the rugged part of the landscape and involves the exchange of high-cost resistance mutations for low-cost ones. This process, which we call exchange compensation, is the result of changing epistatic interactions in the genotype as evolution progresses. The model provides general lessons about the tempo and mode of evolution under universal antagonistic pleiotropy with specific implications for drug resistance evolution.}, archive = {J_PNAS}, author = {Das, Suman G. and Mungan, Muhittin and Krug, Joachim}, doi = {10.1073/pnas.2422520122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2422520122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Epistasis-mediated compensatory evolution in a fitness landscape with adaptational tradeoffs}, volume = {122}, year = {2025}, }
• (2025). Multiplexing of cognitive encoding by oculomotor networks leads to incidental gaze shifts. PNAS, 122(15), e2422331122. (www)

  @article{ , abstract = {Humans and other animals are adept at learning to perform cognitively demanding behavioral tasks. Neurophysiological recordings in nonhuman primates during such tasks find that the requisite cognitive variables are encoded strongly in core oculomotor brain regions. Here, we assembled a large dataset—11 monkeys performing an abstract visual categorization task, surveyed across more than 1,000 neural recording sessions—to reveal that this produces a robust but uninstructed behavioral “tell,” observed in all subjects and experiments: small, cognitively modulated eye movements. We find that these eye movements are causally linked to activity in SC but not LIP, and that they occur following transient alignment of cognitive and saccadic population coding subspaces in SC. This behavioral signature of oculomotor engagement is absent during a similar task that does not require rule-based categorization, suggesting that abstract task behaviors recruit primate oculomotor networks more strongly than previously understood.}, archive = {J_PNAS}, author = {Rosen, Matthew C. and Freedman, David J.}, doi = {10.1073/pnas.2422331122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2422331122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multiplexing of cognitive encoding by oculomotor networks leads to incidental gaze shifts}, volume = {122}, year = {2025}, }
• (2025). New advanced placement course designed to broaden access promotes participation and demographic diversity in computer science education. PNAS, 122(15), e2422298122. (www)

  @article{ , abstract = {Advanced Placement (AP) provides college-level courses to over 1 million US secondary students annually. Black, Hispanic, and female students have historically been underrepresented in AP Computer Science (CS). A new, broadly focused course—AP CS Principles—launched nationally in 2016–17 with the goal of increasing student participation and diversity. We examine its effects on AP CS participation. Combining publicly available sources, we assemble a panel dataset of annual AP exam-taking and course offerings from 2006–07 to 2020–21 at Massachusetts high schools. Using synthetic difference-in-differences, we estimate that offering the new course led to 16 additional yearly AP Computer Science exams per school, more than tripling baseline exam counts for the average adopting school. Exam counts among female and Black or Hispanic students more than quadrupled. The new exams were concentrated in AP Computer Science Principles, with no statistically significant reduction in exam counts for the preexisting AP CS course. We also estimate that offering the new course increased schools’ probability of having any AP CS exam participation by 29 percentage points, with larger gains for female and Black or Hispanic students. We find some evidence of positive spillover effects on several other AP courses. The results suggest the promise of course design and availability in promoting engagement and diversity in advanced STEM education.}, archive = {J_PNAS}, author = {Ganelin, Daniela and Dee, Thomas S.}, doi = {10.1073/pnas.2422298122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2422298122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {New advanced placement course designed to broaden access promotes participation and demographic diversity in computer science education}, volume = {122}, year = {2025}, }
• (2025). Emergent gauge fields in band insulators. PNAS, 122(15), e2421778122. (www)

  @article{ , abstract = {By explicit microscopic construction involving a mapping to a quantum vertex model subject to the “ice rule,” we show that an electronically “trivial” band insulator with suitable vibrational (phonon) degrees of freedom can host a “resonating valence-bond” state—a quantum phase with emergent gauge fields. This type of band insulator is identifiable by the existence of emergent gapless “photon” modes and deconfined excitations, the latter of which carry nonquantized mobile charges. We suggest that such phases may exist in the quantum regimes of various nearly ferroelectric materials.}, archive = {J_PNAS}, author = {Han, Zhaoyu and Kivelson, Steven A.}, doi = {10.1073/pnas.2421778122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2421778122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Emergent gauge fields in band insulators}, volume = {122}, year = {2025}, }
• (2025). DprA recruits ComM to facilitate recombination during natural transformation in gram-negative bacteria. PNAS, 122(15), e2421764122. (www)

  @article{ , abstract = {Natural transformation (NT) represents one of the major modes of horizontal gene transfer in bacterial species. During NT, cells can take up free DNA from the environment and integrate it into their genome by homologous recombination. While NT has been studied for >90 y, the molecular details underlying this recombination remain poorly understood. Recent work has demonstrated that ComM is an NT-specific hexameric helicase that promotes recombinational branch migration in Gram-negative bacteria. How ComM is loaded onto the postsynaptic recombination intermediate during NT, however, remains unclear. Another NT-specific recombination mediator protein that is ubiquitously conserved in both Gram-positive and Gram-negative bacteria is DprA. Here, we uncover that DprA homologs in Gram-negative species contain a C-terminal winged helix domain that is predicted to interact with ComM by AlphaFold. Using Helicobacter pylori and Vibrio cholerae as model systems, we demonstrate that ComM directly interacts with the DprA winged-helix domain, and that this interaction is critical for DprA to recruit ComM to the recombination site to promote branch migration during NT. These results advance our molecular understanding of recombination during this conserved mode of horizontal gene transfer. Furthermore, they demonstrate how structural modeling can help uncover unexpected interactions between well-studied proteins to provide deep mechanistic insight into the molecular coordination required for their activity.}, archive = {J_PNAS}, author = {Dalia, Triana N. and Machouri, Mérick and Lacrouts, Céline and Fauconnet, Yoann and Guerois, Raphaël and Andreani, Jessica and Radicella, J. Pablo and Dalia, Ankur B.}, doi = {10.1073/pnas.2421764122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2421764122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {DprA recruits ComM to facilitate recombination during natural transformation in gram-negative bacteria}, volume = {122}, year = {2025}, }
• (2025). Ultra narrowband geometric-phase resonant metasurfaces. PNAS, 122(15), e2420830122. (www)

  @article{ , abstract = {The concept of a geometric phase has sparked a revolution in photonics. Conventional space-variant polarization manipulation in optical systems only results in broadband geometric phases. Recently emerged nonlocal metasurfaces show an ability to compress the operating bandwidth through modulations of wavelength-dependent amplitudes. However, their geometric phases are still broadband and not linear, posing severe challenges to realize ultra narrowband metadevices. Here, we propose and demonstrate the generation of ultra narrowband and spatially variable geometric phases in resonant metasurfaces. We find that an array of perturbed Mie resonators is able to simultaneously preserve its global symmetry and local transformation. Local transformation provides a pixel-level geometric phase, whereas global symmetry yields an ultranarrow operation bandwidth. We further reveal that this geometric phase can be well pinned to the resonant mode by introducing additional perturbations to individually define the phase at nonresonant wavelengths. Consequently, we realize experimentally pixelated phase-gradient metasurfaces and metalenses with record-breaking Q factors and high confidentiality. We believe that our general approach and demonstrated results will open a paradigm of multiplexed metasurfaces and information encryption.}, archive = {J_PNAS}, author = {Ouyang, Xu and Zeng, Yixuan and Wang, Zi and Bo, Baichuan and Lai, Fangxing and Zhang, Chi and Qiu, Cheng-wei and Song, Qinghai and Yu, Shaohua and Kivshar, Yuri and Xiao, Shumin}, doi = {10.1073/pnas.2420830122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2420830122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ultra narrowband geometric-phase resonant metasurfaces}, volume = {122}, year = {2025}, }
• (2025). Bispecific antibodies against the hepatitis c virus E1E2 envelope glycoprotein. PNAS, 122(15), e2420402122. (www)

  @article{ , abstract = {Hepatitis C virus (HCV) currently causes about one million infections and 240,000 deaths worldwide each year. To reach the goal set by the World Health Organization of global HCV elimination by 2030, it is critical to develop a prophylactic vaccine. Broadly neutralizing antibodies (bNAbs) target the E1E2 envelope glycoproteins on the viral surface, can neutralize a broad range of the highly diverse circulating HCV strains, and are essential tools to inform vaccine design. However, bNAbs targeting a single E1E2 epitope might be limited in neutralization breadth, which can be enhanced by using combinations of bNAbs that target different envelope epitopes. We have generated 60 immunoglobulin G (IgG)-like bispecific antibodies (bsAbs) that can simultaneously target two distinct epitopes on E1E2. We combine non- or partially overlapping E1E2 specificities into three types of bsAbs, each containing a different hinge length. The majority of bsAbs shows retained or increased potency and breadth against a diverse panel of HCV pseudoparticles and HCV produced in cell culture compared to monospecific and cocktail controls. Additionally, we demonstrate that changes in the hinge length of bsAbs can alter the binding stoichiometry to E1E2. These results provide insights into the binding modes and the role of avidity in bivalent targeting of diverse E1E2 epitopes.This study illustrates how potential cooperative effects of HCV bNAbs can be utilized by strategically designing bispecific constructs. These HCV bsAbs can guide vaccine development and unlock novel therapeutic and prophylactic strategies against HCV and other (flavi)viruses.}, archive = {J_PNAS}, author = {Radić, Laura and Offersgaard, Anna and Kadavá, Tereza and Zon, Ian and Capella-Pujol, Joan and Mulder, Fabian and Koekkoek, Sylvie and Spek, Vera and Chumbe, Ana and Bukh, Jens and van Gils, Marit J. and Sanders, Rogier W. and Yin, Victor C. and Heck, Albert J. R. and Gottwein, Judith M. and Sliepen, Kwinten and Schinkel, Janke}, doi = {10.1073/pnas.2420402122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2420402122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bispecific antibodies against the hepatitis c virus E1E2 envelope glycoprotein}, volume = {122}, year = {2025}, }
• (2025). NAL1 forms a molecular cage to regulate FZP phase separation. PNAS, 122(15), e2419961122. (www)

  @article{ , abstract = {NARROW LEAF 1 ( NAL1 ), originally identified for its role in shaping leaf morphology, plant architecture, and various agronomic traits in rice, has remained enigmatic in terms of the molecular mechanisms governing its multifaceted functions. In this study, we present a comprehensive structural analysis of NAL1 proteins, shedding light on how NAL1 regulates the phase separation of its physiological substrate, FRIZZY PANICLE (FZP), a transcription factor. We determined that NAL1 assembles as a hexamer and forms a molecular cage with a wide central channel and three narrower lateral channels, which could discriminate its different substrates into the catalytic sites. Most notably, our investigation unveils that FZP readily forms molecular condensates via phase separation both in vitro and in vivo. NAL1 fine-tunes FZP condensation, maintaining optimal concentrations to enhance transcriptional activity. While phase separation roles include sequestration and suppression of transcriptional or enzymatic activity, our study highlights its context-dependent contribution to transcriptional regulation. NAL1 assumes a pivotal role in regulating the states of these molecular condensates through its proteolytic activity, subsequently enhancing transcriptional cascades. Our findings offer insights into comprehending the molecular mechanisms underpinning NAL1’s diverse functions, with far-reaching implications for the field of plant biology. Additionally, these insights provide valuable guidance for the development of rational breeding strategies aimed at enhancing crop productivity.}, archive = {J_PNAS}, author = {Huang, Ling-Yun and Wang, Ting-Ting and Shi, Peng-Tao and Song, Ze-Yu and Chen, Wei-Fei and Liu, Na-Nv and Ai, Xia and Li, Hai-Hong and Hou, Xi-Miao and Wang, Li-Bing and Chen, Kun-Ming and Rety, Stephane and Xi, Xu-Guang}, doi = {10.1073/pnas.2419961122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2419961122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {NAL1 forms a molecular cage to regulate FZP phase separation}, volume = {122}, year = {2025}, }
• (2025). Host ZAP activity correlates with the levels of CpG suppression in primate lentiviruses. PNAS, 122(15), e2419489122. (www)

  @article{ , abstract = {Zinc-finger antiviral protein (ZAP) is thought to drive the suppression of CpG dinucleotides in many viruses to mimic the composition of their host genomes. However, in vivo evidence is sparse. Here, we investigated the reasons for unusually high CpG levels in SIVmus and SIVmon from mustached and mona monkeys, descendants of one of the precursors of HIV-1. We show that SIVmus is not resistant to ZAP inhibition. Instead, these Cercopithecus monkey hosts differ from other primate species by a splice site mutation and express the poorly active extralarge XL rather than the highly active L isoform of ZAP. Similarly, higher CpG levels in endogenous prosimian lentiviruses were associated with low activity of the corresponding host lemur ZAPs. In addition, lemur genes also show lower CpG suppression than other primates. Thus, the antiviral activity of ZAP not only affects suppression of CpG dinucleotides in viral transcripts but possibly also host genomes.}, archive = {J_PNAS}, author = {Nchioua, Rayhane and Kmiec, Dorota and Krchlikova, Veronika and Mattes, Sarah and Noettger, Sabrina and Bibollet-Ruche, Frederic and Russell, Ronnie M. and Sparrer, Konstantin M. J. and Charpentier, Thomas and Tardy, Frédéric and Bosinger, Steven E. and Sauter, Daniel and Hahn, Beatrice H. and Kirchhoff, Frank}, doi = {10.1073/pnas.2419489122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2419489122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Host ZAP activity correlates with the levels of CpG suppression in primate lentiviruses}, volume = {122}, year = {2025}, }
• (2025). Arf1 and ARFGEF2/Sec71 control neuroblast polarity by anchoring nonmuscle myosin II. PNAS, 122(15), e2419468122. (www)

  @article{ , abstract = {Neural stem cells (NSCs) can self-renew and undergo differentiation via asymmetric division. Dysregulation in the balance between self-renewal and differentiation can lead to tumor formation or neurodevelopmental disorders. However, the regulation of phosphatidylinositol transfer protein (PITP)-dependent PI(4)P pools and myosin localization during asymmetric division in dividing cells is not well established. Here, we show that the Golgi proteins Arf1 and ARFGEF2/Sec71 control asymmetric division of Drosophila NSCs by facilitating the localization of myosin II regulatory light chain, Sqh, to the NSC cortex. Arf1 can physically associate with Sqh and Vibrator, a type I PITP that stimulates phospholipid PI4K activity for PI(4)P production. Further, Arf1 and Sec71 facilitate PI(4)P localization to the cell cortex of neuroblasts. Our data provide evidence that the Golgi proteins Arf1 and its GEF Sec71 facilitate neuroblast polarity through phospholipid-dependent nonmuscle myosin II cortical localization.}, archive = {J_PNAS}, author = {Gujar, Mahekta R. and Tan, Ye Sing and Gao, Yang and Wang, Hongyan}, doi = {10.1073/pnas.2419468122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2419468122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Arf1 and ARFGEF2/Sec71 control neuroblast polarity by anchoring nonmuscle myosin II}, volume = {122}, year = {2025}, }
• (2025). Structural and functional characterization of the brain-specific dynamin superfamily member RNF112. PNAS, 122(15), e2419449122. (www)

  @article{ , abstract = {Most members of the dynamin superfamily of large guanosine triphophatases (GTPases) have an ability to remodel membranes in response to guanosine triphosphate (GTP) hydrolysis. Ring Finger Protein 112 (RNF112) (ZNF179/neurolastin) is a recently identified brain-specific dynamin-like protein possessing a really interesting new gene (RING) finger domain. Despite its essential role as an E3 ligase in neuron development, the architecture of RNF112 and the exact role of its GTPase activity remain unknown. Here, we determined the crystal structure of truncated RNF112 (RNF112 T ) containing a GTPase domain (GD) and three-helical middle domain (MD) at different nucleotide-loading states. In the nucleotide-free (apo) state, the monomeric RNF112 T remained in a unique self-restraint conformation characterized by docking of the proximal end of the MD to a groove in the GD. At the transition state of GTP hydrolysis, the MD was released from the GD and stretched aside to form an intertwined RNF112 T homodimer. Engineered RNF112 equipped with the C-terminal elements of ATL1 or the two transmembrane domains of yeast Sac1p relocated to the endoplasmic reticulum and was capable of mediating membrane remodeling. Taken together, our results offer necessary understandings of RNF112 as a dynamin-like large GTPase in its cellular function and provide insights into the functional mechanisms of dynamin superfamily proteins.}, archive = {J_PNAS}, author = {Zhong, Ya-Ting and Huang, Li-Li and Li, Kangning and Yang, Bingke and Ye, Xueting and Zhong, Hao-Ran and Yu, Bing and Ma, Menghan and Yuan, Yuerong and Meng, Yang and Pan, Runfeng and Zhang, Haiqing and Shi, Lijun and Wang, Yunyun and Tian, Ruijun and Gao, Song and Bian, Xin}, doi = {10.1073/pnas.2419449122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2419449122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural and functional characterization of the brain-specific dynamin superfamily member RNF112}, volume = {122}, year = {2025}, }
• (2025). In situ generated hydrogen-bonding microenvironment in functionalized MOF nanosheets for enhanced CO2 electroreduction. PNAS, 122(15), e2419434122. (www)

  @article{ , abstract = {The microenvironment around catalytic sites plays crucial roles in enzymatic catalysis while its precise control in heterogeneous catalysts remains challenging. Herein, the coordinatively unsaturated metal nodes of Hf-based metal-organic framework nanosheets are simultaneously codecorated with catalytically active Co(salen) units and adjacent pyridyl-substituted alkyl carboxylic acids via a post modification route. By varying pyridyl-substituted alkyl carboxylic acids, the spatial positioning of the N atom in pyridine group relative to adjacent Co(salen) can be precisely controlled. Notably, the 3-(pyridin-4-yl)propionic acid, with para -position pyridine N atom, maximally improves the electrocatalytic CO 2 reduction performance of Co(salen) unit, far superior to other counterparts. Mechanism investigations reveal that the pyridine unit of 3-(pyridin-4-yl)propionic acid is optimally positioned relative to Co(salen) and undergoes in situ reduction to pyridinyl radical under working potentials. This greatly facilitates the stabilization of *COOH intermediate via hydrogen-bonding interaction, lowering the formation energy barrier of *COOH and therefore boosting CO 2 electroreduction.}, archive = {J_PNAS}, author = {Yang, Ge and Huang, Jiajia and Gu, Weizhi and Lin, Zhongyuan and Wang, Qingyu and Kang, Rong and Liu, Jing-Yao and Sun, Zhihu and Zheng, Xusheng and Jiao, Long and Jiang, Hai-Long}, doi = {10.1073/pnas.2419434122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2419434122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In situ generated hydrogen-bonding microenvironment in functionalized MOF nanosheets for enhanced CO2 electroreduction}, volume = {122}, year = {2025}, }
• (2025). Motion artifact–controlled micro–brain sensors between hair follicles for persistent augmented reality brain–computer interfaces. PNAS, 122(15), e2419304122. (www)

  @article{ , abstract = {Modern brain–computer interfaces (BCI), utilizing electroencephalograms for bidirectional human–machine communication, face significant limitations from movement-vulnerable rigid sensors, inconsistent skin–electrode impedance, and bulky electronics, diminishing the system’s continuous use and portability. Here, we introduce motion artifact–controlled micro–brain sensors between hair strands, enabling ultralow impedance density on skin contact for long-term usable, persistent BCI with augmented reality (AR). An array of low-profile microstructured electrodes with a highly conductive polymer is seamlessly inserted into the space between hair follicles, offering high-fidelity neural signal capture for up to 12 h while maintaining the lowest contact impedance density (0.03 kΩ·cm −2 ) among reported articles. Implemented wireless BCI, detecting steady-state visually evoked potentials, offers 96.4% accuracy in signal classification with a train-free algorithm even during the subject’s excessive motions, including standing, walking, and running. A demonstration captures this system’s capability, showing AR-based video calling with hands-free controls using brain signals, transforming digital communication. Collectively, this research highlights the pivotal role of integrated sensors and flexible electronics technology in advancing BCI’s applications for interactive digital environments.}, archive = {J_PNAS}, author = {Kim, Hodam and Kim, Ju Hyeon and Lee, Yoon Jae and Lee, Jimin and Han, Hyojeong and Yi, Hoon and Kim, Hyeonseok and Kim, Hojoong and Kang, Tae Woog and Chung, Suyeong and Ban, Seunghyeb and Lee, Byeongjun and Lee, Haran and Im, Chang-Hwan and Cho, Seong J. and Sohn, Jung Woo and Yu, Ki Jun and Kang, Tae June and Yeo, Woon-Hong}, doi = {10.1073/pnas.2419304122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2419304122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Motion artifact–controlled micro–brain sensors between hair follicles for persistent augmented reality brain–computer interfaces}, volume = {122}, year = {2025}, }
• (2025). Enamel–dentine junction morphology reveals population replacement and mobility in the late prehistoric middle nile valley. PNAS, 122(15), e2419122122. (www)

  @article{ , abstract = {Transitions from foraging to food-production represent a worldwide turning point in recent human history. In the Middle Nile Valley this cultural shift occurred between the sixth and beginning of the fifth millennium BCE. Significant craniodental morphological differences remain inadequately tested by biometric analyses of ancestry and may reflect population origins or diet change between the last hunter-fisher-gatherers (Mesolithic) and first food-producers (Neolithic). Moreover, with no ancient DNA data for this region and very few morphological studies including large samples of Mesolithic individuals, the late prehistoric population history of the Nile Valley remains unclear. Here, we present enamel–dentine junction (EDJ) morphological analyses (based on X-ray microtomography) and biological affinities for 88 individuals spanning 14,000 y from Sudan and southern Egypt. Significant EDJ morphological differences between the last foragers and first food-producers suggest major biological discontinuity at the Neolithic transition. Nevertheless, the persistence of the earlier forager population in the Sudanese Eastern Sahara indicates settlement and population replacement mainly along the Nile. We also present biological evidence of interaction and mobility between these contemporaneous populations during the middle Holocene in the region. It supports the phylogenetic value of EDJ morphology for investigating population affinities at a microevolutionary scale. These results yield insights into the deep population history of the Nile Valley. They provide firm evidence for population replacement and migration toward the region at the onset of the Neolithic transition, attesting that these key changes were not solely triggered by cultural diffusion and diet change.}, archive = {J_PNAS}, author = {Martin, Nicolas and Thibeault, Adrien and Varadzinová, Lenka and Usai, Donatella and Ambrose, Stanley H. and Antoine, Daniel and Brukner Havelková, Petra and Honegger, Matthieu and Irish, Joel D. and Jesse, Friederike and Maréchal, Laura and Osypińska, Marta and Osypiński, Piotr and Santos, Frédéric and Vanderesse, Nicolas and Varadzin, Ladislav and Whiting, Rebecca J. and Zanolli, Clément and Velemínský, Petr and Crevecoeur, Isabelle}, doi = {10.1073/pnas.2419122122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2419122122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Enamel–dentine junction morphology reveals population replacement and mobility in the late prehistoric middle nile valley}, volume = {122}, year = {2025}, }
• (2025). The genetic legacy of a global marine invader. PNAS, 122(15), e2418730122. (www)

  @article{ , abstract = {The massive geographic expansion of terrestrial plant crops, livestock, and marine aquacultured species during the 19th and 20th centuries provided local economic benefits, stabilized food demands, and altered local ecosystems. The invasion history of these translocations remains uncertain for most species, limiting our understanding of their future adaptive potential and historical roles as vectors for coinvaded species. We provide a framework for filling this gap in invasion biology using the widely transplanted Pacific oyster as a case study. A two-dimensional summary of population-level variation in single nucleotide polymorphisms in native Japan reflected the geographical map of Japan and allowed identification of the source regions for the worldwide expansion. Pacific oysters proliferate in nonnative areas with environmental temperatures similar to those areas where native lineages evolved. Using Approximate Bayesian Computation, we ranked the likelihood of historical oyster or shipping vectors to explain current-day distribution of genotypes in 14 coinvaded algal and animal species. Oyster transplants were a more likely vector than shipping for six species, shipping activity was more likely for five species, and a vector was ambiguous for three species. Applying this approach to other translocated species should reveal similar legacy effects, especially for economically important foundation species that also served as vectors for nonnative species.}, archive = {J_PNAS}, author = {Sotka, Erik E. and Carnegie, Ryan B. and Carlton, James T. and Couceiro, Lucia and Crooks, Jeffrey A. and Endo, Hikaru and Hayford, Hilary and Hori, Masakazu and Kamiya, Mitsunobu and Kanaya, Gen and Kochmann, Judith and Lee, Kun-Seop and Lees, Lauren and Miller, Hannah and Nakaoka, Masahiro and Pante, Eric and Ruesink, Jennifer L. and Schwindt, Evangelina and Strand, Åsa and Taylor, Richard B. and Terada, Ryuta and Thiel, Martin and Yorisue, Takefumi and Zacherl, Danielle and Strand, Allan E.}, doi = {10.1073/pnas.2418730122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2418730122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The genetic legacy of a global marine invader}, volume = {122}, year = {2025}, }
• (2025). The impact of sampling bias on preferences for skewed distributions in decisions from experience. PNAS, 122(15), e2418336122. (www)

  @article{ , archive = {J_PNAS}, author = {Vanunu, Yonatan and Newell, Ben R.}, doi = {10.1073/pnas.2418336122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2418336122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The impact of sampling bias on preferences for skewed distributions in decisions from experience}, volume = {122}, year = {2025}, }
• (2025). Structural basis for immune cell binding of fusobacterium nucleatum via the trimeric autotransporter adhesin CbpF. PNAS, 122(15), e2418155122. (www)

  @article{ , abstract = {Fusobacterium nucleatum (Fn), a commensal in the human oral cavity, is overrepresented in the colon microbiota of colorectal cancer (CRC) patients and is linked to tumor chemoresistance, metastasis, and a poor therapeutic prognosis. Fn produces numerous adhesins that mediate tumor colonization and downregulation of the host’s antitumor immune response. One of these, the trimeric autotransporter adhesin (TAA) CEACAM binding protein of Fusobacterium (CbpF), targets CEACAM1 on T-cells and has been associated with immune evasion of Fn-colonized tumors. Whereas the role of CEACAM1 in homophilic and heterophilic cell interactions and immune evasion is well described, the mechanistic details of its interaction with fusobacterial CbpF remain unknown due to the lack of a high-resolution structure of the adhesin–receptor complex. Here, we present two structures of CbpF alone and in complex with CEACAM1, obtained by cryogenic electron microscopy and single particle analysis. They reveal that CbpF forms a stable homotrimeric complex whose N-terminal part of the extracellular domain comprises a 64 Å long β roll domain with a unique lateral loop extension. CEACAM1 binds to this loop with high affinity via its N-terminal IgV-like domain with a nanomolar dissociation constant as determined by surface plasmon resonance. This study provides a comprehensive structural description of a fusobacterial TAA, illustrates a yet undescribed CEACAM1 binding mode, and paves the way for rational drug design targeting Fn in CRC.}, archive = {J_PNAS}, author = {Marongiu, Gian Luca and Fink, Uwe and Schöpf, Felix and Oder, Andreas and von Kries, Jens Peter and Roderer, Daniel}, doi = {10.1073/pnas.2418155122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2418155122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis for immune cell binding of fusobacterium nucleatum via the trimeric autotransporter adhesin CbpF}, volume = {122}, year = {2025}, }
• (2025). Glassy ionogels with high compressibility and strength for impact protection. PNAS, 122(15), e2417978122. (www)

  @article{ , abstract = {Solvents within gels enhance the mobility of polymer chain segments while concurrently diminishing interchain interactions, thereby facilitating the ductility of glassy polymers at the cost of their mechanical strength. Here, we develop a solvent toughening strategy for the preparation of highly compressible and high-strength ionogels in the glassy state. This approach leverages the synergistic effects of the slow dissociation-shift kinetics of solvent ionic liquids and polymer crystallization. Ionogels exhibit an ultimate compressive stress of 2.3 GPa (at 98% compressive strain), toughness of 1219.3 MJ m −3 , and energy dissipation rate of 81.9% (at 70% compression strain). The highly interacting ionic bonds of solvent and the fast crystallization of polymers under load toughen the ionogels and confer impact hardening and efficient energy dissipation behavior under fast impact. A 500-μm-thick ionogel coating can protect fragile items, such as glass, from impact damage. Ionogels, renowned for their impact resistance, hold promise for various applications across industries including human body implants, equipment, transportation, and aerospace.}, archive = {J_PNAS}, author = {Wang, Jiayu and Zhang, Shilong and Li, Lingling and Wang, Xiaoliang and Xiong, Jiaofeng and Li, Qingning and Li, Weizheng and Yan, Feng}, doi = {10.1073/pnas.2417978122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2417978122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Glassy ionogels with high compressibility and strength for impact protection}, volume = {122}, year = {2025}, }
• (2025). Astrocytic ryk signaling coordinates scarring and wound healing after spinal cord injury. PNAS, 122(15), e2417400122. (www)

  @article{ , abstract = {Wound healing after spinal cord injury involves highly coordinated interactions among multiple cell types, which are poorly understood. Astrocytes play a central role in creating a border against the non-neural lesion core. To do so, astrocytes undergo dramatic morphological changes by first thickening and elongating their processes and then overlapping them to form a physical barrier. We show here that the expression of a cell-surface receptor, Ryk, is induced in astrocytes after injury in both rodent and human spinal cords. Astrocyte-specific knockout of Ryk dramatically elongated the reactive astrocytes, accelerated the formation of the border, and reduced the size of the scar. Astrocyte-specific knockout of Ryk also accelerated the injury responses of multiple cell types. Single-cell transcriptomics analyses revealed a broad range of changes in cell signaling among astrocytes, microglia, fibroblasts, and endothelial cells after astrocyte-specific Ryk knockout, suggesting that Ryk not only regulates injury responses of astrocytes but may also regulate signals emanating from astrocytes and coordinate the responses of these cell types. The elongation of astrocyte processes is mediated by NrCAM, a cell adhesion molecule induced by astrocyte-specific conditional knockout of Ryk after spinal cord injury. Our findings suggest that Ryk is a promising therapeutic target to accelerate wound healing, promote neuronal survival, and enhance functional recovery.}, archive = {J_PNAS}, author = {Shen, Zhe and Feng, Bo and Lim, Wei Ling and Woo, Timothy and Liu, Yanlin and Vicenzi, Silvia and Wang, Jingyi and Kwon, Brian K. and Zou, Yimin}, doi = {10.1073/pnas.2417400122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2417400122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Astrocytic ryk signaling coordinates scarring and wound healing after spinal cord injury}, volume = {122}, year = {2025}, }
• (2025). A computational analysis of lexical elaboration across languages. PNAS, 122(15), e2417304122. (www)

  @article{ , abstract = {Claims about lexical elaboration (e.g. Mongolian has many horse-related terms) are widespread in the scholarly and popular literature. Here, we show that computational analyses of bilingual dictionaries can be used to test claims about lexical elaboration at scale. We validate our approach by introducing BILA, a dataset including 1,574 bilingual dictionaries, and showing that it confirms 147 out of 163 previous claims from the literature. We then identify previously unreported examples of lexical elaboration, and analyze how lexical elaboration is influenced by ecological and cultural variables. Claims about lexical elaboration are sometimes dismissed as either obvious or fanciful, but our work suggests that large-scale computational approaches to the topic can produce nonobvious and well-grounded insights into language and culture.}, archive = {J_PNAS}, author = {Khishigsuren, Temuulen and Regier, Terry and Vylomova, Ekaterina and Kemp, Charles}, doi = {10.1073/pnas.2417304122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2417304122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A computational analysis of lexical elaboration across languages}, volume = {122}, year = {2025}, }
• (2025). Substrate stress relaxation regulates monolayer fluidity and leader cell formation for collectively migrating epithelia. PNAS, 122(15), e2417290122. (www)

  @article{ , abstract = {Collective migration of epithelial tissues is a critical feature of developmental morphogenesis and tissue homeostasis. Coherent motion of cell collectives requires large-scale coordination of motion and force generation and is influenced by mechanical properties of the underlying substrate. While tissue viscoelasticity is a ubiquitous feature of biological tissues, its role in mediating collective cell migration is unclear. Here, we have investigated the impact of substrate stress relaxation on the migration of micropatterned epithelial monolayers. Epithelial monolayers exhibit faster collective migration on viscoelastic alginate substrates with slower relaxation timescales, which are more elastic, relative to substrates with faster stress relaxation, which exhibit more viscous loss. Faster migration on slow-relaxing substrates is associated with reduced substrate deformation, greater monolayer fluidity, and enhanced leader cell formation. In contrast, monolayers on fast-relaxing substrates generate substantial substrate deformations and are more jammed within the bulk, with reduced formation of transient lamellipodial protrusions past the monolayer edge leading to slower overall expansion. This work reveals features of collective epithelial dynamics on soft, viscoelastic materials and adds to our understanding of cell–substrate interactions at the tissue scale.}, archive = {J_PNAS}, author = {Charbonier, Frank and Zhu, Junqin and Slyman, Raleigh and Allan, Cole and Chaudhuri, Ovijit}, doi = {10.1073/pnas.2417290122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2417290122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Substrate stress relaxation regulates monolayer fluidity and leader cell formation for collectively migrating epithelia}, volume = {122}, year = {2025}, }
• (2025). Structural basis of the cysteinyl leukotriene receptor type 2 activation by LTD4. PNAS, 122(15), e2417148122. (www)

  @article{ , abstract = {The G protein–coupled cysteinyl leukotriene receptor CysLT2R plays intricate roles in the physiology and pathogenesis of inflammation-related processes. It has garnered increasing attention as a potential therapeutic target for atopic asthma, brain injury, central nervous system disorders, and various types of cancer. In this study, we present the cryo-electron microscopy structure of the cysteinyl leukotriene D4 (LTD4)-bound human CysLT2R in complex with a Gα q protein, adopting an active conformation at a resolution of 3.15 Å. The structure elucidates a spacious polar pocket designed to accommodate the two branched negative ends of LTD4 and reveals a lateral ligand access route into the orthosteric pocket located on transmembrane domain helix (TM) 4 and 5. Furthermore, our findings highlight the crucial role of transmembrane domain helix 3 in sensing agonist moieties, representing the pivotal mechanism of receptor activation for both CysLT1R and CysLT2R. Collectively, the insights derived from our structural investigation establish a foundation for comprehending CysLT2R activation by its endogenous ligand LTD4, offering a rational basis for the design of drugs targeting CysLT2R.}, archive = {J_PNAS}, author = {Jiang, Mengting and Xu, Youwei and Luan, Xiaodong and Wu, Kai and Li, Zhen and Xu, H. Eric and Zhang, Shuyang and Jiang, Yi and Yin, Wanchao}, doi = {10.1073/pnas.2417148122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2417148122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis of the cysteinyl leukotriene receptor type 2 activation by LTD4}, volume = {122}, year = {2025}, }
• (2025). Cortical scaling of the neonatal brain in typical and altered development. PNAS, 122(15), e2416423122. (www)

  @article{ , abstract = {Theoretically derived scaling laws capture the nonlinear relationships between rapidly expanding brain volume and cortical gyrification across mammalian species and in adult humans. However, the preservation of these laws has not been comprehensively assessed in typical or pathological brain development. Here, we assessed the scaling laws governing cortical thickness (CT), surface area (SA), and cortical folding in the neonatal brain. We also assessed multivariate morphological terms that capture brain size, shape, and folding processes. The sample consisted of 345 typically developing infants, 73 preterm infants, and 107 infants with congenital heart disease (CHD) who underwent brain MRI. Our results show that typically developing neonates and those with CHD follow the cortical folding scaling law obtained from mammalian brains, children, and adults which captures the relationship between exposed SA, total SA, and CT. Cortical folding scaling was not affected by gestational age at birth, postmenstrual age at scan, sex, or multiple birth in these populations. CHD was characterized by a unique reduction in the multivariate morphological term capturing size, suggesting that CHD affects cortical growth overall but not cortical folding processes. In contrast, preterm birth was characterized by altered cortical folding scaling and altered shape, suggesting that the developmentally programmed processes of cortical folding are disrupted in this population. The degree of altered shape was associated with cognitive abilities in early childhood in preterm infants.}, archive = {J_PNAS}, author = {Bonthrone, Alexandra F. and Cromb, Daniel and Chew, Andrew and Gal-Er, Barat and Kelly, Christopher and Falconer, Shona and Arichi, Tomoki and Pushparajah, Kuberan and Simpson, John and Rutherford, Mary A. and Hajnal, Joseph V. and Nosarti, Chiara and Edwards, A. David and O’Muircheartaigh, Jonathan and Counsell, Serena J.}, doi = {10.1073/pnas.2416423122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2416423122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cortical scaling of the neonatal brain in typical and altered development}, volume = {122}, year = {2025}, }
• (2025). Closure of orbits of the pure mapping class group in the character variety. PNAS, 122(15), e2416120122. (www)

  @article{ , abstract = {The pure mapping class group of an oriented surface acts on the character variety of the surface. We investigate the closure of its orbits under either Zariski or analytic topologies. We show that a generic infinite orbit is dense in an open subset of the corresponding modified relative character variety. Moreover, we specify that being generic can be captured as a combination of passing to a Zariski-open subscheme and avoiding a concrete set of exceptional cases. In addition, the functorial behavior of the involved schemes is described in detail. In particular, we answer a question posed by Goldman and place the recent work of Bourgain, Gamburd, and Sarnak on Markoff triples in a more general context.}, archive = {J_PNAS}, author = {Golsefidy, Alireza S. and Tamam, Nattalie}, doi = {10.1073/pnas.2416120122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2416120122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Closure of orbits of the pure mapping class group in the character variety}, volume = {122}, year = {2025}, }
• (2025). FLIPL permits apoptotic and inflammatory signaling and inhibits necroptosis in mice without caspase-8 oligomerization. PNAS, 122(15), e2415992122. (www)

  @article{ , abstract = {Caspase-8 signaling has proapoptotic, antinecroptotic, and proinflammatory signaling roles dependent on interaction with the adapter molecule FADD, oligomerization, and autocleavage. Previously, a Caspase-8 binding partner cFLIP L (FLIP, encoded by Cflar ) was shown to prevent Caspase-8-dependent apoptosis, but permit Caspase-8-dependent inhibition of necroptosis. We sought to explore the role of FLIP in Caspase-8-dependent apoptosis induction, necroptosis inhibition, and inflammatory signaling inhibition in vitro and in vivo. We provide evidence that in mice with a mutation that prevents Caspase-8 oligomerization ( Casp8 FGLG/FGLG ), FLIP is necessary to inhibit necroptosis, promote apoptosis, regulate inflammation, and control lymphoproliferative disease. Unlike Casp8 FGLG/FGLG mice, Casp8 FGLG/FGLG ,Cflar −/− mice do not survive embryogenesis, but ablation of Mlkl , required for necroptosis, allows their survival to adulthood. Further, unlike Casp8 FGLG/FGLG ,Mlkl −/− mice, Casp8 FGLG/FGLG ,Cflar −/− ,Mlkl −/− mice display lymphoproliferative disease. We analyzed apoptosis, necroptosis, and inflammatory signaling in Casp8 FGLG/FGLG mice with or without FLIP, gaining insights into the functions of the Caspase-8–FLIP heterodimer in vitro and in vivo.}, archive = {J_PNAS}, author = {Shaw, Jeremy J. P. and Guy, Cliff and Tummers, Bart and Green, Douglas R.}, doi = {10.1073/pnas.2415992122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2415992122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {FLIPL permits apoptotic and inflammatory signaling and inhibits necroptosis in mice without caspase-8 oligomerization}, volume = {122}, year = {2025}, }
• (2025). Structure of a gcn2 dimer in complex with the large 60S ribosomal subunit. PNAS, 122(15), e2415807122. (www)

  @article{ , abstract = {The integrated stress response (ISR) is a central signaling network that enables eukaryotic cells to respond to a variety of different environmental stresses. Such stresses cause ribosome collisions that lead to activation of the kinase Gcn2, resulting in the phosphorylation and inactivation of eukaryotic initiation factor 2 and thereby promoting selective translation of mRNAs to restore homeostasis. Despite the importance of the ISR and intensive study over the past decades, structural insight into how Gcn2 interacts with ribosomal particles has been lacking. Using ex vivo affinity purification approaches, we have obtained a cryoelectron microscopy structure of a yeast Gcn2 dimer in complex with the ribosomal 60S subunit. The Gcn2 dimer is formed by dimerization of the histidine tRNA synthetase-like domains, which establish extensive interactions with the stalk-base and sarcin–ricin loop of the 60S subunit. The C-terminal domain of Gcn2 is also dimerized and occupies the A- and P-site tRNA binding sites at the peptidyl-transferase center of the 60S subunit. Complementary functional studies indicate that binding of Gcn2 to the 60S subunit does not require the coactivators Gcn1 or Gcn20, nor does it lead to phosphorylation of eIF2α. Instead, upon stress, we observe a shift of Gcn2 from the 60S subunit into the colliding ribosome fraction, suggesting that the Gcn2–60S complex represents an inactive stand-by state to enable a rapid redistribution to collided ribosomes, and thereby facilitating a quick and efficient response to stress.}, archive = {J_PNAS}, author = {Paternoga, Helge and Xia, Lu and Dimitrova-Paternoga, Lyudmila and Li, Sihan and Yan, Liewei L. and Oestereich, Malte and Kasvandik, Sergo and Nanjaraj Urs, Ankanahalli N. and Beckert, Bertrand and Tenson, Tanel and Zaher, Hani and Inada, Toshifumi and Wilson, Daniel N.}, doi = {10.1073/pnas.2415807122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2415807122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure of a gcn2 dimer in complex with the large 60S ribosomal subunit}, volume = {122}, year = {2025}, }
• (2025). On hodge polynomials for nonalgebraic complex manifolds. PNAS, 122(15), e2415722122. (www)

  @article{ , abstract = {Hodge theory is pivotal in studying algebraic varieties’ intricate geometry and topology: it provides essential insights into their structure. The Hodge decomposition theorem establishes a profound link between the geometry of varieties and their cohomology groups, helping to understand their underlying properties. Moreover, Hodge theory was crucial at the inception of the field of mirror symmetry, revealing deep connections among seemingly disparate algebraic varieties. It also sheds light on studying algebraic cycles and motives, crucial objects in algebraic geometry. This article explores Hodge polynomials and their properties, specifically focusing on non-Kähler complex manifolds. We investigate a diverse range of such manifolds, including (quasi-)Hopf, (quasi-)Calabi–Eckmann, and LVM manifolds, alongside a class of definable complex manifolds encompassing both algebraic varieties and the aforementioned special cases. Our research establishes the preservation of the motivic nature of Hodge polynomials inside this broader context. Through explicit calculations and thorough analyses, this work contributes to a deeper understanding of complex manifold geometry beyond the realm of algebraic varieties. The outcomes of this study have potential applications in various areas of mathematics and physics where complex manifolds play a significant role.}, archive = {J_PNAS}, author = {Katzarkov, Ludmil and Lee, Kyoung-Seog and Lupercio, Ernesto and Meersseman, Laurent}, doi = {10.1073/pnas.2415722122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2415722122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {On hodge polynomials for nonalgebraic complex manifolds}, volume = {122}, year = {2025}, }
• (2025). Seismic fault slip at depths simulated by high-velocity friction experiments under hydrothermal conditions. PNAS, 122(15), e2415700122. (www)

  @article{ , abstract = {Seismic fault slip and rupture propagation often occur at crustal depths in the presence of hot and pressurized aqueous fluids (i.e., hydrothermal conditions). Previous experiments investigated fault frictional properties under hydrothermal conditions, but at imposed subseismic fault slip velocities ( V ~μm/s). Here, using a rotary-shear apparatus equipped with a hydrothermal pressure vessel, we study friction at seismic slip velocities ( V = 1.5 m/s) of gabbro- and marble-built faults under temperatures of 40 to 400 °C and pore water pressure of 30 MPa. We find that with increasing initial water temperature ( T amb ), the dynamic friction during initial slip acceleration and subsequent high-velocity sliding decreases for both gabbro- and marble-built faults, while the slip-weakening distance decreases for gabbro but increases for marble. Then, during rapid deceleration at the end of sliding, frictional strength recovery decreases for gabbro with increasing T amb and increases for marble independently of T amb . As in previous experiments performed at room T amb , the mechanical and microstructural data, plus numerical modeling, suggest that the seismic fault weakening mechanisms shift from flash heating to bulk melting for gabbro, and from flash heating to grain boundary sliding accommodated by diffusion creep for marble, with their activation processes depending on T amb . Our results demonstrate the effects of ambient temperature on seismic fault friction, which contribute to changes in fault strength and dynamic weakening processes at crustal depths and should be considered in earthquake rupture modeling.}, archive = {J_PNAS}, author = {Yao, Lu and Feng, Wei and Cornelio, Chiara and Shimamoto, Toshihiko and Ma, Shengli and Di Toro, Giulio}, doi = {10.1073/pnas.2415700122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2415700122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Seismic fault slip at depths simulated by high-velocity friction experiments under hydrothermal conditions}, volume = {122}, year = {2025}, }
• (2025). Alpha-tubulin tails regulate axoneme differentiation. PNAS, 122(15), e2414731122. (www)

  @article{ , abstract = {The tubulin tail is a key element for microtubule (MT) functionality, but the functional redundancy of tubulin genes complicates the genetic determination of their physiological functions. Here, we removed the C-terminal tail of five alpha- and four beta-tubulin genes in the C. elegans genome. Sensory cilia typically exhibit an axoneme that longitudinally differentiates into a middle segment with doublet MTs and a distal segment with singlet MTs. However, the excision of the alpha-tubulin tail, but not the beta-tubulin tail, resulted in the ectopic formation of doublet MTs in the distal segments. Molecular dynamics simulations suggest that the alpha-tubulin tail could prevent the B-tubule from docking on the surface of A-tubule. Using recombinant tubulins, we demonstrated that removing the alpha-tubulin tail efficiently promoted doublet MTs formation in vitro. These results reveal the vital and unique contributions of tubulin tails to the structural integrity and accuracy of axoneme MT organization.}, archive = {J_PNAS}, author = {Li, Ming and Chen, Zhe and Guo, Zhengyang and Wang, Yang and Chai, Yongping and Li, Wei and Ou, Guangshuo}, doi = {10.1073/pnas.2414731122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2414731122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Alpha-tubulin tails regulate axoneme differentiation}, volume = {122}, year = {2025}, }
• (2025). Probing ultraweak in-plane magnetic anisotropy within a two-dimensional layered antiferromagnet. PNAS, 122(15), e2414668122. (www)

  @article{ , abstract = {Magnetic anisotropy plays a crucial role in determining the critical behavior and phase transitions in two-dimensional magnetic systems. It is also required for the design of thin-film spintronic devices. Despite its significance, sensing extremely weak anisotropy has proven challenging in van der Waals antiferromagnetic/ferrimagnetic materials. Here, we first employ simulations of micromagnetic energy function in few-layer easy-plane antiferromagnetic systems with a weak additional uniaxial anisotropy and unveil an intriguing even–odd effect closely linked to low-field spin–flop behaviors. We further perform tunneling magneto-conductance measurements on a model 2D antiferromagnetic insulator, CrCl 3 , exhibiting near-ideal easy-plane anisotropy. The magnetic field-controlled tunneling current at low temperature aligns well with simulated in-plane anisotropic spin-configuration, providing direct experimental evidence for detecting magnetic anisotropy field around 1 mT. Our work creates opportunities for finely characterizing magnetic structures and behaviors in 2D antiferromagnetic/ferrimagnetic systems, with potential applications in spintronics such as data storage and magnetic sensing.}, archive = {J_PNAS}, author = {Fan, Yijie and Xu, Yihong and Bian, Renji and Zhang, Ruan and Mei, Junning and Wu, Jiaxin and Xie, Binghe and Zhu, Shuangxing and Chen, Yu and Gu, Feifan and Liu, Ying and Taniguchi, Takashi and Watanabe, Kenji and Liu, Fucai and Cai, Xinghan}, doi = {10.1073/pnas.2414668122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2414668122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Probing ultraweak in-plane magnetic anisotropy within a two-dimensional layered antiferromagnet}, volume = {122}, year = {2025}, }
• (2025). The beholder’s share: Bridging art and neuroscience to study individual differences in subjective experience. PNAS, 122(15), e2413871122. (www)

  @article{ , abstract = {Our experience of the world is inherently subjective, shaped by individual history, knowledge, and perspective. Art offers a framework within which this subjectivity is practiced and promoted, inviting viewers to engage in interpretation. According to art theory, different forms of art—ranging from the representational to the abstract—challenge these interpretive processes in different ways. Yet, much remains unknown about how art is subjectively interpreted. In this study, we sought to elucidate the neural and cognitive mechanisms that underlie the subjective interpretation of art. Using brain imaging and written descriptions, we quantified individual variability in responses to paintings by the same artists, contrasting figurative and abstract paintings. Our findings revealed that abstract art elicited greater interindividual variability in activity within higher-order, associative brain areas, particularly those comprising the default-mode network. By contrast, no such differences were found in early visual areas, suggesting that subjective variability arises from higher cognitive processes rather than differences in sensory processing. These findings provide insight into how the brain engages with and perceives different forms of art and imbues it with subjective interpretation.}, archive = {J_PNAS}, author = {Durkin, Celia and Apicella, Marc and Baldassano, Christopher and Kandel, Eric and Shohamy, Daphna}, doi = {10.1073/pnas.2413871122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2413871122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The beholder’s share: Bridging art and neuroscience to study individual differences in subjective experience}, volume = {122}, year = {2025}, }
• (2025). Pulsatile basal gene expression as a fitness determinant in bacteria. PNAS, 122(15), e2413709122. (www)

  @article{ , abstract = {Active regulation of gene expression, orchestrated by complex interactions of activators and repressors at promoters, controls the fate of organisms. In contrast, basal expression at uninduced promoters is considered to be a dynamically inert mode of nonfunctional “promoter leakiness,” merely a byproduct of transcriptional regulation. Here, we investigate the basal expression mode of the mar operon, the main regulator of intrinsic multiple antibiotic resistance in Escherichia coli , and link its dynamic properties to the noncanonical, yet highly conserved start codon of marR across Enterobacteriaceae . Real-time, single-cell measurements across tens of generations reveal that basal expression consists of rare stochastic gene expression pulses, which maximize variability in wildtype and, surprisingly, transiently accelerate cellular elongation rates. Competition experiments show that basal expression confers fitness advantages to wildtype across several transitions between exponential and stationary growth by shortening lag times. The dynamically rich basal expression of the mar operon has likely been evolutionarily maintained for its role in growth homeostasis of Enterobacteria within the gut environment, thereby allowing other ancillary gene regulatory roles to evolve, e.g., control of costly-to-induce multidrug efflux pumps. Understanding the complex selection forces governing genetic systems involved in intrinsic multidrug resistance is crucial for effective public health measures.}, archive = {J_PNAS}, author = {Jain, K. and Hauschild, R. and Bochkareva, O. O. and Roemhild, R. and Tkačik, G. and Guet, C. C.}, doi = {10.1073/pnas.2413709122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2413709122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pulsatile basal gene expression as a fitness determinant in bacteria}, volume = {122}, year = {2025}, }
• (2025). Transferring climate change physical knowledge. PNAS, 122(15), e2413503122. (www)

  @article{ , abstract = {Precise and reliable climate projections are required for climate adaptation and mitigation, but Earth system models still exhibit great uncertainties. Several approaches have been developed to reduce the spread of climate projections and feedbacks, yet those methods cannot capture the nonlinear complexity inherent in the climate system. Using a Transfer Learning approach, we show that Machine Learning can be used to optimally leverage and merge the knowledge gained from global temperature maps simulated by Earth system models and observed in the historical period to reduce the spread of global surface air temperature fields projected in the 21st century. We reach an uncertainty reduction of more than 50% with respect to state-of-the-art approaches while giving evidence that our method provides improved regional temperature patterns together with narrower projections uncertainty, urgently required for climate adaptation.}, archive = {J_PNAS}, author = {Immorlano, Francesco and Eyring, Veronika and le Monnier de Gouville, Thomas and Accarino, Gabriele and Elia, Donatello and Mandt, Stephan and Aloisio, Giovanni and Gentine, Pierre}, doi = {10.1073/pnas.2413503122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2413503122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transferring climate change physical knowledge}, volume = {122}, year = {2025}, }
• (2025). Melting of nonreciprocal solids: How dislocations propel and fission in flowing crystals. PNAS, 122(15), e2412993122. (www)

  @article{ , abstract = {When soft matter is driven out of equilibrium its constituents interact via effective interactions that escape Newton’s action–reaction principle. Prominent examples include the hydrodynamic interactions between colloidal particles driven in viscous fluids, phoretic interactions between chemically active colloids, and quorum-sensing interactions in bacterial colonies. Despite a recent surge of interest in nonreciprocal physics, a fundamental question remains: do nonreciprocal interactions alter or strengthen the ordered phases of matter driven out of equilibrium? Here, through a combination of experiments and simulations, we show how nonreciprocal forces propel and fission dislocations formed in hydrodynamically driven Wigner crystals. We explain how dislocation motility results in the continuous reshaping of grain-boundary networks, and how their fission reaction melts driven crystals from their interfaces. Beyond the specifics of hydrodynamics, we argue theoretically that topological defects and nonreciprocal interactions should invariably conspire to deform and ultimately destroy crystals.}, archive = {J_PNAS}, author = {Guillet, Stéphane and Poncet, Alexis and Le Blay, Marine and Irvine, William T. M. and Vitelli, Vincenzo and Bartolo, Denis}, doi = {10.1073/pnas.2412993122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2412993122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Melting of nonreciprocal solids: How dislocations propel and fission in flowing crystals}, volume = {122}, year = {2025}, }
• (2025). Indigenous knowledge as a sole data source in habitat selection functions. PNAS, 122(15), e2411946122. (www)

  @article{ , abstract = {While Indigenous Knowledge (IK) contains a wealth of information on the behavior and habitat use of species, it is rarely included in the species–habitat models frequently used by Western species management authorities. As decisions from these authorities can limit access to species that are important culturally and for subsistence, exclusion of IK in conservation and management frameworks can negatively impact both species and Indigenous communities. In partnership with Iñupiat hunters, we developed methods to statistically characterize IK of species–habitat relationships and developed models that rely solely on IK to identify species habitat use and important areas. We provide methods for different types of IK documentation and for dynamic habitat types (e.g., ice concentration). We apply the method to ringed seals (natchiq in Iñupiaq) in Alaskan waters, a stock for which the designated critical habitat has been debated in part due to minimal inclusion of IK. Our work demonstrates that IK of species–habitat relationships, with the inclusion of dynamic habitat types, expands on existing mapping approaches and provides another method to identify species habitat use and important areas. The results of this work provide a straightforward and meaningful approach to include IK in species management, especially through comanagement processes.}, archive = {J_PNAS}, author = {Gryba, Rowenna and Von Duyke, Andrew and Huntington, Henry P. and Adams, Billy and Frantz, Brower and Gatten, Justin and Harcharek, Qaiyaan and Sarren, Robert and Henry, Greg and Auger-Méthé, Marie}, doi = {10.1073/pnas.2411946122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2411946122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Indigenous knowledge as a sole data source in habitat selection functions}, volume = {122}, year = {2025}, }
• (2025). Neddylation modification stabilizes LC3B by antagonizing its ubiquitin-mediated degradation and promoting autophagy in skin. PNAS, 122(15), e2411429122. (www)

  @article{ , abstract = {The Atg8-family proteins, including LC3B (microtubule-associated protein 1 light chain 3 beta), are pivotal for key steps in the autophagy process. Proper regulation of LC3B homeostasis is essential for its function. Although LC3B is modulated by various posttranslational modifications (PTMs), the impact of these modifications on LC3B protein homeostasis remains unclear. Neddylation, a recently identified ubiquitin-like modification, plays diverse biological roles. Here, we identify LC3B as a specific target for neddylation. This modification weakens LC3B’s interaction with the ubiquitin E3 ligases VHL and BIRC6, thereby reducing LC3B ubiquitination. Depletion of ubiquitin-conjugating enzyme E2M (UBE2M), the primary E2 enzyme in the neddylation pathway, destabilizes LC3B and suppresses autophagy activity. Heterozygous Ube2m knockout ( Ube2m +/− ) mice exhibit pronounced aging-like phenotypes, with reduced LC3B expression and impaired autophagy in skin tissues. Our findings demonstrate that LC3B neddylation is vital for maintaining its stability and regulating autophagy flux, offering a potential therapeutic avenue to mitigate aging-related processes.}, archive = {J_PNAS}, author = {Xu, Linlin and Lyu, Xinxing and Wang, Yibo and Ni, Li and Li, Pin and Zeng, Piao and Wang, Qixia and Chang, Yunhao and Pan, Chenglong and Hu, Qingxia and Huang, Shuhong and Dang, Ningning}, doi = {10.1073/pnas.2411429122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2411429122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neddylation modification stabilizes LC3B by antagonizing its ubiquitin-mediated degradation and promoting autophagy in skin}, volume = {122}, year = {2025}, }
• (2025). FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis. PNAS, 122(15), e2411241122. (www)

  @article{ , abstract = {Metastasis is an inefficient process requiring cancer cells to adapt metabolically for survival and colonization in new environments. The contributions of tumor metabolic reprogramming to lymph node (LN) metastasis and its underlying mechanisms remain elusive. Through single-cell RNA sequencing, we identified rare metastasis-initiating cells (MICs) with stem-like properties that drive early LN metastasis. Integrated transcriptome, lipidomic, metabolomic, and functional analyses demonstrated that MICs depend on oxidative phosphorylation (OXPHOS) fueled by fatty acid oxidation (FAO) in the lipid-rich LN microenvironment. Mechanistically, the NRF2-SLC7A11 axis promotes glutathione synthesis to mitigate oxidative stress, thereby enhancing stress resistance and metastatic potential of MICs. Inhibition of NRF2-SLC7A11 reduced LN metastasis and sensitized tumors to cisplatin. Clinically, elevated NRF2-SLC7A11 expression was observed in tumors, with high expression correlating with LN metastasis, chemoresistance, and poor prognosis in esophageal squamous cell carcinoma (ESCC). These findings highlight the pivotal roles of FAO-fueled OXPHOS and NRF2 in LN metastasis and suggest targeting these pathways as a promising therapeutic strategy for metastatic ESCC.}, archive = {J_PNAS}, author = {Li, Shan-Shan and Zhang, Baifeng and Huang, Cuicui and Fu, Yuying and Zhao, Yuying and Gong, Lanqi and Tan, Yanan and Wang, Huali and Chen, Wenqi and Luo, Jie and Zhang, Yu and Ma, Stephanie and Fu, Li and Liu, Chenli and Huang, Jiandong and Ju, Huai-Qiang and Lee, Anne Wing-Mui and Guan, Xin-Yuan}, doi = {10.1073/pnas.2411241122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2411241122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis}, volume = {122}, year = {2025}, }
• (2025). Interactions among nutrients govern the global grassland biomass–precipitation relationship. PNAS, 122(15), e2410748122. (www)

  @article{ , abstract = {Ecosystems are experiencing changing global patterns of mean annual precipitation (MAP) and enrichment with multiple nutrients that potentially colimit plant biomass production. In grasslands, mean aboveground plant biomass is closely related to MAP, but how this relationship changes after enrichment with multiple nutrients remains unclear. We hypothesized the global biomass–MAP relationship becomes steeper with an increasing number of added nutrients, with increases in steepness corresponding to the form of interaction among added nutrients and with increased mediation by changes in plant community diversity. We measured aboveground plant biomass production and species diversity in 71 grasslands on six continents representing the global span of grassland MAP, diversity, management, and soils. We fertilized all sites with nitrogen, phosphorus, and potassium with micronutrients in all combinations to identify which nutrients limited biomass at each site. As hypothesized, fertilizing with one, two, or three nutrients progressively steepened the global biomass–MAP relationship. The magnitude of the increase in steepness corresponded to whether sites were not limited by nitrogen or phosphorus, were limited by either one, or were colimited by both in additive, or synergistic forms. Unexpectedly, we found only weak evidence for mediation of biomass–MAP relationships by plant community diversity because relationships of species richness, evenness, and beta diversity to MAP and to biomass were weak or opposing. Site-level properties including baseline biomass production, soils, and management explained little variation in biomass–MAP relationships. These findings reveal multiple nutrient colimitation as a defining feature of the global grassland biomass–MAP relationship.}, archive = {J_PNAS}, author = {Fay, Philip A. and Gherardi, Laureano A. and Yahdjian, Laura and Adler, Peter B. and Bakker, Jonathan D. and Bharath, Siddharth and Borer, Elizabeth T. and Harpole, W. Stanley and Hersch-Green, Erika and Huxman, Travis E. and MacDougall, Andrew S. and Risch, Anita C. and Seabloom, Eric W. and Bagchi, Sumanta and Barrio, Isabel C. and Biederman, Lori and Buckley, Yvonne M. and Bugalho, Miguel N. and Caldeira, Maria C. and Catford, Jane A. and Chen, QingQing and Cleland, Elsa E. and Collins, Scott L. and Daleo, Pedro and Dickman, Christopher R. and Donohue, Ian and DuPre, Mary E. and Eisenhauer, Nico and Eskelinen, Anu and Hagenah, Nicole and Hautier, Yann and Heckman, Robert W. and Jónsdóttir, Ingibjörg S. and Knops, Johannes M. H. and Laungani, Ramesh and Martina, Jason P. and McCulley, Rebecca L. and Morgan, John W. and Olde Venterink, Harry and Peri, Pablo L. and Power, Sally A. and Raynaud, Xavier and Ren, Zhengwei and Roscher, Christiane and Smith, Melinda D. and Spohn, Marie and Stevens, Carly J. and Tedder, Michelle J. and Virtanen, Risto and Wardle, Glenda M. and Wheeler, George R.}, doi = {10.1073/pnas.2410748122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2410748122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Interactions among nutrients govern the global grassland biomass–precipitation relationship}, volume = {122}, year = {2025}, }
• (2025). Inactivation of microglial LXRβ in early postnatal mice impairs microglia homeostasis and causes long-lasting cognitive dysfunction. PNAS, 122(15), e2410698122. (www)

  @article{ , abstract = {Microglia, the largest population of brain immune cells, play an essential role in regulating neuroinflammation by removing foreign materials and debris and in cognition by pruning synapses. Since liver X receptor β (LXRβ) has been identified as a regulator of microglial homeostasis, this study examined whether its removal from microglia affects neuroinflammation and cognitive function. We used a cell-specific tamoxifen-inducible Cre-loxP-mediated recombination to remove LXRβ from microglia specifically. We now report that ablation of LXRβ in microglia in early postnatal life led to a reduction in microglial numbers, distinct morphological changes indicative of microglial activation, and enhanced synapse engulfment accompanied by cognitive deficits. Removal of LXRβ from microglia in adult mice caused no cognitive defects. RNAseq analysis of microglia revealed that loss of LXRβ led to reduced expression of SAll1, a master regulator of microglial homeostasis, while increasing expression of genes associated with microglial activation and CNS disease. This study demonstrates distinctly different functions of microglial LXRβ in developing and adult mice and points to long-term consequences of defective LXRβ signaling in microglia in early life.}, archive = {J_PNAS}, author = {Lv, Keyi and Luo, Yi and Liu, Tianyao and Xia, Meiling and Gong, Hong and Zhang, Dandan and Chen, Xuan and Jiang, Xin and Liu, Yulong and Liu, Jiayin and Cai, Yulong and Antonson, Per and Warner, Margaret and Xu, Haiwei and Gustafsson, Jan-Åke and Fan, Xiaotang}, doi = {10.1073/pnas.2410698122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2410698122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inactivation of microglial LXRβ in early postnatal mice impairs microglia homeostasis and causes long-lasting cognitive dysfunction}, volume = {122}, year = {2025}, }
• (2025). Perturbing nuclear glycosylation in the mouse preimplantation embryo slows down embryonic development. PNAS, 122(15), e2410520122. (www)

  @article{ , abstract = {The main form of intracellular protein glycosylation (O-GlcNAc) is reversible and has been mapped on thousands of cytoplasmic and nuclear proteins, including RNA polymerase II, transcription factors, and chromatin modifiers. The O-GlcNAc modification is catalyzed by a single enzyme known as O-GlcNAc Transferase, that is required for mammalian early development. Yet, neither the regulatory function of protein O-GlcNAcylation in the embryo nor the embryonic O-GlcNAc proteome have been documented. Here, we devised a strategy to enzymatically remove O-GlcNAc from preimplantation embryonic nuclei, where this modification accumulates coincidently with embryonic genome activation (EGA). Unexpectedly, the depletion of nuclear O-GlcNAc to undetectable levels has no impact on EGA, but dampens the transcriptional upregulation of the translational machinery, and triggers a spindle checkpoint response. These molecular alterations were phenotypically associated with a developmental delay starting from early cleavage stages and persisting after embryo implantation, establishing a link between nuclear glycosylation and the pace of embryonic development.}, archive = {J_PNAS}, author = {Formichetti, Sara and Serrano, Joana B. and Chitnavis, Urvashi and Sadowska, Agnieszka and Liu, Na and Boskovic, Ana and Boulard, Matthieu}, doi = {10.1073/pnas.2410520122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2410520122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Perturbing nuclear glycosylation in the mouse preimplantation embryo slows down embryonic development}, volume = {122}, year = {2025}, }
• (2025). Whole-brain white matter variation across childhood environments. PNAS, 122(15), e2409985122. (www)

  @article{ , abstract = {White matter develops over the course of childhood in an experience-dependent manner. However, its role in the relationship between the early environment and later cognition is unclear, in part due to focus on changes in specific gray matter regions. This study examines white matter differences across adolescents from diverse environments, evaluating both their extent throughout the brain and their contribution to cognitive outcomes. Using data from the Adolescent Brain Cognitive Development (ABCD) study (N = 9,082, female = 4,327), we found extensive cross-sectional associations with lower white matter fractional anisotropy (FA) and streamline count in the brains of 9- and 10-y-old children exposed to a range of experiences, including prenatal risk factors, interpersonal adversity, household economic deprivation, and neighborhood adversity. Lower values of FA were associated with later difficulties with mental arithmetic and receptive language. Furthermore, white matter FA partially mediated the detrimental relationship between adversity and cognition later in adolescence. These findings advance a white matter-based account of the neural and cognitive effects of adversity, which supports leading developmental theories that place interregional connectivity prior to gray matter maturation.}, archive = {J_PNAS}, author = {Carozza, Sofia and Kletenik, Isaiah and Astle, Duncan and Schwamm, Lee and Dhand, Amar}, doi = {10.1073/pnas.2409985122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2409985122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Whole-brain white matter variation across childhood environments}, volume = {122}, year = {2025}, }
• (2025). SRP19 and the protein secretion machinery is a targetable vulnerability in cancers with APC loss. PNAS, 122(15), e2409677122. (www)

  @article{ , abstract = {Loss of the tumor suppressor gene (TSG) Adenomatous Polyposis Coli ( APC ) is a hallmark event in colorectal cancers. Since it is not possible to directly target a TSG, no treatment options are available for these patients. Here, we identify SRP19 and the protein secretion machinery as a unique vulnerability in cancers with heterozygous APC loss. SRP19 is located 15 kb from APC and is almost always codeleted in these tumors. Heterozygous APC/SRP19 loss leads to lower levels of SRP19 mRNA and protein. Consequently, cells with APC/SRP19 loss are vulnerable to partial suppression of SRP19 . Moreover, we show that SRP19 is rate limiting for the formation of the Signal Recognition Particle, a complex that mediates ER-protein translocation, and thus, heterozygous SRP19 loss leads to less protein secretion and higher levels of ER-stress. As a result, low-dose arsenic trioxide induces ER-stress and inhibits proliferation in cultured cell lines and animal models. Our work identifies a strategy to treat cancers with APC deletion and provides a framework for identifying and translating vulnerabilities associated with loss of a TSG.}, archive = {J_PNAS}, author = {Xi, Xinqi and Liu, Ling and Tuano, Natasha and Tailhades, Julien and Mouradov, Dmitri and Steen, Jason and Sieber, Oliver and Cryle, Max and Nguyen-Dumont, Tu and Segelov, Eva and Rosenbluh, Joseph}, doi = {10.1073/pnas.2409677122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2409677122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SRP19 and the protein secretion machinery is a targetable vulnerability in cancers with APC loss}, volume = {122}, year = {2025}, }
• (2025). Activity of spinal RORβ neurons is related to functional improvements following combination treatment after complete SCI. PNAS, 122(15), e2406333122. (www)

  @article{ , abstract = {Various strategies targeting spinal locomotor circuitry have been associated with functional improvements after spinal cord injury (SCI). However, the neuronal populations mediating beneficial effects remain largely unknown. Using a combination therapy in a mouse model of complete SCI, we show that virally delivered brain-derived neurotrophic factor (BDNF) (AAV-BDNF) activates hindlimb stepping and causes hyperreflexia, whereas submotor threshold epidural stimulation (ES) reduces BDNF-induced hyperreflexia. Given their role in gating proprioceptive afferents and as a potential convergence point of BDNF and ES, we hypothesized that an enhanced excitability of inhibitory RORβ neurons would be associated with locomotor improvements. Ex vivo spinal slice recordings from mice with a range of locomotor and hyperreflexia scores revealed that the excitability of RORβ neurons was related to functional outcome post-SCI. Mice with poor locomotor function after SCI had less excitable RORβ neurons, but the excitability of RORβ neurons was similar between the uninjured and “best stepping” SCI groups. Further, chemogenetic activation of RORβ neurons reduced BDNF-induced hyperreflexia and improved stepping, similar to ES. Our findings identify inhibitory RORβ neurons as a target population to limit hyperreflexia and enhance locomotor function after SCI.}, archive = {J_PNAS}, author = {Stachowski, Nicholas J. and Wheel, Jaimena H. and Singh, Shayna and Atoche, Sebastian J. and Yao, Lihua and Garcia-Ramirez, D. Leonardo and Giszter, Simon F. and Dougherty, Kimberly J.}, doi = {10.1073/pnas.2406333122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2406333122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Activity of spinal RORβ neurons is related to functional improvements following combination treatment after complete SCI}, volume = {122}, year = {2025}, }
• (2025). Chemically active wetting. PNAS, 122(15), e2403083122. (www)

  @article{ , abstract = {Wetting of liquid droplets on passive surfaces is ubiquitous in our daily lives, and the governing physical laws are well understood. When surfaces become active, however, the governing laws of wetting remain elusive. Here, we propose chemically active wetting as a class of active systems where the surface is active due to a binding process that is maintained away from equilibrium. We derive the corresponding nonequilibrium thermodynamic theory and show that active binding fundamentally changes the wetting behavior, leading to steady, nonequilibrium states with droplet shapes reminiscent of a pancake or a mushroom. The origin of such anomalous shapes can be explained by mapping to electrostatics, where pairs of binding sinks and sources correspond to electrostatic dipoles along the triple line. This is an example of a more general analogy, where localized chemical activity gives rise to a multipole field of the chemical potential. The underlying physics is relevant for cells, where droplet-forming proteins can bind to membranes accompanied by the turnover of biological fuels.}, archive = {J_PNAS}, author = {Liese, Susanne and Zhao, Xueping and Weber, Christoph A. and Jülicher, Frank}, doi = {10.1073/pnas.2403083122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2403083122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chemically active wetting}, volume = {122}, year = {2025}, }
• (2025). Downregulation of nesprin1 by runx2 deficiency is critical for the development of skeletal laminopathy-like pathology. PNAS, 122(15), e2320138122. (www)

  @article{ , abstract = {Runx2 is a master regulator of bone formation, and its dysfunction causes cleidocranial dysplasia (CCD) in humans. When iPS cells were generated from patients with CCD and Runx2-deficient iPS cells were generated using gene-editing techniques, abnormal laminopathy-like nuclei were observed. Runx2-deficient cells showed reduced Lamin A/C expression, but not protein levels. However, in Runx2-deficient cells, both the gene expression and protein levels of Nesprin1 were reduced, perinuclear actin fibers were sparser, and nuclear stiffness was reduced. Forced expression of Lamin A/C increased nuclear stiffness but did not improve nuclear morphology. In contrast, the induction of Nesprin1 expression alone normalized nuclear stiffness and restored nuclear morphology and perinuclear actin distribution. In Runx2-null cells, mechanical stress-induced phosphorylation of emerin was not observed. In contrast, forced expression of Nesprin1 in Runx2-null cells resulted in phosphorylation of emerin, indicating the restoration of intracellular tension. These observations were confirmed by atomic force microscopy. Therefore, the intracellular tension was inferred to pull the nuclear membrane into its normal shape. CUT&RUN assay and single RNA-seq analysis showed that an aberrant nuclear membrane caused loss of nuclear lamina gene regulation machinery, making the progression of normal osteogenic differentiation impossible; however, supplementation with Nesprin1 restored gene regulation mechanisms and promoted preosteoblast formation with normal nuclear morphology. Nesprin1 expression induced by Runx2 is essential for epigenetic regulation of the nuclear lamina. We propose CCD as a type of laminopathy involving defective expression of Nesprin1 regulated by Runx2.}, archive = {J_PNAS}, author = {Saito, Akiko and Nagayama, Kazuaki and Okada, Hiroyuki and Onodera, Shoko and Aida, Natsuko and Nakamura, Takashi and Sawada, Takashi and Hojo, Hironori and Kato, Shigeaki and Azuma, Toshifumi}, doi = {10.1073/pnas.2320138122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2320138122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Downregulation of nesprin1 by runx2 deficiency is critical for the development of skeletal laminopathy-like pathology}, volume = {122}, year = {2025}, }
• (2025). Richardson’s law and the origins of alcohol research. PNAS, 122(15), e2318863122. (www)

  @article{ , abstract = {Interest in the biological actions of alcohols, ethanol in particular, dates back to the earliest historical texts. Alcohol research is now a highly active field with roots in physiology, pharmacology, toxicology, and neuroscience. But at what point did interest and speculation evolve into bona fide science? Here, we set out to identify the earliest systematic empirical investigations into the biological actions of alcohols and unearthed a surprisingly rigorous literature which included a fundamental insight with significant implications for modern research and policy. Through manual backward citation mapping of archived texts, much of which was digitally inaccessible, we outline the origins of alcohol research beginning with a transcribed lecture from Benjamin Ward Richardson in 1869. In the years immediately following, the field of alcohol research was legitimized around what came to be briefly known as “Richardson’s law.” Richardson’s law states that the acute toxicity of straight-chain monohydroxy alcohols is directly proportional to the carbon chain length of the molecule. This law was recognized only briefly not because it was disproven, but rather because it was simply forgotten during the decades that passed between its inception and the advent of systematic bibliographic databases which paved the way for digital archiving. Quantitative analysis of studies spanning a century revealed that across monohydroxy alcohols with one (methanol) to thirteen (tridecanol) carbons, there is a near-deterministic relationship between chain-length and lethal dose (R 2 = 0.96). Richardson’s law of alcohol potency has silently stood the test of time and is among functional biology’s oldest and least challenged scientific laws.}, archive = {J_PNAS}, author = {Mukerjee, Snigdha and Siciliano, Cody A.}, doi = {10.1073/pnas.2318863122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {15}, pages = {e2318863122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Richardson’s law and the origins of alcohol research}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(14), eiti1425122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti1425122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {eiti1425122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Digital phenotyping using smartphones could help steer mental health treatment. PNAS, 122(14), e2505700122. (www)

  @article{ , archive = {J_PNAS}, author = {Adam, David}, doi = {10.1073/pnas.2505700122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2505700122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Digital phenotyping using smartphones could help steer mental health treatment}, volume = {122}, year = {2025}, }
• (2025). QnAs with inara s. tareque, jorge guzman, and dan j. wang. PNAS, 122(14), e2505341122. (www)

  @article{ , archive = {J_PNAS}, author = {Hardcastle, Matthew}, doi = {10.1073/pnas.2505341122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2505341122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {QnAs with inara s. tareque, jorge guzman, and dan j. wang}, volume = {122}, year = {2025}, }
• (2025). Correction for benn et al., phase separation in the outer membrane of escherichia coli. PNAS, 122(14), e2505082122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2505082122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2505082122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for benn et al., phase separation in the outer membrane of escherichia coli}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for chakraborty et al., cryo-ET suggests tubulin chaperones form a subset of microtubule lumenal particles with a role in maintaining neuronal microtubules. PNAS, 122(14), e2505071122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2505071122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2505071122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for chakraborty et al., cryo-ET suggests tubulin chaperones form a subset of microtubule lumenal particles with a role in maintaining neuronal microtubules}, volume = {122}, year = {2025}, }
• (2025). Correction for jenewein et al., concomitant formation of protocells and prebiotic compounds under a plausible early earth atmosphere. PNAS, 122(14), e2505069122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2505069122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2505069122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for jenewein et al., concomitant formation of protocells and prebiotic compounds under a plausible early earth atmosphere}, volume = {122}, year = {2025}, }
• (2025). Correction for singh et al., structural and functional dynamics of human cone cGMP-phosphodiesterase important for photopic vision. PNAS, 122(14), e2505043122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2505043122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2505043122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for singh et al., structural and functional dynamics of human cone cGMP-phosphodiesterase important for photopic vision}, volume = {122}, year = {2025}, }
• (2025). Correction for pitzen et al., comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer. PNAS, 122(14), e2504762122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504762122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2504762122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for pitzen et al., comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for ikeda et al., seesaw protein: Design of a protein that adopts interconvertible alternative functional conformations and its dynamics. PNAS, 122(14), e2504749122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504749122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2504749122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for ikeda et al., seesaw protein: Design of a protein that adopts interconvertible alternative functional conformations and its dynamics}, volume = {122}, year = {2025}, }
• (2025). Correction for zhu et al., asymmetric arginine dimethylation of cytosolic RNA and DNA sensors by PRMT3 attenuates antiviral innate immunity. PNAS, 122(14), e2504746122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504746122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2504746122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for zhu et al., asymmetric arginine dimethylation of cytosolic RNA and DNA sensors by PRMT3 attenuates antiviral innate immunity}, volume = {122}, year = {2025}, }
• (2025). Correction for kuan et al., behavioral nudges prevent loan delinquencies at scale: A 13-million-person field experiment. PNAS, 122(14), e2504666122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504666122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2504666122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for kuan et al., behavioral nudges prevent loan delinquencies at scale: A 13-million-person field experiment}, volume = {122}, year = {2025}, }
• (2025). Peto’s paradox revisited (revisited, revisited, revisited, and revisited yet again). PNAS, 122(14), e2502696122. (www)

  @article{ , archive = {J_PNAS}, author = {Lynch, Vincent J.}, doi = {10.1073/pnas.2502696122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2502696122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Peto’s paradox revisited (revisited, revisited, revisited, and revisited yet again)}, volume = {122}, year = {2025}, }
• (2025). Bilateral astrocyte reaction to unilateral insult in the optic projection to the brain. PNAS, 122(14), e2502602122. (www)

  @article{ , archive = {J_PNAS}, author = {Holden, Joseph M. and Calkins, David J.}, doi = {10.1073/pnas.2502602122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2502602122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bilateral astrocyte reaction to unilateral insult in the optic projection to the brain}, volume = {122}, year = {2025}, }
• (2025). DNA bending mediated by ORC is essential for replication licensing in budding yeast. PNAS, 122(14), e2502277122. (www)

  @article{ , abstract = {In eukaryotes, the origin recognition complex (ORC) promotes the assembly of minichromosome maintenance 2 to 7 complexes into a head-to-head double hexamer at origin DNA in a process known as replication licensing. In this study, we present a series of cryoelectron microscopy structures of yeast ORC mutants in complex with origin DNA. We show that Orc6, the smallest subunit of ORC, utilizes its transcription factor II B-B domain to orchestrate the sequential binding of ORC to origin DNA. In addition, Orc6 plays the role of a scaffold by stabilizing the basic patch (BP) of Orc5 for ORC to capture and bend origin DNA. Importantly, disrupting DNA bending through mutating three key residues in Orc5-BP impairs ORC’s ability to promote replication initiation at two points during the pre-RC assembly process. This study dissects the multifaceted role of Orc6 in orchestrating ORC’s activities on DNA and underscores the vital role of DNA bending by ORC in replication licensing.}, archive = {J_PNAS}, author = {Lam, Wai Hei and Yu, Daqi and Zhang, Qiongdan and Lin, Yuhan and Li, Ningning and Li, Jian and Wu, Yue and Zhang, Yingyi and Gao, Ning and Tye, Bik Kwoon and Zhai, Yuanliang and Dang, Shangyu}, doi = {10.1073/pnas.2502277122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2502277122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {DNA bending mediated by ORC is essential for replication licensing in budding yeast}, volume = {122}, year = {2025}, }
• (2025). A conserved ARF–DNA interface underlies auxin-triggered transcriptional response. PNAS, 122(14), e2501915122. (www)

  @article{ , abstract = {Auxin Response Factor (ARF) plant transcription factors are the key effectors in auxin signaling. Their DNA-Binding Domain (DBD) contains a B3 domain that allows base-specific interactions with Auxin Response Elements (AuxREs) in DNA target sites. Land plants encode three phylogenetically distinct ARF classes: the closely related A- and B-classes have overlapping DNA binding properties, contrasting with the different DNA-binding properties of the divergent C-class ARFs. ARF DNA-binding divergence likely occurred early in the evolution of the gene family, but the molecular determinants underlying it remain unclear. Here, we show that the B3 DNA-binding residues are deeply conserved in ARFs, and variability within these is only present in tracheophytes, correlating with greatly expanded ARF families. Using the liverwort Marchantia polymorpha , we confirm the essential role of conserved DNA-contacting residues for ARF function. We further show that ARF B3–AuxRE interfaces are not mutation-tolerant, suggesting low evolvability that has led to the conservation of the B3–DNA interface between ARF classes. Our data support the almost complete interchangeability between A/B-class ARF B3 by performing interspecies domain swaps in M. polymorpha , even between ARF lineages that diverged over half a billion years ago. Our analysis further suggests that C-class ARF DNA-binding specificity diverged early during ARF evolution in a common streptophyte ancestor, followed by strong selection in A and B-class ARFs as part of a competition-based auxin response system.}, archive = {J_PNAS}, author = {Rienstra, Juriaan and Carrillo-Carrasco, Vanessa Polet and de Roij, Martijn and Hernandez-Garcia, Jorge and Weijers, Dolf}, doi = {10.1073/pnas.2501915122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2501915122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A conserved ARF–DNA interface underlies auxin-triggered transcriptional response}, volume = {122}, year = {2025}, }
• (2025). Painting rich six-dimensional pictures using polarized fluorescence microscopy. PNAS, 122(14), e2501914122. (www)

  @article{ , archive = {J_PNAS}, author = {Lew, Matthew D.}, doi = {10.1073/pnas.2501914122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2501914122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Painting rich six-dimensional pictures using polarized fluorescence microscopy}, volume = {122}, year = {2025}, }
• (2025). Reply to falkingham et al.: Trackway shows flap-running in feathered dinosaurs. PNAS, 122(14), e2501832122. (www)

  @article{ , archive = {J_PNAS}, author = {Dececchi, T. Alexander and Kim, Kyung Soo and Lockley, Martin G. and Larsson, Hans C. E. and Holtz, Thomas H. and Farlow, James O. and Pittman, Michael}, doi = {10.1073/pnas.2501832122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2501832122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to falkingham et al.: Trackway shows flap-running in feathered dinosaurs}, volume = {122}, year = {2025}, }
• (2025). Removing masculine defaults in the hiring process. PNAS, 122(14), e2501630122. (www)

  @article{ , archive = {J_PNAS}, author = {Cheryan, Sapna and Muragishi, Gregg A.}, doi = {10.1073/pnas.2501630122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2501630122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Removing masculine defaults in the hiring process}, volume = {122}, year = {2025}, }
• (2025). MicroRNA-218-5p coordinates scaling of excitatory and inhibitory synapses during homeostatic synaptic plasticity. PNAS, 122(14), e2500880122. (www)

  @article{ , abstract = {Homeostatic synaptic plasticity (HSP) is a neuronal mechanism that allows networks to compensate for prolonged changes in activity by adjusting synaptic strength. This process is crucial for maintaining stable brain function and has been implicated in memory consolidation during sleep. While scaling of both excitatory and inhibitory synapses plays an important role during homeostatic synaptic plasticity, molecules coordinating these processes are unknown. In this study, we investigate the role of miR-218-5p as a regulator of inhibitory and excitatory synapses in the context of picrotoxin (PTX)-induced homeostatic synaptic downscaling (HSD) in rat hippocampal neurons. Using enrichment analysis of microRNA-binding sites in genes changing upon PTX-induced HSD, we bioinformatically predict and experimentally validate increased miR-218-5p activity upon PTX treatment. By electrophysiological recordings and confocal microscopy, we demonstrate that inhibiting miR-218-5p activity exerts a dual effect during HSD: It occludes the downscaling of excitatory synapses and dendritic spines, while at the same time attenuating inhibitory synapse upscaling. Furthermore, we identify the Neuroligin2 interacting molecule Mdga1 as a direct miR-218-5p target which potentially mediates the effect of miR-218-5p on homeostatic upscaling of inhibitory synapses. By performing long-term electroencephalographic recordings, we further reveal that local inhibition of miR-218-5p in the somatosensory cortex reduces local slow-wave activity during non-rapid-eye-movement sleep. In summary, this study uncovers miR-218-5p as a key player in coordinating inhibitory and excitatory synapses during homeostatic plasticity and sleep. Our findings contribute to a deeper understanding of how neural circuits maintain stability in the face of activity-induced perturbations, with implications for pathophysiology.}, archive = {J_PNAS}, author = {Colameo, David and Maley, Sara M. and Winterer, Jochen and ElGrawani, Waleed and Gilardi, Carlotta and Galkin, Simon and Fiore, Roberto and Brown, Steven A. and Schratt, Gerhard}, doi = {10.1073/pnas.2500880122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2500880122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MicroRNA-218-5p coordinates scaling of excitatory and inhibitory synapses during homeostatic synaptic plasticity}, volume = {122}, year = {2025}, }
• (2025). Quirks of track preservation and formation are more likely than pre-avian flight and ultrafast dinosaurs. PNAS, 122(14), e2500877122. (www)

  @article{ , archive = {J_PNAS}, author = {Falkingham, Peter L. and Lallensack, Jens N.}, doi = {10.1073/pnas.2500877122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2500877122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quirks of track preservation and formation are more likely than pre-avian flight and ultrafast dinosaurs}, volume = {122}, year = {2025}, }
• (2025). Design of a halogen bond catalyzed DNA endonuclease. PNAS, 122(14), e2500099122. (www)

  @article{ , abstract = {In this study, we expand the repertoire of biological catalysts by showing that a halogen bond (X-bond) can functionally replace the magnesium (Mg 2+ ) cofactor in mouse endonuclease G ( m EndoG). We mutated the metal coordinating glutamate E136 in m EndoG to a meta- halotyrosine ( m X Y, X = chlorine or iodine) to form a m X Y- m EndoG construct that is both acid and base catalyzed. Under basic conditions, the enzyme is inactivated by the metal chelator ethylene diamine tetraacetic acid (EDTA), indicating that the halogen substituent facilitates deprotonation of the tyrosyl hydroxyl group, allowing recruitment of Mg 2+ to restore the metal-dependent catalytic center. At low pHs, we observe that the m X Y- m EndoG is resistant to EDTA inactivation and that the iodinated constructed is significantly more active than the chlorinated analogue. These results implicate a hydrogen bond (H-bond) enhanced X-bond as the catalyst in the m X Y- m EndoG, with asparagine N103 serving as the H-bond donor that communicates the protonation state of histidine H104 to the halogen. This model is supported by mutation studies and electrostatic potential (ESP) calculations on models for the protonated and unprotonated m X Y···N103···H104 system compared to the Mg 2+ coordination complex of the wild type. Thus, we have designed and engineered an enzyme that utilizes an unnatural catalyst in its active site—a catalytic X-bonding enzyme, or cX- Zyme—by controverting what constitutes a metal catalyst in biochemistry.}, archive = {J_PNAS}, author = {Walker, Margaret G. and Mendez, Cesar Gustavo and Ho, Alexander N. and Czarny, Ryan S. and Rappé, Anthony K. and Ho, Pui Shing}, doi = {10.1073/pnas.2500099122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2500099122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Design of a halogen bond catalyzed DNA endonuclease}, volume = {122}, year = {2025}, }
• (2025). Therapeutic targeting of the NOTCH1 and neddylation pathways in t cell acute lymphoblastic leukemia. PNAS, 122(14), e2426742122. (www)

  @article{ , abstract = {Gamma Secretase Inhibitors (GSIs) effectively block oncogenic Notch homolog-1 (NOTCH1), a characteristic feature of T cell acute lymphoblastic leukemias (T-ALL). However, their clinical application has been stalled by the induction of severe gastrointestinal toxicity resulting from the inhibition of NOTCH signaling in the gut, which translates into increased goblet cell differentiation. Genome-wide CRISPR loss-of-function screen in the colon cancer cell line LS174T identified the neddylation pathway as a main regulator of goblet cell differentiation upon NOTCH1 inhibition. Consistently, pharmacologic inhibition of the neddylation pathway with the small molecule inhibitor MLN4924, rescued GSI-induced differentiation in LS174T cells. Mechanistically, neddylation inhibition by MLN4924 increases the protein stability of Hairy and enhancer of split-1, a direct NOTCH1 transcriptional target and key regulator of absorptive and secretory cell fate decisions. Combined treatment with GSI and MLN4924 in a murine Notch1 -dependent model of T-ALL led to leukemia regression and improved overall survival in the absence of gut toxicity. Overall, these results support the combined targeting of the NOTCH1 and neddylation pathways for the treatment of NOTCH1-induced T-ALL.}, archive = {J_PNAS}, author = {Bertulfo, Kalay and Perez-Duran, Pablo and Miller, Hannah and Ma, Cindy and Ambesi-Impiombato, Alberto and Samon, Jeremy and Mackey, Adam and Lin, Wen-Hsuan Wendy and Ferrando, Adolfo A. and Palomero, Teresa}, doi = {10.1073/pnas.2426742122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2426742122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Therapeutic targeting of the NOTCH1 and neddylation pathways in t cell acute lymphoblastic leukemia}, volume = {122}, year = {2025}, }
• (2025). Reply to brown et al.: Significant sex differences in accelerated cortical thinning associated with the COVID-19 lockdowns. PNAS, 122(14), e2426640122. (www)

  @article{ , archive = {J_PNAS}, author = {Corrigan, Neva M. and Rokem, Ariel and Kuhl, Patricia K.}, doi = {10.1073/pnas.2426640122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2426640122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to brown et al.: Significant sex differences in accelerated cortical thinning associated with the COVID-19 lockdowns}, volume = {122}, year = {2025}, }
• (2025). Single cell–resolved cellular, transcriptional, and epigenetic changes in mouse t cell populations linked to age-associated immune decline. PNAS, 122(14), e2425992122. (www)

  @article{ , abstract = {Splenic T cells are pivotal to the immune system, yet their function deteriorates with age. To elucidate the specific aspects of T cell biology affected by aging, we conducted a comprehensive multi–time point single-cell RNA sequencing study, complemented by single-cell Assay for Transposase Accessible Chromatin (ATAC) sequencing and single-cell T cell repertoire (TCR) sequencing on splenic T cells from mice across 10 different age groups. This map of age-related changes in the distribution of T cell lineages and functional states reveals broad changes in T cell function and composition, including a prominent enrichment of Gzmk+ T cells in aged mice, encompassing both CD4+ and CD8+ T cell subsets. Notably, there is a marked decrease in TCR diversity across specific T cell populations in aged mice. We identified key pathways that may underlie the perturbation of T cell functions with aging, supporting cytotoxic T cell clonal expansion with age. This study provides insights into the aging process of splenic T cells and also highlights potential targets for therapeutic intervention to enhance immune function in the elderly. The dataset should serve as a resource for further research into age-related immune dysfunction and for identifying potential therapeutic strategies.}, archive = {J_PNAS}, author = {He, Jing and Burova, Elena and Taduriyasas, Chandrika and Ni, Min and Adler, Christina and Wei, Yi and Negron, Nicole and Xiong, Kun and Bai, Yu and Shavlakadze, Tea and Ioffe, Ella and Lin, John C. and Ferrando, Adolfo and Glass, David J.}, doi = {10.1073/pnas.2425992122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2425992122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Single cell–resolved cellular, transcriptional, and epigenetic changes in mouse t cell populations linked to age-associated immune decline}, volume = {122}, year = {2025}, }
• (2025). Searching permutations for constructing uniformly distributed point sets. PNAS, 122(14), e2424464122. (www)

  @article{ , abstract = {Uniformly distributed point sets of low discrepancy are heavily used in experimental design and across a very wide range of applications such as numerical integration, computer graphics, and finance. Recent methods based on Graph Neural Networks [T. K. Rusch, N. Kirk, M. M. Bronstein, C. Lemieux, D. Rus, Proc. Natl. Acad. Sci. U.S.A. 121, e2409913121 (2024).] and solver-based optimization identified point sets having much lower discrepancy than previously known constructions. We show in this note that further substantial improvements are possible by separating the construction of low-discrepancy point sets into i) the relative position of the points, and ii) the optimal placement respecting these relationships. Using tailored permutations, we construct point sets that are of 20% smaller discrepancy on average than those proposed by Rusch et al. In terms of inverse discrepancy, our sets reduce the number of points in dimension 2 needed to obtain a discrepancy of 0.005 from more than 500 points to less than 350. For applications where the sets are used to query time-consuming models, this is a significant reduction.}, archive = {J_PNAS}, author = {Clément, François and Doerr, Carola and Klamroth, Kathrin and Paquete, Luís}, doi = {10.1073/pnas.2424464122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2424464122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Searching permutations for constructing uniformly distributed point sets}, volume = {122}, year = {2025}, }
• (2025). Microparticle impact–induced bond strength in metals peaks with velocity. PNAS, 122(14), e2424355122. (www)

  @article{ , abstract = {Supersonic impact of metallic microparticles onto metallic substrates generates extreme interfacial deformation and high contact pressures, enabling solid-state metallic bonding. Although higher impact velocities are generally believed to improve bond quality and mechanical properties in materials formed by supersonic impact deposition, here we report a peak in bond strength for single microparticle impact bonding, followed by a decline at higher impact velocities. Our in situ micromechanical measurements of interfacial strength for Al microparticles bonded to Al substrates reveal a three-fold increase from the critical bonding velocity (800 m/s) to a peak strength around 1,060 m/s. Interestingly, further increase in impact velocity results in a rapid decline in local interfacial strength. The decline continues up to the highest velocity studied, 1,337 m/s, which is well below the threshold required to induce melting or erosion. We show that a mechanistic transition from material strengthening to intensified elastic recovery is responsible for the peak strength in impact-induced bonding, with evidence linking the intensified elastic recovery to adiabatic softening at high impact velocities. Beyond 1,000 m/s for Al, interfacial damage induced by the intensified elastic recovery offsets the strength gain from higher impact velocities, resulting in a net decline in interfacial strength. This mechanistic understanding shall offer insights into the optimal design of processes that rely on impact bonding.}, archive = {J_PNAS}, author = {Tang, Qi and Ichikawa, Yuji and Hassani, Mostafa}, doi = {10.1073/pnas.2424355122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2424355122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Microparticle impact–induced bond strength in metals peaks with velocity}, volume = {122}, year = {2025}, }
• (2025). Colony pattern multistability emerges from a bistable switch. PNAS, 122(14), e2424112122. (www)

  @article{ , abstract = {Microbial colony development hinges upon a myriad of factors, including mechanical, biochemical, and environmental niches, which collectively shape spatial patterns governed by intricate gene regulatory networks. The inherent complexity of this phenomenon necessitates innovative approaches to comprehend and compare the mechanisms driving pattern formation. Here, we unveil the multistability of bacterial colony patterns, where bacterial colony patterns can stabilize into multiple distinct types including ring-like patterns and sector-like patterns on hard agar, orchestrated by a simple synthetic bistable switch. Utilizing quantitative imaging and spatially resolved transcriptome approaches, we explore the deterministic process of a ring-like colony pattern formation from a single cell. This process is primarily driven by bifurcation events programmed by the gene regulatory network and microenvironmental cues. Additionally, we observe a noise-induced process amplified by the founder effect, leading to patterns of symmetry-break during range expansion. The degrees of asymmetry are profoundly influenced by the initial conditions of single progenitor cells during the nascent stages of colony development. These findings underscore how the process of range expansion enables individual cells, exposed to a uniform growth-promoting environment, to exhibit inherent capabilities in generating emergent, self-organized behavior.}, archive = {J_PNAS}, author = {Chu, Pan and Zhu, Jingwen and Ma, Zhixin and Fu, Xiongfei}, doi = {10.1073/pnas.2424112122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2424112122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Colony pattern multistability emerges from a bistable switch}, volume = {122}, year = {2025}, }
• (2025). Nuclear galectin-1 promotes KRAS-dependent activation of pancreatic cancer stellate cells. PNAS, 122(14), e2424051122. (www)

  @article{ , abstract = {Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, primarily due to its complex tumor microenvironment (TME), which drives both disease progression and therapy resistance. Understanding the molecular mechanisms governing TME dynamics is essential for developing new treatment strategies for this devastating disease. In this study, we uncover an oncogenic role for Galectin-1 (Gal1), a glycan-binding protein abundantly expressed by activated pancreatic stellate cells (PSCs), a key component of the PDAC TME that orchestrates tumor progression. Our findings reveal that Gal1 expression is elevated in the nucleus of human PSCs in both tissue samples and cultured cell lines. Using chromatin immunoprecipitation followed by sequencing analysis (ChIP-seq), we identify Gal1 occupancy at the promoters of several cancer-associated genes, including KRAS , a pivotal oncogene involved in PDAC pathogenesis. We demonstrate that Gal1 binds to the KRAS promoter, sustaining KRAS expression in PSCs, which, in turn, maintains PSC activation and promotes the secretion of protumorigenic cytokines. Mechanistically, Gal1 is required to preserve histone H3 lysine 4 monomethylation levels and to recruit the histone methyltransferase MLL1 to target promoters. Collectively, our findings define a nuclear function of Gal1 in modulating the transcriptional landscape of cancer-associated genes in PSCs within the PDAC TME, mediated through an epigenetic mechanism. These insights enhance our understanding of PDAC pathology and open potential avenues for therapeutic interventions targeting intracellular Gal1.}, archive = {J_PNAS}, author = {Vinaixa, Judith and Martínez-Bosch, Neus and Gibert, Joan and Manero-Rupérez, Noemí and Santofimia-Castaño, Patricia and Baudou, Federico G. and Vera, Renzo E. and Pease, David R. and Iglesias, Mar and Sen, Sandhya and Wang, Xiyin and Almada, Luciana L. and Marks, David L. and Moreno, Mireia and Iovanna, Juan L. and Rabinovich, Gabriel A. and Fernandez-Zapico, Martin E. and Navarro, Pilar}, doi = {10.1073/pnas.2424051122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2424051122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nuclear galectin-1 promotes KRAS-dependent activation of pancreatic cancer stellate cells}, volume = {122}, year = {2025}, }
• (2025). Cryo-EM structure of cyanopodophage a4 reveals a pentameric pre-ejectosome in the double-stabilized capsid. PNAS, 122(14), e2423403122. (www)

  @article{ , abstract = {Upon infection, the podophages usually eject a couple of proteins from the capsid to form a transmembrane ejectosome on the host cell membrane that facilitates the ejection of viral genome. However, it remains unclear how these proteins of pre-ejectosome are finely assembled at the center of highly packaged genome. Here, we report the intact structure of Anabaena cyanopodophage A4, which consists of a capsid stabilized by two types of cement proteins and a short tail attached with six tail fibers. Notably, we find a pentameric pre-ejectosome at the core of capsid, which is composed of four ejection proteins wrapped into a coaxial cylinder of triple layers. Moreover, a segment of genomic DNA runs along the positively charged circular cleft formed by two ejection proteins. Based on the mortise-and-tenon architecture of pre-ejectosome in combination with previous studies, we propose a putative DNA packaging process and ejection mechanism for podophages. These findings largely enrich our knowledge on the assembly mechanism of podophages, which might facilitate the application of A4 as a chassis cyanophage in synthetic biology.}, archive = {J_PNAS}, author = {Hou, Pu and Zhou, Rui-Qian and Jiang, Yong-Liang and Yu, Rong-Cheng and Du, Kang and Gan, Nanqin and Ke, Fei and Zhang, Qi-Ya and Li, Qiong and Zhou, Cong-Zhao}, doi = {10.1073/pnas.2423403122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2423403122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryo-EM structure of cyanopodophage a4 reveals a pentameric pre-ejectosome in the double-stabilized capsid}, volume = {122}, year = {2025}, }
• (2025). Unbalanced growth and land overvaluation. PNAS, 122(14), e2423295122. (www)

  @article{ , abstract = {Historical trends suggest the decline in the importance of land as a production factor, as evidenced by the decline in the employment and gross domestic product (GDP) shares of land-intensive industries. However, land continues to be a prominent store of value, as over half of household wealth in major countries is real estate. To explain this apparent disconnection between land output and land value, in a plausible economic model with land and aggregate risk, we theoretically study the long-run behavior of land prices and identify economic conditions under which land becomes overvalued relative to the fundamentals defined by the present value of land rents. Unbalanced growth together with the elasticity of substitution between production factors plays a critical role. We establish the Land Overvaluation Theorem: When the elasticity of substitution between land and nonland factors exceeds 1 (which is natural because we can create more space by constructing taller buildings with fixed land) and technological progress is faster in nonland sectors, land overvaluation necessarily emerges. As applications of the Theorem, we present three examples: i) land overvaluation emerges along the long-run transition from the Malthusian agricultural economy to the modern knowledge- and service-based economy; ii) with aggregate uncertainty, land prices exhibit recurrent stochastic fluctuations around the trend, with expansions and contractions in the size of land overvaluation; and iii) in modern economies, land use is also changing and urban land has high value. We present a model of urban land prices and show that land overvaluation emerges in the process of urban formation characterized by unbalanced growth.}, archive = {J_PNAS}, author = {Hirano, Tomohiro and Toda, Alexis Akira}, doi = {10.1073/pnas.2423295122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2423295122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unbalanced growth and land overvaluation}, volume = {122}, year = {2025}, }
• (2025). AcrIE7 inhibits the CRISPR-cas system by directly binding to the R-loop single-stranded DNA. PNAS, 122(14), e2423205122. (www)

  @article{ , abstract = {The CRISPR-Cas system is a well-known adaptive immune system in bacteria, and a prominent mechanism for evading this immunity involves anti-CRISPR (Acr) proteins, which employ various methods to neutralize the CRISPR-Cas system. In this study, using structural and biochemical analyses, we revealed that AcrIE7 binds to the single-stranded DNA in the R-loop formed when Cascade encounters the target DNA, thereby preventing Cas3 from cleaving the DNA. This represents a different inhibition strategy distinct from previously reported Acr mechanisms and offers insights into CRISPR-Cas inhibition.}, archive = {J_PNAS}, author = {Kim, Do Yeon and Lee, So Yeon and Ha, Hyun Ji and Park, Hyun Ho}, doi = {10.1073/pnas.2423205122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2423205122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {AcrIE7 inhibits the CRISPR-cas system by directly binding to the R-loop single-stranded DNA}, volume = {122}, year = {2025}, }
• (2025). Unveiling cas8 dynamics and regulation within a transposon-encoded Cascade–TniQ complex. PNAS, 122(14), e2422895122. (www)

  @article{ , abstract = {The Vibrio cholerae Cascade–TniQ complex unveiled a new paradigm in biology, demonstrating that CRISPR-associated proteins can direct DNA transposition. Despite the tremendous potential of “knocking-in” genes at desired sites, the mechanisms underlying DNA binding and transposition remain elusive. In this system, a conformational change of the Cas8 protein is essential for DNA binding, yet how it occurs is unclear. Here, structural modeling and free energy simulations reconstruct the Cas8 helical bundle and reveal an open–closed conformational change that is key for the complex’s function. We show that when Cascade–TniQ binds RNA, the Cas8 bundle changes conformation mediated by the interaction with the Cas7.1 protein. This interaction promotes the bundle’s transition toward the open state, priming the complex for DNA binding. As the target DNA binds the guide RNA, the opening of the Cas8 bundle becomes more favorable, exposing positively charged residues and facilitating their interaction with DNA, which ultimately leads the DNA-binding process to completion. These outcomes provide a dynamic representation of a critical conformational change in one of the largest CRISPR systems and illustrate its role at critical steps of the Cascade–TniQ biophysical function, advancing our understanding of nucleic acid binding and transposition mechanisms.}, archive = {J_PNAS}, author = {Patel, Amun C. and Sinha, Souvik and Arantes, Pablo R. and Palermo, Giulia}, doi = {10.1073/pnas.2422895122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2422895122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unveiling cas8 dynamics and regulation within a transposon-encoded Cascade–TniQ complex}, volume = {122}, year = {2025}, }
• (2025). An unusual potassium conductance protects caenorhabditis elegans pharyngeal muscle rhythms against environmental noise. PNAS, 122(14), e2422709122. (www)

  @article{ , abstract = {The nematode Caenorhabditis elegans feeds by rhythmic contraction and relaxation of a neuromuscular organ called the pharynx, which draws in and filters water and bacterial food. This behavior is driven by myogenic plateau potentials, long-lasting depolarizations of the pharyngeal muscle, which are timed by neuronal input from a dedicated pharyngeal nervous system. While the timing of these plateaus’ initiation has received significant attention, their mechanisms of termination remain incompletely understood. In particular, it is unclear how plateaus resist early termination by hyperpolarizing current noise. Here, we present a computational model of pharyngeal plateaus against a noisy background. We propose that an unusual, rapidly inactivating potassium conductance confers exceptional noise robustness on the system. We further investigate the possibility that a similar mechanism in other systems permits switching between plateau and spiking behavior under noisy conditions.}, archive = {J_PNAS}, author = {Kenngott, Max and Sengupta, Piali and Lockery, Shawn and Marder, Eve}, doi = {10.1073/pnas.2422709122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2422709122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An unusual potassium conductance protects caenorhabditis elegans pharyngeal muscle rhythms against environmental noise}, volume = {122}, year = {2025}, }
• (2025). RPE-specific MCT2 expression promotes cone survival in models of retinitis pigmentosa. PNAS, 122(14), e2421978122. (www)

  @article{ , abstract = {Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration worldwide. It is characterized by the sequential death of rod and cone photoreceptors, the cells responsible for night and daylight vision, respectively. Although the expression of most RP genes occurs only in rods, there is a secondary degeneration of cones. One possible mechanism of cone death is metabolic dysregulation. Photoreceptors are highly metabolically active, consuming large quantities of glucose and producing substantial amounts of lactate. The retinal pigment epithelium (RPE) mediates the transport of glucose from the blood to photoreceptors and, in turn, removes lactate, which can influence the rate of consumption of glucose by the RPE. One model for metabolic dysregulation in RP suggests that following the death of rods, lactate levels are substantially diminished causing the RPE to withhold glucose, resulting in nutrient deprivation for cones. Here, we present adeno-associated viral vector-mediated delivery of monocarboxylate transporter 2 (MCT2, Slc16a7 ) into the eye, with expression limited to RPE cells, with the aim of promoting lactate uptake from the blood and encouraging the passage of glucose to cones. We demonstrate prolonged survival and function of cones in rat and mouse RP models, revealing a possible gene-agnostic therapy for preserving vision in RP. We also present the use of fluorescence lifetime imaging-based biosensors for lactate and glucose within the eye. Using this technology, we show changes to lactate and glucose levels within MCT2-expressing RPE, suggesting that cone survival is impacted by changes in RPE metabolism.}, archive = {J_PNAS}, author = {Chandler, Laurel C. and Gardner, Apolonia and Cepko, Constance L.}, doi = {10.1073/pnas.2421978122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2421978122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RPE-specific MCT2 expression promotes cone survival in models of retinitis pigmentosa}, volume = {122}, year = {2025}, }
• (2025). The cryo-EM structure and physical basis for anesthetic inhibition of the THIK1 K2P channel. PNAS, 122(14), e2421654122. (www)

  @article{ , abstract = {THIK1 tandem pore domain (K2P) potassium channels regulate microglial surveillance of the central nervous system and responsiveness to inflammatory insults. With microglia recognized as critical to the pathogenesis of neurodegenerative diseases, THIK1 channels are putative therapeutic targets to control microglia dysfunction. While THIK channels can principally be distinguished from other K2Ps by their distinctive inhibitory response to volatile anesthetics (VAs), molecular details governing THIK channel gating remain largely unexplored. Here, we report a 3.2 Å cryo-electron microscopy structure of the THIK1 channel in a closed conformation. A central pore gate located directly below the THIK1 selectivity filter is formed by inward-facing TM4 helix tyrosine residues that occlude the ion conduction pathway. VA inhibition of THIK requires closure of this central pore gate. Using a combination of anesthetic photolabeling, electrophysiology, and molecular dynamics simulation, we identify a functionally critical THIK1 VA binding site positioned between the central gate and a structured section of the THIK1 TM2/TM3 loop. Our results demonstrate the molecular architecture of the THIK1 channel and elucidate critical structural features involved in regulation of THIK1 channel gating and anesthetic inhibition.}, archive = {J_PNAS}, author = {Riel, Elena B. and Bu, Weiming and Joseph, Thomas T. and Khajoueinejad, Leila and Eckenhoff, Roderic G. and Riegelhaupt, Paul M.}, doi = {10.1073/pnas.2421654122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2421654122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The cryo-EM structure and physical basis for anesthetic inhibition of the THIK1 K2P channel}, volume = {122}, year = {2025}, }
• (2025). No compelling evidence of sex differences in brain maturation during COVID-19 lockdowns when the sexes are compared statistically. PNAS, 122(14), e2421462122. (www)

  @article{ , archive = {J_PNAS}, author = {Brown, Andrew W. and Chung, Simon and Koscik, Timothy and Vorland, Colby J. and Maney, Donna L.}, doi = {10.1073/pnas.2421462122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2421462122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {No compelling evidence of sex differences in brain maturation during COVID-19 lockdowns when the sexes are compared statistically}, volume = {122}, year = {2025}, }
• (2025). Validating new limits for human thermoregulation. PNAS, 122(14), e2421281122. (www)

  @article{ , abstract = {Recent projections suggest that large geographical areas will soon experience heat and humidity exceeding limits for human thermoregulation. The survivability limits modeled in that research were based on laboratory studies suggesting that humans cannot effectively thermoregulate in wet bulb temperatures (T wb ) above 26 to 31 °C, values considerably lower than the widely publicized theoretical threshold of 35 °C. The newly proposed empirical limits were derived from the T wb corresponding to the core temperature inflection point in participants exposed to stepped increases in air temperature or relative humidity in a climate-controlled chamber. Despite the increasing use of these thermal-step protocols, their validity has not been established. We used a humidity-step protocol to estimate the T wb threshold for core temperature inflection in 12 volunteers. To determine whether this threshold truly demarcates the T wb above which thermoregulation is impossible, each participant was subsequently exposed to T wb above (~33.7 °C, T above ) and below (~30.9 °C, T below ) their respective inflection point (~32.3 °C, T wb ) for up to 9 h (in random order). Core temperature rose continuously in T above . It was projected that core temperatures associated with heat stroke (40.2 °C) would occur within 10 h. While T below was also uncompensable, the core temperature rate of rise was considerably lower than in T above such that it would take >24 h to reach 40.2 °C. Our study supports thermal-step protocols as an effective technique for evaluating survivability limits for heat exposure and provides a direct assessment of the limits of human thermoregulation.}, archive = {J_PNAS}, author = {Meade, Robert D. and O’Connor, Fergus K. and Richards, Brodie J. and Tetzlaff, Emily J. and Wagar, Katie E. and Harris-Mostert, Roberto C. and Egube, Theodore and McCormick, James J. and Kenny, Glen P.}, doi = {10.1073/pnas.2421281122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2421281122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Validating new limits for human thermoregulation}, volume = {122}, year = {2025}, }
• (2025). Monomers and short oligomers of human RAD52 promote single-strand annealing. PNAS, 122(14), e2420771122. (www)

  @article{ , abstract = {Genome maintenance and stability rely on the repair of DNA double-strand breaks. Breaks can be repaired via the single-strand-annealing pathway mediated by the protein RAD52. RAD52 oligomerizes to rings that are thought to promote annealing. However, rings have only been observed at micromolar concentrations at which annealing activity is impaired. Thus, it is unclear which oligomeric form is responsible for annealing. We combined single-molecule mass photometry with biochemical assays to determine the in vitro oligomeric states of human RAD52. We found that RAD52 was mostly monomeric at lower nanomolar concentrations. With increasing concentration, RAD52 oligomerized and formed rings with a variable stoichiometry from heptamers to tridecamers consistent with an oligomerization model of noncooperative assembly coupled with preferential cyclization. Under conditions where hardly any rings were present, RAD52 already promoted single-strand annealing in vitro. Our findings indicate that in vitro single-strand annealing can be mediated by monomers and short oligomers of RAD52. The oligomerization model suggests that ring formation is similar to a phase transition whereby rings are a reservoir to replenish the monomer and short oligomer pool. This pool has a nearly constant concentration which may be optimal for annealing and would be independent, for example, of the amount of DNA damage, protein upregulation, or the cell cycle.}, archive = {J_PNAS}, author = {Kharlamova, Maria A. and Kushwah, Manish S. and Jachowski, Tobias J. and Subramaniam, Sivaraman and Schiff, Viktor and Stewart, A. Francis and Kukura, Philipp and Schäffer, Erik}, doi = {10.1073/pnas.2420771122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2420771122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Monomers and short oligomers of human RAD52 promote single-strand annealing}, volume = {122}, year = {2025}, }
• (2025). Order–disorder transition in multidirectional crowds. PNAS, 122(14), e2420697122. (www)

  @article{ , abstract = {One of the archetypal examples of active flows is a busy concourse crossed by people moving in different directions according to their personal destinations. When the crowd is isotropic—comprising individuals moving in all different directions—the collective motion is disordered. In contrast, if it is possible to identify two dominant directions of motion, for example in a corridor, the crowd spontaneously organizes into contraflowing lanes or stripes. In this article, we characterize the physics of the transition between these two distinct phases by using a synergy of theoretical analysis, numerical simulations, and stylized experiments. We develop a hydrodynamic theory for collisional flows of heterogeneous populations, and we analyze the stability of the disordered configuration. We identify an order–disorder transition occurring as population heterogeneity exceeds a theoretical threshold determined by the collision avoidance maneuvers of the crowd. Our prediction for the onset of pedestrian ordering is consistent with results of agent-based simulations and controlled experiments with human crowds.}, archive = {J_PNAS}, author = {Bacik, Karol A. and Sobota, Grzegorz and Bacik, Bogdan S. and Rogers, Tim}, doi = {10.1073/pnas.2420697122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2420697122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Order–disorder transition in multidirectional crowds}, volume = {122}, year = {2025}, }
• (2025). HEATR3 recognizes membrane rupture and facilitates xenophagy in response to salmonella invasion. PNAS, 122(14), e2420544122. (www)

  @article{ , abstract = {Bacterial invasion into the cytoplasm of epithelial cells triggers the activation of the cellular autophagic machinery as a defense mechanism, a process known as xenophagy. In this study, we identified HEATR3, an LC3-interacting region (LIR)-containing protein, as a factor involved in this defense mechanism using quantitative mass spectrometry analysis. HEATR3 localizes intracellularly invading Salmonella , and HEATR3 deficiency promotes Salmonella proliferation in the cytoplasm. HEATR3 also localizes to lysosomes damaged by chemical treatment, suggesting that Salmonella recognition is facilitated by damage to the host cell membrane. HEATR3 deficiency impairs LC3 recruitment to damaged membranes and blocks the delivery of the target to the lysosome. These phenotypes were rescued by exogenous expression of wild-type HEATR3 but not by the LIR mutant, indicating the crucial role of the HEATR3–LC3 interaction in the receptor for selective autophagy. HEATR3 is delivered to lysosomes in an autophagy-dependent manner. Although HEATR3 recruitment to the damaged membrane was unaffected by ATG5 or FIP200 deficiency, it was markedly impaired by treatment with a calcium chelator, suggesting involvement upstream of the autophagic pathway. These findings suggest that HEATR3 serves as a receptor for selective autophagy and is able to identify damaged membranes, facilitate the removal of damaged lysosomes, and target invading bacteria within cells.}, archive = {J_PNAS}, author = {Arakawa, Masashi and Uriu, Keiya and Saito, Koki and Hirose, Mai and Katoh, Kaoru and Asano, Krisana and Nakane, Akio and Saitoh, Tatsuya and Yoshimori, Tamotsu and Morita, Eiji}, doi = {10.1073/pnas.2420544122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2420544122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {HEATR3 recognizes membrane rupture and facilitates xenophagy in response to salmonella invasion}, volume = {122}, year = {2025}, }
• (2025). Lenacapavir disrupts HIV-1 core integrity while stabilizing the capsid lattice. PNAS, 122(14), e2420497122. (www)

  @article{ , abstract = {Lenacapavir (GS-6207; LEN) is a potent HIV-1 capsid inhibitor approved for treating multidrug-resistant infection. LEN binds to a hydrophobic pocket between neighboring capsid (CA) proteins in hexamers and stabilizes the capsid lattice, but its effect on HIV-1 capsids is not fully understood. Here, we labeled HIV-1 capsids with green fluorescent protein fused to CA (GFP-CA) or a fluid-phase GFP content marker (cmGFP) to assess LEN’s impact on HIV-1 capsids. HIV-1 cores labeled with GFP-CA, but not cmGFP, could be immunostained with an anti-GFP antibody and were less sensitive to the capsid-binding host restriction factor MX2, demonstrating that GFP-CA is incorporated into the capsid lattice and is a marker for capsid lattice stability, whereas cmGFP is an indicator of core integrity. LEN treatment of isolated HIV-1 cores resulted in a dose-dependent loss of cmGFP signal while preserving the GFP-CA signal, indicating that LEN disrupts core integrity but stabilizes the capsid lattice. In contrast, capsid inhibitor PF-3450074 (PF74) induced loss of core integrity and the capsid lattice. Electron microscopy of LEN- or PF74-treated viral cores revealed frequent breakage at the narrow end of the capsid and other morphological changes. Our results suggest that LEN treatment does not prevent nuclear envelope docking but inhibits nuclear import of cores with or without loss of core integrity. In contrast, PF74 treatment blocks nuclear import by inhibiting the nuclear envelope docking of viral cores, highlighting their different mechanisms of nuclear import inhibition.}, archive = {J_PNAS}, author = {Li, Chenglei and Burdick, Ryan C. and Siddiqui, Rokeya and Janaka, Sanath Kumar and Hsia, Ru-ching and Hu, Wei-Shau and Pathak, Vinay K.}, doi = {10.1073/pnas.2420497122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2420497122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lenacapavir disrupts HIV-1 core integrity while stabilizing the capsid lattice}, volume = {122}, year = {2025}, }
• (2025). Academic achievement helps coordination on mutually advantageous outcomes. PNAS, 122(14), e2420306122. (www)

  @article{ , abstract = {This study examines the relationship between academic achievement and strategic ability to coordinate among middle school students. We designed an experimental framework using repeated asymmetric Battle of the Sexes and Hawk–Dove games, to explore how cognitive and social skills related to academic success influence behavior. A total of 132 students participated, divided into groups of high and low academic achievers based on their performance at school. Our results show that, on average, high achievers coordinate better on equilibrium outcomes with simple but effective strategies and obtain higher payoffs compared to low achievers. However, we notice also substantial heterogeneity within groups. Finally, performance in pairs with one high and one low achiever is intermediate but closer to the level of high achievers, suggesting potential peer learning effects and the educational value of mixed groups to promote guidance and joint improvements. These findings suggest that academic success may reflect broader cognitive abilities–such as strategic thinking, anticipation of others’ choices, and cooperation–crucial for navigating real-world interactions in complex environments.}, archive = {J_PNAS}, author = {Brocas, Isabelle and Carrillo, Juan D.}, doi = {10.1073/pnas.2420306122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2420306122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Academic achievement helps coordination on mutually advantageous outcomes}, volume = {122}, year = {2025}, }
• (2025). The TRPV3 channel is a mediator of zinc influx and homeostasis in murine oocytes. PNAS, 122(14), e2420194122. (www)

  @article{ , abstract = {Zinc (Zn 2+ ) homeostasis is essential for gametogenesis and reproduction, and its deficiency causes infertility. Oocytes contain higher Zn 2+ levels than somatic cells, and Zn 2+ concentrations in oocytes are far higher than those of other transition metals and increase even more during maturation in preparation for fertilization. Remarkably, it is unknown what transporter(s) or channel(s) mediate Zn 2+ influx in oocytes and whether they are expressed uniformly throughout folliculogenesis. Here, we showed that the functional expression of a member of the t ransient r eceptor p otential family, vanilloid 3, TRPV3, closely follows the dynamics of intracellular Zn 2+ during oocyte maturation, raising the prospect that these events may be functionally linked. Using microfluorometry, we monitored in oocytes of Trpv3 null females the expected rise in Zn 2+ concentrations during maturation. Surprisingly, Zn 2+ levels did not climb, and the overall FluoZin3 signal in Trpv3 null eggs was lower than in control eggs. Electrophysiological recordings showed a large TRPV3 current induced by the agonist 2-APB in WT eggs supplemented with extracellular Zn 2+ that was absent in Trpv3 null eggs; TRPV3 showed a clear preference for Zn 2+ over Ca 2+ . Trpv3 null eggs displayed features associated with Zn 2+ deficient conditions, such as lower IP 3 R1 function, abnormal cortical granule distribution, and disturbed cytoskeletal organization with distinct actin nucleation disorders. Notably, Trpv3 null eggs demonstrated undisturbed Zn 2+ sparks. Our results suggest that TRPV3 is a pivotal member of the Zn 2+ toolkit, mediating Zn 2+ intake during maturation. They also indicate that distinct transporters or channels mediate Zn 2+ influx throughout folliculogenesis.}, archive = {J_PNAS}, author = {Lopes, Emily M. and Akizawa, Hiroki and Koc, Oguz C. and Soto-Moreno, Edgar and Gupta, Neha and Ardestani, Goli and Balboula, Ahmed Z. and Carvacho, Ingrid and Fissore, Rafael A.}, doi = {10.1073/pnas.2420194122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2420194122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The TRPV3 channel is a mediator of zinc influx and homeostasis in murine oocytes}, volume = {122}, year = {2025}, }
• (2025). MDA5 ISGylation is crucial for immune signaling to control viral replication and pathogenesis. PNAS, 122(14), e2420190122. (www)

  @article{ , abstract = {The posttranslational modification (PTM) of innate immune sensor proteins by ubiquitin or ubiquitin-like proteins is crucial for regulating antiviral host responses. The cytoplasmic dsRNA receptor melanoma differentiation-associated protein 5 (MDA5) undergoes several PTMs including ISGylation within its first caspase activation and recruitment domain (CARD), which promotes MDA5 signaling. However, the relevance of MDA5 ISGylation for antiviral immunity in an infected organism has been elusive. Here, we generated knock-in mice (MDA5 K23R/K43R ) in which the two major ISGylation sites, K23 and K43, in MDA5, were mutated. Primary cells derived from MDA5 K23R/K43R mice exhibited abrogated endogenous MDA5 ISGylation and an impaired ability of MDA5 to form oligomeric assemblies, leading to blunted cytokine responses to MDA5 RNA-agonist stimulation or infection with encephalomyocarditis virus (EMCV) or West Nile virus. Phenocopying MDA5 −/− mice, the MDA5 K23R/K43R mice infected with EMCV displayed increased myocardial injury and mortality, elevated viral titers, and an ablated induction of cytokines and chemokines compared to WT mice. Molecular studies identified human HERC5 (and its functional murine homolog HERC6) as the primary E3 ligases responsible for MDA5 ISGylation and activation. Taken together, these findings establish the importance of CARD ISGylation for MDA5-mediated RNA virus restriction, promoting potential avenues for immunomodulatory drug design for antiviral or anti-inflammatory applications.}, archive = {J_PNAS}, author = {Sarkar, Lucky and Liu, GuanQun and Acharya, Dhiraj and Zhu, Junji and Sayyad, Zuberwasim and Gack, Michaela U.}, doi = {10.1073/pnas.2420190122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2420190122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MDA5 ISGylation is crucial for immune signaling to control viral replication and pathogenesis}, volume = {122}, year = {2025}, }
• (2025). Following phospholipid transfer through the OmpF3–MlaA–MlaC lipid shuttle with native mass spectrometry. PNAS, 122(14), e2420041122. (www)

  @article{ , abstract = {The maintenance of lipid asymmetry (Mla) system in gram-negative bacteria transfers phospholipids between the outer and inner membrane to maintain the outer membrane asymmetry. Misplaced phospholipids are extracted from the outer leaflet of the outer membrane by MlaA, transferred to the periplasmic lipid transporter MlaC, and shuttled to the inner membrane. We set out to investigate the lipid transfer between MlaA and MlaC using native mass spectrometry, with the aim of determining the lipid preferences of MlaC and whether MlaA preselected lipids for MlaC. First, we characterized the lipids that copurified with overexpressed MlaC, phosphatidylglycerol (PG), and phosphatidylethanolamine (PE), and following delipidation noted a headgroup-independent enrichment of cyclopropane lipids. Under native expression conditions, we found that PG is three-fold enriched on MlaC compared to its abundance in the membrane. Next, we isolated and characterized OmpF 3 –MlaA complexes and demonstrated their ability to enhance loading of delipidated MlaC with bacterial and nonbacterial phospholipids. We then captured the intact ternary lipid shuttle (OmpF 3 –MlaA–MlaC) and demonstrated that PG dissociates this transient complex, releasing lipid-bound MlaC. Together our results point to a high population of endogenous PG on periplasmic MlaC, which likely arises from disassembly of the lipid shuttle to maintain lipid asymmetry for cell viability.}, archive = {J_PNAS}, author = {Kirschbaum, Carla and Bennett, Jack L. and Tian, Qiaoyu and Sen, Navoneel and Smith, Iain P. S. and Wu, Di and Benesch, Justin L. P. and Khalid, Syma and Isom, Georgia and Robinson, Carol V.}, doi = {10.1073/pnas.2420041122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2420041122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Following phospholipid transfer through the OmpF3–MlaA–MlaC lipid shuttle with native mass spectrometry}, volume = {122}, year = {2025}, }
• (2025). Breaking the mobility–stability dichotomy in organic semiconductors through adaptive surface doping. PNAS, 122(14), e2419673122. (www)

  @article{ , abstract = {Organic semiconductors (OSCs) are pivotal for next-generation flexible electronics but are limited by an intrinsic trade-off between mobility and stability. We introduce adaptive surface doping (ASD), an innovative strategy to overcome this dichotomy in OSCs. ASD's adaptive mechanism accommodates a broad range of dopant concentrations, optimally passivating trap states as needed. This approach significantly lowers the trap energy level from 84 meV to 14 meV above the valence band edge, promoting a transition from hopping to band-like transport mechanisms. ASD boosts carrier mobility by over 60%, reaching up to 30.7 cm 2 V −1 s −1 , while extending the extrapolated operational lifetime of treated devices beyond 57.5 y. This breakthrough sets a standard in organic electronics, positioning ASD as a powerful method for simultaneously enhancing performance and stability in OSC devices.}, archive = {J_PNAS}, author = {Wang, Zhaofeng and Wu, Xianshuo and Zhang, Siyuan and Yang, Shuyuan and Gao, Pichao and Huang, Panhui and Xiao, Yanling and Shen, Xianfeng and Yao, Ximeng and Zeng, Dong and Jie, Jiansheng and Zhou, Yecheng and Yang, Fangxu and Li, Rongjin and Hu, Wenping}, doi = {10.1073/pnas.2419673122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2419673122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Breaking the mobility–stability dichotomy in organic semiconductors through adaptive surface doping}, volume = {122}, year = {2025}, }
• (2025). Structural basis for neutralizing antibody binding to pertussis toxin. PNAS, 122(14), e2419457122. (www)

  @article{ , abstract = {Pertussis toxin (PT) is a key protective antigen in vaccine- and natural immunity-mediated protection from Bordetella pertussis infection. Despite its importance, no PT-neutralizing epitopes have been characterized structurally. To define neutralizing epitopes and identify key structural elements to preserve during PT antigen design, we determined a 3.6 Å cryoelectron microscopy structure of genetically detoxified PT (PTg) bound to hu11E6 and hu1B7, two potently neutralizing anti-PT antibodies with complementary mechanisms: disruption of toxin adhesion to cells and intracellular activities, respectively. Hu11E6 binds the paralogous S2 and S3 subunits of PTg via a conserved epitope but surprisingly did not span the previously identified sialic acid–binding site implicated in toxin adhesion. Hu11E6 specifically prevented PTg binding to sialylated N-glycans and a sialylated model receptor, as demonstrated by high-throughput glycan array analysis and ELISA, while a T cell activation assay showed that it blocks PTg mitogenic activities to define its neutralizing mechanism. Hu1B7 bound a quaternary epitope spanning the S1 and S5 subunits, although functional studies of hu1B7 variants suggested that S5 binding is not involved in its PT neutralization mechanism. These results structurally define neutralizing epitopes on PT, improving our molecular understanding of immune protection from B. pertussis and providing key information for the future development of PT immunogens.}, archive = {J_PNAS}, author = {Goldsmith, Jory A. and Nguyen, Annalee W. and Wilen, Rebecca E. and Wijagkanalan, Wassana and McLellan, Jason S. and Maynard, Jennifer A.}, doi = {10.1073/pnas.2419457122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2419457122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis for neutralizing antibody binding to pertussis toxin}, volume = {122}, year = {2025}, }
• (2025). Allosterically switchable network orients β-flap in clostridioides difficile toxins. PNAS, 122(14), e2419263122. (www)

  @article{ , abstract = {Allosteric proteins exhibit a functional response upon ligand binding far from the active site. Clostridioides difficile toxins use allosteric binding by the endogenous cofactor myo -inositol hexakisphosphate to orchestrate self-cleavage from within the target cell. This binding event induces a conformational shift, primarily effecting a lever-like β -flap region, with two known orientations. We uncovered a mechanism for this allosteric transition using extensive atomistic molecular dynamics simulations and computational and experimental mutagenesis. The mechanism relies on a switchable interaction network. The most prominent interaction pair is K600-E743, with K600 interactions explaining ∼70% of the allosteric effect. Rather than gradually morphing between two end states, the interaction network adopts two mutually exclusive configurations in the active and inactive state. Similar switchable networks may explain allostery more broadly. This mechanism in particular could aid in drug development targeting the C. difficile toxins autoproteolysis.}, archive = {J_PNAS}, author = {Finn, Lauren M. and Cummer, Rebecca and Castagner, Bastien and Keller, Bettina G.}, doi = {10.1073/pnas.2419263122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2419263122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Allosterically switchable network orients β-flap in clostridioides difficile toxins}, volume = {122}, year = {2025}, }
• (2025). Disease resistance is more costly at younger ages: An explanation for the maintenance of juvenile susceptibility in a wild plant. PNAS, 122(14), e2419192122. (www)

  @article{ , abstract = {High juvenile susceptibility drives infectious disease epidemics across kingdoms, yet the evolutionary mechanisms that maintain this susceptibility are unclear. We tested the hypothesis that juvenile susceptibility is maintained by high costs of resistance by quantifying the genetic correlation between host fitness and age-specific innate resistance to a fungal pathogen in a wild plant. We separately measured the resistance of 45 genetic families of the wild plant, Silene latifolia, to its endemic fungal pathogen, Microbotryum lychnidis-dioicae, at four ages in a controlled inoculation experiment. We then grew these same families in a field common garden and tracked survival and fecundity over a 2-y period and quantified the correlation between age-specific resistance and fitness in the field. We found significant fitness costs associated with disease resistance at juvenile but not at adult host stages. We then used an age-structured compartmental model to show that the magnitude of these costs is sufficient to prevent the evolution of higher juvenile resistance in models, allowing the disease to persist. Taken together, our results show that costs of resistance vary across host lifespan, providing an evolutionary explanation for the maintenance of juvenile susceptibility.}, archive = {J_PNAS}, author = {Slowinski, Samuel P. and Kido, Allyson K. and Alexander, Laura W. and Shirdon, Andrea H. and Bruns, Emily L.}, doi = {10.1073/pnas.2419192122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2419192122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Disease resistance is more costly at younger ages: An explanation for the maintenance of juvenile susceptibility in a wild plant}, volume = {122}, year = {2025}, }
• (2025). Optogenetic stimulation of the dorsal striatum bidirectionally controls seizures. PNAS, 122(14), e2419178122. (www)

  @article{ , abstract = {Despite a century of development of antiseizure medications, up to a third of people with epilepsy do not achieve seizure freedom with drug therapy. Deep brain stimulation is of growing use, but just as with pharmacotherapy, is not universally effective. Identifying new targets for deep brain stimulation—and in particular sites that are effective against a range of seizure types—may close this gap. Engagement of the basal ganglia experimental seizures was first observed almost 75 y ago. However, the role of the basal ganglia’s input nucleus, the striatum, in seizure control is relatively understudied. To address this gap, we used an optogenetic approach to activate and inactivate neurons in the dorsal striatum of rats submitted to the gamma-butyrolactone (GBL) model of absence epilepsy, amygdala kindling model of temporal lobe epilepsy, and pilocarpine-induced Status Epilepticus (SE). Open-loop (continuous light delivery) optogenetic activation of dorsal striatal neurons robustly suppressed seizures in all models. By contrast, open-loop optogenetic silencing increased absence seizure expression and facilitated SE onset but had no effect on kindled seizures. In the GBL model, we also tested the effects of closed-loop modulation (light delivery in response to seizure detection). Closed-loop activation reduced duration of spike-wave discharges (SWDs), while closed-loop inhibition increased SWD duration. These results demonstrated previously unrecognized antiabsence effects associated with striatal neuromodulation. These findings demonstrate a robust, bidirectional role of the dorsal striatum in the control of multiple seizure types, suggesting that the striatum is a site that can exert broad-spectrum control of seizures.}, archive = {J_PNAS}, author = {Hyder, Safwan K. and Lazarini-Lopes, Willian and Toib, Jonathan and Williams, Gabrielle and Sukharev, Alexander and Forcelli, Patrick A.}, doi = {10.1073/pnas.2419178122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2419178122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Optogenetic stimulation of the dorsal striatum bidirectionally controls seizures}, volume = {122}, year = {2025}, }
• (2025). Biphasic mechanochemistry of single-chain polymerization. PNAS, 122(14), e2418844122. (www)

  @article{ , abstract = {Mechanical forces can induce chemical reactions, produce chemical signals, and alter reaction kinetics. Here, using magnetic tweezers–based single-molecule force spectroscopy, we study the force effects on the ring-opening metathesis polymerization (ROMP) of single-polymer chains, during which nonequilibrium conformational entanglements can form and unravel stochastically. We find a surprising, biphasic force dependence of polymerization kinetics: The single-chain polymerization rate initially slows down with increasing stretching forces, reaching a minimum, and then accelerates at higher forces. Analysis of real-time single-chain growth trajectories allows for dissecting the polymerization process into two distinct regimes, one with and the other without entanglement formation, unveiling the biphasic force dependence in both regimes. Two different mechanisms likely operate for the biphasic dependence: a force-induced entanglement tightening and then splitting and a force-induced catalyst structural distortion that switches the reaction pathway between reactant states of different stability and reactivity. These findings and insights point to opportunities of using force to manipulate polymerization reactions and tune the physiochemical properties of synthetic polymers.}, archive = {J_PNAS}, author = {Chakraborty, Udit Kumar and Yang, Muwen and Baral, Susil and Liu, Chunming and Chen, AnQi and Chen, Peng}, doi = {10.1073/pnas.2418844122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2418844122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biphasic mechanochemistry of single-chain polymerization}, volume = {122}, year = {2025}, }
• (2025). A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis. PNAS, 122(14), e2418783122. (www)

  @article{ , abstract = {Recent sero-epidemiological studies have strengthened the hypothesis that Epstein–Barr virus (EBV) may be a causal factor in multiple sclerosis (MS). Given the complexity of the EBV–host interaction, various mechanisms may be responsible for the disease pathogenesis. Furthermore, it remains unclear whether this is a disease-specific process. Here, we showed that genes encoding EBV interactors are enriched in loci associated with MS but not with other diseases and in prioritized therapeutic targets. Analyses of MS blood and brain transcriptomes confirmed a dysregulation of MS-associated EBV interactors affecting the CD40 pathway. Such interactors were strongly enriched in binding sites for the EBV nuclear antigen 2 (EBNA2) viral transcriptional regulator, often in colocalization with CCCTC binding factor (CTCF) and RNA Polymerase II Subunit A (POLR2A). EBNA2 was expressed in the MS brain. The 1.2 EBNA2 allele downregulated the expression of the CD40 MS-associated gene analogously to the CD40 MS-risk variant. Finally, we showed that the 1.2 EBNA2 allele associates with the risk of MS. This study delineates how host and viral genetic variability converge in MS-specific pathogenetic mechanisms.}, archive = {J_PNAS}, author = {Mechelli, Rosella and Umeton, Renato and Bellucci, Gianmarco and Bigi, Rachele and Rinaldi, Virginia and Angelini, Daniela F. and Guerrera, Gisella and Pignalosa, Francesca C. and Ilari, Sara and Patrone, Marco and Srinivasan, Sundararajan and Cerono, Gabriel and Romano, Silvia and Buscarinu, Maria C. and Martire, Serena and Malucchi, Simona and Landi, Doriana and Lorefice, Lorena and Pizzolato Umeton, Raffaella and Anastasiadou, Eleni and Trivedi, Pankaj and Fornasiero, Arianna and Ferraldeschi, Michela and null, null and Di Sapio, Alessia and Marfia, Gerolama and Cocco, Eleonora and Centonze, Diego and Uccelli, Antonio and Di Silvestre, Dario and Mauri, Pierluigi and de Candia, Paola and D’Alfonso, Sandra and Battistini, Luca and Farina, Cinthia and Magliozzi, Roberta and Reynolds, Richard and Baranzini, Sergio E. and Matarese, Giuseppe and Salvetti, Marco and Ristori, Giovanni and Alfredsson, Lars and Søndergaard, Helle Bach and Barcellos, Lisa F. and Bernardinelli, Luisa and Booth, David and Comabella, Manuel and Compston, Alastair and Cotsapas, Chris and Dardiotis, Efthimios and De Jager, Philip L and Dubois, Bénédicte and Esposito, Federica and Fontaine, Betrand and Goris, An and Gourraud, Pierre-Antoine and Hadjigeorgiou, Giorgos and Hafler, David A. and Haines, Jonathan L. and Harbo, Hanne F. and Hauser, Stephen L. and Hemmer, Bernhard and Henry, Roland and Hillert, null and Hintzen, Rogier and Isobe, Noriko and Ivinson, Adrian J. and Kalra, Seema and Khalil, Michael and Kockum, Ingrid and Lechner-Scott, Jeanette and Martin, Roland and Martinelli-Boneschi, Filippo and McCauley, Jacob L. and McVean, Gil and Oksenberg, Jorge R. and Olsson, Tomas and Oturai, Annette and Parnell, Grant P. and Patsopoulos, Nikolaos A. and Pericak-Vance, Margaret A. and Robertson, Neil and Saarela, Janna and Sawcer, Stephen J. and Smolders, Joost and Stewart, Graeme J. and Taylor, Bruce and Yong, V. Wee and Zipp, Frauke and Barroso, Ines and Blackwell, Jenefer M. and Bramon, Elvira and Brown, Matthew A. and Casas, Juan P. and Caulfield, Mark and Clayton, David and Corvin, Aiden and Craddock, Nick and Deloukas, Panos and Donnelly, Peter and Duncanson, Audrey and Farrall, Martin and Hall, Alistair and Hattersley, Andrew and Jankowski, Janusz and Markus, Hugh S. and Mathew, Christopher G. and McCarthy, Mark and Palmer, Colin N.A. and Parkes, Miles and Plomin, Robert and Rautanen, Anna and Samani, Nilesh and Sawcer, Stephen and Todd, John and Trembath, Richard C. and Viswanathan, Ananth C. and Wood, Nicholas W. and Worthington, Jane and Spencer, Chris C.A. and Band, Gavin and Bellenguez, Céline and Freeman, Colin and Hellenthal, Garrett and Giannoulatou, Eleni and Pirinen, Matti and Pearson, Richard and Strange, Amy and Su, Zhan and Vukcevic, Damjan and Langford, Cordelia and Hunt, Sarah E. and Edkins, Sarah and Gwilliam, Rhian and Blackburn, Hannah and Bumpstead, Suzannah J. and Dronov, Serge and Gillman, Matthew and Gray, Emma and Hammond, Naomi and Jayakumar, Alagurevathi and McCann, Owen T. and Liddle, Jennifer and Potter, Simon C. and Ravindrarajah, Rathi and Ricketts, Michelle and Waller, Matthew J. and Weston, Paul and Widaa, Sara and Whittaker, Pamela and Dilthey, Alexander and Leslie, Stephen and Moutsianas, Loukas and Perez, Marc L.}, doi = {10.1073/pnas.2418783122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2418783122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis}, volume = {122}, year = {2025}, }
• (2025). Elevated extinction risk in over one-fifth of native north american pollinators. PNAS, 122(14), e2418742122. (www)

  @article{ , abstract = {Pollinators are critical for food production and ecosystem function. Although native pollinators are thought to be declining, the evidence is limited. This first, taxonomically diverse assessment for mainland North America north of Mexico reveals that 22.6% (20.6 to 29.6%) of the 1,579 species in the best-studied vertebrate and insect pollinator groups have elevated risk of extinction. All three pollinating bat species are at risk and bees are the insect group most at risk (best estimate, 34.7% of 472 species assessed, range 30.3 to 43.0%). Substantial numbers of butterflies (19.5% of 632 species, range 19.1 to 21.0%) and moths (16.1% of 142 species, range 15.5 to 19.0%) are also at risk, with flower flies (14.7% of 295 species, range 11.5 to 32.9%), beetles (12.5% of 18 species, range 11.1 to 22.2%), and hummingbirds (0% of 17 species) more secure. At-risk pollinators are concentrated where diversity is highest, in the southwestern United States. Threats to pollinators vary geographically: climate change in the West and North, agriculture in the Great Plains, and pollution, agriculture, and urban development in the East. Woodland, shrubland/chaparral, and grassland habitats support the greatest numbers of at-risk pollinators. Strategies for improving pollinator habitat are increasingly available, and this study identifies species, habitats, and threats most in need of conservation actions at state, provincial, territorial, national, and continental levels.}, archive = {J_PNAS}, author = {Cornelisse, Tara and Inouye, David W. and Irwin, Rebecca E. and Jepsen, Sarina and Mawdsley, Jonathan R. and Ormes, Margaret and Daniels, Jaret and Debinski, Diane M. and Griswold, Terry and Klymko, John and Orr, Michael C. and Richardson, Leif and Sears, Nicole and Schweitzer, Dale and Young, Bruce E.}, doi = {10.1073/pnas.2418742122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2418742122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Elevated extinction risk in over one-fifth of native north american pollinators}, volume = {122}, year = {2025}, }
• (2025). Structural switching dynamically controls the doubly pseudoknotted rous sarcoma virus–programmed ribosomal frameshifting element. PNAS, 122(14), e2418418122. (www)

  @article{ , abstract = {A hallmark of retrovirus replication is the translation of two different polyproteins from one RNA through programmed –1 frameshifting. This is a mechanism in which the actively translating ribosome is induced to slip in the 5′ direction at a defined codon and then continues translating in the new reading frame. Programmed frameshifting controls the stoichiometry of viral proteins and is therefore under stringent evolutionary selection. Forty years ago, the first frameshifting stimulatory element was discovered in the Rous sarcoma virus. The ~120 nt RNA segment was predicted to contain a pseudoknot, but its 3D structure has remained elusive. Now, we have determined cryoEM and X-ray crystallographic structures of this classic retroviral element, finding that it adopts a butterfly-like double-pseudoknot fold. One “wing” contains a dynamic pyrimidine-rich helix, observed crystallographically in two conformations and in a third conformation via cryoEM. The other wing encompasses the predicted pseudoknot, which interacts with a second unexpected pseudoknot through a toggle residue, A2546. This key purine switches conformations between structural states and tunes the stability of interacting residues in the two wings. We find that its mutation can modulate frameshifting by as much as 50-fold, likely by altering the relative abundance of different structural states in the conformational ensemble of the RNA. Taken together, our structure–function analyses reveal how a dynamic double pseudoknot junction stimulates frameshifting by taking advantage of conformational heterogeneity, supporting a multistate model in which high Shannon entropy enhances frameshifting efficiency.}, archive = {J_PNAS}, author = {Jones, Christopher P. and Ferré-D’Amaré, Adrian R.}, doi = {10.1073/pnas.2418418122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2418418122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural switching dynamically controls the doubly pseudoknotted rous sarcoma virus–programmed ribosomal frameshifting element}, volume = {122}, year = {2025}, }
• (2025). The rising income gradient in life expectancy in sweden over six decades. PNAS, 122(14), e2418145122. (www)

  @article{ , abstract = {This study examines the long-term association between income and life expectancy in Sweden between 1960 and 2021. The study is based on register data that include all Swedish permanent residents aged 40 y and older. The results show that the gap in life expectancy between the top and bottom income percentiles widened substantially: For men, it increased from 3.5 y in the 1960s to 10.9 y by the 2010s, and for women, from 3.8 y in the 1970s to 8.6 y by the 2010s. Despite a reduction in income inequality and an expansion of social spending from the 1960s to the 1990s, health inequality continuously increased over the period under study. The changes of the relation between real income and life expectancy, the so-called Preston curve, reveal a much faster improvement in life expectancy in the upper half of the income distribution than suggested by the cross-sectional relation between income and life expectancy. Analysis of causes of death identified circulatory diseases as the main contributor to improved longevity, while cancer contributed more to the increased gap in life expectancy for women and equally for men. Finally, analysis of the change in the income gradient in avoidable causes of death showed the strongest contribution of preventable causes, both for men and women.}, archive = {J_PNAS}, author = {Hagen, Johannes and Laun, Lisa and Lucke, Charlotte and Palme, Mårten}, doi = {10.1073/pnas.2418145122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2418145122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The rising income gradient in life expectancy in sweden over six decades}, volume = {122}, year = {2025}, }
• (2025). Quina lithic technology indicates diverse late pleistocene human dynamics in east asia. PNAS, 122(14), e2418029122. (www)

  @article{ , abstract = {The Late Pleistocene of Eurasia is key for understanding interactions between early modern humans and different types of archaic human groups. During this period, lithic technology shows more diversity and complexity, likely indicating flexible adaptative strategies. However, cultural variability as expressed by technological types remains vague in large parts of eastern Eurasia, like in China. Here, we report a complete Quina technological system identified from the study of the Longtan site in Southwest China. The site has been securely dated to ca. 60 to 50 thousand years ago (ka), with compelling evidence of core exploitation, production of large and thick flakes, shaping and maintenance of scrapers exhibiting the whole Quina concept, typical of contemporary European Middle Paleolithic technologies developed by Neanderthal groups adapted to climatic oscillations during Marine Isotope Stage (MIS) 4 and early MIS 3. The finding of a Quina lithic assemblage in China not only demonstrates the existence of a Middle Paleolithic technology in the region but also shows large-scale analogies with Neanderthal behaviors in western Europe. Longtan substantially extends the geographic distribution of this technical behavior in East Asia. Although its origin remains unclear, implications for Pleistocene hominin dispersal and adaptation to diverse ecological settings are considered. The Longtan lithic evidence also provides perspectives for understanding the cultural evolutionary situation before the large-scale arrivals of early modern humans in East Asia predating ~45 ka.}, archive = {J_PNAS}, author = {Ruan, Qi-Jun and Li, Hao and Xiao, Pei-Yuan and Li, Bo and Monod, Hélène and Sumner, Alexandra and Zhao, Ke-Liang and Liu, Jian-Hui and Jia, Zhen-Xiu and Wang, Chun-Xin and Fan, An-Chuan and Moncel, Marie-Hélène and Marwick, Ben and Peresani, Marco and Wang, You-Ping and Chen, Fa-Hu and Delpiano, Davide}, doi = {10.1073/pnas.2418029122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2418029122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quina lithic technology indicates diverse late pleistocene human dynamics in east asia}, volume = {122}, year = {2025}, }
• (2025). Reconfigurable homochiral colloidal clusters assembled under orthogonally applied electric and magnetic fields. PNAS, 122(14), e2418006122. (www)

  @article{ , abstract = {Chiral structures assembled from colloids are of great interest for applications in metamaterials and micromachines. However, similar to their molecular counterparts, these assemblies often result in racemic mixtures. Achieving homochirality by breaking the symmetry remains a significant challenge. Here, we report an approach to obtain single-handed clusters from colloidal dimers using orthogonal electric and magnetic fields. Applying an alternating-current electric field perpendicular to the substrate generates a mixture of chiral clusters with both handedness. However, symmetry is broken by superimposing a planar rotating magnetic field, favoring one chirality over the other. The cluster’s chirality can be precisely controlled in situ by adjusting the magnetic field’s direction and strength, as well as the electric field frequency. Remarkably, this method also induces uniform chirality in initially achiral clusters when exposed solely to the electric field. Both experimental and numerical analyses reveal that the stability of specific handedness depends on the competition between forces and torques generated by the magnetic field, electric field, and electrohydrodynamic flow. Furthermore, we propose a strategy for producing colloidal clusters with uniform sizes and single-handedness through dynamic tuning of the electric and magnetic fields. This work not only demonstrates the potential of integrating external fields but also provides a viable way to create reconfigurable chiral colloidal structures.}, archive = {J_PNAS}, author = {Zhu, Xingrui and Zhang, Yuanxing and Hanson, Benjamin L. and Wu, David T. and Wu, Ning}, doi = {10.1073/pnas.2418006122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2418006122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reconfigurable homochiral colloidal clusters assembled under orthogonally applied electric and magnetic fields}, volume = {122}, year = {2025}, }
• (2025). PHLPP2 is a pseudophosphatase that lost activity in the metazoan ancestor. PNAS, 122(14), e2417218122. (www)

  @article{ , archive = {J_PNAS}, author = {Husremović, Tarik and Meier, Vanessa and Piëch, Lucas and Siess, Katharina M. and Antonioli, Sumire and Grishkovskaya, Irina and Kircheva, Nikoleta and Angelova, Silvia E. and Wenzl, Karoline and Brandstätter, Andreas and Veis, Jiri and Miočić-Stošić, Fran and Anrather, Dorothea and Hartl, Markus and Truebestein, Linda and Cerron-Alvan, Luis M. and Leeb, Martin and Žagrović, Bojan and Hann, Stephan and Bock, Christoph and Ogris, Egon and Dudev, Todor and Irwin, Nicholas A. T. and Haselbach, David and Leonard, Thomas A.}, doi = {10.1073/pnas.2417218122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2417218122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PHLPP2 is a pseudophosphatase that lost activity in the metazoan ancestor}, volume = {122}, year = {2025}, }
• (2025). Critical dynamics predicts cognitive performance and provides a common framework for heterogeneous mechanisms impacting cognition. PNAS, 122(14), e2417117122. (www)

  @article{ , abstract = {The brain criticality hypothesis postulates that brain dynamics are set at a phase transition where information processing is optimized. Long-range temporal correlations (TCs) characterizing the dissipation of information within a signal have been shown to be a hallmark of brain criticality. However, the experimental link between cognitive performance, criticality, and thus TCs has remained elusive due to limitations in recording length and spatial and temporal resolution. In this study, we investigate multiday invasive EEG recordings of 104 persons with epilepsy (PwE) together with an extensive cognitive test battery. We show that short TCs predict cognitive impairment. Further, we show that heterogeneous factors, including interictal epileptiform discharges (IEDs), antiseizure medications (ASMs), and intermittent periods with slow-wave activity (SWSs), all act directly to perturb critical dynamics and thus cognition. Our work suggests critical dynamics to be the setpoint to measure optimal network function, thereby providing a unifying framework for the heterogeneous mechanisms impacting cognition in conditions like epilepsy.}, archive = {J_PNAS}, author = {Müller, Paul Manuel and Miron, Gadi and Holtkamp, Martin and Meisel, Christian}, doi = {10.1073/pnas.2417117122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2417117122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Critical dynamics predicts cognitive performance and provides a common framework for heterogeneous mechanisms impacting cognition}, volume = {122}, year = {2025}, }
• (2025). Lung b cells in ectopic germinal centers undergo affinity maturation. PNAS, 122(14), e2416855122. (www)

  @article{ , abstract = {The lungs are constantly exposed to the external environment and a myriad of antigenic challenges within the air. Chronic exposure to allergens and other airborne antigens can result in the formation of lymphocyte aggregates in the lung, which can harbor ectopic germinal centers (GCs). After allergen exposure, GCs that form in the lung are much smaller and less densely packed with B cells than lymph node GCs. Despite this, ectopic lung GCs support somatic hypermutation and affinity-based maturation as in lymph node GCs, and export memory B cells (MBCs) directly into the lung tissue. This demonstrates that the lung can locally diversify B cell responses and supports the generation of tissue MBC populations in situ.}, archive = {J_PNAS}, author = {Guillaume, Stephane M. and Foster, William S. and San Martín Molina, Isabel and Watson, Emily M. and Innocentin, Silvia and Kennedy, Grant M. and Denton, Alice E. and Linterman, Michelle A.}, doi = {10.1073/pnas.2416855122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2416855122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lung b cells in ectopic germinal centers undergo affinity maturation}, volume = {122}, year = {2025}, }
• (2025). Phosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5. PNAS, 122(14), e2416738122. (www)

  @article{ , abstract = {The human voltage-gated potassium channels KCNQ2, KCNQ3, and KCNQ5 can form homo- and heterotetrameric channels that are responsible for generating the neuronal M current and maintaining the membrane potential stable. Activation of KCNQ channels requires both the depolarization of membrane potential and phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Here, we report cryoelectron microscopy structures of the human KCNQ5–calmodulin (CaM) complex in the apo, PIP 2 -bound, and both PIP 2 - and the activator HN37-bound states in either a closed or an open conformation. In the closed conformation, a PIP 2 molecule binds in the middle of the groove between two adjacent voltage-sensing domains (VSDs), whereas in the open conformation, one additional PIP 2 binds to the interface of VSD and the pore domain, accompanying structural rearrangement of the cytosolic domain of KCNQ and CaM. The structures, along with electrophysiology analyses, reveal the two different binding modes of PIP 2 and elucidate the PIP 2 activation mechanism of KCNQ5.}, archive = {J_PNAS}, author = {Yang, Zhenni and Zheng, Yueming and Ma, Demin and Wang, Long and Zhang, Jiatong and Song, Tiefeng and Wang, Yong and Zhang, Yan and Nan, Fajun and Su, Nannan and Gao, Zhaobing and Guo, Jiangtao}, doi = {10.1073/pnas.2416738122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2416738122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5}, volume = {122}, year = {2025}, }
• (2025). Childhood muscle growth: Reference curves for lower leg muscle volumes and their clinical application in cerebral palsy. PNAS, 122(14), e2416660122. (www)

  @article{ , abstract = {Skeletal muscles grow substantially during childhood. However, quantitative information about the size of typically developing children’s muscles is sparse. Here, the objective was to construct muscle-specific reference curves for lower leg muscle volumes in children aged 5 to 15 y. Volumes of 10 lower leg muscles were measured from magnetic resonance images of 208 typically developing children and 78 ambulant children with cerebral palsy. Deep learning was used to automatically segment the images. Reference curves for typical childhood muscle volumes were constructed with quantile regression. The median total leg muscle volume of a 15-y-old child is nearly five times that of a 5-y-old child. Between the ages of 5 and 15, boys typically have larger muscles than girls, both in absolute terms (medians are greater by 5 to 20%) and per unit of body weight (1 to 13%). Muscle volumes vary widely between children of a particular age: the range of volumes for the central 80% of the distribution (i.e., between the 10th and 90th centiles) is more than 40% of the median volume. Reference curves for individual muscle volumes have a similar shape to reference curves for total lower leg muscle volume. Confidence bands about the centile curves were wide, especially at the youngest and oldest ages. Nonetheless, the reference curves can be used with confidence to identify small-for-age muscles (centile < 10). We show that 56% of children with cerebral palsy in our cohort had total lower leg muscle volumes that were small-for-age and that 80% had at least one lower leg muscle that was small-for-age.}, archive = {J_PNAS}, author = {Bolsterlee, Bart and Chow, Brian V. Y. and Yu, Jonathan and Davies, Suzanne and Morgan, Catherine and Rae, Caroline D. and Warton, David I. and Novak, Iona and Lancaster, Ann and Popovic, Gordana C. and Rizzo, Rodrigo R. N. and Rizzo, Claudia Y. and Ball, Iain K. and Herbert, Robert D.}, doi = {10.1073/pnas.2416660122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2416660122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Childhood muscle growth: Reference curves for lower leg muscle volumes and their clinical application in cerebral palsy}, volume = {122}, year = {2025}, }
• (2025). Demographic interactions between the last hunter-gatherers and the first farmers. PNAS, 122(14), e2416221122. (www)

  @article{ , abstract = {Demographic interaction processes play a pivotal role during episodes of cultural diffusion between different populations, particularly when these episodes can lead to competition for the same resources and geographic space. The diffusion of farming is one prototypical case within this broader scenario, where groups of incumbent hunter-gatherers occupied a space which would later be claimed by expanding farmers. In this work, we tackle such processes through a two-population mathematical model, where farmers and foragers compete and interact in the same geographic space. We present this work as a conceptual approach where, first, we assess the implications of our theoretical model and its general applicability and, second, we empirically test it on three case studies: Denmark, Eastern Iberia, and the island of Kyushu (Japan). While these regional case studies do not encompass the full range of processes observed in the interaction between migrant farmers and incumbent hunter-gatherers they provide reasonable variation to illustrate how our model can be fitted to a diverse range of empirical data and provide insights into these demographic processes. In particular, our theoretical model and case studies illustrate how endogenous interaction processes alone can explain the demographic fluctuations observed in the archaeological record during this transition, highlighting how these should be accounted for before invoking external forces as primary drivers.}, archive = {J_PNAS}, author = {Cortell-Nicolau, Alfredo and Rivas, Javier and Crema, Enrico R. and Shennan, Stephen and García-Puchol, Oreto and Kolář, Jan and Staniuk, Robert and Timpson, Adrian}, doi = {10.1073/pnas.2416221122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2416221122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Demographic interactions between the last hunter-gatherers and the first farmers}, volume = {122}, year = {2025}, }
• (2025). Anatomy of a range contraction: Flow–phenology mismatches threaten salmonid fishes near their trailing edge. PNAS, 122(14), e2415670122. (www)

  @article{ , abstract = {Climate change is redistributing life on Earth, with profound impacts for ecosystems and human well-being. While repeat surveys separated by multidecadal intervals can determine whether observed shifts are in the expected direction (e.g., poleward or upslope due to climate change), they do not reveal their mechanisms or time scales: whether they were gradual responses to environmental trends or punctuated responses to disturbance events. Here, we document population reductions and temporary range contractions at multiple sites resulting from drought for three Pacific salmonids at their ranges’ trailing edge. During California’s 2012 to 2016 historic multiyear drought, the 2013 to 2014 winter stood apart because rainfall was both reduced and delayed. Extremely low river flows during the breeding season (“flow–phenology mismatch”) reduced or precluded access to breeding habitat. While Chinook ( Oncorhynchus tshawytscha) experienced a down-river range shift, entire cohorts failed in individual tributaries (steelhead trout, O. mykiss ) and in entire watersheds (coho salmon, O. kisutch) . Salmonids returned to impacted sites in subsequent years, rescued by reserves in the ocean, life history diversity, and, in one case, a conservation broodstock program. Large population losses can, however, leave trailing-edge populations vulnerable to extinction due to demographic stochasticity, making permanent range contraction more likely. When only a few large storms occur during high flow season, the timing of particular storms plays an outsized role in determining which migratory fish species are able to access their riverine breeding grounds and persist.}, archive = {J_PNAS}, author = {Carlson, Stephanie M. and Pregler, Kasey C. and Obedzinski, Mariska and Gallagher, Sean P. and Rhoades, Suzanne J. and Woelfle-Hazard, Cleo and Queener, Nathan and Thompson, Sally E. and Power, Mary E.}, doi = {10.1073/pnas.2415670122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2415670122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Anatomy of a range contraction: Flow–phenology mismatches threaten salmonid fishes near their trailing edge}, volume = {122}, year = {2025}, }
• (2025). Reconciling ecology and evolutionary game theory or “When not to think cooperation”. PNAS, 122(14), e2413847122. (www)

  @article{ , abstract = {Evolutionary game theory (EGT)—overwhelmingly employed today for the study of cooperation in various systems, from microbes to cancer and from insect to human societies—started with the seminal 1973 paper by Maynard Smith and Price showing that limited animal conflict can be selected at the individual level. Owing to the explanatory potential of this paper and enabled by the powerful machinery of the soon-to-be-developed replicator dynamics, EGT took off at an accelerated pace and began to shape expectations across systems and scales. But, even as EGT has expanded its reach, and even as its mathematical foundations expanded with the development of adaptive dynamics and inclusion of stochastic processes, the replicator equation remains, half a century later, its most widely used equation. Owing to its early development and its staying power, the replicator dynamics has helped set both the baseline expectations and the terminology of the field. However, much like the original 1973 paper, replicator dynamics rests on the assumption that individual differences in reproduction are determined only by the payoff from the game (i.e., in isolation, all individuals, regardless of their strategy, have identical intrinsic growth rates). Here, we argue that this assumption limits the scope of replicator dynamics to such an extent as to warrant not just a more deliberative application process, but also a reconsideration of the broad predictions and terminology that it has generated. Simultaneously, we reestablish a dialog with ecology that can be mutually fruitful, e.g., by providing an explanation for how diverse ecological communities can assemble evolutionarily.}, archive = {J_PNAS}, author = {Tarnita, Corina E. and Traulsen, Arne}, doi = {10.1073/pnas.2413847122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2413847122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reconciling ecology and evolutionary game theory or “When not to think cooperation”}, volume = {122}, year = {2025}, }
• (2025). The histone variant H2A.W restricts heterochromatic crossovers in arabidopsis. PNAS, 122(14), e2413698122. (www)

  @article{ , abstract = {Meiotic crossovers rearrange allele combinations and create offspring diversity. Crossovers occur nonrandomly along chromosomes, predominantly in distal euchromatin and less in pericentromeric heterochromatin marked with histone H3 lysine 9 dimethylation (H3K9me2) and the H2A variant H2A.W in Arabidopsis thaliana . Loss of H3K9me2 increases heterochromatic crossovers, but how H2A.W affects crossover formation in pericentromeric regions is unknown. Here, we report that H2A.W is required to restrict heterochromatic crossovers in Arabidopsis . Using meiosis-specific microRNA-induced gene silencing (meiMIGS) and fluorescence-tagged recombination reporters, we show that meiotic knockdown of H2A.W.6 , H2A.W.7 , and H2A.W.12 ( meiMIGS-H2A.W.6/7/12 ) increases pericentromeric crossovers. High-resolution genomic maps of crossovers show that meiMIGS-H2A.W.6/7/12 enhances heterochromatic crossovers, similar to meiMIGS plants silencing the H3K9me2 pathway. Consistently, genome-wide crossover maps show that the mutants h2a.w.6 , h2a.w.7 , h2a.w.6 h2a.w.7 , and h2a.w.6 h2a.w.7 h2a.w.12, but not h2a.w.12, exhibit a similar increase in heterochromatic crossovers to meiMIGS-H2A.W.6/7/12 , demonstrating that H2A.W.6 and H2A.W.7 limit heterochromatic crossovers. Profiling of genome-wide nucleosome density using micrococcal nuclease sequencing reveals that h2a.w mutants with increased heterochromatic crossovers have increased heterochromatin accessibility, with lower H3K9me2 levels during meiosis. Our findings shed light on the role of H2A.W variants as heterochromatin compaction factors that suppress meiotic crossovers within the pericentromeric regions.}, archive = {J_PNAS}, author = {Son, Namil and Kim, Heejin and Kim, Jaeil and Park, Jihye and Byun, Dohwan and Park, Sang-jun and Kim, Hyein and Park, Yeong Mi and Bourguet, Pierre and Berger, Frédéric and Choi, Kyuha}, doi = {10.1073/pnas.2413698122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2413698122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The histone variant H2A.W restricts heterochromatic crossovers in arabidopsis}, volume = {122}, year = {2025}, }
• (2025). Quirks of cognition explain why we dramatically overestimate the size of minority groups. PNAS, 122(14), e2413064122. (www)

  @article{ , abstract = {Americans dramatically overestimate the size of African American, Latino, Muslim, Asian, Jewish, immigrant, and LGBTQ populations, leading to concerns about downstream racial attitudes and policy preferences. Such errors are common whenever the public is asked to estimate proportions relevant to political issues, from refugee crises and polarization to climate change and COVID-19. Researchers across the social sciences interpret these errors as evidence of widespread misinformation that is topic-specific and potentially harmful. Here, we show that researchers and journalists have misinterpreted the origins and meaning of these misestimates by overlooking systematic distortions introduced by the domain-general psychological processes involved in estimating proportions under uncertainty. In general, people systematically rescale estimates of proportions toward more central prior expectations, resulting in the consistent overestimation of smaller groups and underestimation of larger groups. We formalize this process and show that it explains much of the systematic error in estimates of demographic groups ( N = 100 , 170 estimates from 22 countries). This domain-general account far outperforms longstanding group-specific explanations (e.g., biases toward specific groups). We find, moreover, that people make the same errors when estimating the size of racial, nonracial, and entirely nonpolitical groups, such as the proportion of Americans who have a valid passport or own a washing machine. Our results call for researchers, journalists, and pundits alike to reconsider how to interpret misperceptions about the demographic structure of society.}, archive = {J_PNAS}, author = {Guay, Brian and Marghetis, Tyler and Wong, Cara and Landy, David}, doi = {10.1073/pnas.2413064122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2413064122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quirks of cognition explain why we dramatically overestimate the size of minority groups}, volume = {122}, year = {2025}, }
• (2025). Signaling networks in cancer stromal senescent cells establish malignant microenvironment. PNAS, 122(14), e2412818122. (www)

  @article{ , abstract = {The tumor microenvironment (TME) encompasses various cell types, blood and lymphatic vessels, and noncellular constituents like extracellular matrix (ECM) and cytokines. These intricate interactions between cellular and noncellular components contribute to the development of a malignant TME, such as immunosuppressive, desmoplastic, angiogenic conditions, and the formation of a niche for cancer stem cells, but there is limited understanding of the specific subtypes of stromal cells involved in this process. Here, we utilized p16-Cre ERT2 -tdTomato mouse models to investigate the signaling networks established by senescent cancer stromal cells, contributing to the development of a malignant TME. In pancreatic ductal adenocarcinoma (PDAC) allograft models, these senescent cells were found to promote cancer fibrosis, enhance angiogenesis, and suppress cancer immune surveillance. Notably, the selective elimination of senescent cancer stromal cells improves the malignant TME, subsequently reducing tumor progression in PDAC. This highlights the antitumor efficacy of senolytic treatment alone and its synergistic effect when combined with conventional chemotherapy. Taken together, our findings suggest that the signaling crosstalk among senescent cancer stromal cells plays a key role in the progression of PDAC and may be a promising therapeutic target.}, archive = {J_PNAS}, author = {Zhang, Yue and Wang, Teh-Wei and Tamatani, Maho and Zeng, Xinyi and Nakamura, Lindo and Omori, Satotaka and Yamaguchi, Kiyoshi and Hatakeyama, Seira and Shimizu, Eigo and Yamazaki, Satoshi and Furukawa, Yoichi and Imoto, Seiya and Johmura, Yoshikazu and Nakanishi, Makoto}, doi = {10.1073/pnas.2412818122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2412818122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Signaling networks in cancer stromal senescent cells establish malignant microenvironment}, volume = {122}, year = {2025}, }
• (2025). Cotranslational membrane insertion of the voltage-sensitive k+ channel KvAP. PNAS, 122(14), e2412492122. (www)

  @article{ , abstract = {Voltage-sensor domains (VSDs), found in many voltage-sensitive ion channels and enzymes, are composed of four transmembrane helices (TMHs), including the atypical, highly positively charged S4 helix. VSDs are cotranslationally inserted into the membrane, raising the question of how the highly charged S4 helix is integrated into the lipid bilayer as it exits the ribosome. Here, we have used force profile analysis (FPA) to follow the cotranslational insertion of the six-TMH KvAP voltage-sensitive ion channel into the Escherichia coli inner membrane. We find that the insertion process proceeds through three semi-independent steps: i) insertion of the S1-S2 helix hairpin, ii) insertion of the S3-S5 helices, and iii) insertion of the Pore and S6 helices. Our analysis highlights the importance of the concerted insertion of helical hairpins, the dramatic influence of the positively charged residues in S4, and the unexpectedly strong forces and effects on downstream TMHs elicited by amphipathic and re-entrant helices.}, archive = {J_PNAS}, author = {Westerfield, Justin M. and Kozojedová, Petra and Juli, Cara and Metola, Ane and von Heijne, Gunnar}, doi = {10.1073/pnas.2412492122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2412492122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cotranslational membrane insertion of the voltage-sensitive k+ channel KvAP}, volume = {122}, year = {2025}, }
• (2025). The cingulate cortex facilitates auditory perception under challenging listening conditions. PNAS, 122(14), e2412453122. (www)

  @article{ , abstract = {We often exert greater cognitive resources (i.e., listening effort) to understand speech under challenging acoustic conditions. This mechanism can be overwhelmed in those with hearing loss, resulting in cognitive fatigue in adults and potentially impeding language acquisition in children. However, the neural mechanisms that support listening effort are uncertain. Evidence from human studies suggests that the cingulate cortex is engaged under difficult listening conditions and may exert top–down modulation of the auditory cortex (AC). Here, we asked whether the gerbil cingulate cortex (Cg) sends anatomical projections to the AC that facilitate perceptual performance. To model challenging listening conditions, we used a sound discrimination task in which stimulus parameters were presented in either “Easy” or “Hard” blocks (i.e., long or short stimulus duration, respectively). Gerbils achieved statistically identical psychometric performance in Easy and Hard blocks. Anatomical tracing experiments revealed a strong, descending projection from layer 2/3 of the Cg1 subregion of the cingulate cortex to superficial and deep layers of the primary and dorsal AC. To determine whether Cg improves task performance under challenging conditions, we bilaterally infused muscimol to inactivate Cg1 and found that psychometric thresholds were degraded for only Hard blocks. To test whether the Cg-to-AC projection facilitates task performance, we chemogenetically inactivated these inputs and found that performance was only degraded during Hard blocks. Taken together, the results reveal a descending cortical pathway that facilitates perceptual performance during challenging listening conditions.}, archive = {J_PNAS}, author = {Anbuhl, Kelsey L. and Diez Castro, Marielisa and Lee, Nikki A. and Lee, Vivian S. and Sanes, Dan H.}, doi = {10.1073/pnas.2412453122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2412453122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The cingulate cortex facilitates auditory perception under challenging listening conditions}, volume = {122}, year = {2025}, }
• (2025). Stability of the cnidarian–dinoflagellate symbiosis is primarily determined by symbiont cell-cycle arrest. PNAS, 122(14), e2412396122. (www)

  @article{ , abstract = {The cnidarian–dinoflagellate symbiosis relies on the regulation of resident symbiont populations to maintain biomass stability; however, the relative importance of host regulatory mechanisms [cell-cycle arrest (CC), apoptosis (AP), autophagy (AU), and expulsion (EX)] during symbiosis onset and maintenance is largely unknown. Here, we inoculated a symbiont-free (aposymbiotic) model cnidarian ( Exaiptasia diaphana : “Aiptasia”) with either its native symbiont Breviolum minutum or one of three non-native symbionts: Symbiodinium microadriaticum , Cladocopium goreaui, and Durusdinium trenchii . We then measured and compared host AP, host AU, symbiont EX, and symbiont cell-cycle phase for up to a year with these different symbionts and used these discrete measurements to inform comparative models of symbiont population regulation. Our models showed a general pattern, where regulation through AP and AU is reduced after onset, followed by an overshoot of the symbiont population that requires a strong regulatory response, dealt with by strong CC and increased EX. As colonization progresses into symbiosis maintenance, CC remains crucial for achieving steady-state symbiont populations, with our models estimating that CC regulates 10-fold more cells (60 to 90%) relative to the other mechanisms. Notably though, our models also revealed that D. trenchii is less tightly regulated than B. minutum , consistent with D. trenchii’s reputation as a suboptimal partner for this cnidarian. Overall, our models suggest that single regulatory mechanisms do not accurately replicate observed symbiont colonization patterns, reflecting the importance of all mechanisms working concomitantly. This ultimately sheds light on the cell biology underpinning the stability of this ecologically significant symbiosis.}, archive = {J_PNAS}, author = {Gorman, Lucy M. and Tivey, Trevor R. and Raymond, Evan H. and Ashley, Immy A. and Oakley, Clinton A. and Grossman, Arthur R. and Weis, Virginia M. and Davy, Simon K.}, doi = {10.1073/pnas.2412396122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2412396122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stability of the cnidarian–dinoflagellate symbiosis is primarily determined by symbiont cell-cycle arrest}, volume = {122}, year = {2025}, }
• (2025). Phenotypic changes of auditory nerve fibers after excitotoxicity. PNAS, 122(14), e2412332122. (www)

  @article{ , abstract = {There is a substantial body of evidence elucidating the pathophysiological aspects of excitotoxicity in the mammalian cochlea. However, the question of whether the resultant damage is reversible remains unresolved. To replicate an excitotoxic event, we investigated the long-term effects of kainate application in gerbil cochleae. Surprisingly, despite persistent synapse loss, the compound action potential of the auditory nerve fully recovered. This functional retrieval was associated with a phenotypic change in auditory nerve fibers. Thresholds were improved along the tonotopic axis. High-spontaneous rate (SR) fibers largely populated the apical region, while low-SR fibers from the basal region exhibited sound-driven activity indistinguishable from control high-SR fibers. This functional phenotype change may support the full recovery of neural response thresholds and amplitudes after excitotoxicity. Furthermore, hyperresponsiveness of the auditory nerve fibers could be a crucial factor in the development of hyperactivity in the central auditory pathways, a common occurrence following acoustic overstimulation.}, archive = {J_PNAS}, author = {Diuba, Artem and Gratias, Paul and Jeffers, Penelope W. C. and Nouvian, Régis and Puel, Jean-Luc and Kujawa, Sharon G. and Bourien, Jérôme}, doi = {10.1073/pnas.2412332122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2412332122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phenotypic changes of auditory nerve fibers after excitotoxicity}, volume = {122}, year = {2025}, }
• (2025). DDX54 downregulation enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden. PNAS, 122(14), e2412310122. (www)

  @article{ , abstract = {High tumor mutational burden (TMB-H) is a predictive biomarker for the responsiveness of cancer to immune checkpoint inhibitor (ICI) therapy that indicates whether immune cells can sufficiently recognize cancer cells as nonself. However, about 30% of all cancers from The Cancer Genome Atlas (TCGA) are classified as immune-desert tumors lacking T cell infiltration despite TMB-H. Since the underlying mechanism of these immune-desert tumors has yet to be unraveled, there is a pressing need to transform such immune-desert tumors into immune-inflamed tumors and thereby enhance their responsiveness to anti-PD1 therapy. Here, we present a systems framework for identifying immuno-oncotargets, based on analysis of gene regulatory networks, and validating the effect of these targets in transforming immune-desert into immune-inflamed tumors. In particular, we identify DEAD-box helicases 54 (DDX54) as a master regulator of immune escape in immune-desert lung cancer with TMB-H and show that knockdown of DDX54 can increase immune cell infiltration and lead to improved sensitivity to anti-PD1 therapy.}, archive = {J_PNAS}, author = {Gong, Jeong-Ryeol and Lee, Jungeun and Han, Younghyun and Cho, Kwang-Hyun}, doi = {10.1073/pnas.2412310122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2412310122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {DDX54 downregulation enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden}, volume = {122}, year = {2025}, }
• (2025). LMX1B missense-perturbation of regulatory element footprints disrupts serotonergic forebrain axon arborization. PNAS, 122(14), e2411716122. (www)

  @article{ , abstract = {Pathogenic coding mutations are prevalent in human neuronal transcription factors (TFs) but how they disrupt development is poorly understood. Lmx1b is a master transcriptional regulator of postmitotic Pet1 neurons that give rise to mature serotonin (5-HT) neurons; over two hundred pathogenic heterozygous mutations have been discovered in human LMX1B, yet their impact on brain development has not been investigated. Here, we developed mouse models with different LMX1B DNA-binding missense mutations. Missense heterozygosity broadly altered Pet1 neuron transcriptomes, but expression changes converged on axon and synapse genes. Missense heterozygosity effected highly specific deficits in the postnatal maturation of forebrain serotonin axon arbors, primarily in the hippocampus and motor cortex, which was associated with spatial memory defects. Digital genomic footprinting (DGF) revealed that missense heterozygosity caused complete loss of Lmx1b motif protection and chromatin accessibility at sites enriched for a distal active enhancer/active promoter histone signature and homeodomain binding motifs; at other bound Lmx1b motifs, varying levels of losses, gains, or no change in motif binding and accessibility were found. The spectrum of footprint changes was strongly associated with synapse and axon genes. Further, Lmx1b missense heterozygosity caused wide disruption of Lmx1b-dependent GRNs comprising diverse TFs expressed in Pet1 neurons. These findings reveal an unanticipated continuum of Lmx1b missense-forced perturbations on Pet1 neuron regulatory element TF binding and accessibility. Our work illustrates DGF’s utility for gaining unique insight into how expressed TF missense mutations interfere with developing neuronal GRNs.}, archive = {J_PNAS}, author = {Eastman, Brent and Tabuchi, Nobuko and Zhang, Xinrui L. and Spencer, William C. and Deneris, Evan S.}, doi = {10.1073/pnas.2411716122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2411716122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {LMX1B missense-perturbation of regulatory element footprints disrupts serotonergic forebrain axon arborization}, volume = {122}, year = {2025}, }
• (2025). The hippo pathway and p27Kip1 cooperate to suppress mitotic regeneration in the organ of corti and the retina. PNAS, 122(14), e2411313122. (www)

  @article{ , abstract = {The mature mammalian auditory sensory organ, the organ of Corti (OC), lacks the capacity for regenerating hair cells, leading to permanent hearing impairment. In contrast, the vestibular system has a limited capacity for hair cell regeneration, which we have shown to be further enhanced by inhibiting the Hippo pathway. Here, we demonstrate that, despite similar transcriptional responses, only vestibular and not auditory supporting cells proliferate as a result of Yap activation following Hippo inhibition. Mechanistically, we identify p27 Kip1 , a cell cycle kinase inhibitor encoded by Cdkn1b , as an additional barrier preventing cell cycle reentry specifically in the OC. We show that while in both systems Yap stimulates p27 Kip1 degradation through activation of its direct target gene Skp2 , this protein-level control is antagonized by an unusually high level of Cdkn1b transcription in the cochlea. Consequently, p27 Kip1 activity is maintained in the OC even in the presence of constitutively active Yap5SA, counteracting its mitogenic effects. Supporting this model, inactivation of the Hippo pathway in the Cdkn1b -deficient background is sufficient to induce adult auditory supporting cell proliferation in vivo. Furthermore, we show that the synergistic interaction between Hippo and p27 Kip1 is conserved in the retina where inhibition of both pathways potently induces Müller glia proliferation and initiates neuronal regeneration. Our work uncovers the molecular mechanism preventing quiescent adult sensory progenitor cells, supporting cells in the ear and Müller glia in the eye, from reentering the cell cycle after damage—the key step toward sensory receptor regeneration blocked in mammals.}, archive = {J_PNAS}, author = {Jahanshir, Eva and Llamas, Juan and Kim, Yeeun and Biju, Kevin and Oak, Sanyukta and Gnedeva, Ksenia}, doi = {10.1073/pnas.2411313122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2411313122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The hippo pathway and p27Kip1 cooperate to suppress mitotic regeneration in the organ of corti and the retina}, volume = {122}, year = {2025}, }
• (2025). Reactivation of memory-associated neurons induces downstream suppression of competing neuronal populations. PNAS, 122(14), e2410101122. (www)

  @article{ , abstract = {Inducing apparent memory recall by tagging and optogenetically reactivating cells in the hippocampus was demonstrated over a decade ago. However, the hippocampal dynamics resulting from this reactivation remain largely unknown. While calcium imaging is commonly used as a measure of neuronal activity, GCaMP, the most common calcium indicator, cannot be used with optogenetic neuronal reactivation because both require blue light excitation. To resolve this overlap, we demonstrate optogenetic reactivation with a red-shifted opsin, ChrimsonR. We then conduct dual-color calcium imaging in CA1 during memory reactivation in DG. In addition to measuring population dynamics in CA1, CA1 cells tagged during the original experience were identified. In the fear-conditioned animals (FC+), nontagged cells in CA1 decreased their firing rate during stimulation, while tagged cells maintained their activity level. In the FC+ animals, as the behavioral effect of stimulation decreased across days, so did the changes in neural activity during stimulation. Our results both demonstrate the technical feasibility of calcium imaging during optogenetic reactivation of memory-associated neurons and advance our understanding of the dynamics underlying this reactivation.}, archive = {J_PNAS}, author = {Norman, Jacob F. and Rahsepar, Bahar and Vena, Anna and Thunemann, Martin and Devor, Anna and Ramirez, Steve and White, John A.}, doi = {10.1073/pnas.2410101122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2410101122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reactivation of memory-associated neurons induces downstream suppression of competing neuronal populations}, volume = {122}, year = {2025}, }
• (2025). A mechanically resilient soft hydrogel improves drug delivery for treating post-traumatic osteoarthritis in physically active joints. PNAS, 122(14), e2409729122. (www)

  @article{ , abstract = {Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in the early stages of post-traumatic osteoarthritis (PTOA), when symptoms are minimal, and patients remain physically active. To ensure effective therapy, DMOAD delivery systems therefore must withstand repeated mechanical loading without altering the kinetics of drug release. While soft materials are typically preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt controlled drug release. In this study, we present a mechanically resilient soft hydrogel that rapidly self-heals under conditions simulating human running while maintaining sustained release of the cathepsin-K inhibitor L-006235, used as a proof-of-concept DMOAD. This hydrogel demonstrated superior performance compared to a previously reported hydrogel designed for intra-articular drug delivery, which, in our study, neither recovered its structure nor maintained drug release under mechanical loading. When injected into mouse knee joints, the hydrogel provided consistent release kinetics of the encapsulated drug in both treadmill-running and nonrunning mice. In a mouse model of severe PTOA exacerbated by treadmill-running, the L-006235 hydrogel significantly reduced cartilage degeneration, whereas the free drug did not. Overall, our data underscore the hydrogel’s potential for treating PTOA in physically active patients.}, archive = {J_PNAS}, author = {Joshi, Nitin and Yan, Jing and Dang, Mickael and Slaughter, Kai and Wang, Yufeng and Wu, Dana and Ung, Trevor and Bhingaradiya, Nutan and Pandya, Virja and Chen, Mu Xian and Kaur, Shahdeep and Bhagchandani, Sachin and Alfassam, Haya A. and Joseph, John and Gao, Jingjing and Dewani, Mahima and Chu, Rachel Wai Chun and Yip, Ryan Chak Sang and Weldon, Eli and Shah, Purna and Pisal, Nishkal Dhiraj and Shukla, Chetan and Sherman, Nicholas E. and Luo, James N. and Conway, Thomas and Eickhoff, James P. and Botelho, Luis and Alhasan, Ali H. and Karp, Jeffrey M. and Ermann, Joerg}, doi = {10.1073/pnas.2409729122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2409729122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A mechanically resilient soft hydrogel improves drug delivery for treating post-traumatic osteoarthritis in physically active joints}, volume = {122}, year = {2025}, }
• (2025). Onboard recordings reveal how bats maneuver under severe acoustic interference. PNAS, 122(14), e2407810122. (www)

  @article{ , abstract = {Echolocating bats rely on active acoustic sensing to perceive their environment. When multiple bats fly together, echolocating simultaneously, the calls emitted by nearby conspecifics could interfere with and mask the echoes necessary for orientation. Nowhere is this impairment of sensing more dramatic than when thousands of bats emerge from a cave at the same time. Here, we tracked the movement of tens of greater mouse-tailed bats flying within a group of thousands. By mounting miniature microphones onboard some of the bats, we monitored the acoustic scene from the point of view of an individual bat within the echolocating collective. We found that bats experienced a very high level of conspecific acoustic masking when emerging from their cave, which dropped within seconds as the bats spread out in space. A comprehensive sensorimotor model, based on the unique data that we collected, revealed how bats content with this severe echo masking almost without collisions. Our results demonstrate that even under severe masking, bats are hardly impaired sensorially, and we suggest how they are able to maneuver smoothly and avoid collisions, even at high densities, without applying a jamming avoidance response.}, archive = {J_PNAS}, author = {Goldshtein, Aya and Mazar, Omer and Harten, Lee and Amichai, Eran and Assa, Reut and Levi, Anat and Orchan, Yotam and Toledo, Sivan and Nathan, Ran and Yovel, Yossi}, doi = {10.1073/pnas.2407810122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2407810122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Onboard recordings reveal how bats maneuver under severe acoustic interference}, volume = {122}, year = {2025}, }
• (2025). Prolonged signaling of backbone-modified glucagon‐like peptide‐1 analogues with diverse receptor trafficking. PNAS, 122(14), e2407574122. (www)

  @article{ , abstract = {Signal duration and subcellular location are emerging as important facets of G protein–coupled receptor (GPCR) function. The glucagon-like peptide-1 receptor (GLP-1R), a clinically relevant class B1 GPCR, stimulates production of the second messenger cyclic adenosine monophosphate (cAMP) upon activation by the native hormone, GLP-1. cAMP production continues after the hormone–receptor complex has been internalized via endocytosis. Here, we report GLP-1 analogues that induce prolonged signaling relative to GLP-1. A single β-amino acid substitution at position 18, with the residue derived from ( S , S )- trans -2-aminocyclopentanecarboxylic acid (ACPC), enhances signaling duration with retention of receptor endocytosis. Pairing ACPC at position 18 with a second substitution, α-aminoisobutyric acid (Aib) at position 16, abrogates endocytosis, but prolonged signaling is maintained. Prolonged signaling is sensitive to the structure of the β residue at position 18. Cryoelectron microscopy structures of two GLP-1 analogues bound to the GLP-1R:Gs complex suggest substantial alterations to bound peptide structure and dynamics compared to the GLP-1:GLP-1R:Gs complex. These structural findings strengthen an emerging view that agonist dynamics in the receptor-bound state influence signaling profiles. Our results advance understanding of the structural underpinnings of receptor activation and introduce tools for exploring the impact of spatiotemporal signaling profiles following GLP-1R activation.}, archive = {J_PNAS}, author = {Cary, Brian P. and Hager, Marlies V. and Mariam, Zamara and Morris, Rylie K. and Belousoff, Matthew J. and Deganutti, Giuseppe and Sexton, Patrick M. and Wootten, Denise and Gellman, Samuel H.}, doi = {10.1073/pnas.2407574122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2407574122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prolonged signaling of backbone-modified glucagon‐like peptide‐1 analogues with diverse receptor trafficking}, volume = {122}, year = {2025}, }
• (2025). Transparency by chinese cities reduces pollution violations and improves air quality. PNAS, 122(14), e2406761122. (www)

  @article{ , abstract = {We provide national-scale experimental evidence from China showing that transparency by local governments improves the management of air pollution. Governments that perform better have more reasons to be transparent, making the causal relationship between transparency and policy outcomes difficult to disentangle. In 2015, we randomly assigned municipal governments in China to a high-visibility, public rating of their adherence to national requirements for transparency about their regulation of pollution. By 2016, this treatment significantly boosted transparency in treated cities relative to control cities, allowing us to observe the effect of randomly increasing transparency in the years that followed. Subsequently, high-polluting firms in treated cities cut their violations by 37% compared to similar firms in control cities. Inspections by local governments increased by about 90% in treated cities relative to control cities. Ambient air pollution decreased between 8 and 10% in treated cities relative to control cities, which likely generated significant health benefits. This study provides strong evidence that governmental transparency causes improved environmental quality, at least in a setting where the public and higher governments want to hold local governments accountable.}, archive = {J_PNAS}, author = {Liu, Mengdi and Buntaine, Mark T. and Anderson, Sarah E. and Zhang, Bing}, doi = {10.1073/pnas.2406761122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2406761122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transparency by chinese cities reduces pollution violations and improves air quality}, volume = {122}, year = {2025}, }
• (2025). Dual genetic tracing demonstrates the heterogeneous differentiation and function of neuromesodermal progenitors in vivo. PNAS, 122(14), e2402305122. (www)

  @article{ , abstract = {In recent decades, the traditional paradigm of three distinct germ layers formed during gastrulation has been revised with the identification of neuromesodermal progenitors (NMPs). These progenitors emerge during gastrulation and contribute to both the neural ectoderm, particularly the spinal cord, and the adjacent paraxial mesoderm [D. Henrique et al. , Development 142 , 2864–2875 (2015); R. J. Garriock et al. , Development 142 , 1628–1638 (2015); E. Tzouanacou et al. , Dev. Cell 17 , 365–376 (2009)]. However, effective genetic tools for lineage tracing and functional assessments of NMPs in vivo are currently lacking. Here, we developed a dual recombinase–mediated genetic system to specifically trace and ablate Brachyury + Sox2 + NMPs. Our genetic tracing and single-cell RNA sequencing analyses revealed that NMPs consist of three distinct unipotent and bipotent progenitor populations that progressively differentiate into neural and mesodermal fates. Genetic depletion of NMPs demonstrated their critical role in trunk and tail formation. This study provides in vivo genetic evidence supporting the heterogeneity of NMPs in terms of cell fate determination and their functional roles in the developing embryo.}, archive = {J_PNAS}, author = {Jin, Hengwei and Liu, Zixin and Mou, Jialing and Tang, Muxue and Huang, Xiuzhen and Liu, Kuo and Zhang, Qianyu and Lui, Kathy O. and Zhou, Bin}, doi = {10.1073/pnas.2402305122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2402305122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dual genetic tracing demonstrates the heterogeneous differentiation and function of neuromesodermal progenitors in vivo}, volume = {122}, year = {2025}, }
• (2025). Meltdown of trust in weakly governed economies. PNAS, 122(14), e2320528122. (www)

  @article{ , abstract = {A well-functioning society requires well-functioning institutions that ensure prosperity, fair distribution of wealth, social participation, security, and informative media. Such institutions are built on a foundation of trust. However, while trust is essential for economic success and good governance, interconnected mechanisms inherent in weakly governed market economies tend to undermine the very trust on which such success depends. These mechanisms include the intrinsic tendency for inequality to grow, media to boost perceived unfairness, and self-interest to gain rewards at the expense of others. These mechanisms, if left unchecked, allow wealth concentration to result in state capture where institutions facilitate further wealth concentration instead of the promoting the common good. As a result, people may become alienated and untrusting of fellow citizens and of institutions. Several democracies now experience such dynamics, the United States being a prime example. We discuss ways in which well-functioning democracies can design institutions to help avoid this social trap, and the much harder challenge of escaping the trap once in it. Successful cases such as the ability of Scandinavian democracies to maintain high-trust, and the US progressive era in the early 20th century provide instructive examples.}, archive = {J_PNAS}, author = {Polasky, Stephen and Scheffer, Marten and Anderies, John M.}, doi = {10.1073/pnas.2320528122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {14}, pages = {e2320528122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Meltdown of trust in weakly governed economies}, volume = {122}, year = {2025}, }
• (2025). Climate change impacts have potentially big repercussions for kids’ education. PNAS, 122(13), e2505073122. (www)

  @article{ , archive = {J_PNAS}, author = {Sidik, Saima}, doi = {10.1073/pnas.2505073122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2505073122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Climate change impacts have potentially big repercussions for kids’ education}, volume = {122}, year = {2025}, }
• (2025). Correction for ganguli et al., a culture-free biphasic approach for sensitive and rapid detection of pathogens in dried whole-blood matrix. PNAS, 122(13), e2504650122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504650122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2504650122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for ganguli et al., a culture-free biphasic approach for sensitive and rapid detection of pathogens in dried whole-blood matrix}, volume = {122}, year = {2025}, }
• (2025). Correction for quach et al., deep learning–driven bacterial cytological profiling to determine antimicrobial mechanisms in mycobacterium tuberculosis. PNAS, 122(13), e2504475122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504475122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2504475122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for quach et al., deep learning–driven bacterial cytological profiling to determine antimicrobial mechanisms in mycobacterium tuberculosis}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for walters et al., identification of FSH-regulated and estrous stage–specific transcriptional networks in mouse ovaries. PNAS, 122(13), e2504347122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504347122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2504347122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for walters et al., identification of FSH-regulated and estrous stage–specific transcriptional networks in mouse ovaries}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for wang et al., metabolomic insights into pathogenesis and therapeutic potential in adult acute lymphoblastic leukemia. PNAS, 122(13), e2504173122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504173122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2504173122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for wang et al., metabolomic insights into pathogenesis and therapeutic potential in adult acute lymphoblastic leukemia}, volume = {122}, year = {2025}, }
• (2025). Correction for magesh et al., co-zorbs: Motile, multispecies biofilms aid transport of diverse bacterial species. PNAS, 122(13), e2504171122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504171122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2504171122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for magesh et al., co-zorbs: Motile, multispecies biofilms aid transport of diverse bacterial species}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for struve et al., systematic changes in circumpolar dust transport to the subantarctic pacific ocean over the last two glacial cycles. PNAS, 122(13), e2504158122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504158122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2504158122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for struve et al., systematic changes in circumpolar dust transport to the subantarctic pacific ocean over the last two glacial cycles}, volume = {122}, year = {2025}, }
• (2025). Striking the balance: Complexity, simplicity, and credibility in mathematical biology. PNAS, 122(13), e2504067122. (www)

  @article{ , archive = {J_PNAS}, author = {Rodero, Cristobal and Niederer, Steven A.}, doi = {10.1073/pnas.2504067122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2504067122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Striking the balance: Complexity, simplicity, and credibility in mathematical biology}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for schmidt et al., archaeological adhesives made from podocarpus document innovative potential in the african middle stone age. PNAS, 122(13), e2503875122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2503875122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2503875122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for schmidt et al., archaeological adhesives made from podocarpus document innovative potential in the african middle stone age}, volume = {122}, year = {2025}, }
• (2025). Magnetic suppression of quantum tunneling: Insights from fefferman, shapiro, and weinstein. PNAS, 122(13), e2503477122. (www)

  @article{ , archive = {J_PNAS}, author = {Deift, Percy A.}, doi = {10.1073/pnas.2503477122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2503477122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Magnetic suppression of quantum tunneling: Insights from fefferman, shapiro, and weinstein}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for stransky et al., toward a CRISPR-based mouse model of vhl-deficient clear cell kidney cancer: Initial experience and lessons learned. PNAS, 122(13), e2503473122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2503473122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2503473122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for stransky et al., toward a CRISPR-based mouse model of vhl-deficient clear cell kidney cancer: Initial experience and lessons learned}, volume = {122}, year = {2025}, }
• (2025). Bacteria on steroids. PNAS, 122(13), e2503396122. (www)

  @article{ , archive = {J_PNAS}, author = {Mrnjavac, Natalia and Martin, William F.}, doi = {10.1073/pnas.2503396122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2503396122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bacteria on steroids}, volume = {122}, year = {2025}, }
• (2025). Reply to wang: Improving large language model approaches for identifying social determinants of health from clinical notes. PNAS, 122(13), e2503187122. (www)

  @article{ , archive = {J_PNAS}, author = {Gabriel, Rodney A.}, doi = {10.1073/pnas.2503187122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2503187122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to wang: Improving large language model approaches for identifying social determinants of health from clinical notes}, volume = {122}, year = {2025}, }
• (2025). Social control drove ant evolution. PNAS, 122(13), e2502664122. (www)

  @article{ , archive = {J_PNAS}, author = {Linksvayer, Timothy A.}, doi = {10.1073/pnas.2502664122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2502664122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Social control drove ant evolution}, volume = {122}, year = {2025}, }
• (2025). Reply to deter-wolf et al.: Laser-stimulated fluorescence of chancay tattoos. PNAS, 122(13), e2501912122. (www)

  @article{ , archive = {J_PNAS}, author = {Kaye, Thomas G. and Bąk, Judyta and Marcelo, Henry William and Pittman, Michael}, doi = {10.1073/pnas.2501912122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2501912122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to deter-wolf et al.: Laser-stimulated fluorescence of chancay tattoos}, volume = {122}, year = {2025}, }
• (2025). Explaining human motor coordination via the synergy expansion hypothesis. PNAS, 122(13), e2501705122. (www)

  @article{ , abstract = {The search for an answer to Bernstein’s degrees of freedom problem has propelled a large portion of research studies in human motor control over the past six decades. Different theories have been developed to explain how humans might use their incredibly complex neuro-musculo-skeletal system with astonishing ease. Among these theories, motor synergies appeared as one possible explanation. In this work, the authors investigate the nature and role of synergies and propose a theoretical framework, namely the “expansion hypothesis,” to answer Bernstein’s problem. The expansion hypothesis is articulated in three propositions: mechanical, developmental, and behavioral. Each proposition addresses a different question on the nature of synergies: i) How many synergies can humans have? ii) How do we learn and develop synergies? iii) How do we use synergies? An example numerical simulation is presented and analyzed to clarify the hypothesis propositions. The expansion hypothesis is contextualized with respect to the existing literature on motor synergies both in healthy and impaired individuals, as well as other prominent theories in human motor control and development. The expansion hypothesis provides a framework to better comprehend and explain the nature, use, and evolution of human motor skills.}, archive = {J_PNAS}, author = {Tessari, Federico and West, A. Michael and Hogan, Neville}, doi = {10.1073/pnas.2501705122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2501705122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Explaining human motor coordination via the synergy expansion hypothesis}, volume = {122}, year = {2025}, }
• (2025). Large language models for identifying social determinants of health. PNAS, 122(13), e2501506122. (www)

  @article{ , archive = {J_PNAS}, author = {Wang, Yu}, doi = {10.1073/pnas.2501506122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2501506122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Large language models for identifying social determinants of health}, volume = {122}, year = {2025}, }
• (2025). Laser imaging of ancient tattoos: New tools illuminate established knowledge. PNAS, 122(13), e2501049122. (www)

  @article{ , archive = {J_PNAS}, author = {Deter-Wolf, Aaron and Robitaille, Benoît and Krutak, Lars}, doi = {10.1073/pnas.2501049122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2501049122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Laser imaging of ancient tattoos: New tools illuminate established knowledge}, volume = {122}, year = {2025}, }
• (2025). Nanosilica supplementation in tomato increases oviposition on stems and caterpillar mortality in the tomato pinworm. PNAS, 122(13), e2427314122. (www)

  @article{ , abstract = {Silicon-induced responses play a key role in plant defense against herbivory, though the underlying mechanisms remain underexplored. In this study, we examined how mesoporous silica nanoparticles (MSNs) affect tomato ( Solanum lycopersicum ) defense against an invasive and highly destructive lepidopteran herbivore, the tomato pinworm (TPW), Phthorimaea absoluta . In tomato plants supplemented with MSN, prior exposure to TPW oviposition shifted subsequent egg-laying from a preference for leaves to an even distribution between stems and leaves. This shift was not observed in nonsilicon-supplemented plants. Prolonged oviposition triggered pigmentation in the basal cells of type I glandular trichomes on the stems of silicon-supplemented plants. Chemical analysis by coupled gas chromatography-mass spectrometry revealed that the pigmented trichome was rich in soluble sugars (sucrose and l -arabinose) and waxes, dominated by the saturated hydrocarbon tetracosane. Bioassays with the crude extract of the pigmented trichome and a three-component sugar–wax blend replicated the oviposition and caterpillar response observed with the pigmented trichome, while individual components produced variable effects. While l -arabinose alone replicated the oviposition effects of the three-component sugar–wax blend, sucrose increased oviposition and caterpillar feeding and survival, while l -arabinose and tetracosane caused the highest caterpillar mortality. Additionally, these treatments altered caterpillar gut microbiota composition and influenced frass volatiles, which attracted the TPW natural enemies, Nesidiocoris tenuis (predator) and Neochrysocharis formosa (parasitoid). Our findings suggest that silicon supplementation increases tomato defense against TPW through oviposition-induced responses, which promotes recruitment of natural enemies.}, archive = {J_PNAS}, author = {Fiaboe, Kokou R. and Khamis, Fathiya M. and Cheseto, Xavier and Yusuf, Abdullahi A. and Torto, Baldwyn}, doi = {10.1073/pnas.2427314122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2427314122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nanosilica supplementation in tomato increases oviposition on stems and caterpillar mortality in the tomato pinworm}, volume = {122}, year = {2025}, }
• (2025). Lysosomal PIP3 revealed by genetically encoded lipid biosensors. PNAS, 122(13), e2426929122. (www)

  @article{ , abstract = {3-Phosphoinositides (3-PIs), phosphatidylinositol (3,4) bisphosphate [PI(3,4)P 2 ] and phosphatidylinositol (3,4,5) trisphosphate (PIP 3 ), are important lipid second messengers in the Phosphoinositide 3-Kinase (PI3K)/Akt signaling pathway, which is crucial to cell growth and frequently dysregulated in cancer. Emerging evidence suggests these lipid second messengers may be present in membranes beyond the plasma membrane, yet their spatial regulation within other membrane compartments is not well understood. To dissect the spatial regulation of specific 3-PI species, we developed genetically encodable biosensors with selectivity for PIP 3 or PI(3,4)P 2 . Using these biosensors, we showed that PIP 3 significantly accumulated at the lysosome upon growth factor stimulation, in contrast to the conventional view that PIP 3 is exclusively present in the plasma membrane. Furthermore, we showed that lysosomal PIP 3 originates from the plasma membrane and relies on dynamin-dependent endocytosis for lipid internalization. Thus, PIP 3 can exploit dynamic trafficking pathways to access subcellular compartments and regulate signaling in a spatially selective manner.}, archive = {J_PNAS}, author = {Sahan, Ayse Z. and Chen, Mingyuan and Su, Qi and Li, Qingrong and Wang, Dong and Zhang, Jin}, doi = {10.1073/pnas.2426929122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2426929122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lysosomal PIP3 revealed by genetically encoded lipid biosensors}, volume = {122}, year = {2025}, }
• (2025). Mechanistic insights into dengue virus inhibition by a clinical trial compound NITD-688. PNAS, 122(13), e2426922122. (www)

  @article{ , abstract = {Dengue, caused by the dengue virus (DENV), presents a significant public health challenge with limited effective treatments. NITD-688 is a potent panserotype DENV inhibitor currently in Phase II clinical trials. However, its mechanism of action is not fully understood. Here, we present the molecular details of how NITD-688 inhibits DENV. NITD-688 binds directly to the nonstructural protein 4B (NS4B) with nanomolar affinities across all four DENV serotypes and specifically disrupts the interaction between NS4B and nonstructural protein 3 (NS3) without significantly changing the interactions between NS4B and other viral or host proteins. NS4B mutations that confer resistance to NITD-688 reduce both NITD-688 binding to NS4B and disruption of the NS4B/NS3 interaction. Specifically, NITD-688 blocks the interaction of NS3 with a cytosolic loop within NS4B. This inhibits the formation of new NS4B/NS3 complexes and disrupts preexisting complexes in vitro and DENV-infected cells, ultimately inhibiting viral replication. Consistent with this mechanism, NITD-688 retains greater potency in cellular assays with delayed treatment compared to JNJ-1802, another NS4B inhibitor that has been studied in Phase II clinical trials. Together, these findings provide critical insights into the mechanism of action of NITD-688, facilitating the development of novel flavivirus NS4B inhibitors and informing future clinical interventions against DENV.}, archive = {J_PNAS}, author = {Wang, Yan and Sun, Long and Fernandes, Luciana and Wang, Yu-Hsiu and Zou, Jing and Franklin, Samuel J. and Hu, Yanping and Palmer, Lee K. and Yeung, Jason and Barriga, Daniela and Russell, William K. and Moquin, Stephanie A. and Shi, Pei-Yong and Skepper, Colin and Xie, Xuping}, doi = {10.1073/pnas.2426922122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2426922122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mechanistic insights into dengue virus inhibition by a clinical trial compound NITD-688}, volume = {122}, year = {2025}, }
• (2025). Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination. PNAS, 122(13), e2426786122. (www)

  @article{ , abstract = {We investigated the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in myelin regeneration in the brain. TREM2 is a receptor that activates microglia, which are crucial for clearing myelin debris and promoting remyelination. Previous studies in a mouse model of demyelination induced by the copper-chelating agent Cuprizone (CPZ) have shown that stimulation of TREM2 with a monoclonal antibody reduces demyelination, while deleting the Trem2 gene in mice impairs remyelination. Here, we blocked TREM2 function acutely with an antibody during both the demyelination and remyelination phases of the CPZ model and analyzed the impact of the antibody treatment on myelination and gene expression in single cells. We found that blocking TREM2 depleted a distinct population of microglia with high expression of the transcription factor MAFB during remyelination. The loss of these MAFB-high microglia was linked to impaired generation of myelinating oligodendrocytes. Importantly, we identified MAFB + microglia in acute and acute-chronic brain lesions from individuals with multiple sclerosis (MS), but not in inactive lesions. We conclude that TREM2 is essential for maintaining a population of MAFB-high microglia that is associated with myelin repair. This finding has significant implications for understanding demyelinating diseases like MS and suggests that stimulating TREM2 could be a promising therapeutic approach for myelin repair.}, archive = {J_PNAS}, author = {Hou, Jinchao and Magliozzi, Roberta and Chen, Yun and Wu, Junjie and Wulf, John and Strout, Gregory and Fang, Xiangming and Colonna, Marco}, doi = {10.1073/pnas.2426786122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2426786122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination}, volume = {122}, year = {2025}, }
• (2025). Targeted degradation of α-synuclein using an evolved botulinum toxin protease. PNAS, 122(13), e2426745122. (www)

  @article{ , abstract = {There is considerable interest in the targeted degradation of proteins implicated in human disease. The use of sequence-specific proteases for this purpose is severely limited by the difficulty in engineering the numerous enzyme–substrate interactions required to yield highly selective proteases while maintaining catalytic activity. Herein, we report a strategy to evolve a protease for the programmed degradation of α-Synuclein, a presynaptic protein closely linked to Parkinson’s disease. Our structure-guided evolution campaign uses the protease from botulinum neurotoxin and showcases the stepwise change of specificity from its native substrate SNAP25 to the selective degradation of α-Synuclein. The protease’s selectivity is further demonstrated in human cells where near complete degradation of overexpressed human α-Synuclein is observed with no significant effects on cell proliferation. This stepwise strategy may serve as a general approach to evolve highly selective proteases targeting dysregulated proteins.}, archive = {J_PNAS}, author = {Sondermann, Philipp and Diercks, Christian S. and Rong, Cynthia and Schultz, Peter G.}, doi = {10.1073/pnas.2426745122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2426745122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Targeted degradation of α-synuclein using an evolved botulinum toxin protease}, volume = {122}, year = {2025}, }
• (2025). Allosteric mechanism in the distinctive coupling of gq and gs to the parathyroid hormone type 1 receptor. PNAS, 122(13), e2426178122. (www)

  @article{ , abstract = {The mechanism determining the preferential stimulation of one heterotrimeric G protein signaling pathway over another by a ligand remains undetermined. By reporting the cryogenic electron microscopy (cryo-EM) structure of the parathyroid hormone (PTH) type 1 receptor (PTH1R) complexed with Gq and comparing its allosteric dynamics with that of PTH1R in complex with G s , we uncover a mechanism underlying such preferences. We show that an allosteric coupling between the ligand PTH and the C-terminal helix α5 of the Gα subunit controls the stability of the PTH1R complex with the specific G protein, G s or G q . Single-cell-level experiments further validate the G protein–selective effects of the PTH binding pose by demonstrating the differential, G protein–dependent residence times and affinity of this ligand at the PTH1R binding site. The findings deepen our understanding of the selective coupling of PTH1R to G s or G q and how it relates to the stability and kinetics of ligand binding. They explain the observed variability in the ligand-binding affinity of a GPCR when coupled to different G proteins.}, archive = {J_PNAS}, author = {Zhang, Xuan and Lee, Ji Young and Pacheco, Jonathan and Sutkeviciute, Ieva and Anitha, Anju Krishnan and Liu, Heng and Singh, Stephanie and Ventura, Carlos and Savransky, Sofya and Khatri, Ashok and Zhang, Cheng and Bahar, Ivet and Vilardaga, Jean-Pierre}, doi = {10.1073/pnas.2426178122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2426178122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Allosteric mechanism in the distinctive coupling of gq and gs to the parathyroid hormone type 1 receptor}, volume = {122}, year = {2025}, }
• (2025). De novo discovery of a molecular glue–like macrocyclic peptide that induces MCL1 homodimerization. PNAS, 122(13), e2426006122. (www)

  @article{ , abstract = {Macrocyclic peptides have emerged as promising drug candidates, filling the gap between small molecules and large biomolecules in drug discovery. The antiapoptotic protein myeloid cell leukemia 1 (MCL1) is crucial for numerous cancers, yet it presents challenges for selective targeting by traditional inhibitors. In this study, we identified a macrocyclic peptide, 5L1, that strongly binds to MCL1, with a dissociation constant ( K D ) of 7.1 nM. This peptide shows the potential to specifically inhibit the function of MCL1, and demonstrates effective antitumor activity against several blood tumor cell lines with the half maximal inhibitory concentration (IC 50 ) values for cell-penetrating peptide-conjugated 5L1 in the range of 0.6 to 3 μM. Structural analysis revealed that it functions similarly to molecular glue, capable of binding to two MCL1 molecules simultaneously and inducing their homodimerization. This unique mechanism of action distinguishes it from traditional small-molecule MCL1 inhibitors, underscoring the potential of macrocyclic peptides functioning as molecular glues. Moreover, it inspires the development of highly selective inhibitors targeting MCL1 and other related targets with this glue-like mechanism.}, archive = {J_PNAS}, author = {Li, Fengwei and Zhang, Mengmeng and Liu, Chao and Cheng, Jie and Yang, Yawen and Peng, Xiangda and Li, Zhifeng and Cai, Wenfeng and Yu, Haipeng and Wu, Junjie and Guo, Yuyu and Geng, Hongkun and Fa, Yun and Zhang, Youming and Wu, Dalei and Yin, Yizhen}, doi = {10.1073/pnas.2426006122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2426006122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {De novo discovery of a molecular glue–like macrocyclic peptide that induces MCL1 homodimerization}, volume = {122}, year = {2025}, }
• (2025). Structure of ATP synthase from an early photosynthetic bacterium chloroflexus aurantiacus. PNAS, 122(13), e2425824122. (www)

  @article{ , abstract = {F-type ATP synthase (F 1 F O ) catalyzes proton motive force-driven ATP synthesis in mitochondria, chloroplasts, and bacteria. Different from the mitochondrial and bacterial enzymes, F 1 F O from photosynthetic organisms have evolved diverse structural and mechanistic details to adapt to the light-dependent reactions. Although complete structure of chloroplast F 1 F O has been reported, no high-resolution structure of an F 1 F O from photosynthetic bacteria has been available. Here, we report cryo-EM structures of an intact and functionally competent F 1 F O from Chloroflexus aurantiacus ( Ca F 1 F O ), a filamentous anoxygenic phototrophic bacterium from the earliest branch of photosynthetic organisms. The structures of Ca F 1 F O in its ADP-free and ADP-bound forms for three rotational states reveal a previously unrecognized architecture of ATP synthases. A pair of peripheral stalks connect to the Ca F 1 head through a dimer of δ-subunits, and associate with two membrane-embedded a-subunits that are asymmetrically positioned outside and clamp Ca F O ’s c 10 -ring. The two a-subunits constitute two proton inlets on the periplasmic side and two proton outlets on the cytoplasmic side, endowing Ca F 1 F O with unique proton translocation pathways that allow more protons being translocated relative to single a-subunit F 1 F O . Our findings deepen understanding of the architecture and proton translocation mechanisms of F 1 F O synthases and suggest innovative strategies for modulating their activities by altering the number of a-subunit.}, archive = {J_PNAS}, author = {Zhang, Xin and Wu, Jingyi and Min, Zhenzhen and Wang, Jiamao and Hong, Xin and Pei, Xinkai and Rao, Zihe and Xu, Xiaoling}, doi = {10.1073/pnas.2425824122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2425824122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure of ATP synthase from an early photosynthetic bacterium chloroflexus aurantiacus}, volume = {122}, year = {2025}, }
• (2025). Manipulation of interoceptive signaling biases decision making in rhesus macaques. PNAS, 122(13), e2424680122. (www)

  @article{ , abstract = {Several influential theories have proposed that interoceptive signals, sent from the body to the brain, contribute to neural processes that coordinate complex behaviors. We altered the physiological state of the body using compounds that have minimal effect on the brain and evaluated their effect on decision making in rhesus monkeys. We used glycopyrrolate, a nonspecific muscarinic (parasympathetic) antagonist, and isoproterenol, a beta-1/2 (sympathetic) agonist, to create a sympathetic-dominated state in the periphery, that was indexed by increased heart rate. Rhesus monkeys were trained on two variants of an approach-avoidance conflict task. The tasks offered a choice between enduring mildly aversive stimuli in exchange for a steady flow of rewards, or canceling the aversive stimuli, forgoing the rewards. The latency to interrupt the aversive stimuli was used as a measure of monkeys’ tolerance for contact with a hot but not painful stimulus or airflow directed at their muzzle. Both drugs reduced tolerance for the aversive stimuli. To determine whether the drug-induced autonomic state reduced the subjective value of the reward, we tested the effects of glycopyrrolate on a food preference task. Food preference was unaltered, suggesting that the sympathetic dominated state in the periphery selectively reduces tolerance for aversive stimuli without altering reward-seeking behaviors. As the drugs used are expected to have little or no direct effect on the brain, the observed biases in decision making are likely induced by interoceptive afferents that signal to the brain the physiological state of the body.}, archive = {J_PNAS}, author = {Cardenas, Michael A. and Le, Ryan P. and Champ, Tess M. and O’Neill, Derek and Fuglevand, Andrew J. and Gothard, Katalin M.}, doi = {10.1073/pnas.2424680122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2424680122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Manipulation of interoceptive signaling biases decision making in rhesus macaques}, volume = {122}, year = {2025}, }
• (2025). Cytoplasmic mg2+ supersedes carbon source preference to dictate salmonella metabolism. PNAS, 122(13), e2424337122. (www)

  @article{ , abstract = {Glucose is the preferred carbon source of most studied microorganisms. However, we now report that glucose loses preferred status when the intracellular pathogen Salmonella enterica serovar Typhimurium experiences cytoplasmic magnesium (Mg 2+ ) starvation. We establish that this infection-relevant stress drastically reduces synthesis of cyclic adenosine monophosphate (cAMP), the allosteric activator of the cAMP receptor protein (CRP), master regulator of carbon utilization. The resulting reduction in cAMP concentration, which is independent of carbon source, decreases transcription of CRP-cAMP-activated carbon utilization genes, hinders carbon source uptake, and restricts metabolism, rendering wild-type bacteria phenotypically CRP − . A cAMP-independent allele of CRP overcame the transcriptional, uptake, and metabolic restrictions caused by cytoplasmic Mg 2+ starvation and significantly increased transcription of the glucose uptake gene when S. Typhimurium was inside murine macrophages. The reduced preference for glucose exhibited by S. Typhimurium inside macrophages reflects that transcription of the glucose uptake gene requires higher amounts of active CRP-cAMP than transcription of uptake genes for preferred carbon sources, such as gluconate and glycerol. By reducing CRP-cAMP activity, low cytoplasmic Mg 2+ alters carbon source preference, adjusting metabolism and growth.}, archive = {J_PNAS}, author = {Pokorzynski, Nick D. and Jones, Katarina A. and Campagna, Shawn R. and Groisman, Eduardo A.}, doi = {10.1073/pnas.2424337122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2424337122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cytoplasmic mg2+ supersedes carbon source preference to dictate salmonella metabolism}, volume = {122}, year = {2025}, }
• (2025). Rolling vesicles: From confined rotational flows to surface-enabled motion. PNAS, 122(13), e2424236122. (www)

  @article{ , abstract = {Friction forces are essential for cell movement, yet they also trigger numerous active cellular responses, complicating their measurement in vivo. Here, we introduce a synthetic model designed to measure friction forces between biomimetic membranes and substrates. The model consists of a vesicle with precisely controlled properties, fabricated via microfluidics, encapsulating a single ferromagnetic particle that is magnetically driven to rotate. The rotation of the particle generates a confined rotational flow, setting the vesicle membrane into motion. By adjusting the magnetic field frequency and vesicle size, the rotation frequency of the vesicle can be finely controlled, resulting in a rolling vesicle that functions as an effective tribological tool across a wide frequency range. At low frequencies, molecular contact between the membrane and substrate dominates frictional interactions, which enables determination of the contact friction coefficient. At higher frequencies, lubrication becomes predominant, causing the vesicles to slip rather than roll. Adjusting membrane fluidity and incorporating specific ligand–receptor interactions within this model will enable detailed studies of frictional forces in more complex biomimetic systems, providing key insights into the mechanisms of cell movement and mechanotransduction.}, archive = {J_PNAS}, author = {Magrinya, Paula and Palacios-Alonso, Pablo and Llombart, Pablo and Delgado-Buscalioni, Rafael and Alexander-Katz, Alfredo and Arriaga, Laura R. and Aragones, Juan L.}, doi = {10.1073/pnas.2424236122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2424236122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rolling vesicles: From confined rotational flows to surface-enabled motion}, volume = {122}, year = {2025}, }
• (2025). Actuating superparamagnetic nanoparticle monolayers. PNAS, 122(13), e2424073122. (www)

  @article{ , abstract = {Magnetically responsive, mechanically flexible microstructures are desirable for applications ranging from smart sensors to remote-controlled actuation for surgery or robotics. Embedding magnetic nanoparticles into a thin matrix of elastic material enables high flexibility while exploiting the magnetic response of the individual particles. However, in the ultrathin limit of such nanocomposite materials, the particles become too small to sustain a permanent dipole moment. This implies that now large magnetic field gradients are required for actuation, which are difficult to achieve with externally applied fields. Here, we demonstrate through experiment and simulation that monolayer sheets of close-packed paramagnetic nanoparticles in a uniform applied field can generate large local field gradients through particle interactions. As a result, a strong collective magnetization is obtained that leads to large deflections of freestanding sheets already in moderate applied fields. Exploiting the vector nature of the applied field, we furthermore find that it is possible to induce more complex curvature and twist the sheets. Finally, we show that paramagnetic nanoparticle monolayers applied as coatings can generate sufficient force to deflect strips of nonmagnetic material that is several orders of magnitude thicker.}, archive = {J_PNAS}, author = {Esposito, Edward P. and Lopez Rios, Hector Manuel and Olvera de la Cruz, Monica and Jaeger, Heinrich M.}, doi = {10.1073/pnas.2424073122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2424073122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Actuating superparamagnetic nanoparticle monolayers}, volume = {122}, year = {2025}, }
• (2025). Control of circadian muscle glucose metabolism through the BMAL1–HIF axis in obesity. PNAS, 122(13), e2424046122. (www)

  @article{ , abstract = {Disruptions of circadian rhythms are widespread in modern society and lead to accelerated and worsened symptoms of metabolic syndrome. In healthy mice, the circadian clock factor BMAL1 is required for skeletal muscle function and metabolism. However, the importance of muscle BMAL1 in the development of metabolic diseases, such as diet-induced obesity (DIO), remains unclear. Here, we demonstrate that skeletal muscle–specific BMAL1-deficient mice exhibit worsened glucose tolerance upon high-fat diet feeding, despite no evidence of increased weight gain. Metabolite profiling from Bmal1 -deficient muscles revealed impaired glucose utilization specifically at early steps in glycolysis that dictate the switch between anabolic and catabolic glucose fate. We provide evidence that this is due to abnormal control of the nutrient stress–responsive hypoxia-inducible factor (HIF) pathway. Genetic HIF1α stabilization in muscle Bmal1 -deficient mice restores glucose tolerance and expression of 217/736 dysregulated genes during DIO, including glycolytic enzymes. Together, these data indicate that during DIO, skeletal muscle BMAL1 is an important regulator of HIF-driven glycolysis and metabolic flexibility, which influences the development of high-fat-diet-induced glucose intolerance.}, archive = {J_PNAS}, author = {Chaikin, Claire A. and Thakkar, Abhishek V. and Steffeck, Adam W. T. and Pfrender, Eric M. and Hung, Kaitlyn and Zhu, Pei and Waldeck, Nathan J. and Nozawa, Rino and Song, Weimin and Futtner, Christopher R. and Quattrocelli, Mattia and Bass, Joseph and Ben-Sahra, Issam and Peek, Clara B.}, doi = {10.1073/pnas.2424046122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2424046122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Control of circadian muscle glucose metabolism through the BMAL1–HIF axis in obesity}, volume = {122}, year = {2025}, }
• (2025). Neural basis for individual differences in the attention-enhancing effects of methylphenidate. PNAS, 122(13), e2423785122. (www)

  @article{ , abstract = {Stimulant drugs that boost dopamine, like methylphenidate (MP), enhance attention and are effective treatments for attention-deficit hyperactivity disorder (ADHD). Yet there is large individual variation in attentional capacity and response to MP. It is unclear whether this variation is driven by individual differences in relative density of dopamine receptor subtypes, magnitude of dopamine increases induced by MP, or both. Here, we extensively characterized the brain dopamine system with positron emission tomography (PET) imaging (including striatal dopamine D1 and D2/3 receptor availability and MP-induced dopamine increases) and measured attention task-evoked fMRI brain activity in two separate sessions (placebo and 60 mg oral MP; single-blind, counterbalanced) in 37 healthy adults. A network of lateral frontoparietal and visual cortices was sensitive to increasing attentional (and working memory) load, whose activity positively correlated with performance across individuals (partial r = 0.474, P = 0.008; controlling for age). MP-induced change in activity within this network correlated with MP-induced change in performance (partial r = 0.686, P < 0.001). The ratio of D1-to-D2/3 receptors in dorsomedial caudate positively correlated with baseline attentional network activity and negatively correlated with MP-induced changes in activity (all pFWE < 0.02). MP-induced changes in attentional load network activity mediated the association between D1-to-D2/3 ratio and MP-induced improvements in performance (mediation estimate = 23.20 [95%CI: −153.67 −81.79], P = 0.004). MP attention-boosting effects were not linked to the magnitude of striatal dopamine increases, but rather showed dependence on an individual’s baseline receptor density. Individuals with lower D1-to-D2/3 ratios tended to have lower frontoparietal activity during sustained attention and experienced greater improvement in brain function and task performance with MP.}, archive = {J_PNAS}, author = {Manza, Peter and Tomasi, Dardo and Demiral, Şükrü Barış and Shokri-Kojori, Ehsan and Lildharrie, Christina and Lin, Esther and Wang, Gene-Jack and Volkow, Nora D.}, doi = {10.1073/pnas.2423785122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2423785122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neural basis for individual differences in the attention-enhancing effects of methylphenidate}, volume = {122}, year = {2025}, }
• (2025). Cancer-associated SF3B1 mutation K700E causes widespread changes in u2/branchpoint recognition without altering splicing. PNAS, 122(13), e2423776122. (www)

  @article{ , abstract = {Myelodysplastic syndromes and other cancers are often associated with mutations in the U2 snRNP protein SF3B1. Common SF3B1 mutations, including K700E, disrupt SF3B1 interaction with the protein SUGP1 and induce aberrant activation of alternative 3′ splice sites (ss), presumably resulting from aberrant U2/branch site (BS) recognition by the mutant spliceosome. Here, we apply a method of U2 IP-seq to profile BS binding across the transcriptome of K562 leukemia cells carrying the SF3B1 K700E mutation. For alternative 3′ ss activated by K700E, we identify their associated BSs and show that they are indeed shifted from the WT sites. Unexpectedly, we also identify thousands of additional changes in BS binding in the mutant cells that do not alter splicing. These new BSs are usually very close to the natural sites, occur upstream or downstream, and either exhibit stronger base-pairing potential with U2 snRNA or are adjacent to stronger polypyrimidine tracts than the WT sites. The widespread imprecision in BS recognition induced by K700E with limited changes in 3′ ss selection expands the physiological consequences of this oncogenic mutation.}, archive = {J_PNAS}, author = {Damianov, Andrey and Lin, Chia-Ho and Zhang, Jian and Manley, James L. and Black, Douglas L.}, doi = {10.1073/pnas.2423776122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2423776122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cancer-associated SF3B1 mutation K700E causes widespread changes in u2/branchpoint recognition without altering splicing}, volume = {122}, year = {2025}, }
• (2025). The FBXW7–KMT2 axis in cancer-associated fibroblasts controls tumor growth via an epigenetic-paracrine mechanism. PNAS, 122(13), e2423130122. (www)

  @article{ , abstract = {F-box and WD repeat domain-containing 7 (FBXW7) is a tumor suppressor that targets various oncoproteins for degradation, but its role in modulating cancer-associated fibroblasts (CAFs) in the tumor microenvironment remains elusive. Here, we report that FBXW7 expression is gradually downregulated in CAFs during the progression of human pancreatic and lung cancers. Mechanically, FBXW7 inhibits histone lysine methyltransferase 2 (KMT2) methyltransferase activity via retinoblastoma binding protein 5 (RbBP5) binding, whereas FBXW7 depletion abrogates the binding to activate KMT2, leading to increased H3K4 methylations and global upregulation of gene expression. Activation of the interleukin-17 (IL-17) signaling pathway triggers the secretion of cytokines and chemokines to promote migration, invasion, and sphere formation of lung cancer cells. Coinjection of Fbxw7-depleted mouse embryonic fibroblasts with cancer cells enhances in vivo tumor growth, demonstrating a paracrine effect. Hypoxia downregulates CAF FBXW7 via ETS proto-oncogene 1 (ETS1) to increase H3K4 methylation, whereas conditioned media from hypoxia-exposed CAFs promotes migration and invasion of pancreatic cancer cells, highlighting FBXW7’s tumor-suppressing role through KMT2 inactivation.}, archive = {J_PNAS}, author = {Yin, Lu and Zhang, Jiagui and Zhu, Zhipeng and Peng, Xiaojuan and Lan, Huiyin and Ayoub, Alex and Tan, Mingjia and Zhou, Bo and He, Yaohui and Wang, Siyuan and Lu, Yan and Liu, Wen and Xiong, Xiufang and Huang, Jing and Dou, Yali and Mao, Fengbiao and Sun, Yi}, doi = {10.1073/pnas.2423130122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2423130122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The FBXW7–KMT2 axis in cancer-associated fibroblasts controls tumor growth via an epigenetic-paracrine mechanism}, volume = {122}, year = {2025}, }
• (2025). How circuits for habits are formed within the basal ganglia. PNAS, 122(13), e2423068122. (www)

  @article{ , abstract = {Recent findings show that stereotyped movement sequences (habits) need the cortex in the learning phase, but after learning, the cortex can be inactivated, and the movement still be performed flawlessly. The motor program is dependent on the sensorimotor part of the dorsolateral striatum (DLS) and on synaptic plasticity in the thalamostriatal synapses. New findings from several laboratories have revealed a highly precise spatially interactive organization within the basal ganglia [DLS, substantia nigra pars reticulata (SNr), and the thalamostriatal parafascicular nucleus (PF)] and with precise input from the cortex. The DLS-SNr-PF-DLS loop is subdivided into many parallel loops. I now propose that these parallel loops can act to reinforce the activity of the different striatal projection neurons in the DLS that take part and that the synaptic transmission in DLS becomes potentiated each time the motor sequence is performed successfully, if rewarded through a dopamine burst. It is argued that after learning the DLS-SNr-PF-DLS loop can operate in isolation.}, archive = {J_PNAS}, author = {Grillner, Sten}, doi = {10.1073/pnas.2423068122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2423068122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How circuits for habits are formed within the basal ganglia}, volume = {122}, year = {2025}, }
• (2025). The emergence of eukaryotes as an evolutionary algorithmic phase transition. PNAS, 122(13), e2422968122. (www)

  @article{ , abstract = {The origin of eukaryotes represents one of the most significant events in evolution since it allowed the posterior emergence of multicellular organisms. Yet, it remains unclear how existing regulatory mechanisms of gene activity were transformed to allow this increase in complexity. Here, we address this question by analyzing the length distribution of proteins and their corresponding genes for 6,519 species across the tree of life. We find a scale-invariant relationship between gene mean length and variance maintained across the entire evolutionary history. Using a simple model, we show that this scale-invariant relationship naturally originates through a simple multiplicative process of gene growth. During the first phase of this process, corresponding to prokaryotes, protein length follows gene growth. At the onset of the eukaryotic cell, however, mean protein length stabilizes around 500 amino acids. While genes continued growing at the same rate as before, this growth primarily involved noncoding sequences that complemented proteins in regulating gene activity. Our analysis indicates that this shift at the origin of the eukaryotic cell was due to an algorithmic phase transition equivalent to that of certain search algorithms triggered by the constraints in finding increasingly larger proteins.}, archive = {J_PNAS}, author = {Muro, Enrique M. and Ballesteros, Fernando J. and Luque, Bartolo and Bascompte, Jordi}, doi = {10.1073/pnas.2422968122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2422968122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The emergence of eukaryotes as an evolutionary algorithmic phase transition}, volume = {122}, year = {2025}, }
• (2025). Central TYK2 inhibition identifies TYK2 as a key neuroimmune modulator. PNAS, 122(13), e2422172122. (www)

  @article{ , abstract = {GWAS have identified tyrosine kinase 2 (TYK2) variants in multiple inflammatory disorders, specifically a protective hypomorphic TYK2 allele (P1104A) in multiple sclerosis (MS). Impaired TYK2 signaling within the central nervous system (CNS) may impart the protective effects of TYK2 P1104A allele in MS. We deployed brain-penetrant TYK2 inhibitors (cTYK2i) alongside the peripherally restricted TYK2 inhibitor (pTYK2i; BMS-986165) to untangle the contributions of central TYK2 inhibition in diverse models of neuroinflammation. While pTYK2i had little impact, cTYK2i reduced clinical score, lymphoid cell infiltration, and cytokines/chemokines in experimental autoimmune encephalomyelitis (EAE). Microglial activation was attenuated in cTYK2i-treated EAE spinal cords and circulating neurofilament light (NfL) was reduced in plasma and cerebral spinal fluid (CSF). Additionally, cTYK2i was protective in an antibody-mediated mouse model of primary progressive MS (PPMS). Finally, we demonstrate TYK2 inhibition has a robust impact on a unique subset of activated astrocytes termed Interferon-Responsive-Reactive-Astrocytes (IRRA). The data presented herein identify a key role for CNS TYK2 signaling in regulating neuroinflammation and solidify TYK2 as a potential therapeutic target for MS.}, archive = {J_PNAS}, author = {Molitor, Tyler P. and Hayashi, Genki and Lin, Mei-Yao and Dunn, Carissa J. and Peterson, Nathan G. and Poston, Robert G. and Kurnellas, Michael P. and Traver, David A. and Patel, Seona and Akgungor, Zeynep and Leonardi, Virginia and Lewis, Colizel and Segales, Joshua S. and Bennett, Dylan S. and Truong, Anh P. and Dani, Manjari and Naphade, Swati and Wong, Jamie K. and McDermott, Annie E. and Kovalev, Sarah M. and Ciaccio, Gillian L. and Sadiq, Saud A. and Pei, Zhonghua and Wood, Stephen and Rassoulpour, Arash}, doi = {10.1073/pnas.2422172122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2422172122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Central TYK2 inhibition identifies TYK2 as a key neuroimmune modulator}, volume = {122}, year = {2025}, }
• (2025). Climate change amplifies neurotoxic methylmercury threat to asian fish consumers. PNAS, 122(13), e2421921122. (www)

  @article{ , abstract = {Climate change is intricately influencing the accumulation of neurotoxic methylmercury (MeHg) in human food webs, potentially leading to uneven exposure risks across regions. Here, we reveal that climate change will elevate MeHg risks in China, with implications for regional inequalities in Asia through a climate-mercury-food-health nexus. Using a compiled fish mercury dataset from 13,000 samples and machine learning, we find that freshwater wild fish—an essential component of the Asian diet—is an underappreciated MeHg source. Specifically, MeHg concentrations in freshwater wild fish are 2.9 to 6.2 times higher than in freshwater farmed fish and 1.7 times higher than in marine wild fish. Individual climate factors influence MeHg accumulation differently, while their combined effects significantly increase MeHg concentrations in freshwater wild fish. Under SSP2–4.5 and SSP5–8.5 by 2031 to 2060, national average MeHg concentrations in freshwater wild fish are projected to increase by about 60%, adding a maximum annual economic loss of US$18 million (2022 USD) from intelligence quotient decrements in Chinese newborns. This loss may vary regionally within China and among Asian countries, disproportionately affecting less developed areas. Coordinating climate action with mercury emission reduction strategies could mitigate these overlooked regional risks, reduce regional inequalities in food safety, and ultimately contribute to sustainable development.}, archive = {J_PNAS}, author = {Wu, Mengjie and Wu, Xinda and Saiz-Lopez, Alfonso and Blanchfield, Paul J. and Ren, Hongqiang and Zhong, Huan}, doi = {10.1073/pnas.2421921122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2421921122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Climate change amplifies neurotoxic methylmercury threat to asian fish consumers}, volume = {122}, year = {2025}, }
• (2025). The PVD neuron has male-specific structure and mating function in caenorhabditis elegans. PNAS, 122(13), e2421376122. (www)

  @article{ , abstract = {Neurons display unique shapes and establish intricate networks, which may differ between sexes. In complex organisms, studying sex differences in structure and function of individual neurons is difficult. The nematode Caenorhabditis elegans hermaphrodites and males present an exceptional model for studying neuronal morphogenesis in a simple, sexually dimorphic system. We focus on the polymodal sensory bilateral neuron pair PVD, which forms a complex but stereotypic dendritic tree composed of multiple subunits that resemble candelabra. PVD is well studied in hermaphrodites, but not in males. We show here that during larval development, male PVD extends a similar architecture to the hermaphrodite utilizing the sexually shared Menorin patterning mechanism. In early adulthood, however, male PVD develops a unique extension into the copulatory tail structure. Alongside established tail ray neurons RnA and RnB, we show PVD is a third, previously unrecognized, neuron within the tail rays. Unlike RnA and RnB, PVD extends anterogradely, branches and turns within the ray hypodermis, and is nonciliated. This PVD sexually dimorphic arborization is absent in mutant backgrounds which perturb the Menorin guidance complex. SAX-7/L1CAM, a hypodermal component of this complex, shows a male-specific expression pattern which precedes PVD extension, and its presence allows PVD to enter the tail rays. Further, our results reveal that genetically altered arborization or ablation of the PVD results in male mating behavioral defects, particularly as males turn around the hermaphrodite. These results uncover an adult-stage sexual dimorphism of dendritic branching and a function for PVD in male sexual behavior.}, archive = {J_PNAS}, author = {Iosilevskii, Yael and Hall, David H. and Katz, Menachem and Podbilewicz, Benjamin}, doi = {10.1073/pnas.2421376122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2421376122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The PVD neuron has male-specific structure and mating function in caenorhabditis elegans}, volume = {122}, year = {2025}, }
• (2025). Discovery and functional characterization of a bombesin-type neuropeptide signaling system in an invertebrate. PNAS, 122(13), e2420966122. (www)

  @article{ , abstract = {Neuropeptide signaling systems are key regulators of physiological and behavioral processes in animals. However, the evolutionary history of some neuropeptides originally discovered in vertebrates is unknown. The peptide bombesin (BN) was first isolated from the skin of the toad Bombina bombina and subsequently BN-related neuropeptides have been identified in other chordates, including gastrin-releasing peptide (GRP) and neuromedin B (NMB) in mammals, and a GRP-like peptide in the cephalochordate Branchiostoma japonicum . However, BN-type neuropeptides have hitherto not been identified in any nonchordate animals. Here, we report the discovery and functional characterization of a BN-type neuropeptide signaling system in an echinoderm—the starfish Asterias rubens . BN-type precursor proteins were identified in several echinoderm species based on their amino acid sequences and gene structures, and the mature structure of the A. rubens BN-type neuropeptide ArBN was determined using mass spectrometry. A protein related to vertebrate GRP/NMB-type G protein–coupled receptors was identified experimentally as the receptor for ArBN in A. rubens . Analysis of the distribution of the ArBN precursor in A. rubens using mRNA in situ hybridization and immunohistochemistry revealed a widespread pattern of expression in the central nervous system, digestive system, and locomotory organs. Moreover, effects of ArBN in A. rubens included contraction and retraction of the evertible stomach and inhibition of feeding behavior. Our findings show that the evolutionary history of BN-type neuropeptide signaling can be traced back to the deuterostome common ancestor of echinoderms and chordates. Furthermore, an ancient role of BN-type neuropeptides as regulators of feeding behavior has been revealed.}, archive = {J_PNAS}, author = {Huang, Weiling and Zhong, Xingxing and Zampronio, Cleidiane G. and Bottrill, Andrew R. and Jones, Kite G. E. and Tinoco, Ana B. and Guo, Lijin and Egertová, Michaela and Mirabeau, Olivier and Elphick, Maurice R.}, doi = {10.1073/pnas.2420966122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2420966122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Discovery and functional characterization of a bombesin-type neuropeptide signaling system in an invertebrate}, volume = {122}, year = {2025}, }
• (2025). Modulation of host gene expression by the zinc finger antiviral protein. PNAS, 122(13), e2420819122. (www)

  @article{ , abstract = {The zinc finger antiviral protein (ZAP) depletes nonself RNAs through recognition of their elevated CpG dinucleotide content. CpG dinucleotides are sparse in most endogenous mammalian mRNAs, but a subset might potentially be modulated by ZAP. While CpG frequency alone is insufficient to predict ZAP-regulation, we developed an algorithm using experimentally determined compositional features to predict which endogenous mRNAs may be ZAP-regulated. Using ZAP-knockout mice, we demonstrate that levels of many host mRNAs that are algorithmically predicted ZAP targets are indeed increased when ZAP is absent. ZAP is interferon-inducible, and we also identify genes that are downregulated by ZAP during an innate immune response. Many ZAP-regulated gene products are extracellular matrix or of nucleosome components, whose ZAP-mediated control is conserved in human cells. Overall, we provide a tool for the prediction of ZAP target genes and reveal host mRNAs that are ZAP-regulated.}, archive = {J_PNAS}, author = {Gonçalves-Carneiro, Daniel and Mastrocola, Emily and Lei, Xiao and Bieniasz, Paul D.}, doi = {10.1073/pnas.2420819122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2420819122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Modulation of host gene expression by the zinc finger antiviral protein}, volume = {122}, year = {2025}, }
• (2025). Bayesian inference by visuomotor neurons in the prefrontal cortex. PNAS, 122(13), e2420815122. (www)

  @article{ , abstract = {Perceptual judgments of the environment emerge from the concerted activity of neural populations in decision-making areas downstream of the sensory cortex. When the sensory input is ambiguous, perceptual judgments can be biased by prior expectations shaped by environmental regularities. These effects are examples of Bayesian inference, a reasoning method in which prior knowledge is leveraged to optimize uncertain decisions. However, it is not known how decision-making circuits combine sensory signals and prior expectations to form a perceptual decision. Here, we study neural population activity in the prefrontal cortex of macaque monkeys trained to report perceptual judgments of ambiguous visual stimuli under two different stimulus distributions. We isolate the component of the neural population response that represents the formation of the perceptual decision (the decision variable, DV), and find that its dynamical evolution reflects the integration of sensory signals and prior expectations. Prior expectations impact the DV’s trajectory both before and during stimulus presentation such that DV trajectories with a smaller dynamic range result in more biased and less sensitive perceptual decisions. We show that these results resemble a specific variant of Bayesian inference known as approximate hierarchical inference. Our findings expand our understanding of the mechanisms by which prefrontal circuits can execute Bayesian inference.}, archive = {J_PNAS}, author = {Langlois, Thomas A. and Charlton, Julie A. and Goris, Robbe L. T.}, doi = {10.1073/pnas.2420815122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2420815122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bayesian inference by visuomotor neurons in the prefrontal cortex}, volume = {122}, year = {2025}, }
• (2025). Xylem embolism refilling revealed in stems of a weedy grass. PNAS, 122(13), e2420618122. (www)

  @article{ , abstract = {Plant hydraulic dysfunction by embolism formation can impair photosynthesis, growth, and reproduction and, in severe cases, lead to death. Embolism reversal, or “refilling,” is a hypothesized adaptive process in which xylem functionality is rapidly and sustainably restored. This study investigated xylem embolism refilling during recovery from severe drought stress using entirely noninvasive measurements of the same plants. These results were considered in relation to functional traits to address long-standing gaps in understanding the consequences of severe drought stress. Leaf and stem xylem embolism as well as transpiration, photosynthesis, and stem water potential were characterized nondestructively on intact barnyard grass plants during an acute drought event. Plants were rewatered and returned to growth conditions for 10 d, during which time recovery of stem xylem embolism and transpiration were monitored. Leaf xylem embolism and declines in leaf gas exchange occurred mostly between −1.0 MPa and −2.0 MPa, whereas stem xylem embolism occurred mostly between −3.0 MPa and −4.0 MPa. In all measured plants, which included embolism levels up to 88%, stem xylem embolism reversed completely within 24 h after rewatering, and this refilling supported recovery of transpiration and growth after plants were returned to growth conditions. This study provides direct evidence of complete and functional stem xylem refilling. These results present a clear need to elucidate underlying mechanisms and the adaptive significance of this phenomenon as well as its prevalence in nature.}, archive = {J_PNAS}, author = {Stewart, Jared J. and Allen, Brendan S. and Polutchko, Stephanie K. and Ocheltree, Troy W. and Gleason, Sean M.}, doi = {10.1073/pnas.2420618122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2420618122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Xylem embolism refilling revealed in stems of a weedy grass}, volume = {122}, year = {2025}, }
• (2025). Long-chain alkanes preserved in a martian mudstone. PNAS, 122(13), e2420580122. (www)

  @article{ , abstract = {Organic molecules preserved in ancient Martian rocks provide a critical record of the past habitability of Mars and could be chemical biosignatures. Experiments conducted by the Sample Analysis at Mars instrument onboard the Curiosity rover have previously reported several classes of indigenous chlorinated and sulfur-containing organic compounds in Gale crater sedimentary rocks, with chemical structures of up to six carbons. Here, we report the detection of decane (C 10 H 22 ), undecane (C 11 H 24 ), and dodecane (C 12 H 26 ) at the tens of pmol level, released from the Cumberland drilled mudstone sample, using a modified SAM analytical procedure optimized for the detection of larger organic molecules. Laboratory experiments support the hypothesis that the alkanes detected were originally preserved in the mudstone as long-chain carboxylic acids. The origin of these molecules remains uncertain, as they could be derived from either abiotic or biological sources.}, archive = {J_PNAS}, author = {Freissinet, Caroline and Glavin, Daniel P. and Archer, P. Douglas and Teinturier, Samuel and Buch, Arnaud and Szopa, Cyril and Lewis, James M. T. and Williams, Amy J. and Navarro-Gonzalez, Rafael and Dworkin, Jason P. and Franz, Heather. B. and Millan, Maëva and Eigenbrode, Jennifer L. and Summons, R. E. and House, Christopher H. and Williams, Ross H. and Steele, Andrew and McIntosh, Ophélie and Gómez, Felipe and Prats, Benito and Malespin, Charles A. and Mahaffy, Paul R.}, doi = {10.1073/pnas.2420580122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2420580122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Long-chain alkanes preserved in a martian mudstone}, volume = {122}, year = {2025}, }
• (2025). Revealing the roles of the solid–electrolyte interphase in designing stable, fast-charging, low-temperature li-ion batteries. PNAS, 122(13), e2420398122. (www)

  @article{ , abstract = {Designing the solid–electrolyte interphase (SEI) is critical for stable, fast-charging, low-temperature Li-ion batteries. Fostering a “fluorinated interphase,” SEI enriched with LiF, has become a popular design strategy. Although LiF possesses low Li-ion conductivity, many studies have reported favorable battery performance with fluorinated SEIs. Such a contradiction suggests that optimizing SEI must extend beyond chemical composition design to consider spatial distributions of different chemical species. In this work, we demonstrate that the impact of a fluorinated SEI on battery performance should be evaluated on a case-by-case basis. Sufficiently passivating the anode surface without impeding Li-ion transport is key. We reveal that a fluorinated SEI containing excessive and dense LiF severely impedes Li-ion transport. In contrast, a fluorinated SEI with well-dispersed LiF (i.e., small LiF aggregates well mixed with other SEI components) is advantageous, presumably due to the enhanced Li-ion transport across heterointerfaces between LiF and other SEI components. An electrolyte, 1 M LiPF 6 in 2-methyl tetrahydrofuran (2MeTHF), yields a fluorinated SEI with dispersed LiF. This electrolyte allows anodes of graphite, μSi/graphite composite, and pure Si to all deliver a stable Coulombic efficiency of 99.9% and excellent rate capability at low temperatures. Pouch cells containing layered cathodes also demonstrate impressive cycling stability over 1,000 cycles and exceptional rate capability down to −20 °C. Through experiments and theoretical modeling, we have identified a balanced SEI-based approach that achieves stable, fast-charging, low-temperature Li-ion batteries.}, archive = {J_PNAS}, author = {Tao, Lei and Zhang, Hanrui and Shah, Sameep Rajubhai and Yang, Xixian and Lai, Jianwei and Guo, Yanjun and Russell, Joshua A. and Xia, Dawei and Min, Jungki and Huang, Weibo and Shi, Chenguang and Liang, Zhaohui and Yu, Deyang and Hwang, Sooyeon and Xiong, Hui and Madsen, Louis A. and Zhao, Kejie and Shi, Feifei and Lin, Feng}, doi = {10.1073/pnas.2420398122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2420398122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Revealing the roles of the solid–electrolyte interphase in designing stable, fast-charging, low-temperature li-ion batteries}, volume = {122}, year = {2025}, }
• (2025). Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes. PNAS, 122(13), e2420343122. (www)

  @article{ , abstract = {Congenital heart disease (CHD) is a leading cause of infant mortality. We analyzed de novo mutations (DNMs) and very rare transmitted/unphased damaging variants in 248 prespecified genes in 11,555 CHD probands. The results identified 60 genes with a significant burden of heterozygous damaging variants. Variants in these genes accounted for CHD in 10.1% of probands with similar contributions from de novo and transmitted variants in parent–offspring trios that showed incomplete penetrance. DNMs in these genes accounted for 58% of the signal from DNMs. Thirty-three genes were linked to a single CHD subtype while 12 genes were associated with 2 to 4 subtypes. Seven genes were only associated with isolated CHD, while 37 were associated with 1 or more extracardiac abnormalities. Genes selectively expressed in the cardiomyocyte lineage were associated with isolated CHD, while those widely expressed in the brain were also associated with neurodevelopmental delay (NDD). Missense variants introducing or removing cysteines in epidermal growth factor (EGF)-like domains of NOTCH1 were enriched in tetralogy of Fallot and conotruncal defects, unlike the broader CHD spectrum seen with loss of function variants. Transmitted damaging missense variants in MYH6 were enriched in multiple CHD phenotypes and account for ~1% of all probands. Probands with characteristic mutations causing syndromic CHD were frequently not diagnosed clinically, often due to missing cardinal phenotypes. CHD genes that were positively or negatively associated with development of NDD suggest clinical value of genetic testing. These findings expand the understanding of CHD genetics and support the use of molecular diagnostics in CHD.}, archive = {J_PNAS}, author = {Sierant, Michael C. and Jin, Sheng Chih and Bilguvar, Kaya and Morton, Sarah U. and Dong, Weilai and Jiang, Wei and Lu, Ziyu and Li, Boyang and López-Giráldez, Francesc and Tikhonova, Irina and Zeng, Xue and Lu, Qiongshi and Choi, Jungmin and Zhang, Junhui and Nelson-Williams, Carol and Knight, James R. and Zhao, Hongyu and Cao, Junyue and Mane, Shrikant and Sedore, Stanley C. and Gruber, Peter J. and Lek, Monkol and Goldmuntz, Elizabeth and Deanfield, John and Giardini, Alessandro and Mital, Seema and Russell, Mark and Gaynor, J. William and King, Eileen and Wagner, Michael and Srivastava, Deepak and Shen, Yufeng and Bernstein, Daniel and Porter, George A. and Newburger, Jane W. and Seidman, Jonathan G. and Roberts, Amy E. and Yandell, Mark and Yost, H. Joseph and Tristani-Firouzi, Martin and Kim, Richard and Chung, Wendy K. and Gelb, Bruce D. and Seidman, Christine E. and Brueckner, Martina and Lifton, Richard P.}, doi = {10.1073/pnas.2420343122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2420343122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes}, volume = {122}, year = {2025}, }
• (2025). In situ cavitation bubble manometry reveals a lack of light-activated guard cell turgor modulation in bryophytes. PNAS, 122(13), e2419887122. (www)

  @article{ , abstract = {Diversification of plant hydraulic architecture and stomatal function coincides with radical changes in the Earth’s atmosphere over the past 400 my. Due to shared stomatal anatomy with the earliest land plants, bryophyte stomatal behavior may provide insights into the evolution of stomatal function, but significant uncertainty remains due to technical limitations of measuring guard cell turgor pressure in situ. Here, we introduce a method for monitoring cell turgor pressure by nucleating microbubbles within the guard cells of intact plant tissue and then examining microbubble growth and dissolution dynamics. First, we show that maximum microbubble radius decreases with increasing pressure as the pressure of the surrounding fluid constrains its growth according to a modified version of the Epstein–Plesset equation. We then apply this method to monitor turgor pressure in dark- vs. light-acclimated guard cells across bryophyte taxa with stomata, where their role in gas-exchange remains ambiguous, and in vascular plants with well-documented light-dependent turgor modulation. Our findings show no light-activated change in turgor in bryophyte guard cells, with pressures not significantly different than neighboring epidermal cells. In contrast, vascular plants show distinct pressure modulation in response to light that drives reversible changes in stomatal aperture. Complete guard cell turgor loss had no effect on bryophyte stomatal aperture but resulted in partial or complete closure in vascular plants. These results suggest that despite conserved stomatal morphology, the sampled bryophytes lack dynamic control over guard cell turgor that is critical for sustaining photosynthesis and inhibiting desiccation.}, archive = {J_PNAS}, author = {Brodersen, Craig R. and Brodribb, Tim J. and Hochberg, Uri and Holbrook, N. Michele and McAdam, Scott A. M. and Zailaa, Joseph and Huggett, Brett A. and Marmottant, Philippe}, doi = {10.1073/pnas.2419887122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2419887122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In situ cavitation bubble manometry reveals a lack of light-activated guard cell turgor modulation in bryophytes}, volume = {122}, year = {2025}, }
• (2025). Observation of odd-parity superconductivity in UTe2. PNAS, 122(13), e2419734122. (www)

  @article{ , abstract = {Symmetry properties of the order parameter are among the most fundamental characteristics of a superconductor. UTe 2 , which was found to feature an exceedingly large upper critical field and striking reentrant behavior at low temperatures, is widely believed to possess a spin-triplet pairing symmetry. However, unambiguous evidence for such a pairing symmetry is still lacking, especially at zero and low magnetic fields. The presence of an inversion crystalline symmetry in UTe 2 requires that, if it is indeed a spin-triplet superconductor, the order parameter must be of odd parity. We report here phase-sensitive measurements of the symmetry of the orbital part of the order parameter using the Josephson effect. The selection rule in the orientation dependence of the Josephson coupling between In, an s -wave superconductor, and UTe 2 suggests strongly that UTe 2 possesses the odd-parity pairing state of B 1 u symmetry near zero magnetic field, making it a spin-triplet superconductor. We also report the apparent formation of Andreev surface bound states on the (1−10) surface of UTe 2 .}, archive = {J_PNAS}, author = {Li, Zixuan and Moir, Camilla M. and McKee, Nathan J. and Lee-Wong, Eric and Baumbach, Ryan E. and Maple, M. Brian and Liu, Ying}, doi = {10.1073/pnas.2419734122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2419734122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Observation of odd-parity superconductivity in UTe2}, volume = {122}, year = {2025}, }
• (2025). Most christian american religious leaders silently believe in climate change, and informing their congregation can help open dialogue. PNAS, 122(13), e2419705122. (www)

  @article{ , abstract = {Religious leaders shape the attitudes and beliefs of their congregations. In a nationally representative sample of U.S. religious leaders ( N = 1,600), the majority of which were of a Christian faith, we find that nearly 90% believe in anthropogenic climate change to some degree. From this 90%, a total of 60% believe humans play a major role and an additional 30% believe they play a role, but a more minor one. Yet roughly half have never discussed it with their congregation, and only a quarter have mentioned it more than once or twice. In a sample of Christian Americans representative of the proportions of major national denominations ( N = 987), we find that Christians underestimate the prevalence of their leaders who believe in climate change by 39 to 45 percentage points. Conversely, having a religious leader who talks about climate change predicts greater willingness to discuss it with fellow churchgoers and attend climate events. In an experimental intervention on another sample matching major Christian American denomination ( N = 959), we find that providing the actual consensus level of religious leaders’ belief in climate change reduces congregants’ misperception of religious leaders, increases their perception that other church members believe in and are open to discussing climate change, and leads Christians to believe that taking climate action is consistent with their church’s values while voting for politicians who will not take climate action is not.}, archive = {J_PNAS}, author = {Syropoulos, Stylianos and Sparkman, Gregg}, doi = {10.1073/pnas.2419705122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2419705122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Most christian american religious leaders silently believe in climate change, and informing their congregation can help open dialogue}, volume = {122}, year = {2025}, }
• (2025). Adaptive ATP-induced molecular condensation in membranized protocells. PNAS, 122(13), e2419507122. (www)

  @article{ , abstract = {Liquid–liquid phase separation (LLPS) has been achieved in various cytomimetic (protocell) models, but controlling molecular condensation using noninert crowders to systematically alter protocell function remains challenging. Intracellular ATP levels influence protein–protein interactions, and dysregulation of ATP can alter cellular crowding dynamics, thereby disrupting the normal formation or dissolution of condensates. Here, we develop a membranized protocell model capable of endogenous LLPS and liquid–gel-like phase separation through precise manipulation of intermolecular interactions within semipermeable polysaccharide-based microcapsules (polysaccharidosomes, P-somes), prepared using microtemplate-guided assembly. We demonstrate that intraprotocellular diffusion-mediated LLPS can be extended into the liquid–gel-like domain by the uptake of the biologically active crowder ATP, resulting in a range of modalities dependent on the fine-tuning of molecular condensation. Endogenous enzyme activity in these crowded polysaccharidosomes is enhanced compared to free enzymes in solution, though this enhancement diminishes at higher levels of intraprotocellular condensation. Additionally, increased molecular crowding inhibits intraprotocell DNA strand displacement reactions. Our findings introduce an expedient and optimized approach to the batch construction of membranized protocell models with controllable molecular crowding and functional diversity. Our mix–incubate–wash protocol for inducing endogenous LLPS in membranized protocells offers potential applications in microreactor technology, environmental sensing, and the delivery and sustained release of therapeutics.}, archive = {J_PNAS}, author = {Mukwaya, Vincent and Yu, Xiaolei and Yang, Shuo and Mann, Stephen and Dou, Hongjing}, doi = {10.1073/pnas.2419507122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2419507122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Adaptive ATP-induced molecular condensation in membranized protocells}, volume = {122}, year = {2025}, }
• (2025). Tetrapod species–area relationships across the Cretaceous–Paleogene mass extinction. PNAS, 122(13), e2419052122. (www)

  @article{ , abstract = {Mass extinctions are rare but catastrophic events that profoundly disrupt biodiversity. Widely accepted consequences of mass extinctions, such as biodiversity loss and the appearance of temporary “disaster taxa,” imply that species–area relationships (SARs, or how biodiversity scales with area) should change dramatically across these events: Specifically, both the slope (the rate of accumulation of new species with increasing area) and intercept (the density of species at local scales) of the power–law relationship should decrease. However, these hypotheses have not been tested, and the contribution of variation in the SAR to diversity dynamics in deep time has been neglected. We use fossil data to quantify nested SARs in North American terrestrial tetrapods through the Cretaceous–Paleogene (K/Pg) mass extinction (Campanian–Ypresian). We show that SARs vary substantially through time and among groups. In the pre-extinction interval (Maastrichtian), unusually shallow SAR slopes (indicating low beta diversity or provinciality) drive low total regional diversity in dinosaurs, mammals, and other tetrapods. In the immediate postextinction interval (Danian), the explosive diversification of mammals drove high regional diversity via a large increase in SAR slope (indicating higher beta diversity or provinciality), and only a limited increase in SAR intercept. This contradicts the expectation that postextinction biotas should be regionally homogenized by the spread of disaster taxa and impoverished by diversity loss. This early postextinction increase in SAR slope was followed in the Thanetian–Selandian ( ∼ 4.4. myr later) by increases in the intercept, indicating that diversity dynamics at local and regional scales did not change in synchrony.}, archive = {J_PNAS}, author = {Close, Roger Adam and Reijenga, Bouwe Rutger}, doi = {10.1073/pnas.2419052122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2419052122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tetrapod species–area relationships across the Cretaceous–Paleogene mass extinction}, volume = {122}, year = {2025}, }
• (2025). A national megastudy shows that email nudges to elementary school teachers boost student math achievement, particularly when personalized. PNAS, 122(13), e2418616122. (www)

  @article{ , abstract = {In response to the alarming recent decline in US math achievement, we conducted a national megastudy in which 140,461 elementary school teachers who collectively taught 2,992,027 students were randomly assigned to receive a variety of behaviorally informed email nudges aimed at improving students’ progress in math. Specifically, we partnered with the nonprofit educational platform Zearn Math to compare the impact of 15 different interventions with a reminder-only megastudy control condition. All 16 conditions entailed weekly emails delivered to teachers over 4-wk in the fall of 2021. The best-performing intervention, which encouraged teachers to log into Zearn Math for an updated report on how their students were doing that week, produced a 5.06% increase in students’ math progress (3.30% after accounting for the winner’s curse). In exploratory analyses, teachers who received any behaviorally informed email nudge (vs. a reminder-only megastudy control) saw their students’ math progress boosted by an average of 1.89% during the 4-wk intervention period; emails referencing personalized data (i.e., classroom-specific statistics) outperformed emails that did not by 2.26%. While small in size, these intervention effects were consistent across school socioeconomic status and school type (public, private, etc.) and, further, persisted in the 8-wk post-intervention period. Collectively, these findings underscore both how difficult it is to change behavior and the need for large-scale, rigorous, empirical research of the sort undertaken in this megastudy.}, archive = {J_PNAS}, author = {Duckworth, Angela L. and Ko, Ahra and Milkman, Katherine L. and Kay, Joseph S. and Dimant, Eugen and Gromet, Dena M. and Halpern, Aden and Jung, Youngwoo and Paxson, Madeline K. and Zumaran, Ramon A. Silvera and Berman, Ron and Brody, Ilana and Camerer, Colin F. and Canning, Elizabeth A. and Dai, Hengchen and Gallo, Marcos and Hershfield, Hal E. and Hilchey, Matthew D. and Kalil, Ariel and Kroeper, Kathryn M. and Lyon, Amy and Manning, Benjamin S. and Mazar, Nina and Michelini, Michelle and Mayer, Susan E. and Murphy, Mary C. and Oreopoulos, Philip and Parker, Sharon E. and Rondina, Renante and Soman, Dilip and Bulte, Christophe Van den}, doi = {10.1073/pnas.2418616122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2418616122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A national megastudy shows that email nudges to elementary school teachers boost student math achievement, particularly when personalized}, volume = {122}, year = {2025}, }
• (2025). Potassium-sensitive loss of muscle force in the setting of reduced inward rectifier k+ current: Implications for Andersen–Tawil syndrome. PNAS, 122(13), e2418021122. (www)

  @article{ , abstract = {Andersen–Tawil syndrome (ATS) is an ion channelopathy with variable penetrance for the triad of periodic paralysis, arrhythmia, and dysmorphia. Dominant-negative mutations of KCNJ2 encoding the Kir2.1 potassium channel subunit are found in 60% of ATS families. As with most channelopathies, episodic attacks in ATS are frequently triggered by environmental stresses: exercise for periodic paralysis or stress with adrenergic stimulation for arrhythmia. Fluctuations in K + , either low or high, are potent triggers for attacks of weakness in other variants of periodic paralysis (hypokalemic periodic paralysis or hyperkalemic periodic paralysis). For ATS, the [K + ] dependence is less clear; with reports describing weakness in high-K + or low-K + . Patient trials with controlled K + challenges are not possible, due to arrhythmias. We have developed two mouse models (genetic and pharmacologic) with reduced Kir currents, to address the question of K + -sensitive loss of force. These animal models and computational simulations both show K + -dependent weakness occurs only when Kir current is <30% of wildtype. As the Kir deficit becomes more severe, the phenotype shifts from high-K + -induced weakness to a combination where either high-K + or low-K + triggers weakness. A K + channel agonist, retigabine, protects muscle from K + -sensitive weakness in our mouse models of the skeletal muscle involvement in ATS.}, archive = {J_PNAS}, author = {Elia, Nathaniel and Quiñonez, Marbella and Wu, Fenfen and Mokhonova, Ekaterina and DiFranco, Marino and Spencer, Melissa J. and Cannon, Stephen C.}, doi = {10.1073/pnas.2418021122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2418021122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Potassium-sensitive loss of muscle force in the setting of reduced inward rectifier k+ current: Implications for Andersen–Tawil syndrome}, volume = {122}, year = {2025}, }
• (2025). Prediction of phase-separation propensities of disordered proteins from sequence. PNAS, 122(13), e2417920122. (www)

  @article{ , abstract = {Phase separation is one possible mechanism governing the selective cellular enrichment of biomolecular constituents for processes such as transcriptional activation, mRNA regulation, and immune signaling. Phase separation is mediated by multivalent interactions of macromolecules including intrinsically disordered proteins and regions (IDRs). Despite considerable advances in experiments, theory, and simulations, the prediction of the thermodynamics of IDR phase behavior remains challenging. We combined coarse-grained molecular dynamics simulations and active learning to develop a fast and accurate machine learning model to predict the free energy and saturation concentration for phase separation directly from sequence. We validate the model using computational and previously measured experimental data, as well as new experimental data for six proteins. We apply our model to all 27,663 IDRs of chain length up to 800 residues in the human proteome and find that 1,420 of these (5%) are predicted to undergo homotypic phase separation with transfer free energies < −2 k B T . We use our model to understand the relationship between single-chain compaction and phase separation and find that changes from charge- to hydrophobicity-mediated interactions can break the symmetry between intra- and intermolecular interactions. We also provide proof of principle for how the model can be used in force field refinement. Our work refines and quantifies the established rules governing the connection between sequence features and phase-separation propensities, and our prediction models will be useful for interpreting and designing cellular experiments on the role of phase separation, and for the design of IDRs with specific phase-separation propensities.}, archive = {J_PNAS}, author = {von Bülow, Sören and Tesei, Giulio and Zaidi, Fatima Kamal and Mittag, Tanja and Lindorff-Larsen, Kresten}, doi = {10.1073/pnas.2417920122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2417920122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prediction of phase-separation propensities of disordered proteins from sequence}, volume = {122}, year = {2025}, }
• (2025). Matrix degradation enhances stress relaxation, regulating cell adhesion and spreading. PNAS, 122(13), e2416771122. (www)

  @article{ , abstract = {In native extracellular matrices (ECM), cells utilize matrix metalloproteinases (MMPs) to degrade and remodel their microenvironment. Accordingly, synthetic matrices have been engineered to permit MMP-mediated cleavage, facilitating cell spreading, migration, and interactions. However, the interplay between matrix degradability and mechanical properties remains underexplored. We hypothesized that MMP activity induces immediate mechanical alterations in the ECM, which are subsequently detected by cells. We observed that both fibrillar collagen and synthetic degradable matrices exhibit enhanced stress relaxation following MMP exposure. Cells responded to these variations in relaxation by modulating their spreading and focal adhesions. Furthermore, we demonstrated that stress relaxation and cell spreading can be precisely controlled through the rational design of matrix degradability. These findings establish a fundamental link between matrix degradability and stress relaxation, with potential implications for a broad spectrum of biological applications.}, archive = {J_PNAS}, author = {Narasimhan, Badri Narayanan and Fraley, Stephanie I.}, doi = {10.1073/pnas.2416771122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2416771122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Matrix degradation enhances stress relaxation, regulating cell adhesion and spreading}, volume = {122}, year = {2025}, }
• (2025). The visuomotor transformations underlying target-directed behavior. PNAS, 122(13), e2416215122. (www)

  @article{ , abstract = {The visual system can process diverse stimuli and make the decision to execute appropriate behaviors, but it remains unclear where and how this transformation takes place. Innate visually evoked behaviors such as hunting, freezing, and escape are thought to be deeply conserved, and have been described in a range of species from insects to humans. We found that zebrafish larvae would respond to predator-like visual stimuli with immobility and bradycardia, both hallmarks of freezing, in a head-fixed behavioral paradigm. We then imaged the zebrafish visual system while larvae responded to different visual stimuli with hunting, freezing, and escape behaviors and systematically identified visually driven neurons and behaviorally correlated sensorimotor neurons. Our analyses indicate that within the optic tectum, broadly tuned sensory neurons are functionally correlated with sensorimotor neurons which respond specifically during one behavior, indicating that it contains suitable information for sensorimotor transformation. We also identified sensorimotor neurons in four other areas downstream of the tectum, and these neurons are also specific for one behavior, indicating that the segregation of the pathways continues in other areas. While our findings shed light on how sensorimotor neurons may integrate visual inputs, further investigation will be required to determine how sensorimotor neurons in different regions interact and where the decision to behave is made.}, archive = {J_PNAS}, author = {Zhao, Peixiong and Tong, Yuxin and Lazarte, Ivan P. and Khan, Biswadeep and Tian, Guangnan and Chen, Kenny K. Y. and Lam, Thomas K. C. and Hu, Yu and Semmelhack, Julie L.}, doi = {10.1073/pnas.2416215122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2416215122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The visuomotor transformations underlying target-directed behavior}, volume = {122}, year = {2025}, }
• (2025). Intravital imaging of translocated bacteria via fluorogenic labeling of gut microbiota in situ. PNAS, 122(13), e2415845122. (www)

  @article{ , abstract = {The translocation of bacteria from intestinal tracts into blood vessels and distal organs plays pivotal roles in the pathogenesis of numerous severe diseases. Intravital monitoring of bacterial translocation, however, is not yet feasible, which greatly hinders us from comprehending this spatially and temporally dynamic process. Here we report an in vivo fluorogenic labeling method, which enables in situ imaging of mouse gut microbiota and real-time tracking of the translocated bacteria. By mimicking the peptidoglycan stem peptide in bacteria, a tetrapeptide probe composed of alternating D- and L-amino acids and separately equipped with a fluorophore and a quencher on the N- and C-terminal amino acid, is designed. Because of its resistance to host proteases, it can be directly used in gavage and achieves fluorogenic labeling of the microbiota in the gut via the functioning of the L,D-transpeptidases of the labeled bacteria. Using intravital two-photon microscopy, we then successfully visualize the translocation of gut bacteria into the bloodstream and liver in obesity mouse models. This technique can help further exploration into the spatiotemporal activities of gut microbiota in vivo, and be valuable in investigating the less understood pathogenicity of bacterial translocation in many severe diseases.}, archive = {J_PNAS}, author = {Fan, Xinqi and Zhou, Yingjun and Bai, Wenjuan and Li, Xue and Lin, Liyuan and Lin, Huibin and Yang, Ming and Yu, Xiaofei and Wang, Jing and Lin, Liang and Wang, Wei}, doi = {10.1073/pnas.2415845122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2415845122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intravital imaging of translocated bacteria via fluorogenic labeling of gut microbiota in situ}, volume = {122}, year = {2025}, }
• (2025). Superficial auditory (dis)fluency biases higher-level social judgment. PNAS, 122(13), e2415254122. (www)

  @article{ , abstract = {When talking to other people, we naturally form impressions based not only on what they say but also on how they say it—e.g., how confident they sound. In modern life, however, the sounds of voices are often determined not only by intrinsic qualities (such as vocal anatomy) but also by extrinsic properties (such as videoconferencing microphone quality). Here, we show that such superficial auditory properties can have surprisingly deep consequences for higher-level social judgments. Listeners heard short narrated passages (e.g., from job application essays) and then made various judgments about the speakers. Critically, the recordings were modified to simulate different microphone qualities, while carefully equating listeners’ comprehension of the words. Though the manipulations carried no implications about the speakers themselves, common disfluent auditory signals (as in “tinny” speech) led to decreased judgments of intelligence, hireability, credibility, and romantic desirability. These effects were robust across speaker gender and accent, and they occurred for both human and clearly artificial (computer-synthesized) speech. Thus, just as judgments from written text are influenced by factors such as font fluency, judgments from speech are not only based on its content but also biased by the superficial vehicle through which it is delivered. Such effects may become more relevant as daily communication via videoconferencing becomes increasingly widespread.}, archive = {J_PNAS}, author = {Walter-Terrill, Robert and Ongchoco, Joan Danielle K. and Scholl, Brian J.}, doi = {10.1073/pnas.2415254122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2415254122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Superficial auditory (dis)fluency biases higher-level social judgment}, volume = {122}, year = {2025}, }
• (2025). An atlas of protein phosphorylation dynamics during interferon signaling. PNAS, 122(13), e2412990122. (www)

  @article{ , abstract = {Interferons (IFNs, types I-III) have pleiotropic functions in promoting antiviral and antitumor responses, as well as in modulating inflammation. Dissecting the signaling mechanisms elicited by different IFNs is therefore critical to understand their phenotypes. Here, we use mass spectrometry to investigate the early temporal dynamics of cellular protein phosphorylation in a human lung epithelial cell-line as it responds to stimulation with IFNα2, IFNβ, IFNω, IFNγ, or IFNλ1, representing all IFN types. We report an atlas of over 700 common or unique phosphorylation events reprogrammed by these different IFNs, revealing both previously known and uncharacterized modifications. While the proteins differentially phosphorylated following IFN stimulation have diverse roles, there is an enrichment of factors involved in chromatin remodeling, transcription, and RNA splicing. Functional screening and mechanistic studies identify that several proteins modified in response to IFNs contribute to host antiviral responses, either directly or by supporting IFN-stimulated gene or protein production. Among these, phosphorylation of PLEKHG3 at serine-1081 creates a phospho-regulated binding motif for the docking of 14-3-3 proteins, and together these factors contribute to coordinating efficient IFN-stimulated gene expression independent of early Janus kinase/signal transducer and activator of transcription signaling. Our findings map the global phosphorylation landscapes regulated by IFN types I, II, and III, and provide a key resource to explore their functional consequences.}, archive = {J_PNAS}, author = {Busnadiego, Idoia and Lork, Marie and Fernbach, Sonja and Schiefer, Samira and Tsolakos, Nikos and Hale, Benjamin G.}, doi = {10.1073/pnas.2412990122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2412990122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An atlas of protein phosphorylation dynamics during interferon signaling}, volume = {122}, year = {2025}, }
• (2025). Competition response of cloud supersaturation explains diminished twomey effect for smoky aerosol in the tropical atlantic. PNAS, 122(13), e2412247122. (www)

  @article{ , abstract = {The Twomey effect brightens clouds by increasing aerosol concentrations, which activates more droplets and decreases cloud supersaturation in response to more competition for water vapor. To quantify this competition response, we used marine low cloud observations in clean and smoky conditions at Ascension Island in the tropical South Atlantic during the Layered Aerosol Smoke Interactions with Cloud (LASIC) campaign. These observations show similar increases in droplet number for increased accumulation-mode particles from surface-based and satellite cloud retrievals, demonstrating the importance of below-cloud aerosol measurements for retrieving aerosol–cloud interactions (ACI) in clean and smoky aerosol conditions. Four methods for estimating cloud supersaturation from aerosol–cloud measurements were compared, with cloud scene-based and parcel-based methods showing sufficient variability for a strong dependence on both aerosol accumulation number concentration and cloud-base updraft velocities. Decomposing aerosol-related changes in cloud albedo and optical depth shows the calculated competition response accounts for dampening the activation response by 12 to 35%, explaining the diminished Twomey effect at high aerosol concentrations observed for smoky conditions at LASIC and previously around the world. This result was consistent for independent supersaturation retrievals by cloud scene-based droplet number and cloud condensation nuclei and parcel-based multimode size-resolving Lagrangian methods. Translating aerosol effects to local radiative forcing with clean conditions as a proxy for preindustrial and smoky conditions for present-day showed that the competition response reduces cooling from the Twomey radiative forcing by 12 to 35%, providing an essential process-specific constraint for improving the representation of aerosol competition in climate model simulation of indirect aerosol forcing.}, archive = {J_PNAS}, author = {Dedrick, Jeramy L. and Pelayo, Christian N. and Russell, Lynn M. and Lubin, Dan and Mülmenstädt, Johannes and Miller, Mark}, doi = {10.1073/pnas.2412247122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2412247122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Competition response of cloud supersaturation explains diminished twomey effect for smoky aerosol in the tropical atlantic}, volume = {122}, year = {2025}, }
• (2025). Jellyfish shape as a mechanical balance. PNAS, 122(13), e2412082122. (www)

  @article{ , abstract = {Why are jellyfish round? Animals get their shapes as they develop. After development, however, how animals keep their shapes is less understood. Moon jellies respond to perturbations to body shape, such as being halved or quartered, by reorganizing existing body parts and regaining radial symmetry, i.e., their round shape. The robust recovery of radial symmetry led us to investigate, in this study, how being round is encoded. We tested perturbing shape by grafting body sections in varying configurations. Testing these perturbations confirms the moon jellies’ ability to recover their round shape from many perturbations. However, in response to some perturbations, the jellies can also adopt other stable body shapes, such as oval, quadrilateral, and triangular. Thus, although the jellies are characterized by a radially symmetrical body plan, perturbations can lead to them recovering to bilateral shapes. Employing mathematical modeling, we find that interactions between forces from muscle contractions and viscoelastic tissues can explain the recovery to different shapes. A stable body shape is achieved when the mechanical forces are locally balanced, regardless of symmetry. Consistent with the model prediction that stable shape is the outcome of balancing mechanical forces, modulating the mechanical parameter in the system, i.e., the muscle contraction rate, can produce shape-shifting. Maintaining shapes dynamically as the balance of mechanical forces may enable the animals to readily adapt to changing physical environments.}, archive = {J_PNAS}, author = {Gong, Mengsha and Ashok, Minakshi and Helou, Ariane and Goentoro, Lea}, doi = {10.1073/pnas.2412082122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2412082122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Jellyfish shape as a mechanical balance}, volume = {122}, year = {2025}, }
• (2025). Linear recursive feature machines provably recover low-rank matrices. PNAS, 122(13), e2411325122. (www)

  @article{ , abstract = {A fundamental problem in machine learning is to understand how neural networks make accurate predictions, while seemingly bypassing the curse of dimensionality. A possible explanation is that common training algorithms for neural networks implicitly perform dimensionality reduction—a process called feature learning. Recent work [A. Radhakrishnan, D. Beaglehole, P. Pandit, M. Belkin, Science 383 , 1461–1467 (2024).] posited that the effects of feature learning can be elicited from a classical statistical estimator called the average gradient outer product (AGOP). The authors proposed Recursive Feature Machines (RFMs) as an algorithm that explicitly performs feature learning by alternating between 1) reweighting the feature vectors by the AGOP and 2) learning the prediction function in the transformed space. In this work, we develop theoretical guarantees for how RFM performs dimensionality reduction by focusing on the class of overparameterized problems arising in sparse linear regression and low-rank matrix recovery. Specifically, we show that RFM restricted to linear models (lin-RFM) reduces to a variant of the well-studied Iteratively Reweighted Least Squares (IRLS) algorithm. Furthermore, our results connect feature learning in neural networks and classical sparse recovery algorithms and shed light on how neural networks recover low rank structure from data. In addition, we provide an implementation of lin-RFM that scales to matrices with millions of missing entries. Our implementation is faster than the standard IRLS algorithms since it avoids forming singular value decompositions. It also outperforms deep linear networks for sparse linear regression and low-rank matrix completion.}, archive = {J_PNAS}, author = {Radhakrishnan, Adityanarayanan and Belkin, Mikhail and Drusvyatskiy, Dmitriy}, doi = {10.1073/pnas.2411325122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2411325122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Linear recursive feature machines provably recover low-rank matrices}, volume = {122}, year = {2025}, }
• (2025). Avian cranial kinesis is the result of increased encephalization during the origin of birds. PNAS, 122(13), e2411138122. (www)

  @article{ , abstract = {The origin of birds represents a pivotal transition in vertebrate evolution, marked by significant changes in both brain size and feeding biomechanics. The evolution of the avian skull involved dramatic modifications, such as a segmented palate and the development of powered cranial kinesis in neognath birds. Powered kinesis, the ability to move parts of the skull independently, is considered a key innovation behind the dietary diversity and evolutionary success of birds. However, the processes driving the emergence of avian kinesis have remained unclear until recently. By analyzing data from Mesozoic birds, including reinterpretations of palate homology, 3D jaw muscle biomechanics, and linkage analysis, researchers have quantified changes in muscle forces and their effects on palate mechanics during the transition from theropods to birds. As the neurocranium expanded in non-avian theropods, temporal muscles shifted to more rostrocaudal positions in birds, aiding in the segmentation of the pterygoid. This musculoskeletal transformation increased fore-aft muscle force in neognaths, enabling powered cranial kinesis. A critical change was the separation of the epipterygoid ossification from the braincase, leading to the breakdown of primitive kinematic linkages and the development of a new basicranial joint, which allowed for greater cranial flexibility. These findings shed light on how the neurosensory and feeding systems coevolved during bird origins and offer new methods for identifying cranial kinesis in extinct vertebrates.}, archive = {J_PNAS}, author = {Wilken, Alec T. and Sellers, Kaleb C. and Cost, Ian N. and Davis, Julian and Middleton, Kevin M. and Witmer, Lawrence M. and Holliday, Casey M.}, doi = {10.1073/pnas.2411138122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2411138122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Avian cranial kinesis is the result of increased encephalization during the origin of birds}, volume = {122}, year = {2025}, }
• (2025). Dopaminergic neurons in the paraventricular hypothalamus extend the food consumption phase. PNAS, 122(13), e2411069122. (www)

  @article{ , abstract = {Feeding behavior is controlled by various neural networks in the brain that are involved in different feeding phases: Food procurement, consumption, and termination. However, the specific neural circuits controlling the food consumption phase remain poorly understood. Here, we investigated the roles of dopaminergic neurons in the paraventricular nucleus of the hypothalamus (PVH) in the feeding behavior in mice. Our results indicated that the PVH dopaminergic neurons were critical for extending the food consumption phase and involved in the development of obesity through epigenetic mechanisms. These neurons synchronized with proopiomelanocortin neurons during consumption, were stimulated by proopiomelanocortin activation, and projected to the lateral habenula (LHb), where dopamine receptor D2 was involved in the increase in food consumption. In addition, upregulated tyrosine hydroxylase (TH) expression in PVH was associated with obesity and indispensable for obesity induction in mice lacking Dnmt3a . Taken together, our results highlight the roles of PVH dopaminergic neurons in promoting food consumption and obesity induction.}, archive = {J_PNAS}, author = {Ariyani, Winda and Yoshikawa, Chiharu and Tsuneoka, Haruka and Amano, Izuki and Imayoshi, Itaru and Ichinose, Hiroshi and Sumi-Ichinose, Chiho and Koibuchi, Noriyuki and Kitamura, Tadahiro and Kohno, Daisuke}, doi = {10.1073/pnas.2411069122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2411069122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dopaminergic neurons in the paraventricular hypothalamus extend the food consumption phase}, volume = {122}, year = {2025}, }
• (2025). Using net-zero carbon debt to track climate overshoot responsibility. PNAS, 122(13), e2409316122. (www)

  @article{ , abstract = {Current emissions trends will likely deplete a 1.5 °C consistent carbon budget around the year 2030, resulting in at least a temporary exceedance, or overshoot. To clarify responsibilities for this budget exceedance, we consider “net-zero carbon debt,” a forward-looking measure of the extent to which a party is expected to breach its “fair share” of the remaining budget by the time it achieves net-zero carbon emissions. We apply this measure to all vetted mitigation scenarios assessed in the Intergovernmental Panel on Climate Change’s Sixth Assessment Report and two scenarios that model current policies and pledges, using an illustrative equal per capita allocation of a remaining 1.5 °C carbon budget starting in 1990. The resulting regional carbon debt estimates inform i) the scale and pace of regional carbon drawdown obligations necessary to address budget exceedance and ii) relative regional responsibilities for increased lifetime exposure to extreme heatwaves across age cohorts due to budget exceedance. Our work strengthens intergenerational equity considerations within an international climate equity discourse and informs the implementation of effort-sharing mechanisms that persist beyond the exhaustion of a rapidly dwindling remaining carbon budget.}, archive = {J_PNAS}, author = {Pelz, Setu and Ganti, Gaurav and Lamboll, Robin and Grant, Luke and Smith, Chris and Pachauri, Shonali and Rogelj, Joeri and Riahi, Keywan and Thiery, Wim and Gidden, Matthew J.}, doi = {10.1073/pnas.2409316122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2409316122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Using net-zero carbon debt to track climate overshoot responsibility}, volume = {122}, year = {2025}, }
• (2025). The narrow search effect and how broadening search promotes belief updating. PNAS, 122(13), e2408175122. (www)

  @article{ , abstract = {Information search platforms, from Google to AI-assisted search engines, have transformed information access but may fail to promote a shared factual foundation. We demonstrate that the combination of users’ prior beliefs influencing their search terms and the narrow scope of search algorithms can limit belief updating from search. We test this “narrow search effect” across 21 studies (14 preregistered) using various topics (e.g., health, financial, societal, political) and platforms (e.g., Google, ChatGPT, AI-powered Bing, our custom-designed search engine and AI chatbot interfaces). We then test user-based and algorithm-based interventions to counter the “narrow search effect” and promote belief updating. Studies 1 to 5 show that users’ prior beliefs influence the direction of the search terms, thereby generating narrow search results that limit belief updating. This effect persists across various domains (e.g., beliefs related to coronavirus, nuclear energy, gas prices, crime rates, bitcoin, caffeine, and general food or beverage health concerns; Studies 1a to 1b, 2a to 2g, 3, 4), platforms (e.g., Google—Studies 1a to 1b, 2a to 2g, 4, 5; ChatGPT, Study 3), and extends to consequential choices (Study 5). Studies 6 and 7 demonstrate the limited efficacy of prompting users to correct for the impact of narrow searches on their beliefs themselves. Using our custom-designed search engine and AI chatbot interfaces, Studies 8 and 9 show that modifying algorithms to provide broader results can encourage belief updating. These findings highlight the need for a behaviorally informed approach to the design of search algorithms.}, archive = {J_PNAS}, author = {Leung, Eugina and Urminsky, Oleg}, doi = {10.1073/pnas.2408175122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2408175122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The narrow search effect and how broadening search promotes belief updating}, volume = {122}, year = {2025}, }
• (2025). Expectation-dependent stimulus selectivity in the ventral visual cortical pathway. PNAS, 122(13), e2406684122. (www)

  @article{ , abstract = {The hierarchical view of the ventral object recognition pathway is primarily based on feedforward mechanisms, starting from a fixed basis set of object primitives and ending on a representation of whole objects in the inferotemporal cortex. Here, we provide a different view. Rather than being a fixed “labeled line” for a specific feature, neurons are continually changing their stimulus selectivities on a moment-to-moment basis, as dictated by top–down influences of object expectation and perceptual task. Here, we also derive the selectivity for stimulus features from an ethologically curated stimulus set, based on a delayed match-to-sample task, that finds components that are informative for object recognition in addition to full objects, though the top–down effects were seen for both informative and uninformative components. Cortical areas responding to these stimuli were identified with functional MRI in order to guide placement of chronically implanted electrode arrays.}, archive = {J_PNAS}, author = {Altavini, Tiago S. and Chen, Minggui and Astorga, Guadalupe and Yan, Yin and Li, Wu and Freiwald, Winrich and Gilbert, Charles D.}, doi = {10.1073/pnas.2406684122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2406684122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Expectation-dependent stimulus selectivity in the ventral visual cortical pathway}, volume = {122}, year = {2025}, }
• (2025). Bridging the human–AI knowledge gap through concept discovery and transfer in AlphaZero. PNAS, 122(13), e2406675122. (www)

  @article{ , abstract = {AI systems have attained superhuman performance across various domains. If the hidden knowledge encoded in these highly capable systems can be leveraged, human knowledge and performance can be advanced. Yet, this internal knowledge is difficult to extract. Due to the vast space of possible internal representations, searching for meaningful new conceptual knowledge can be like finding a needle in a haystack. Here, we introduce a method that extracts new chess concepts from AlphaZero, an AI system that mastered chess via self-play without human supervision. Our method excavates vectors that represent concepts from AlphaZero’s internal representations using convex optimization, and filters the concepts based on teachability (whether the concept is transferable to another AI agent) and novelty (whether the concept contains information not present in human chess games). These steps ensure that the discovered concepts are useful and meaningful. For the resulting set of concepts, prototypes (chess puzzle–solution pairs) are presented to experts for final validation. In a preliminary human study, four top chess grandmasters (all former or current world chess champions) were evaluated on their ability to solve concept prototype positions. All grandmasters showed improvement after the learning phase, suggesting that the concepts are at the frontier of human understanding. Despite the small scale, our result is a proof of concept demonstrating the possibility of leveraging knowledge from a highly capable AI system to advance the frontier of human knowledge; a development that could bear profound implications and shape how we interact with AI systems across many applications.}, archive = {J_PNAS}, author = {Schut, Lisa and Tomašev, Nenad and McGrath, Thomas and Hassabis, Demis and Paquet, Ulrich and Kim, Been}, doi = {10.1073/pnas.2406675122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2406675122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bridging the human–AI knowledge gap through concept discovery and transfer in AlphaZero}, volume = {122}, year = {2025}, }
• (2025). Belief in belief: Even atheists in secular countries show intuitive preferences favoring religious belief. PNAS, 122(13), e2404720122. (www)

  @article{ , abstract = {We find evidence of belief in belief —intuitive preferences for religious belief over atheism, even among atheist participants—across eight comparatively secular countries. Religion is a cross-cultural human universal, yet explicit markers of religiosity have rapidly waned in large parts of the world in recent decades. We explored whether intuitive religious influence lingers, even among nonbelievers in largely secular societies. We adapted a classic experimental philosophy task to test for this intuitive belief in belief among people in eight comparatively nonreligious countries: Canada, China, Czechia, Japan, the Netherlands, Sweden, the United Kingdom, and Vietnam (total N = 3,804). Our analyses revealed strong evidence that 1) people intuitively favor religious belief over atheism and that 2) this pattern was not moderated by participants’ own self-reported atheism. Indeed, 3) even atheists in relatively secular societies intuitively prefer belief to atheism. These inferences were robust across different analytic strategies and across other measures of individual differences in religiosity and religious instruction. Although explicit religious belief has rapidly declined in these countries, it is possible that belief in belief may still persist. These results speak to the complex psychological and cultural dynamics of secularization.}, archive = {J_PNAS}, author = {Gervais, Will M. and McKay, Ryan T. and Brown-Iannuzzi, Jazmin L. and Ross, Robert M. and Pennycook, Gordon and Jong, Jonathan and Lanman, Jonathan A.}, doi = {10.1073/pnas.2404720122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2404720122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Belief in belief: Even atheists in secular countries show intuitive preferences favoring religious belief}, volume = {122}, year = {2025}, }
• (2025). Large-scale combination screens reveal small-molecule sensitization of antibiotic-resistant gram-negative ESKAPE pathogens. PNAS, 122(13), e2402017122. (www)

  @article{ , abstract = {Antibiotic resistance, especially in multidrug-resistant ESKAPE pathogens, remains a worldwide problem. Combination antimicrobial therapies may be an important strategy to overcome resistance and broaden the spectrum of existing antibiotics. However, this strategy is limited by the ability to efficiently screen large combinatorial chemical spaces. Here, we deployed a high-throughput combinatorial screening platform, DropArray, to evaluate the interactions of over 30,000 compounds with up to 22 antibiotics and 6 strains of gram-negative ESKAPE pathogens, totaling to over 1.3 million unique strain-antibiotic-compound combinations. In this dataset, compounds more frequently exhibited synergy with known antibiotics than single-agent activity. We identified a compound, P2-56, and developed a more potent analog, P2-56-3, which potentiated rifampin (RIF) against antibiotic-resistant strains of Acinetobacter baumannii and Klebsiella pneumoniae . Using phenotypic assays, we showed P2-56-3 disrupts the outer membrane of A. baumannii . To identify pathways involved in the mechanism of synergy between P2-56-3 and RIF, we performed genetic screens in A. baumannii . CRISPRi-induced partial depletion of lipooligosaccharide transport genes ( lptA - D , lptFG ) resulted in hypersensitivity to P2-56-3/RIF treatment, demonstrating the genetic dependency of P2-56-3 activity and RIF sensitization on lpt genes in A. baumannii. Consistent with outer membrane homeostasis being an important determinant of P2-56-3/RIF tolerance, knockout of maintenance of lipid asymmetry complex genes and overexpression of certain resistance-nodulation-division efflux pumps—a phenotype associated with multidrug-resistance—resulted in hypersensitivity to P2-56-3. These findings demonstrate the immense scale of phenotypic antibiotic combination screens using DropArray and the potential for such approaches to discover new small molecule synergies against multidrug-resistant ESKAPE strains.}, archive = {J_PNAS}, author = {Tse, Megan W. and Zhu, Meilin and Peters, Benjamin and Hamami, Efrat and Chen, Julie and Davis, Kathleen P. and Nitz, Samuel and Weller, Juliane and Warrier, Thulasi and Hunt, Diana K. and Morales, Yoelkys and Kawate, Tomohiko and Gaulin, Jeffrey L. and Come, Jon H. and Hernandez-Bird, Juan and Huo, Wenwen and Neisewander, Isabelle and Yu, Xiao and Aceves-Salvador, Jose A. and Kiessling, Laura L. and Hung, Deborah T. and Mecsas, Joan and Aldridge, Bree B. and Isberg, Ralph R. and Blainey, Paul C.}, doi = {10.1073/pnas.2402017122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2402017122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Large-scale combination screens reveal small-molecule sensitization of antibiotic-resistant gram-negative ESKAPE pathogens}, volume = {122}, year = {2025}, }
• (2025). Cholesterol-dependent enzyme activity of human TSPO1. PNAS, 122(13), e2323045122. (www)

  @article{ , abstract = {The amino acid sequence of the tryptophan-rich sensory proteins (TSPO) is substantially conserved throughout all kingdoms of life. Human mitochondrial TSPO1 ( Hs TSPO1) binds to porphyrins and steroids, although its interactions with these molecules remains unknown. Hs TSPO1 is associated with numerous physiological and pathological disorders, but the underlying molecular mechanisms are unknown. Here, we disclose the finding of human mitochondrial TSPO as a cholesterol-dependent protoporphyrin IX oxygenase. The results of our biochemical characterization are consistent with structural data and evolutionary analysis. The dependence of Hs TSPO1 activity on cholesterol may be the result of the coevolution of this membrane protein with the membrane system. Our study provides a molecular foundation for comprehending the various roles played by mitochondrial TSPO in normal physiological and pathological situations.}, archive = {J_PNAS}, author = {Qiu, Weihua and Trinh, Thi Kim Hoang and Catalano, Claudio and Mehta, Akul and Desai, Umesh R. and Kellogg, Glen E. and Hendrickson, Wayne A. and Guo, Youzhong}, doi = {10.1073/pnas.2323045122}, journal = {Proceedings of the National Academy of Sciences}, month = {4}, number = {13}, pages = {e2323045122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cholesterol-dependent enzyme activity of human TSPO1}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(12), eiti1225122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti1225122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {eiti1225122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Correction for xu et al., BCL6 promotes glioma and serves as a therapeutic target. PNAS, 122(12), e2504152122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504152122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2504152122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for xu et al., BCL6 promotes glioma and serves as a therapeutic target}, volume = {122}, year = {2025}, }
• (2025). Correction for kharrat et al., the antimicrobial activity of ETD151 defensin is dictated by the presence of glycosphingolipids in the targeted organisms. PNAS, 122(12), e2504079122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2504079122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2504079122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for kharrat et al., the antimicrobial activity of ETD151 defensin is dictated by the presence of glycosphingolipids in the targeted organisms}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for utzschneider et al., force balance of opposing diffusive motors generates polarity-sorted microtubule patterns. PNAS, 122(12), e2503982122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2503982122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2503982122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for utzschneider et al., force balance of opposing diffusive motors generates polarity-sorted microtubule patterns}, volume = {122}, year = {2025}, }
• (2025). Correction for yao et al., an organic electrochemical neuron for a neuromorphic perception system. PNAS, 122(12), e2503547122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2503547122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2503547122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for yao et al., an organic electrochemical neuron for a neuromorphic perception system}, volume = {122}, year = {2025}, }
• (2025). Correction for sauciuc et al., blobs form during the single-file transport of proteins across nanopores. PNAS, 122(12), e2503397122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2503397122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2503397122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for sauciuc et al., blobs form during the single-file transport of proteins across nanopores}, volume = {122}, year = {2025}, }
• (2025). Correction for rashid et al., nonpathological inflammation drives the development of an avian flight adaptation. PNAS, 122(12), e2503260122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2503260122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2503260122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for rashid et al., nonpathological inflammation drives the development of an avian flight adaptation}, volume = {122}, year = {2025}, }
• (2025). John brauman (1937–2024): Physical organic chemist, sage, and servant of science. PNAS, 122(12), e2502896122. (www)

  @article{ , archive = {J_PNAS}, author = {Craig, Stephen L.}, doi = {10.1073/pnas.2502896122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2502896122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {John brauman (1937–2024): Physical organic chemist, sage, and servant of science}, volume = {122}, year = {2025}, }
• (2025). Tumor immune evasion: Systemic immunosuppressive networks beyond the local microenvironment. PNAS, 122(12), e2502597122. (www)

  @article{ , archive = {J_PNAS}, author = {Yan, Chengsong and Wang, Xiao-Fan}, doi = {10.1073/pnas.2502597122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2502597122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tumor immune evasion: Systemic immunosuppressive networks beyond the local microenvironment}, volume = {122}, year = {2025}, }
• (2025). Systemic signals control infection plasticity in parasitic plants. PNAS, 122(12), e2502286122. (www)

  @article{ , archive = {J_PNAS}, author = {Ruwe, Hannes and Spallek, Thomas}, doi = {10.1073/pnas.2502286122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2502286122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Systemic signals control infection plasticity in parasitic plants}, volume = {122}, year = {2025}, }
• (2025). Correction for colen et al., machine learning active-nematic hydrodynamics. PNAS, 122(12), e2502090122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502090122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2502090122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for colen et al., machine learning active-nematic hydrodynamics}, volume = {122}, year = {2025}, }
• (2025). MITD1 is a brain-specific interferon-inducible factor that inhibits flavivirus replication. PNAS, 122(12), e2502064122. (www)

  @article{ , abstract = {West Nile virus (WNV) and Usutu virus (USUV) are closely related mosquito-borne neurotropic flaviviruses that share common transmission cycle and can infect humans. However, while human infections by WNV are widespread, infections by USUV are comparatively less frequent, less severe, and currently limited to Africa and Europe. To identify human host factors that contribute to the pathogenic signatures of these two flaviviruses, we carried out an arrayed expression screen of over 1,300 interferon-stimulated genes (ISGs). Several ISGs known to target flaviviruses, including IFI6, SHFL, and RTP4 were among the strongest hits. Interestingly, we also found MITD1, an ISG with no previously reported antiviral activity, among the strongest hits. We demonstrated that the antiviral activity of MITD1 was not limited to USUV and WNV, since it also inhibited Zika and dengue virus replication. We found MITD1 to interfere with viral RNA replication by sequestering specific endosomal sorting complexes required for transport-III (ESCRT-III) proteins involved in the formation of viral replication factories. MITD1 expression was not increased by type I interferon (IFN-I) in most human cells and mouse tissues that we examined, although WNV and USUV replication was strongly inhibited by IFN-I. Strikingly, MITD1 was induced in the brain of USUV-infected mice and importantly, in human monocyte-derived microglia. Using human microglial-like cells, we confirmed that MITD1 is an essential mediator of the anti-flavivirus activity of IFN-I in these cells. We conclude that MITD1 plays a key role in the cellular defenses against neurotropic flaviviruses.}, archive = {J_PNAS}, author = {Zoladek, Jim and Cannac, Marion and Seite, Maël and Davies, Emma and Quellec, Jordan and Barthelemy, Jonathan and Gorna, Kamila and Desgraupes, Sophie and Bribes, Ines and Salinas, Sara and Coulpier, Muriel and Arhel, Nathalie J. and Palmarini, Massimo and Simonin, Yannick and Wilson, Sam J. and Nisole, Sébastien}, doi = {10.1073/pnas.2502064122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2502064122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MITD1 is a brain-specific interferon-inducible factor that inhibits flavivirus replication}, volume = {122}, year = {2025}, }
• (2025). Red-light signaling pathway activates desert cyanobacteria to prepare for desiccation tolerance. PNAS, 122(12), e2502034122. (www)

  @article{ , abstract = {Desiccation-tolerant cyanobacteria are able to survive frequent cycles of hydration and dehydration, which are closely linked to diurnal light oscillations. Previous studies have shown that light serves as a crucial anticipatory cue, activating desert cyanobacteria to prepare for desiccation. However, the mechanisms underlying their light-coupled desiccation tolerance remain largely unknown. Here, we demonstrate that red-light-induced photosynthetic genes are positively regulated by a LuxR family transcription factor NfSrr1. We further identified the cyanobacteriochrome NfPixJ as interacting with NfSrr1 and functioning as a red light sensor. Phenotypic analysis revealed that the red-light signaling module NfPixJ-NfSrr1 plays a key role in preparing cyanobacteria for desiccation tolerance. This module also regulates the synthesis of protective compatible solutes, suggesting that red light functions as a global regulatory signal for the broader stress response. Phylogenetic analysis indicates that the presence of this red-light signaling pathway, mediated by NfPixJ-NfSrr1 module, correlates with the ability of cyanobacteria to thrive in water-deficit habitats. Overall, our findings uncover a red-light signaling pathway that enhances desiccation tolerance as desert cyanobacteria encounter red light at dawn, before water limitation. These results provide insights into the mechanisms behind light-induced anticipatory stress tolerance in photosynthetic organisms.}, archive = {J_PNAS}, author = {Xu, Hai-Feng and Dai, Guo-Zheng and Li, Ren-Han and Bai, Yang and Zuo, Ai-Wei and Zhao, Lei and Cui, Shu-Ren and Shang, Jin-Long and Cheng, Chao and Wang, Yu-Jie and Feng, Gui-Fang and Duanmu, Deqiang and Kaplan, Aaron and Qiu, Bao-Sheng}, doi = {10.1073/pnas.2502034122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2502034122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Red-light signaling pathway activates desert cyanobacteria to prepare for desiccation tolerance}, volume = {122}, year = {2025}, }
• (2025). Ternary surface complexation promotes simultaneous removal of arsenic and uranium by TiO2. PNAS, 122(12), e2501354122. (www)

  @article{ , abstract = {The co-occurrence of arsenic and uranium in groundwater has been found in many countries, posing a significant challenge to human health. Here, we have demonstrated the efficient simultaneous removal of arsenic and uranyl-carbonate complexes from groundwater using {001}-TiO 2 . Surprisingly, the presence of U(VI) greatly enhanced the adsorption of As(V) on {001}-TiO 2 , while As(V) had a negligible impact on U(VI) adsorption. Through in situ ATR-FTIR spectroscopy, we uncovered a mechanism involving the formation of a ternary surface complex [Ti–U(VI)–As(V)] on the surface of {001}-TiO 2 . This ternary surface complex formed through the substitution of CO 3 2- from uranyl coordination sites. Furthermore, the adsorbed As(V) and U(VI) can be easily recovered using a sodium hydroxide solution, and {001}-TiO 2 can be used repeatedly. Our findings offer a promising solution for the simultaneous removal of As(V) and U(VI) from groundwater and provide valuable insights into the mechanisms involved in their removal.}, archive = {J_PNAS}, author = {Lin, Leiming and Li, Zheng and Ren, Jun and Meng, Ying and Luan, Fubo}, doi = {10.1073/pnas.2501354122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2501354122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ternary surface complexation promotes simultaneous removal of arsenic and uranium by TiO2}, volume = {122}, year = {2025}, }
• (2025). Accelerated peptide bond formation at air–water interfaces. PNAS, 122(12), e2501323122. (www)

  @article{ , abstract = {Peptides and proteins, essential components of living organisms, are composed of amino acids linked by peptide bonds. However, the mechanism of peptide bond formation during the prebiotic era remains unclear. In this study, advanced Born–Oppenheimer molecular dynamics (BOMD) simulations were used to investigate the mechanisms and kinetics of peptide bond formation at air–water interfaces using diglycine, the simplest dipeptide, as a model molecule. The results show that peptide bonds can be rapidly formed via a unique isomerization-then-OH − -elimination pathway. In this mechanism, the diglycine initially isomerizes into its acidic form at the air–water interface, followed by a reaction that releases an OH − anion rather than the previously hypothesized H 2 O. The free-energy barriers for the interfacial pathway with the assistance of an interfacial electric field are much lower than those in the gas phase by >25 kcal/mol. Further calculations suggest that this mechanism can be extended to the formation of some larger peptides, such as tetraglycine. This pathway offers insights into the origin of life and could inform the development of methods for peptide synthesis.}, archive = {J_PNAS}, author = {Xia, Deming and Zeng, Fanqi and Chen, Wanting and Zhao, Hui and Xie, Hong-bin and Chen, Jingwen and Francisco, Joseph S.}, doi = {10.1073/pnas.2501323122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2501323122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Accelerated peptide bond formation at air–water interfaces}, volume = {122}, year = {2025}, }
• (2025). Reply to fiscella: Why study erosion now? and why these risk factors?. PNAS, 122(12), e2501249122. (www)

  @article{ , archive = {J_PNAS}, author = {Rau, Eli G. and Stokes, Susan C.}, doi = {10.1073/pnas.2501249122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2501249122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to fiscella: Why study erosion now? and why these risk factors?}, volume = {122}, year = {2025}, }
• (2025). Bringing pressure-induced superconductivity back to ambient pressure. PNAS, 122(12), e2501048122. (www)

  @article{ , archive = {J_PNAS}, author = {Deng, Yuhang and Maple, M. Brian}, doi = {10.1073/pnas.2501048122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2501048122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bringing pressure-induced superconductivity back to ambient pressure}, volume = {122}, year = {2025}, }
• (2025). Research needed on tipping points and reversal of erosions in democracy. PNAS, 122(12), e2500631122. (www)

  @article{ , archive = {J_PNAS}, author = {Fiscella, Kevin}, doi = {10.1073/pnas.2500631122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2500631122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Research needed on tipping points and reversal of erosions in democracy}, volume = {122}, year = {2025}, }
• (2025). Correction for bednarek et al., how and why funders support engaged research. PNAS, 122(12), e2500542122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2500542122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2500542122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for bednarek et al., how and why funders support engaged research}, volume = {122}, year = {2025}, }
• (2025). Polymorphic transposable elements contribute to variation in recombination landscapes. PNAS, 122(12), e2427312122. (www)

  @article{ , abstract = {Meiotic recombination is a prominent force shaping genome evolution, and understanding why recombination rates vary within and between species has remained a central, though challenging, question. Variation in recombination is widely thought to influence the efficacy of selection in purging transposable elements (TEs), prevalent selfish genetic elements, leading to widely observed negative correlations between TE abundance and recombination rates across taxa. However, accumulating evidence suggests that TEs could instead be the cause rather than the consequence of this relationship. To test this prediction, we formally investigated the influence of polymorphic, putatively active TEs on recombination rates. We developed and benchmarked an approach that uses PacBio long-read sequencing to efficiently, accurately, and cost-effectively identify crossovers (COs), a key recombination product, among large numbers of pooled recombinant individuals. By applying this approach to Drosophila strains with distinct TE insertion profiles, we found that polymorphic TEs, especially RNA-based TEs and TEs with local enrichment of repressive marks, reduce the occurrence of COs. Such an effect leads to different CO frequencies between homologous sequences with and without TEs, contributing to varying CO maps between individuals. The suppressive effect of TEs on CO is further supported by two orthogonal approaches–analyzing the distributions of COs in panels of recombinant inbred lines in relation to TE polymorphism and applying marker-assisted estimations of CO frequencies to isogenic strains with and without transgenically inserted TEs. Our investigations reveal how the constantly changing TE landscape can actively modify recombination, shaping genome evolution within and between species.}, archive = {J_PNAS}, author = {Huang, Yuheng and Gao, Zita Y. and Ly, Kayla and Lin, Leila and Lambooij, Jan-Paul and King, Elizabeth G. and Janssen, Aniek and Wei, Kevin H.-C. and Lee, Yuh Chwen G.}, doi = {10.1073/pnas.2427312122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2427312122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Polymorphic transposable elements contribute to variation in recombination landscapes}, volume = {122}, year = {2025}, }
• (2025). Active matter as the underpinning agency for extraordinary sensitivity of biological membranes to electric fields. PNAS, 122(12), e2427255122. (www)

  @article{ , abstract = {Interaction of electric fields with biological cells is indispensable for many physiological processes. Thermal electrical noise in the cellular environment has long been considered as the minimum threshold for detection of electrical signals by cells. However, there is compelling experimental evidence that the minimum electric field sensed by certain cells and organisms is many orders of magnitude weaker than the thermal electrical noise limit estimated purely under equilibrium considerations. We resolve this discrepancy by proposing a nonequilibrium statistical mechanics model for active electromechanical membranes and hypothesize the role of activity in modulating the minimum electrical field that can be detected by a biological membrane. Active membranes contain proteins that use external energy sources to carry out specific functions and drive the membrane away from equilibrium. The central idea behind our model is that active mechanisms, attributed to different sources, endow the membrane with the ability to sense and respond to electric fields that are deemed undetectable based on equilibrium statistical mechanics. Our model for active membranes is capable of reproducing different experimental data available in the literature by varying the activity. Elucidating how active matter can modulate the sensitivity of cells to electric signals can open avenues for a deeper understanding of physiological and pathological processes.}, archive = {J_PNAS}, author = {Mathew, Anand and Kulkarni, Yashashree}, doi = {10.1073/pnas.2427255122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2427255122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Active matter as the underpinning agency for extraordinary sensitivity of biological membranes to electric fields}, volume = {122}, year = {2025}, }
• (2025). Electric spiking activity in epithelial cells. PNAS, 122(12), e2427123122. (www)

  @article{ , abstract = {Epithelial cells (human keratinocyte cells and the canine MDCK cell line), traditionally viewed as electrically non-self-excitable and involved primarily in physiological functions such as barrier presentation, absorption, secretion, and protection, are shown here to exhibit traveling extracellular electric charge when they recover from spatially focused, laser-induced wounding of confluent monolayers cultured on a multielectrode array chip. Voltage spikes measured on these electrodes display depolarization, repolarization, and hyperpolarization phases with amplitudes similar to the action potentials of neurons but with the markedly slower duration of 1 to 2 s. Some propagate distances up to hundreds of μm from the wound with a mean speed of around 10 mm s −1 . Generation and transmission of bioelectric signals are significantly influenced by the perturbation of mechanosensitive cationic ion channels. These direct measurements confirm bioelectric signaling that previous work has hypothesized to regulate epithelial cell development and may have relevance to the frequency parameter selection of bioelectric devices.}, archive = {J_PNAS}, author = {Yu, Sun-Min and Granick, Steve}, doi = {10.1073/pnas.2427123122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2427123122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electric spiking activity in epithelial cells}, volume = {122}, year = {2025}, }
• (2025). The file drawer problem in social science survey experiments. PNAS, 122(12), e2426937122. (www)

  @article{ , abstract = {The file drawer problem—often operationalized in terms of statistically significant results being published and statistically insignificant not being published—is widely documented in the social sciences. We extend Franco’s et al. [ Science 345 , 1502–1505(2014)] seminal study of the file drawer problem in survey experiments submitted to the Time-sharing Experiments for the Social Sciences (TESS) data collection program. We examine projects begun after Franco et al. The updated period coincides with the contemporary open science movement. We find evidence of the problem, stemming from scholars opting to not write up insignificant results. However, that tendency is substantially smaller than it was in the prior decade. This suggests increased recognition of the importance of null results, even if the problem remains in the domain of survey experiments.}, archive = {J_PNAS}, author = {Moniz, Philip and Druckman, James N. and Freese, Jeremy}, doi = {10.1073/pnas.2426937122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2426937122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The file drawer problem in social science survey experiments}, volume = {122}, year = {2025}, }
• (2025). Functional morphology of gliding motility in benthic diatoms. PNAS, 122(12), e2426910122. (www)

  @article{ , abstract = {Diatoms, a highly successful group of photosynthetic algae, contribute to a quarter of global primary production. Many species are motile, despite having no appendages and a completely rigid cell body. Cells move to seek out nutrients, locate mating partners, and undergo vertical migration. To explore the natural diversity of diatom motility, we perform a comparative study across five common biofilm-forming species. Combining morphological measurements with high-resolution cell tracking, we establish how gliding movements relate to the morphology of the raphe—a specialized slit in the cell wall responsible for motility generation. Our detailed analyses reveal that cells exhibit a rich but species-dependent phenotype, switching stochastically between four stereotyped motility states. We model this behavior and use stochastic simulations to predict how heterogeneity in microscale navigation patterns leads to differences in long-time diffusivity and dispersal. In a representative species, we extend these findings to quantify diatom gliding in complex, naturalistic 3D environments, suggesting that cells may exploit these distinct motility signatures to achieve niche segregation in nature.}, archive = {J_PNAS}, author = {Bondoc-Naumovitz, Karen Grace and Crosato, Emanuele and Wan, Kirsty Y.}, doi = {10.1073/pnas.2426910122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2426910122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Functional morphology of gliding motility in benthic diatoms}, volume = {122}, year = {2025}, }
• (2025). Reply to grossman et al.: The case for a time-varying oxygen isotopic composition of seawater and cooler ordovician oceans. PNAS, 122(12), e2426540122. (www)

  @article{ , archive = {J_PNAS}, author = {Thiagarajan, Nivedita and Lepland, Aivo and Ryb, Uri and Torsvik, Trond H. and Ainsaar, Leho and Hints, Olle and Eiler, John}, doi = {10.1073/pnas.2426540122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2426540122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to grossman et al.: The case for a time-varying oxygen isotopic composition of seawater and cooler ordovician oceans}, volume = {122}, year = {2025}, }
• (2025). Flycodes enable simultaneous preclinical analysis for dozens of antibodies in single cassette–dosed mice. PNAS, 122(12), e2426481122. (www)

  @article{ , abstract = {Protein therapeutics such as antibodies require in-depth in vivo characterization during development and consequently account for a large proportion of laboratory animal consumption in the pharmaceutical industry. Currently, antibody candidates are exhaustively tested one-by-one in animal models to determine pharmacokinetic and pharmacodynamic (PK/PD) profiles. The simultaneous analysis of antibody mixtures in single animals, called cassette-dosing, could in principle overcome this bottleneck, but is currently limited to small cassette sizes. Here, we demonstrate how the use of genetically encoded peptide tags (flycodes), designed for maximal detectability in liquid chromatography-mass spectrometry, can allow for the simultaneous characterization of large pools of drug candidates, from single cassette–dosed mice. We demonstrate the simultaneous assessment of PK parameters for a group of >20 marketed/development-stage antibodies. Biodistribution experiments in mice bearing EGFR-expressing tumors correctly identified the two pool members recognizing EGFR, while organ analysis registered liver accumulation of an antibody targeting glucagon receptor, a protein profoundly expressed in that organ. In analogy to an early-phase drug development campaign, we performed biophysical and PK analysis for a cassette of 80 unique bispecific DARPin-sybody molecules. The data shown in this study originate from only 18 cassette-dosed mice, thereby demonstrating how flycode technology efficiently advances preclinical discovery pipelines allowing a direct comparison of drug candidates under identical experimental conditions.}, archive = {J_PNAS}, author = {Walter, Justin D. and Beffinger, Michal and Egloff, Pascal and Zimmermann, Iwan and Hürlimann, Lea M. and Ackle, Fabian and Seifert, Matthias and Kobold, Sebastian and vom Berg, Johannes and Seeger, Markus A.}, doi = {10.1073/pnas.2426481122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2426481122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Flycodes enable simultaneous preclinical analysis for dozens of antibodies in single cassette–dosed mice}, volume = {122}, year = {2025}, }
• (2025). Entropy is an important design principle in the photosystem II supercomplex. PNAS, 122(12), e2426331122. (www)

  @article{ , abstract = {Photosystem II (PSII) can achieve near-unity quantum efficiency of light harvesting in ideal conditions and can dissipate excess light energy as heat to prevent the formation of reactive oxygen species (ROS) under light stress. Understanding how this pigment–protein complex accomplishes these opposing goals is a topic of great interest that has so far been explored primarily through the lens of the system energetics. Despite PSII’s known flat energy landscape, a thorough consideration of the entropic effects on energy transfer in PSII is lacking. In this work, we aim to discern the free energetic design principles underlying the PSII energy transfer network. To accomplish this goal, we employ a structure-based rate matrix and compute the free energy terms in time following a specific initial excitation to discern how entropy and enthalpy drive ensemble system dynamics. We find that the interplay between the entropy and enthalpy components differ among each protein subunit, which allows each subunit to fulfill a unique role in the energy transfer network. This individuality ensures that PSII can accomplish efficient energy trapping in the reaction center (RC), effective nonphotochemical quenching (NPQ) in the periphery, and robust energy trapping in the other-monomer RC if the same-monomer RC is closed. We also show that entropy, in particular, is a dynamically tunable feature of the PSII free energy landscape accomplished through regulation of LHCII binding. These findings help rationalize natural photosynthesis and provide design principles for more efficient solar energy harvesting technologies.}, archive = {J_PNAS}, author = {Hall, Johanna L. and Yang, Shiun-Jr and Limmer, David T. and Fleming, Graham R.}, doi = {10.1073/pnas.2426331122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2426331122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Entropy is an important design principle in the photosystem II supercomplex}, volume = {122}, year = {2025}, }
• (2025). Androgen receptors in corticotropin-releasing hormone neurons mediate the sexual dimorphism in restraint-induced thymic atrophy. PNAS, 122(12), e2426107122. (www)

  @article{ , abstract = {Sexual dimorphism in immune responses is well documented, but the underlying mechanisms remain incompletely understood. Here, we identified a subset of corticotropin-releasing hormone (CRH) neurons that express androgen receptors (ARs) as key mediators of sex differences in restraint-induced immunosuppression. Mechanistically, androgens directly activate AR-positive CRH neurons, enhancing the hypothalamic–pituitary–adrenal axis activation. This results in elevated corticosterone levels in response to restraint stress, leading to increased immune cell apoptosis and immune organ atrophy in male mice. Conditional knockout of ARs in CRH neurons eliminated this sexual dimorphism, highlighting ARs in CRH neurons as pivotal regulators of sex-specific immune responses to stress.}, archive = {J_PNAS}, author = {Meng, Yutong and Li, Yaning and Gu, Huating and Chen, Ziyao and Cui, Xiaoyang and Wang, Xiaodong}, doi = {10.1073/pnas.2426107122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2426107122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Androgen receptors in corticotropin-releasing hormone neurons mediate the sexual dimorphism in restraint-induced thymic atrophy}, volume = {122}, year = {2025}, }
• (2025). Reply to ahmed and lu: Cluster signals depend on how samples are made and measured. PNAS, 122(12), e2425993122. (www)

  @article{ , archive = {J_PNAS}, author = {Chen, Gang and Lv, Guangxin and Zhang, James H. and Tu, Yaodong}, doi = {10.1073/pnas.2425993122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2425993122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to ahmed and lu: Cluster signals depend on how samples are made and measured}, volume = {122}, year = {2025}, }
• (2025). The TEA domain transcription factors TEAD1 and TEAD3 and WNT signaling determine HLA-G expression in human extravillous trophoblasts. PNAS, 122(12), e2425339122. (www)

  @article{ , abstract = {Maternal–fetal immune tolerance guarantees a successful pregnancy throughout gestation. HLA-G, a nonclassical human leukocyte antigen (HLA) molecule exclusively expressed in extravillous trophoblasts (EVT), is a crucial factor in establishing maternal–fetal immune tolerance by interacting with inhibitory receptors on various maternal immune cells residing in the uterus. While trophoblast-specific cis-regulatory elements impacting HLA-G transcription have been described, the identity of trans-acting factors controlling HLA-G expression in EVT remains poorly understood. Utilizing a genome-wide CRISPR-Cas9 knockout screen, we find that the WNT signaling pathway negatively regulates HLA-G expression in EVT. In addition, we identified two trophoblast-specific transcription factors, TEAD1 and TEAD3, required for HLA-G transcription in EVT in a Yes-associated protein-independent manner. Altogether, we systematically elucidated essential genes and pathways underlying HLA-G expression in EVT, shedding light on the mechanisms of maternal–fetal tolerance and potentially providing insights into controlling HLA-G expression beyond EVT to protect allogeneic cells from immune rejection.}, archive = {J_PNAS}, author = {Gu, Bowen and Ferreira, Leonardo M. R. and Herrera, Sebastian and Brown, Lara and Lieberman, Judy and Sherwood, Richard I. and Meissner, Torsten B. and Strominger, Jack L.}, doi = {10.1073/pnas.2425339122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2425339122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The TEA domain transcription factors TEAD1 and TEAD3 and WNT signaling determine HLA-G expression in human extravillous trophoblasts}, volume = {122}, year = {2025}, }
• (2025). ACOD1-mediated lysosomal membrane permeabilization contributes to mycobacterium tuberculosis–induced macrophage death. PNAS, 122(12), e2425309122. (www)

  @article{ , abstract = {Mycobacterium tuberculosis (Mtb) primarily infects macrophages. In vitro without antibiotics, wild-type Mtb hastens death of the macrophages, but the processes leading to rapid cell death are not well understood. Our earlier work indicated that the death of Mtb-infected mouse macrophages in vitro is markedly exacerbated by induction of interferon-β (IFN-β) [L. Zhang et al., J. Exp. Med. 18 , e20200887 (2021)]. Here, we identified a key downstream response to IFN-β in the context of Mtb infection as the massive induction of cis-aconitate decarboxylase (ACOD1), not only in its canonical subcellular localization in mitochondria but also in the cytosol, where it bound to the lysosome-stabilizing protein HSP70. ACOD1’s product, itaconate, protected Mtb-infected macrophages. However, the contrasting and predominant effect of high-level ACOD1 expression was to act in a noncatalytic manner to promote HSP70’s degradation, leading to lysosomal membrane permeabilization (LMP). Mtb-induced macrophage death was markedly diminished by inhibitors of cysteine proteases, consistent with lysosome-mediated cell death. Neither ACOD1 inhibitors nor cysteine protease inhibitors are suitable for potential host-directed therapy (HDT) of tuberculosis. Instead, this work directs attention to how ACOD1 acts nonenzymatically to promote the degradation of HSP70.}, archive = {J_PNAS}, author = {Yang, Ziwei and Zhang, Li and Ottavi, Samantha and Geri, Jacob B. and Perkowski, Andrew and Jiang, Xiuju and Pfau, Daniel and Bryk, Ruslana and Aubé, Jeffrey and Zimmerman, Matthew and Dartois, Véronique and Nathan, Carl}, doi = {10.1073/pnas.2425309122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2425309122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ACOD1-mediated lysosomal membrane permeabilization contributes to mycobacterium tuberculosis–induced macrophage death}, volume = {122}, year = {2025}, }
• (2025). Energy landscape analysis of the development of the chromosome structure across the cell cycle. PNAS, 122(12), e2425225122. (www)

  @article{ , abstract = {During mitosis, there are significant structural changes in chromosomes. We used a maximum entropy approach to invert experimental Hi-C data to generate effective energy landscapes for chromosomal structures at different stages during the cell cycle. Modeled mitotic structures show a hierarchical organization of helices of helices. High-periodicity loops span hundreds of kilobases or less, while the other low-periodicity ones are larger in genomic separation, spanning several megabases. The structural ensembles reveal a progressive decrease in compartmentalization from interphase to mitosis, accompanied by the appearance of a second diagonal in prometaphase, indicating an organized array of loops. While there is a local tendency to form chiral helices, overall, no preferential left-handed or right-handed chirality appears to develop on the time scale of the cell cycle. Chromatin thus appears to be a liquid crystal containing numerous defects that anneal rather slowly.}, archive = {J_PNAS}, author = {Contessoto, Vinícius G. and Oliveira Jr., Antonio B. and Brahmachari, Sumitabha and Wolynes, Peter G. and Di Pierro, Michele and Onuchic, José N.}, doi = {10.1073/pnas.2425225122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2425225122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Energy landscape analysis of the development of the chromosome structure across the cell cycle}, volume = {122}, year = {2025}, }
• (2025). Hair cell apoptosis and deafness in tmc1 mutations. PNAS, 122(12), e2425215122. (www)

  @article{ , abstract = {Transmembrane channel-like protein 1 (TMC1), a pore-forming component of the mechano-electrical transducer (MET) channel in cochlear outer hair cells, is subject to numerous mutations causing deafness and hair cell death. We studied mice harboring semidominant mutations Tmc1 p.T416K, p.M412K, and p.D569N, which all display functional MET channels at postnatal day (P)6 but become deaf by P21. Early signs of concomitant hair cell apoptosis were assayed in neonatal Tmc1 mutants by labeling with Calcein-acetomethyl ester (AM), MitoTracker, and Annexin V, the latter labeling scramblase externalization of phosphatidyl serine. Reduced labeling with Calcein-AM was correlated with reduced MitoTracker, the targeting of mitochondria being confirmed with the uncoupling agent carbonylcyanide p -trifluoromethoxyphenylhydrazone, and use of MitoLight to monitor mitochondrial membrane potential. These markers demonstrated mitochondrial dysfunction in Tmc1 mutants, even at P6 when MET currents were still present. Acoustic brainstem responses established that Tmc1 p.D569N and Tmc1 p.M412K mice were deaf by P15 and Tmc1 p.T416K by P21. Two methods of blocking the stereociliary PMCA2 Ca 2+ pump both elicited scramblase activity, suggesting that apoptosis is promoted by elevation of hair bundle [Ca 2+ ]. Reduced PMCA2 density was found in the stereocilia of Tmc1 mutants and was correlated with a decrease in MET channel Ca 2+ permeability. Cre-Lox excision of the mutant M412K exon at P1 fully preserved hearing across all frequencies by P19 and promoted recovery to wild type of PMCA2 density. These results demonstrate that hair cells in Tmc1 mutants have embarked on apoptosis at P6 and argue for connections between stereociliary PMCA2 density, hair cell apoptosis, and deafness.}, archive = {J_PNAS}, author = {Beurg, Maryline and Konrad, Dakota Elle and Fettiplace, Robert}, doi = {10.1073/pnas.2425215122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2425215122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hair cell apoptosis and deafness in tmc1 mutations}, volume = {122}, year = {2025}, }
• (2025). Rippled metamaterials with scale-dependent tailorable elasticity. PNAS, 122(12), e2425200122. (www)

  @article{ , abstract = {Thermally induced ripples are intrinsic features of nanometer-thick films, atomically thin materials, and cell membranes, significantly affecting their elastic properties. Despite decades of theoretical studies on the mechanics of suspended thermalized sheets, controversy still exists over the impact of these ripples, with conflicting predictions about whether elasticity is scale-dependent or scale-independent. Experimental progress has been hindered so far by the inability to have a platform capable of fully isolating and characterizing the effects of ripples. This knowledge gap limits the fundamental understanding of thin materials and their practical applications. Here, we show that thermal-like static ripples shape thin films into a class of metamaterials with scale-dependent, customizable elasticity. Utilizing a scalable semiconductor manufacturing process, we engineered nanometer-thick films with precisely controlled frozen random ripples, resembling snapshots of thermally fluctuating membranes. Resonant frequency measurements of rippled cantilevers reveal that random ripples effectively renormalize and enhance the average bending rigidity and sample-to-sample variations in a scale-dependent manner, consistent with recent theoretical estimations. The predictive power of the theoretical model, combined with the scalability of the fabrication process, was further exploited to create kirigami architectures with tailored bending rigidity and mechanical metamaterials with delayed buckling instability.}, archive = {J_PNAS}, author = {Zhou, Jian and Huang, Richard and Moldovan, Nicolaie and Stan, Liliana and Wen, Jianguo and Jin, Dafei and Nelson, David R. and Košmrlj, Andrej and Czaplewski, David A. and López, Daniel}, doi = {10.1073/pnas.2425200122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2425200122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rippled metamaterials with scale-dependent tailorable elasticity}, volume = {122}, year = {2025}, }
• (2025). Molecular mechanisms underlying the evolution of a color polyphenism by genetic accommodation in the tobacco hornworm, manduca sexta. PNAS, 122(12), e2425004122. (www)

  @article{ , abstract = {How organisms evolve under extreme environmental changes is a critical question in the face of global climate change. Genetic accommodation is an evolutionary process by which natural selection acts on novel phenotypes generated through repeated encounters with extreme environments. In this study, polyphenic and monophenic strains of the black mutant tobacco hornworm, Manduca sexta , were evolved via genetic accommodation of heat stress-induced phenotypes, and the molecular differences between the two strains were explored. Transcriptomic analyses showed that epigenetic and hormonal differences underlie the differences between the two strains and their distinct responses to temperature. DNA methylation had diverged between the two strains potentially mediating genetic assimilation. Juvenile hormone (JH) signaling in the polyphenic strain was temperature sensitive, whereas in the monophenic strain, JH signaling remained low at all temperatures. Although 20-hydroxyecdysone titers were elevated under heat shock conditions in both strains, the strains did not differ in the titers. Tyrosine hydroxylase was also found to differ between the two strains at different temperatures, and its expression could be modulated by topical application of a JH analog. Finally, heat shock of unselected black mutants demonstrated that the expression of the JH-response gene, Krüppel-homolog 1 ( Kr-h1 ), increased within the first 30 min of heat shock, suggesting that JH levels respond readily to thermal stress. Our study highlights the critical role that hormones and epigenetics play during genetic accommodation and potentially in the evolution of populations in the face of climate change.}, archive = {J_PNAS}, author = {Suzuki, Yuichiro and Amaya, Stephanie and Gonzalez, Paula and Becerril, Daniela and Aquit, Surisadai and Davis, Maya and Hoesel, Madeline and Chou, Elizabeth and Khong, Hesper and Zaia, Kathryn and Park, Heidi S. and Nijhout, H. Frederik and Tjaden, Brian}, doi = {10.1073/pnas.2425004122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2425004122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular mechanisms underlying the evolution of a color polyphenism by genetic accommodation in the tobacco hornworm, manduca sexta}, volume = {122}, year = {2025}, }
• (2025). Embryonic reprogramming of the tumor vasculature reveals targets for cancer therapy. PNAS, 122(12), e2424730122. (www)

  @article{ , abstract = {A sustained blood supply is critical for tumor growth, as it delivers the nutrients and oxygen required for development. Targeting of blood vessel formation via immunotherapies is an area of great importance. Knowing that certain embryonic genes, such as carcinoembryonic antigens (CEA) and oncofetal fibronectin, become reexpressed in malignant transformation, we hypothesized that a similar phenomenon holds true for tumor endothelial cells (TECs) as well. An approach for identification of highly selective tumor endothelial markers was conducted to develop targeted antiangiogenic immunotherapies. We first queried the transcriptome that is present during embryo development. We then performed a systematic search for genes selectively expressed in the mouse embryo at days E11 and E18, as compared to the transcriptome of the adult mouse. Subsequently, we queried for expression of these embryonic genes in sorted murine TECs. This approach identified among others the tumor endothelial antigens fibrillin-2 (Fbn2), elastin microfibril interface-located protein 2 (Emilin2) as well as the tumor endothelial antigens lysyl oxidase (Lox) and serine/cysteine protease inhibitor, clade E, member 1 (Serpine1; Pai-1). For these selected genes, functional involvement in angiogenesis was confirmed in in vitro bioassays. We subsequently used iBoost conjugate vaccine technology to develop vaccines against the selected targets. For all four targets, vaccination readily induced target-specific antibody responses in mice, resulting in inhibition of tumor growth. Access to highly specific tumor endothelial markers provides opportunities for direct targeting of the tumor vasculature with high specificity, without affecting healthy vasculature.}, archive = {J_PNAS}, author = {Huijbers, Elisabeth J. M. and van Beijnum, Judy R. and van Loon, Karlijn and Griffioen, Christian J. and Volckmann, Richard and Bassez, Ayse and Lambrechts, Diether and Nunes Monteiro, Madalena and Jimenez, Connie R. and Hogendoorn, Pancras C. W. and Koster, Jan and Griffioen, Arjan W.}, doi = {10.1073/pnas.2424730122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2424730122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Embryonic reprogramming of the tumor vasculature reveals targets for cancer therapy}, volume = {122}, year = {2025}, }
• (2025). Highly spatial–temporal electrochemical profiling of molecules trafficking at a single mitochondrion in one living cell. PNAS, 122(12), e2424591122. (www)

  @article{ , abstract = {Simultaneous profiling of multiple molecules trafficking at a single organelle and the surrounding cytosol within a living cell is crucial for elucidating their functions, necessitating advanced techniques that provide high spatial–temporal resolution and molecule specificity. In this study, we present an electrochemical nanodevice based on a θ-nanopipette designed to coanalyze calcium ions (Ca 2+ ) and reactive oxygen species (ROS) at a single mitochondrion and its surrounding cytosol, thereby enhancing our understanding of their trafficking within the signaling pathways of cellular autophagy. Two independent nanosensors integrated within the channels of the θ-nanopipette spatially isolate a single target mitochondrion from the cytosol and simultaneously measure the release of Ca 2+ and ROS with high spatial–temporal resolution. Dynamic tracking reveals the direct trafficking of lysosomal Ca 2+ to the mitochondrion rather than to the cytosol, which triggers ROS-induced ROS release within the mitochondria. Furthermore, highly temporal and concurrent observations revealed a second burst of Ca 2+ in both the mitochondrion and the cytosol, which is not consistent with the change in ROS. These dynamic data elucidate the potential role of a beneficial feedback loop between the Ca 2+ signaling pathway and the subsequent generation of mitochondrial ROS in ML-SA-induced autophagy. More importantly, this innovative platform facilitates detailed profiling of the molecular interactions between trafficking molecules within the mitochondria and the adjacent cytosolic environment, which is hardly realized using the current superresolution optical microscopy.}, archive = {J_PNAS}, author = {Liu, Kang and Wu, Lina and Ma, Yuanyuan and Chen, Desheng and Liu, Rujia and Zhang, Xiaobo and Jiang, Dechen and Pan, Rongrong}, doi = {10.1073/pnas.2424591122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2424591122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Highly spatial–temporal electrochemical profiling of molecules trafficking at a single mitochondrion in one living cell}, volume = {122}, year = {2025}, }
• (2025). Pulsatile flow induces chromatin interaction with lamin-associated proteins to enrich H3K9 methylation in endothelial cells. PNAS, 122(12), e2424566122. (www)

  @article{ , abstract = {Endothelial cells (ECs) are constantly exposed to hemodynamic forces, which play a crucial role in regulating EC functions. Pulsatile laminar shear stress (PS), representing atheroprotective flow, maintains the anti-inflammation and homeostatic phenotype of ECs, but the comprehensive mechanism underlying the PS-repression of inflammatory genes remains to be determined. In this study, we investigated the role of chromatin organization in mediating the effects of PS on inflammatory gene expression in ECs. We demonstrated that PS induced the expression of histone methyltransferase SUV39H1 to promote heterochromatin formation via H3K9 trimethylation (H3K9me3) enrichment, a hallmark gene repression mechanism. SUV39H1 interacts with lamin-associated proteins and facilitates the perinuclear localization of the H3K9me3-enrichment. Silencing the lamin-associated protein emerin (EMD) not only led to the reductions of cytoskeletal F-actin formation and perinuclear H3K9me3 enrichment; but also the impairment of PS-induced SUV39H1 expression, H3K9me3 enrichment at E-selectin and vascular cell adhesion molecule 1 loci to revert their PS-repressed expression. Hence, EMD acts as a hub to transmit mechanical cues from the cytoskeleton to the nucleus and recruits SUV39H1, which regulate nuclear organization, chromatin state, and gene expression. These results accentuate the critical role of nuclear architecture in mechanotransduction and EC responses to mechanical stimuli.}, archive = {J_PNAS}, author = {Chen, Li-Jing and Li, Julie Yi-Shuan and Nguyen, Phu and Norwich, Gerard and Wang, Yingxiao and Teng, Dayu and Shiu, Yan-Ting and Shyy, John Y. J. and Chien, Shu}, doi = {10.1073/pnas.2424566122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2424566122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pulsatile flow induces chromatin interaction with lamin-associated proteins to enrich H3K9 methylation in endothelial cells}, volume = {122}, year = {2025}, }
• (2025). Diversification, niche adaptation, and evolution of a candidate phylum thriving in the deep critical zone. PNAS, 122(12), e2424463122. (www)

  @article{ , abstract = {The deep subsurface soil microbiome encompasses a vast amount of understudied phylogenetic diversity and metabolic novelty, and the metabolic capabilities and ecological roles of these communities remain largely unknown. We observed a widespread and relatively abundant bacterial phylum (CSP1-3) in deep soils and evaluated its phylogeny, ecology, metabolism, and evolutionary history. Genome analysis indicated that members of CSP1-3 were actively replicating in situ and were widely involved in the carbon, nitrogen, and sulfur cycles. We identified potential adaptive traits of CSP1-3 members for the oligotrophic deep soil environments, including a mixotrophic lifestyle, flexible energy metabolisms, and conservation pathways. The ancestor of CSP1-3 likely originated in an aquatic environment, subsequently colonizing topsoil and, later, deep soil environments, with major CSP1-3 clades adapted to each of these distinct niches. The transition into the terrestrial environment was associated with genome expansion, including the horizontal acquisition of a range of genes for carbohydrate and energy metabolism and, in one lineage, high-affinity terminal oxidases to support a microaerophilic lifestyle. Our results highlight the ecology and genome evolution of microbes in the deep Critical Zone.}, archive = {J_PNAS}, author = {Feng, Wenlu and Wan, Xiaonan and Zhang, Yiran and Quensen, John and Williams, Tom A. and Thompson, Michael and Streeter, Matthew and Zhang, Yang and Jiao, Shuo and Wei, Gehong and Zhu, Yuanjun and Gu, Jie and Tiedje, James M. and Qian, Xun}, doi = {10.1073/pnas.2424463122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2424463122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Diversification, niche adaptation, and evolution of a candidate phylum thriving in the deep critical zone}, volume = {122}, year = {2025}, }
• (2025). Substrate specificities of two ketosynthases in eukaryotic microalgal and prokaryotic marine bacterial DHA synthases. PNAS, 122(12), e2424450122. (www)

  @article{ , abstract = {Highly reducing iterative polyketide synthases (HR-iPKSs) are huge enzyme complexes with multiple catalytic domains that biosynthesize polyketides by intrinsically programmed iterative carbon chain extensions and reductions. Unlike most HR-iPKSs, which possess a single ketosynthase (KS) domain for all carbon chain elongations, polyunsaturated fatty acid (PUFA) synthases contain two KS domains. We previously examined the substrate specificities of two KS domains of prokaryotic marine PUFA synthases with several acyl-ACP intermediates and showed that the two KS domains are utilized differentially depending on the carbon chain length. In this study, we investigated two KS domains in a eukaryotic microalgal DHA synthase, KS A and KS B , which show low similarities to those of prokaryotic marine enzymes, together with almost all the acyl-ACP intermediates. C6-, C12-, and C18-ACPs were exclusively accepted by KS A while KS B utilized C-8. C14- and C20-ACPs. In contrast, both KS A and KS B showed activities against C2-, C4-, and C10-ACPs. A general tendency was observed in which both the prokaryotic KS and the eukaryotic KS recognized the acyl structures in the vicinity of the thioester in ACP substrates except for short-chain substrates.}, archive = {J_PNAS}, author = {Ogata, Kaito and Nakama, Riku and Kobayashi, Hiyu and Kawata, Tomoya and Maruyama, Chitose and Tsunoda, Takeshi and Ujihara, Tetsuro and Hamano, Yoshimitsu and Ogasawara, Yasushi and Dairi, Tohru}, doi = {10.1073/pnas.2424450122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2424450122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Substrate specificities of two ketosynthases in eukaryotic microalgal and prokaryotic marine bacterial DHA synthases}, volume = {122}, year = {2025}, }
• (2025). Building better biochronology: New fossils and 40Ar/39Ar radioisotopic dates from central anatolia. PNAS, 122(12), e2424428122. (www)

  @article{ , abstract = {Türkiye’s geographic position between Europe, Asia, and Africa gives it pivotal importance for understanding the local, interregional, and intercontinental dynamics of Neogene vertebrate evolution. Although rich in vertebrate fossil deposits spanning the Middle and Late Miocene, associated geochronology has been limited by the lack of available volcanic materials that allow radioisotopic dating and geochemical correlation. As a result, calibrating mammalian evolution has been largely restricted to the semicircular application of paleomagnetic inferences combined with temporally ill-constrained and geographically remote biochronological deductions. For example, fossils from three Greek localities and one Anatolian locality assigned to the primate genus Ouranopithecus lack datable samples, leaving its ages poorly constrained. Chronological calibration based on the 40 Ar/ 39 Ar results reported here demonstrates how a fauna-focused, precision geochronology can enhance a better understanding of evolving species lineages and the ecosystems they comprise.}, archive = {J_PNAS}, author = {Tholt, Andrew and Başoğlu, Okşan and Bektaş, Yener and Bernor, Raymond and Carlson, Joshua P. and Dağ, Ömer and Doğan, Uğur and Erkman, Ahmet Cem and Kaya, Ferhat and Kaymakçı, Nuretdin and Gözlük Kırmızıoğlu, Pınar and Meijers, Maud J. M. and Parıldar, Özge Kahya and Pehlevan, Cesur and Şimşek, Emrah and White, Tim and Renne, Paul}, doi = {10.1073/pnas.2424428122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2424428122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Building better biochronology: New fossils and 40Ar/39Ar radioisotopic dates from central anatolia}, volume = {122}, year = {2025}, }
• (2025). Chlamydomonas FBB18 is a ubiquitin-like protein essential for the cytoplasmic preassembly of various ciliary dyneins. PNAS, 122(12), e2423948122. (www)

  @article{ , abstract = {Motile cilia are organelles found on many eukaryotic cells that play critical roles in development and fertility. Human CFAP298 has been implicated in the transport/assembly of ciliary dyneins, and defects in this protein cause primary ciliary dyskinesia. However, neither the exact function nor the structure of CFAP298 have been elucidated. Here, we took advantage of Chlamydomonas , a ciliated alga, to study the structure and function of FBB18, an ortholog of CFAP298. Multiple ciliary dyneins were greatly reduced in cilia of Chlamydomonas fbb18 mutants. In addition, we found that both the stability of ciliary dynein heavy chains (HCs) and the association between HCs and intermediate/light chains (IC/LCs) are greatly reduced in fbb18 cytoplasm, strongly suggesting that FBB18 functions in the cytoplasmic assembly (the so-called “preassembly”) of dynein complexes from HC/IC/LCs. Furthermore, X-ray crystallography revealed that FBB18 forms a bilobed structure with globular domains at both ends of the molecule, connected by an α-helical bundle. Unexpectedly, one globular domain shows high similarity to ubiquitin, a small protein critical for the modification of a variety of protein complexes, and this ubiquitin-like domain is indispensable for the molecular function of FBB18. Our results demonstrate that FBB18, a specialized member of the ubiquitin-like protein family, plays a critical role in dynein preassembly, most likely by mediating diverse interactions between dynein HCs, molecular chaperone(s), and other preassembly factor(s) using the ubiquitin-like domain as well as other regions, and by facilitating the proper folding of dynein HCs.}, archive = {J_PNAS}, author = {Yamamoto, Ryosuke and Sahashi, Yui and Shimo-Kon, Rieko and Sakato-Antoku, Miho and Suzuki, Miyuka and Luo, Leo and Tanaka, Hideaki and Ishikawa, Takashi and Yagi, Toshiki and King, Stephen M. and Kurisu, Genji and Kon, Takahide}, doi = {10.1073/pnas.2423948122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2423948122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chlamydomonas FBB18 is a ubiquitin-like protein essential for the cytoplasmic preassembly of various ciliary dyneins}, volume = {122}, year = {2025}, }
• (2025). Substrate recognition by a peptide-aminoacyl-tRNA ligase. PNAS, 122(12), e2423858122. (www)

  @article{ , abstract = {The continuing discovery of new peptide-aminoacyl-tRNA ligases (PEARLs) has unveiled a diverse array of enzymes with the unique potential to append amino acids to the C terminus of substrate peptides in an aminoacyl-tRNA-dependent manner. To date, PEARLs have been reported that can conjugate Cys, Ala, Trp, Gly, Leu, Asn, and Thr residues, but the basis of peptide substrate and aminoacyl-tRNA recognition is not known. Cell-free expression (CFE) has emerged as a powerful tool to rapidly assay activity of substrate variants, and we used the technique in this study to investigate the peptide substrate specificity of the PEARL B h a B C T r p . This enzyme that adds Trp was discovered previously during genome mining for ribosomally synthesized and posttranslational modified peptides (RiPPs). The enzyme is remarkably tolerant of changes to the C-terminal amino acid of the peptide substrate, and truncation and replacement experiments suggest a minimal sequence requirement. An AlphaFold3 model provided insights into binding interactions of the substrate peptide BhaA-Ala to B h a B C T r p and also generated predictions for tRNA, ATP, and Mg 2+ binding modes that were tested by site-directed mutagenesis. The data suggest that several highly conserved residues in PEARLs recognize the 3′-CCA sequence present in all tRNAs. The minimal sequence required for Trp incorporation by B h a B C T r p was employed as a protein tag for C-terminal labeling of eGFP, lysozyme, and MBP with Trp and 5-Br-Trp.}, archive = {J_PNAS}, author = {Ramos-Figueroa, Josseline and Liang, Haoqian and van der Donk, Wilfred A.}, doi = {10.1073/pnas.2423858122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2423858122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Substrate recognition by a peptide-aminoacyl-tRNA ligase}, volume = {122}, year = {2025}, }
• (2025). Unveiling the cold reality of metamorphic proteins. PNAS, 122(12), e2422725122. (www)

  @article{ , abstract = {Metamorphic proteins switch reversibly between two differently folded states under a variety of environmental conditions. Their identification and prediction are gaining attention, but the fundamental physicochemical basis for fold switching remains poorly understood. In this Perspective article, we address this problem by surveying the landscape of well-characterized metamorphic proteins and noting that a significant fraction of them display temperature sensitivity. We then make the case that the dependence on temperature, in particular cold-denaturation effects, is likely to be an underlying property of many metamorphic proteins regardless of their ultimate triggering mechanisms, especially those with a single domain. The argument is supported by rigorous analysis of hydrophobic effects in each well-characterized metamorphic protein pair and a description of how these parameters relate to temperature. The conclusion discusses the relevance of these insights to a better understanding of prediction, evolution, and de novo design strategies for metamorphic proteins.}, archive = {J_PNAS}, author = {LiWang, Andy and Orban, John}, doi = {10.1073/pnas.2422725122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2422725122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unveiling the cold reality of metamorphic proteins}, volume = {122}, year = {2025}, }
• (2025). Spiral spin liquid noise. PNAS, 122(12), e2422498122. (www)

  @article{ , abstract = {An emerging concept for identification of different types of spin liquids [C. Broholm et al. , Science 367 , eaay0668 (2020)] is through the use of spontaneous spin noise [S. Chatterjee, J. F. Rodriguez-Nieva, E. Demler, Phys. Rev. B 99 , 104425 (2019)]. Here, we develop spin noise spectroscopy for spin liquid studies by considering Ca 10 Cr 7 O 28 , a material hypothesized to be either a quantum or a spiral spin liquid (SSL). By enhancing techniques introduced for magnetic monopole noise studies [R. Dusad et al. , Nature 571 , 234–239 (2019)], we measure the time and temperature dependence of spontaneous flux Φ ( t , T ) and thus magnetization M ( t , T ) of Ca 10 Cr 7 O 28 samples. The resulting power spectral density of magnetization noise S M ω , T reveals intense spin fluctuations with S M ω , T ∝ ω - α ( T ) and 0.84 < α T < 1.04 . Both the variance σ M 2 T and the correlation function C M t , T of this spin noise undergo crossovers at a temperature T ∗ ≈ 450 mK . While predictions for quantum spin liquids are inconsistent with this phenomenology, those from Monte–Carlo simulations of a two-dimensional (2D) SSL state in Ca 10 Cr 7 O 28 yield overall quantitative correspondence with the measured frequency and temperature dependences of S M ω , T , C M t , T , and σ M 2 T , thus indicating that Ca 10 Cr 7 O 28 is an SSL.}, archive = {J_PNAS}, author = {Takahashi, Hiroto and Hsu, Chun-Chih and Jerzembeck, Fabian and Murphy, Jack and Ward, Jonathan and Enright, Jack D. and Knapp, Jan and Puphal, Pascal and Isobe, Masahiko and Matsumoto, Yosuke and Takagi, Hidenori and Davis, J. C. Séamus and Blundell, Stephen J.}, doi = {10.1073/pnas.2422498122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2422498122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spiral spin liquid noise}, volume = {122}, year = {2025}, }
• (2025). The PBAP chromatin remodeling complex mediates summer diapause via H3K4me3-driven juvenile hormone regulation in colaphellus bowringi. PNAS, 122(12), e2422328122. (www)

  @article{ , abstract = {Diapause, a developmental arrest mechanism, helps animals to survive seasonal changes via endocrine regulation. While obligate diapause is genetically programmed, facultative diapause is typically triggered by environmental cues such as photoperiod. In insects, this often leads to reproductive diapause characterized by reduced juvenile hormone (JH) signaling, resulting in ovarian arrest and lipid accumulation. However, the molecular link between photoperiod and hormonal control remains poorly understood. In this study, we investigated the cabbage beetle Colaphellus bowringi as our model system. This species exhibits a photoperiodic response, where short-day (SD) conditions promote reproduction, whereas long-day (LD) conditions induce diapause. Our research identified the PBAP chromatin remodeling complex as a key regulator of LD-induced summer diapause entry. Through RNAi screening of 56 transcriptional regulators that were differentially expressed between SD and LD females, we identified BAP170, a PBAP-specific component, as a key mediator of diapause. Knockdown of bap170 in SD females induced reproductive diapause traits, which were reversed by treatment with methoprene, a JH analog, suggesting that the PBAP complex regulates diapause by influencing JH production. We further demonstrated that the PBAP complex modulates JH biosynthesis via SET1/COMPASS-mediated trimethylation of H3K4. Transcriptome analysis and a second RNAi screen identified calmodulin , a calcium-binding messenger protein gene, as a direct target of PBAP-SET1/COMPASS-H3K4me3 signaling in the corpora allata (CA), the primary source of JH. These findings reveal how the chromatin remodeling machinery translates photoperiod signals into endocrine responses governing seasonal adaptation.}, archive = {J_PNAS}, author = {Tian, Zhong and Wang, Kou and Guo, Shuang and Li, Jia-Xu and King-Jones, Kirst and Zhu, Fen and Liu, Wen and Wang, Xiao-Ping}, doi = {10.1073/pnas.2422328122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2422328122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The PBAP chromatin remodeling complex mediates summer diapause via H3K4me3-driven juvenile hormone regulation in colaphellus bowringi}, volume = {122}, year = {2025}, }
• (2025). TAOK1 promotes filament formation in HR repair through phosphorylating USP7. PNAS, 122(12), e2422262122. (www)

  @article{ , abstract = {Poly-ADP-ribose polymerase (PARP) inhibitors are vital therapeutic agents that exploit synthetic lethality, particularly effective in tumors with homologous recombination (HR) defects. However, broadening their clinical utility remains a significant challenge. In this study, we conducted a high-throughput kinase inhibitor screen to identify potential targets exhibiting synthetical lethality with PARP inhibitors. Our results show that thousand and one amino acid protein kinase 1 (TAOK1) plays a pivotal role in the DNA damage response by phosphorylating ubiquitin specific peptidase 7 (USP7), thereby promoting its enzymatic activity and preventing the ubiquitylation and subsequent degradation of RAD51, a crucial protein in the filament formation of HR repair. Notably, genetic depletion or pharmacological inhibition of TAOK1, as well as blocking peptide targeting the USP7 phosphorylation site, impaired USP7 function, leading to RAD51 degradation, disruption of HR repair, and increased tumor cell and sensitivity to PARP inhibition. This study highlights TAOK1 as a critical regulator of HR repair pathway in human cancer cells and presents a therapeutic strategy overcoming resistance to PARPi inhibitors. These findings support the potential clinical application of combining PARP inhibitors with TAOK1 inhibition or peptide treatment to improve therapeutic outcomes.}, archive = {J_PNAS}, author = {Zhu, Tian-Chen and He, Zhang-Ping and Li, Shu-Ting and Zheng, Lin and Zheng, Xue-Yi and Lan, Xia-Lu and Qu, Chun-Hua and Nie, Run-Cong and Gu, Chao and Huang, Li-Ning and Cai, Xiao-Xia and Xiang, Zhi-Cheng and Xie, Dan and Cai, Mu-Yan}, doi = {10.1073/pnas.2422262122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2422262122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TAOK1 promotes filament formation in HR repair through phosphorylating USP7}, volume = {122}, year = {2025}, }
• (2025). Molecular design principles for bipolar spindle organization by two opposing motors. PNAS, 122(12), e2422190122. (www)

  @article{ , abstract = {During cell division in animal cells, a bipolar spindle assembles to segregate the chromosomes. Various motor proteins with different properties are essential for spindle self-organization. The minimal set of components required to organize dynamic microtubules into a bipolar network remains however unknown. Here, we use computer simulations to explore whether two types of microtubule-crosslinking motors with opposite directionality can organize dynamic microtubules into bipolar spindles in three-dimensional space around a local microtubule nucleation source. We find that two motors are indeed sufficient, provided their properties resemble the main human spindle motors kinesin-5 and dynein, revealing the core mechanism of spindle self-organization. It is based on the synergistic interplay of a slow plus-directed symmetric motor and a fast minus-directed asymmetric motor. A hypothetical symmetric minus-directed motor can also support spindle formation together with kinesin-5, but only in a limited and unphysiological parameter range. In agreement with its accessory role in human cells, a minus motor with human kinesin-14 properties does not assemble stable bipolar spindles together with kinesin-5. These results reveal fundamental principles for the self-organization of dynamic bipolar microtubule architectures and highlight how distinct molecular designs of mitotic motors are optimized for their task.}, archive = {J_PNAS}, author = {Chew, Wei-Xiang and Nédélec, François and Surrey, Thomas}, doi = {10.1073/pnas.2422190122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2422190122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular design principles for bipolar spindle organization by two opposing motors}, volume = {122}, year = {2025}, }
• (2025). Ectopic germinal centers in the nasal turbinates contribute to b cell immunity to intranasal viral infection and vaccination. PNAS, 122(12), e2421724122. (www)

  @article{ , abstract = {The nasal mucosa is the first immunologically active site that respiratory viruses encounter and establishing immunity at the initial point of pathogen contact is essential for preventing viral spread. Influenza A virus (IAV) in humans preferentially replicates in the upper respiratory tract (URT) but mouse models of infection result in lower respiratory tract infection. Here, we optimize IAV inoculation to enhance replication in the nasal turbinate (NT) and study local B cell immunity. We demonstrate that URT-targeted IAV infection stimulates robust local B cell responses, including germinal center (GC) B cell formation in the NT, outside of classical nasal-associated lymphoid tissues. NT GC contributes to local tissue-resident B cell generation and enhances local antibody production. Furthermore, URT-focused immunization also induces significant GC formation in the NT. Finally, we detect steady-state GC in the NT of both mice and healthy humans, suggesting continuous immune surveillance triggered by environmental stimuli. These findings highlight the pivotal role of the NT in local and systemic immunity, with important implications for future mucosal vaccines targeting the upper airways.}, archive = {J_PNAS}, author = {Gailleton, Romain and Mathew, Nimitha R. and Reusch, Laura and Schön, Karin and Scharf, Lydia and Strömberg, Anneli and Cvjetkovic, Andrea and Aziz, Luaay and Hellgren, Johan and Tang, Ka-Wei and Bemark, Mats and Angeletti, Davide}, doi = {10.1073/pnas.2421724122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2421724122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ectopic germinal centers in the nasal turbinates contribute to b cell immunity to intranasal viral infection and vaccination}, volume = {122}, year = {2025}, }
• (2025). The architecture of sponge choanocyte chambers is well adapted to mechanical pumping functions. PNAS, 122(12), e2421296122. (www)

  @article{ , abstract = {Sponges, the basalmost members of the animal kingdom, exhibit a range of complex architectures in which microfluidic channels connect multitudes of spherical chambers lined with choanocytes, flagellated filter-feeding cells. Choanocyte chambers can possess scores or even hundreds of such cells, which drive complex flows entering through porous walls and exiting into the sponge channels. One of the mysteries of the choanocyte chamber is its spherical shape, as it seems inappropriate for inducing directional transport since many choanocyte flagella beat in opposition to such a flow. Here, we combine direct imaging of choanocyte chambers in living sponges with computational studies of many-flagella models to understand the connection between chamber architecture and directional flow. We find that those flagella that beat against the flow play a key role in raising the pressure inside the choanocyte chamber, with the result that the flow rate and mechanical pumping efficiency reach a maximum at a small outlet opening angle. Comparison between experimental observations and the results of numerical simulations reveal that the chamber diameter, flagellar wave number, and the outlet opening angle of the freshwater sponge Ephydatia muelleri , as well as several other species, are related in a manner that maximizes the mechanical pumping functions. These results indicate the subtle balances at play during morphogenesis of choanocyte chambers, and give insights into the physiology and body design of sponges.}, archive = {J_PNAS}, author = {Ogawa, Takumi and Koyama, Shuji and Omori, Toshihiro and Kikuchi, Kenji and de Maleprade, Hélène and Goldstein, Raymond E. and Ishikawa, Takuji}, doi = {10.1073/pnas.2421296122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2421296122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The architecture of sponge choanocyte chambers is well adapted to mechanical pumping functions}, volume = {122}, year = {2025}, }
• (2025). Global phase diagram of D-wave superconductivity in the square-lattice t-J model. PNAS, 122(12), e2420963122. (www)

  @article{ , abstract = {The Hubbard and closely related t-J models are exciting platforms for unconventional superconductivity (SC). Through state-of-the-art density matrix renormalization group calculations using the grand canonical ensemble, we address open issues regarding the ground-state phase diagram of the extended t-J model on a square lattice in the parameter regime relevant to cuprate superconductors. On large 8-leg cylinders, we demonstrate that the pure t-J model with only nearest-neighbor hoppings and superexchange interactions, for a wide range of doping ( δ = 0.1 to 0.2 ), hosts robust d-wave superconductivity possibly coexisting with weak unidirectional pair density wave. Furthermore, a small next nearest neighbor hopping t 2 suppresses pair and charge density waves, resulting in a uniform d-wave SC phase in both electron- and hole-doped cuprate model systems. Our work validates the t-J model as a proper minimum model for the emergence of superconductivity in cuprate superconductors.}, archive = {J_PNAS}, author = {Chen, Feng and Haldane, F. D. M. and Sheng, D. N.}, doi = {10.1073/pnas.2420963122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2420963122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global phase diagram of D-wave superconductivity in the square-lattice t-J model}, volume = {122}, year = {2025}, }
• (2025). ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase. PNAS, 122(12), e2420721122. (www)

  @article{ , abstract = {Lipoprotein lipase (LPL) carries out the lipolytic processing of triglyceride-rich lipoproteins (TRL) along the luminal surface of capillaries. LPL activity is regulated by the angiopoietin-like proteins (ANGPTL3, ANGPTL4, ANGPTL8), which control the delivery of TRL-derived lipid nutrients to tissues in a temporal and spatial fashion. This regulation of LPL mediates the partitioning of lipid delivery to adipose tissue and striated muscle according to nutritional status. A complex between ANGPTL3 and ANGPTL8 (ANGPTL3/8) inhibits LPL activity in oxidative tissues, but its mode of action has remained unknown. Here, we used biophysical techniques to define how ANGPTL3/8 and ANGPTL3 interact with LPL and how they drive LPL inactivation. We demonstrate, by mass photometry, that ANGPTL3/8 is a heterotrimer with a 2:1 ANGPTL3:ANGPTL8 stoichiometry and that ANGPTL3 is a homotrimer. Hydrogen–deuterium exchange mass spectrometry (HDX-MS) studies revealed that ANGPTL3/8 and ANGPTL3 use the proximal portion of their N-terminal α-helices to interact with sequences surrounding the catalytic pocket in LPL. That binding event triggers unfolding of LPL’s α/β -hydrolase domain and irreversible loss of LPL catalytic activity. The binding of LPL to its endothelial transporter protein (GPIHBP1) or to heparan-sulfate proteoglycans protects LPL from unfolding and inactivation, particularly against the unfolding triggered by ANGPTL3. Pulse-labeling HDX-MS studies revealed that ANGPTL3/8 and ANGPTL3 catalyze LPL unfolding in an ATP-independent fashion, which categorizes these LPL inhibitors as atypical unfoldases. The catalytic nature of LPL unfolding by ANGPTL3/8 explains why low plasma concentrations of ANGPTL3/8 are effective in inhibiting a molar excess of LPL in capillaries.}, archive = {J_PNAS}, author = {Kumari, Anni and Larsen, Sanne W. R. and Bondesen, Signe and Qian, Yuewei and Tian, Hao D. and Walker, Sydney G. and Davies, Brandon S. J. and Remaley, Alan T. and Young, Stephen G. and Konrad, Robert J. and Jørgensen, Thomas J. D. and Ploug, Michael}, doi = {10.1073/pnas.2420721122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2420721122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase}, volume = {122}, year = {2025}, }
• (2025). Wdr5-mediated H3K4 methylation facilitates HSPC development via maintenance of genomic stability in zebrafish. PNAS, 122(12), e2420534122. (www)

  @article{ , abstract = {During fetal stage, hematopoietic stem and progenitor cells (HSPCs) undergo rapid proliferation with a tight control of genomic stability. Although histone H3 lysine 4 (H3K4) methylation has been reported to stabilize the genome in proliferating cells, its specific role in HSPC development remains elusive. In this study, we demonstrated that tryptophan-aspartic acid (WD) repeat protein 5 (Wdr5)-mediated H3K4 methylation is crucial for maintaining genomic stability of proliferating HSPCs in zebrafish embryos. Loss of wdr5 led to a severe reduction of HSPC pool in the caudal hematopoietic tissue, accompanied with attenuated H3K4 methylation level and evident p53 -dependent apoptosis in the HSPCs. Mechanistically, Wdr5-mediated H3K4 methylation maintains genomic stability by inhibiting the formation of abnormal R-loops in the HSPCs, whereas accumulation of R-loops exacerbates DNA damage. Moreover, the absence of H3K4 trimethylation leads to an inactivated DNA damage response (DDR) pathway, which is deleterious to DNA damage repair and genomic stability. Subsequently, we found that DDR-associated genes, mutL homolog 1 and breast and ovarian cancer interacting helicase 1 , are important to ensure HSPC survival, likely by stabilizing their genome. In summary, these findings reveal that Wdr5-mediated H3K4 methylation is essential for HSPC development through tight control of R-loop accumulation and DDR-associated program to ensure genomic stability and survival of proliferating HSPCs.}, archive = {J_PNAS}, author = {Wang, Xiaohan and Liu, Mengyao and Zhang, Yifan and Ma, Dongyuan and Wang, Lu and Liu, Feng}, doi = {10.1073/pnas.2420534122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2420534122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Wdr5-mediated H3K4 methylation facilitates HSPC development via maintenance of genomic stability in zebrafish}, volume = {122}, year = {2025}, }
• (2025). Age-dependent cytokine surge in blood precedes cancer diagnosis. PNAS, 122(12), e2420502122. (www)

  @article{ , abstract = {Aging is associated with increased variability and dysregulation of the immune system. We performed a system-level analysis of serum cytokines in a longitudinal cohort of 133 healthy individuals over 9 y. We found that cancer incidence is a major contributor to increased cytokine abundance variability. Circulating cytokines increase up to 4 y before a cancer diagnosis in subjects with age over 80 y. We also analyzed cytokine expression in 10 types of early-stage cancers from The Cancer Genome Atlas. We found that a similar set of cytokines is upregulated in tumor tissues, specifically after the age of 80 y. Similarly, cellular senescence activity and CDKN1A/p21 expression increase with age in cancer tissues. Finally, we demonstrated that the cytokine levels in serum can be used to predict cancers among subjects age at 80+ y. Our results suggest that latent senescent cancers contribute to age-related chronic inflammation.}, archive = {J_PNAS}, author = {Chen, Guangbo and Mohsin, Azam and Zheng, Hong and Rosenberg-Hasson, Yael and Padilla, Cindy and Sarin, Kavita Y. and Dekker, Cornelia L. and Grant, Philip and Maecker, Holden T. and Lu, Ying and Furman, David and Shen-Orr, Shai and Khatri, Purvesh and Davis, Mark M.}, doi = {10.1073/pnas.2420502122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2420502122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Age-dependent cytokine surge in blood precedes cancer diagnosis}, volume = {122}, year = {2025}, }
• (2025). An atlas of early human mandibular endochondral and osteogenic paracrine signaling regions of meckel’s cartilage. PNAS, 122(12), e2420466122. (www)

  @article{ , abstract = {The mandible, also known as the lower jaw, is the only bone in the skull that can move and is essential for speaking and chewing. Meckel’s cartilage (MC) is a temporary structure that supports the formation of the mandible, but how MC is involved in the ossification of the mandible is poorly understood. Through the use of single-cell RNA sequencing and single-cell spatial transcriptomics analyses, a spatiotemporal atlas of MC in human fetuses from 7 to 15 wk postconception was established, highlighting the role of MC in the ossification of the mandible. Importantly, we revealed that two populations of MC contributed to mandibular ossification through different mechanisms. The anterior MC can differentiate into osteolineage cells, as shown in an in vivo lineage tracing mouse model. The intermediate MC facilitates intramembranous ossification through cell–cell communications, possibly through signaling ligands like BMP5 , BMP7 , SEMA3A , PDGFC , and FGF7 . This study suggests that MC plays a crucial role in mediating mandibular ossification through distinct mechanisms, providing valuable insights for understanding oral and craniofacial diseases and disorders in the future.}, archive = {J_PNAS}, author = {Shen, Zongshan and Zhang, Ran and Chen, Xinyue and Yang, Guan and Si, Yuanchun and Yan, Tianxing and Chen, Suwen and Cheng, Bin and Wu, Xiaoshan and Chen, Di and Zhang, Dong and Xiao, Guozhi and Zhu, Jian-Kang and Wang, Songlin}, doi = {10.1073/pnas.2420466122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2420466122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An atlas of early human mandibular endochondral and osteogenic paracrine signaling regions of meckel’s cartilage}, volume = {122}, year = {2025}, }
• (2025). Deficiency in platelet 12-lipoxygenase exacerbates inflammation and disease severity during SARS-CoV-2 infection. PNAS, 122(12), e2420441122. (www)

  @article{ , abstract = {Platelets, known for maintaining blood balance, also participate in antimicrobial defense. Upon severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, platelets become hyperactivated, releasing molecules such as cytokines, granule contents, and bioactive lipids. The key effector biolipids produced by platelets include 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-hydroxyeicosatrienoic acid (12-HETrE), produced by 12-lipoxygenase (12-LOX), and prostaglandins and thromboxane, produced by cyclooxygenase-1. While prostaglandin E2 and thromboxane B2 were previously associated with lung inflammation in severe COVID-19, the role of platelet 12-LOX in SARS-CoV-2 infection remains unclear. Using mice deficient for platelets’ 12-LOX, we report that SARS-CoV-2 infection resulted in higher lung inflammation characterized by histopathological tissue analysis, increased leukocyte infiltrates, and cytokine production relative to wild-type mice. In addition, distinct platelet and lung transcriptomic changes, including alterations in NOD-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) inflammasome-related gene expression, were observed. Mass spectrometry lipidomic analysis in 12-LOX-deficient-infected mice revealed significant changes in bioactive lipid content, including reduced levels of 12-HETrE that inversely correlated with disease severity. Finally, platelet 12-LOX deficiency was associated with increased morbidity and lower survival rates relative to wild type (WT) mice. Overall, this study highlights the complex interplay between 12-LOX-related lipid metabolism and inflammatory responses during SARS-CoV-2 infection. The findings provide valuable insights into potential therapeutic targets aimed at mitigating severe outcomes, emphasizing the pivotal role of platelet enzymes in the host response to viral infections.}, archive = {J_PNAS}, author = {dos S. P. Andrade, Ana Claudia and Lacasse, Emile and Dubuc, Isabelle and Gudimard, Leslie and Gravel, Annie and Puhm, Florian and Campolina-Silva, Gabriel and Queiroz-Junior, Celso and Allaeys, Isabelle and Prunier, Julien and Azeggouar Wallen, Oumaima and Dumais, Élizabeth and Belleannée, Clémence and Droit, Arnaud and Flamand, Nicolas and Boilard, Éric and Flamand, Louis}, doi = {10.1073/pnas.2420441122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2420441122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deficiency in platelet 12-lipoxygenase exacerbates inflammation and disease severity during SARS-CoV-2 infection}, volume = {122}, year = {2025}, }
• (2025). ETV5 reduces androgen receptor expression and induces neural stem–like properties during neuroendocrine prostate cancer development. PNAS, 122(12), e2420313122. (www)

  @article{ , abstract = {Neuroendocrine prostate cancer (NEPC), an aggressive subtype induced by hormone therapy, lacks effective treatments. This study explored the role of E26 transformation-specific variant 5 (ETV5) in NEPC development. Analysis of multiple prostate cancer datasets revealed that NEPC is characterized by significantly elevated ETV5 expression compared to other subtypes. ETV5 expression increased progressively under hormone therapy through epigenetic modifications. ETV5 induced neural stem–like features in prostate cancer cells and facilitated their differentiation into NEPC under hormone treatment conditions, both in vitro and in vivo. Our molecular mechanistic study identified PBX3 and TLL1 as target genes of ETV5 that contribute to ETV5 overexpression–induced castration resistance and stemness. Notably, obeticholic acid, identified as an ETV5 inhibitor in this study, exhibited promising efficacy in suppressing NEPC development. This study highlights ETV5 as a key transcription factor that facilitates NEPC development and underscores its potential as a therapeutic target for this aggressive cancer subtype.}, archive = {J_PNAS}, author = {Lee, Jongeun and Park, Jiho and Hur, Yunjung and Um, Dahun and Choi, Hyung-Seok and Park, Joonyoung and Kim, Yewon and Lee, Jeon-Soo and Choi, Kyuha and Kim, Eunjeong and Park, Young Bin and Choi, Jae-Mun and Kim, Tae-Kyung and Lee, Yoontae}, doi = {10.1073/pnas.2420313122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2420313122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ETV5 reduces androgen receptor expression and induces neural stem–like properties during neuroendocrine prostate cancer development}, volume = {122}, year = {2025}, }
• (2025). Connectional axis of individual functional variability: Patterns, structural correlates, and relevance for development and cognition. PNAS, 122(12), e2420228122. (www)

  @article{ , abstract = {The human cerebral cortex exhibits intricate interareal functional synchronization at the macroscale, with substantial individual variability in these functional connections. However, the spatial organization of functional connectivity (FC) variability across the human connectome edges and its significance in cognitive development remain unclear. Here, we identified a connectional axis in the edge-level FC variability. The variability declined continuously along this axis from within-network to between-network connections and from the edges linking association networks to those linking the sensorimotor and association networks. This connectional axis of functional variability is associated with spatial pattern of structural connectivity variability. Moreover, the connectional variability axis evolves in youth with an flatter axis slope. We also observed that the slope of the connectional variability axis was positively related to the performance in the higher-order cognition. Together, our results reveal a connectional axis in functional variability that is linked with structural connectome variability, refines during development, and is relevant to cognition.}, archive = {J_PNAS}, author = {Yang, Hang and Wu, Guowei and Li, Yaoxin and Xu, Xiaoyu and Cong, Jing and Xu, Haoshu and Ma, Yiyao and Li, Yang and Chen, Runsen and Pines, Adam and Xu, Ting and Sydnor, Valerie J. and Satterthwaite, Theodore D. and Cui, Zaixu}, doi = {10.1073/pnas.2420228122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2420228122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Connectional axis of individual functional variability: Patterns, structural correlates, and relevance for development and cognition}, volume = {122}, year = {2025}, }
• (2025). Absence of water clusters in visible light interactions with the air–water interface. PNAS, 122(12), e2419957122. (www)

  @article{ , archive = {J_PNAS}, author = {Ahmed, Musahid and Lu, Wenchao}, doi = {10.1073/pnas.2419957122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2419957122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Absence of water clusters in visible light interactions with the air–water interface}, volume = {122}, year = {2025}, }
• (2025). Redox dye–mediated fluorescence energy transfer of carbon nanotube–based nanosensors. PNAS, 122(12), e2419666122. (www)

  @article{ , abstract = {Single-walled carbon nanotubes (SWCNTs) exhibit nonphotobleaching, near-infrared (NIR) fluorescence suitable for bioimaging applications. In particular, SWCNT fluorescence quenching induced by biopolymer dispersants facilitates flexible design of molecular nanosensors, yet challenges remain in analyte selectivity and lack of rational design strategies. A sought-after alternative to haphazard molecular modulation of SWCNT-based fluorescence is to couple the movement of a quencher to the SWCNT surface, enabling fluorescence energy transfer to modulate molecular recognition with high selectivity. This study presents the rational design of SWCNT-based nanosensors with fluorescence energy transfer, leveraging the unique properties of methylene blue (MB) proximity–mediated fluorescence quenching. MB-SWCNT-based nanosensors exhibit 1- stability in redox environments and 2- analyte-specific displacement-driven fluorescence modulation. By designing hybridization-induced displacement of MB-conjugated ssDNA from the SWCNT surface, we calculate that SWCNT fluorescence modulation can occur within a 6.8 nm fluorescence resonance energy transfer distance from the SWCNT surface and develop a robust and versatile platform to synthesize oligonucleotide nanosensors with tunable Δ F / F 0 of up to 150%. Building upon this strategy, we developed four distinct nanosensors capable of selectively detecting tobacco mosaic virus (TMV) viral RNA fragments, which successfully differentiated TMV-infected plants from mock controls. Finally, we demonstrate the potential expansion of our design to target a wider scope of biomolecules using the biotin-avidin system as a model. Taken together, our study presents a generalizable platform that enables rational engineering of SWCNT NIR fluorescence intensity through MB distance-dependent fluorescence energy transfer, overcoming the intrinsic selectivity challenges of current SWCNT nanosensors.}, archive = {J_PNAS}, author = {Nishitani, Shoichi and Ao, Kevin and Jalil, Amad and Arias-Soto, Octavio I. and Moudi, Ava and Chen, Feiyang and Biyani, Ankita and Muppirala, Padma N. and Landry, Markita P.}, doi = {10.1073/pnas.2419666122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2419666122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Redox dye–mediated fluorescence energy transfer of carbon nanotube–based nanosensors}, volume = {122}, year = {2025}, }
• (2025). Primitive homochiral polyester formation driven by tartaric acid and calcium availability. PNAS, 122(12), e2419554122. (www)

  @article{ , abstract = {α-hydroxy acids (αHAs), simple and prebiotically plausible organic monomers, were likely present in various environments on and off Earth and could have played a role in directing the emergence of the first homochiral living systems. Some αHAs, which could have been of varying chirality, can undergo dehydration polymerization into polyesters, which could assemble into membraneless microdroplets upon rehydration; understanding these processes is critical for unraveling how simple prebiotic molecules transitioned into more complex systems capable of supporting selective chemical reactions, a key step toward the origin of life. Here, we focused on tartaric acid (TA), a prebiotically relevant αHA with multiple chiral forms, to probe plausible mechanisms by which primitive αHA and polyester-based systems could have participated in selective homochiral polymer synthesis. Enantiopure solutions of d -TA or l -TA polymerize efficiently via dehydration, while racemic dl -TA polymerization is inhibited due to stereochemical incompatibility. We found that Ca 2+ ions influence this process in two significant ways: 1) regulating TA monomer availability through selective crystallization, removing equal amounts of both enantiomers in racemic proportion and thereby enriching the enantiomeric excess of the remaining nonracemic TA solution; and 2) modulating polymerization by suppressing enantiopure TA polymerization while enabling dl -TA polymerization. These findings suggest that the differential availability of simple inorganic ions, such as Ca 2+ , could have indirectly mediated the selection of simple organic chiral monomers and the emergence of homochirality in primitive protocell-forming polymers, offering a pathway from nonliving to living matter in early Earth environments.}, archive = {J_PNAS}, author = {Chen, Chen and Yi, Ruiqin and Igisu, Motoko and Afrin, Rehana and Sithamparam, Mahendran and Chandru, Kuhan and Ueno, Yuichiro and Sun, Linhao and Laurenzi, Tommaso and Eberini, Ivano and Fraccia, Tommaso P. and Wang, Anna and James Cleaves, H. and Jia, Tony Z.}, doi = {10.1073/pnas.2419554122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2419554122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Primitive homochiral polyester formation driven by tartaric acid and calcium availability}, volume = {122}, year = {2025}, }
• (2025). The mediator subunit OsMED23 associates with the histone demethylase OsJMJ703 and the transcription factor OsWOX3A to control grain size and yield in rice. PNAS, 122(12), e2419464122. (www)

  @article{ , abstract = {Seed size is one of the important yield traits, and size control is also a fundamental developmental question. The knowledge about the genetic and molecular mechanisms that govern seed size is crucial for improving crop yield. Here, we report that the Mediator subunit OsMED23 associates with the histone demethylase OsJMJ703 and the transcription factor OsWOX3A to control grain size and weight in rice. Loss of function of OsMED23 or OsJMJ703 causes narrow and light grains, while overexpression of OsMED23 or OsJMJ703 results in large and heavy grains. OsMED23 physically interacts with OsJMJ703 and the transcription factor OsWOX3A. OsMED23, OsJMJ703, and OsWOX3A associate with the common promoter regions of two key grain size genes GW2 and OsLAC and repress their transcription by influencing H3K4me3 levels. Field trials demonstrate that overexpression of OsMED23 or OsJMJ703 can significantly increase grain yield. Therefore, our findings identify a mechanism by which the transcriptional repressor complex OsJMJ703-OsMED23-OsWOX3A determines grain size and weight by regulating gene expression and influencing H3K4me3 levels in rice, suggesting that this pathway has a great potential for improving grain yield in key crops.}, archive = {J_PNAS}, author = {Huang, Luojiang and Fang, Na and Zhang, Limin and Xu, Ran and Zhang, Baolan and Duan, Penggen and Li, Guansong and Luo, Yuehua and Li, Yunhai}, doi = {10.1073/pnas.2419464122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2419464122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The mediator subunit OsMED23 associates with the histone demethylase OsJMJ703 and the transcription factor OsWOX3A to control grain size and yield in rice}, volume = {122}, year = {2025}, }
• (2025). Hardware-optimal quantum algorithms. PNAS, 122(12), e2419273122. (www)

  @article{ , abstract = {Quantum hardware is inherently fragile and noisy. We find that the accuracy of traditional quantum error correction algorithms can be improved depending on the hardware. Given different hardware specifications, we automatically synthesize hardware-optimal algorithms for parity correction, qubit resetting, and GHZ (Greenberger–Horne–Zeilinger) state preparation. Using stochastic techniques from computer science, our method presents a computational tool to compute exact accuracy guarantees and synthesize optimal algorithms that are often different from traditional ones. We also show that improvements can be gained with respect to the Qiskit transpiler as we compute the hardware-optimal qubit mapping for the GHZ state-preparation problem.}, archive = {J_PNAS}, author = {Muroya, Stefanie and Chatterjee, Krishnendu and Henzinger, Thomas A.}, doi = {10.1073/pnas.2419273122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2419273122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hardware-optimal quantum algorithms}, volume = {122}, year = {2025}, }
• (2025). Decoding in-cell respiratory enzyme dynamics by label-free in situ electrochemistry. PNAS, 122(12), e2418926122. (www)

  @article{ , abstract = {Deciphering metabolic enzyme catalysis in living cells remains a formidable challenge due to the limitations of in vivo assays, which focus on enzymes isolated from respiration. This study introduces an innovative whole-cell electrochemical assay to reveal the Michaelis–Menten landscape of respiratory enzymes amid complex molecular interactions. We controlled the microbial current generation’s rate-limiting step, extracting in vivo kinetic parameters ( K m , K i , and k cat ) for the periplasmic nitrite (NrfA) and fumarate (FccA) reductases. Notably, while NrfA kinetics mirrored those of its purified form, FccA exhibited unique kinetic behavior. Further exploration using a mutant strain lacking CymA, a periplasmic hub protein, revealed its crucial role in modulating FccA’s kinetics, challenging the prevailing view that molecular crowding is the main cause of discrepancies between in vivo and in vitro enzyme kinetics. This platform offers a groundbreaking approach to studying cellular respiratory enzymatic kinetics, paving the way for future research in bioenergetics and medicine.}, archive = {J_PNAS}, author = {Tokunou, Yoshihide and Yamazaki, Tomohiko and Fujikawa, Takashi and Okamoto, Akihiro}, doi = {10.1073/pnas.2418926122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2418926122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Decoding in-cell respiratory enzyme dynamics by label-free in situ electrochemistry}, volume = {122}, year = {2025}, }
• (2025). Epidemic evolutionarily stable strategies within an age-structured host population. PNAS, 122(12), e2418170122. (www)

  @article{ , abstract = {To understand infectious disease dynamics, we need to understand the inextricably intertwined nature of the ecology and evolution of pathogens and hosts. Epidemiological dynamics of many infectious diseases have highlighted the importance of considering the demographics of the societies in which they spread, particularly with respect to age structure. In addition, the waves of the recent COVID-19 pandemic driven by variant replacements at an unprecedented speed show that it is vital to consider the evolutionary aspects. The classic trade-off theory of virulence addresses aspects of pathogen evolution, but here we explore in more detail the possibility of society-specific evolutionarily stable strategies (ESS) during an unfolding pandemic. Theory posits the existence under some conditions of an ESS representing the evolutionary endpoint of change. By using a demographically realistic model incorporating infection rates that vary with age, we outline which evolutionary scenarios are plausible. Focusing on the rate of infection and duration of infectivity, we ask whether an ESS exists, what characterizes it, and as a result which long-term public-health consequences may be expected. We demonstrate that the ESS of an evolving pathogen depends upon the background age-dependent frailty and mortality rates. Our findings shed important light on the plausible long-term trajectories of highly evolvable novel pathogens.}, archive = {J_PNAS}, author = {Eilersen, Andreas and Bjørnstad, Ottar N. and Li, Ruiyun and Schreiber, Sebastian J. and Pei, Zeyuan and Stenseth, Nils Chr.}, doi = {10.1073/pnas.2418170122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2418170122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Epidemic evolutionarily stable strategies within an age-structured host population}, volume = {122}, year = {2025}, }
• (2025). Dnmt3a-mediated hypermethylation of FoxO3 promotes redox imbalance during osteoclastogenesis. PNAS, 122(12), e2418023122. (www)

  @article{ , abstract = {Redox imbalance contributes to aberrant osteoclastogenesis and osteoporotic bone loss. In this study, we observed lower Forkhead box protein O3 (FoxO3), a transcription factor associated with cellular oxidative stress, enhanced osteoclastogenesis in osteoporosis (OP). Single-cell RNA sequencing (scRNA-seq) analysis on the human femoral head indicated that FoxO3 is widely expressed in macrophages. Furthermore, Lysm-Cre;FoxO3 f/f OVX mice showed increased reactive oxygen species (ROS), enhanced osteoclastogenesis, and more bone loss than normal OVX mice. Mechanistically, we identified FoxO3 promoter methylation as a crucial factor contributing to decreased FoxO3, thereby influencing osteoclastogenesis and OC function. Intriguingly, we observed that Dnmt3a, highly expressed during osteoclastogenesis, played a pivotal role in regulating the methylation of the FoxO3 promoter. Knockdown of Dnmt3a promoted FoxO3 expression, inhibiting osteoclastogenesis and mitigating OP. Interestingly, we observed that Dnmt3a alleviated osteoclastogenesis by suppressing ROS via upregulating FoxO3 rather than inducing the dissociation of RANK and TRAF6. Collectively, this study elucidates the role and mechanism of FoxO3 in osteoclastogenesis and OP, providing a epigenetic target for the treatment of OP.}, archive = {J_PNAS}, author = {Zhang, Wei and Li, Wenming and Du, Jun and Yang, Chen and Yu, Lei and Yang, Peng and Zhang, Haifeng and Wu, Zebin and Ge, Gaoran and Yang, Huilin and Geng, Dechun}, doi = {10.1073/pnas.2418023122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2418023122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dnmt3a-mediated hypermethylation of FoxO3 promotes redox imbalance during osteoclastogenesis}, volume = {122}, year = {2025}, }
• (2025). Day-to-day fluctuations in motivation drive effort-based decision-making. PNAS, 122(12), e2417964122. (www)

  @article{ , abstract = {Internal states like motivation fluctuate substantially over time. However, studies of the neurocomputational mechanims of motivated behavior have failed to capture this. Here, we examined how naturalistic ups and downs in state motivation influence the subjective value of reward and effort. In a microlongitudinal design (N = 155, state timepoints = 3,344, decision-making tasks = 845), we captured fluctuations in state and effort-based decision-making using smartphone-based momentary assessments as people went about their daily lives. We found that both state and trait have independent and multiplicative effects on decision-making. State–behavior coupling was particularly pronounced in individuals with higher trait apathy, meaning that their choices were even more state dependent. Using computational modeling, we demonstrate that state motivation prospectively boosted reward sensitivity, making people more willing to exert effort in future. Our results show that day-to-day fluctuations in state and cognition are tightly linked and critical for understanding fundamental human behaviors and mental ill-health.}, archive = {J_PNAS}, author = {Hewitt, Samuel R. C. and Norbury, Agnes and Huys, Quentin J. M. and Hauser, Tobias U.}, doi = {10.1073/pnas.2417964122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2417964122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Day-to-day fluctuations in motivation drive effort-based decision-making}, volume = {122}, year = {2025}, }
• (2025). Structural elucidation of how ARF small GTPases induce membrane tubulation for vesicle fission. PNAS, 122(12), e2417820122. (www)

  @article{ , abstract = {ADP-Ribosylation Factor (ARF) small GTPases have been found to act in vesicle fission through a direct ability to tubulate membrane. We have pursued cryoelectron microscopy (EM) to reveal at 3.9 Å resolution how ARF6 assembles into a protein lattice on tubulated membrane. Molecular dynamics simulation studies confirm and extend the cryo-EM findings. The ARF6 lattice exhibits features that are distinct from those formed by other membrane-bending proteins. We identify protein contacts critical for lattice assembly and how membrane insertion results in constricted tubules. The lattice structure also enables docking by GTPase-activating proteins (GAP) to achieve vesiculation. We have also modeled ARF1 onto the ARF6 lattice, and then pursued vesicle reconstitution by the Coat Protein I (COPI) complex to further confirm that the ARF lattice acts in vesicle fission. By elucidating how an ARF protein tubulates membrane at the structural level, we have advanced the molecular understanding of how this class of transport factors promote the fission stage of vesicle formation.}, archive = {J_PNAS}, author = {Pang, Xiaoyun and Zhang, Yan and Park, Kunyou and Liao, Zhenyu and Li, Jian and Xu, Jiashu and Hong, Minh-Triet and Yin, Guoliang and Zhang, Tongming and Wang, Yaoyu and Egelman, Edward H. and Fan, Jun and Hsu, Victor W. and Park, Seung-Yeol and Sun, Fei}, doi = {10.1073/pnas.2417820122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2417820122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural elucidation of how ARF small GTPases induce membrane tubulation for vesicle fission}, volume = {122}, year = {2025}, }
• (2025). Realizing a topological diode effect on the surface of a topological kondo insulator. PNAS, 122(12), e2417709122. (www)

  @article{ , abstract = {Introducing the concept of topology into material science has sparked a revolution from classic electronic and optoelectronic devices to topological quantum devices. The latter has potential for transferring energy and information with unprecedented efficiency. Here, we demonstrate a topological diode effect on the surface of a three-dimensional material, SmB 6 , a candidate topological Kondo insulator. The diode effect is evidenced by pronounced rectification and photogalvanic effects under electromagnetic modulation and radiation at radio frequency. Our experimental results and modeling suggest that these prominent effects are intimately tied to the spatially inhomogeneous formation of topological surface states (TSS) at the intermediate temperature. This work provides a manner of breaking the mirror symmetry (in addition to the inversion symmetry), resulting in the formation of pn -junctions between puddles of metallic TSS. This effect paves the way for efficient current rectifiers or energy-harvesting devices working down to radio frequency range at low temperature, which could be extended to high temperatures using other topological insulators with large bulk gap.}, archive = {J_PNAS}, author = {Zhang, Jiawen and Hua, Zhenqi and Wang, Chengwei and Smidman, Michael and Graf, David and Thomas, Sean and Rosa, Priscila F. S. and Wirth, Steffen and Dai, Xi and Xiong, Peng and Yuan, Huiqiu and Wang, Xiaoyu and Jiao, Lin}, doi = {10.1073/pnas.2417709122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2417709122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Realizing a topological diode effect on the surface of a topological kondo insulator}, volume = {122}, year = {2025}, }
• (2025). Comprehensive mutant chemotyping reveals embedding of a lineage-specific biosynthetic gene cluster in wider plant metabolism. PNAS, 122(12), e2417588122. (www)

  @article{ , abstract = {Plants produce diverse specialized metabolites with important ecological functions. It has recently become apparent that the genes for many of these pathways are not dispersed in plant genomes, but rather are arranged like beads on a string in biosynthetic gene clusters (BGCs). Pathways encoded by BGCs are as a rule dedicated linear pathways that do not form parts of wider metabolic networks. In contrast, the genes for the biosynthesis of widely distributed more ancestral metabolites such as carotenoids and anthocyanins are not clustered. Little is known about how these more recently evolved clustered pathways interact with general plant metabolism. We recently characterized a 12-gene BGC for the biosynthesis of the antimicrobial defense compound avenacin A-1, a triterpene glycoside produced by oats. Avenacin A-1 is acylated with the fluorophore N -methyl anthranilate and confers bright blue fluorescence of oat root tips under ultraviolet light. Here, we exploit a suite of >100 avenacin-deficient mutants identified by screening for reduced root fluorescence to identify genes required for the function of this paradigm BGC. Using a combination of mutant chemotyping, biochemical and molecular analysis, and genome resequencing, we identify two nonclustered genes ( Sad4 and Pal2 ) encoding enzymes that synthesize the donors required for avenacin glycosylation and acylation (recruited from the phenylpropanoid and tryptophan pathways). Our finding of these Cluster Auxiliary Enzymes (CAEs) provides insights into the interplay between general plant metabolism and a newly evolved lineage-specific BGC.}, archive = {J_PNAS}, author = {Qiao, Xue and Houghton, Alan and Reed, James and Steuernagel, Burkhard and Zhang, Jiahe and Owen, Charlotte and Leveau, Aymeric and Orme, Anastasia and Louveau, Thomas and Melton, Rachel and Wulff, Brande B. H. and Osbourn, Anne}, doi = {10.1073/pnas.2417588122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2417588122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Comprehensive mutant chemotyping reveals embedding of a lineage-specific biosynthetic gene cluster in wider plant metabolism}, volume = {122}, year = {2025}, }
• (2025). Uncovering bighorn sheep life-history trajectories in multidimensional trait space. PNAS, 122(12), e2417158122. (www)

  @article{ , abstract = {Individual heterogeneity shapes ecoevolutionary processes at multiple scales. Yet, the scarcity of long-term life-history data and limitations in classic statistical tools hinder our capacity to uncover and understand individual heterogeneity in wildlife populations. Here, we apply an underused multivariate statistical method to uncover four heterogenous life-history trajectories in wild female bighorn sheep ( Ovis canadensis ). Remarkably, these trajectories had remained unobserved in the population despite nearly five decades of monitoring. Our results indicate substantial among-trajectory heterogeneity in growth, senescence, life history trade-offs, fitness, and contributions to population growth. Some trajectories suggest the presence of life history trade-offs while others include silver spoon effects, leading to heterogenous life-history outputs. Then, we show that mother identity and year of birth are relatively good predictors of heterogeneity, indicating that individual trajectories could be largely set during early life. Critically, our results demonstrate that heterogeneity in life-history trajectories can be inconspicuous, yet substantial and structured across multiple traits within a population. Uncovering and understanding this heterogeneity in other wild populations will be key to advancing our knowledge of ecoevolutionary processes across populations and species.}, archive = {J_PNAS}, author = {Larue, Benjamin and Pelletier, Fanie and Festa-Bianchet, Marco and Hamel, Sandra}, doi = {10.1073/pnas.2417158122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2417158122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Uncovering bighorn sheep life-history trajectories in multidimensional trait space}, volume = {122}, year = {2025}, }
• (2025). Conserved leucine-rich repeat proteins in the adhesive projectile slime of velvet worms. PNAS, 122(12), e2416282122. (www)

  @article{ , abstract = {The slime of velvet worms (Onychophora) is a protein-based bioadhesive that undergoes rapid, yet reversible transition from a fluid into stiff fibers used for prey capture and defense, but the mechanism by which this phase transition functions is largely unknown. Here, integrating transcriptomic and proteomic approaches with AI-guided structure predictions, we discover a group of evolutionarily conserved leucine-rich repeat (LRR) proteins in velvet worm slime that readily adopt a receptor-like, protein-binding “horseshoe” structure. Our structural predictions suggest dimerization of LRR proteins and support their interactions with conserved β-sheet-rich domains of high-molecular-weight proteins, the primary building blocks of velvet worm slime fibers. This suggests that LRR proteins might be involved in reversible, receptor-based supramolecular interactions in these biofibers, providing potential avenues for fabricating fully recyclable (bio)polymeric materials.}, archive = {J_PNAS}, author = {Hu, Zhaolong and Baer, Alexander and Hering, Lars and de Sena Oliveira, Ivo and Poulhazan, Alexandre and Browne, Darren C. and Guo, Xue and Perrin, Quentin Moana and Sobota, Radoslaw M. and Hoon, Shawn and Mayer, Georg and Kannan, Srinivasaraghavan and Verma, Chandra S. and Harrington, Matthew J. and Miserez, Ali}, doi = {10.1073/pnas.2416282122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2416282122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Conserved leucine-rich repeat proteins in the adhesive projectile slime of velvet worms}, volume = {122}, year = {2025}, }
• (2025). A splendid molecular factory: De- and reconstruction of the mammalian respiratory chain. PNAS, 122(12), e2416162122. (www)

  @article{ , abstract = {Mitochondrial respiratory complexes I to IV and the F 1 F o -ATP synthase (complex V) are large protein assemblies producing the universal cellular energy currency adenosine triphosphate (ATP). Individual complexes have been extensively studied in vitro, but functional co-reconstitution of several mammalian complexes into proteoliposomes, in particular, the combination of a primary pump with the ATP synthase, is less well understood. Here, we present a generic and scalable strategy to purify mammalian respiratory complexes I, III and the ATP synthase from enriched mitochondria in enzymatically fully active form, and procedures to reassemble the complexes into liposomes. A robust functionality can be shown by in situ monitoring of ATP synthesis rates and by using selected inhibitors of the respiratory chain complexes. By inclusion of cytochrome c oxidase, our procedures allowed us to reconstruct the entire mitochondrial respiratory chain (complexes I, III, IV, and V) in ubiquinone Q 10 containing liposomes, demonstrating oxidative phosphorylation by nicotinamide adenine dinucleotide hydrogen driven ATP synthesis. The system was fully coupled at all levels and was used to probe cardiolipin as an essential component to activate the mammalian respiratory chain. Structural characterization using electron cryomicroscopy allowed us to resolve apo-state complex III and complex V at high and medium resolution, respectively, using in silico particle sorting, confirming the presence of all protein subunits and cofactors in native stoichiometry and conformation. The reported findings will facilitate future endeavors to characterize or modulate these key bioenergetic processes.}, archive = {J_PNAS}, author = {Rimle, Lukas and Phillips, Ben P. and Codo Costa Barra, Isabela M. and Arnold, Noëlle and Hennebert, Charlie and Meier, Thomas and von Ballmoos, Christoph}, doi = {10.1073/pnas.2416162122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2416162122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A splendid molecular factory: De- and reconstruction of the mammalian respiratory chain}, volume = {122}, year = {2025}, }
• (2025). The origin of sulfur in canary island magmas and its implications for earth’s deep sulfur cycle. PNAS, 122(12), e2416070122. (www)

  @article{ , abstract = {The global sulfur cycle plays a critical role in the redox evolution of Earth’s surface and upper mantle, yet the distribution and origin of sulfur in the mantle remains largely unconstrained. El Hierro is a volcanic island in the Canary archipelago that is fed by sulfur-rich magmas. To constrain the origin of sulfur in these melts, we combine in situ sulfur isotope analyses with regression modeling. We calculate that undegassed El Hierro melts have δ 34 S values of 0 ± 2‰. The average δ 34 S of undegassed El Hierro melts is 0.3‰ to 1‰ higher than magmas erupting at mid-ocean ridges. Mass balance calculations reveal that El Hierro’s mantle source contains 310 ± 120 μg/g sulfur and that on average 60% of sulfur in the source is of recycled origin. This recycled material should contain >1,800 μg/g sulfur to satisfy isotopic constraints on its mass fraction in the mantle source. The sulfur and oxygen isotopic signature in serpentinites and sediments deviate significantly from the upper mantle, making them unsuitable candidates for the recycled material. An oxidized partial melt of recycled oceanic crust that retained one third of its sulfur budget after subduction zone processing can explain excess sulfur in the Canary Island mantle. Recycled oceanic crust is expected to contain sulfur as sulfide, which is not capable of oxidizing the mantle. The presence of ferric iron in the recycled component is necessary to produce metasomatic melts that are oxidizing enough to carry sufficient sulfur into the mantle source of ocean island basalts.}, archive = {J_PNAS}, author = {Taracsák, Zoltán and Hartley, Margaret E. and Burgess, Ray and Edmonds, Marie and Longpré, Marc-Antoine and Monteleone, Brian D. and Tartèse, Romain and Turchyn, Alexandra V.}, doi = {10.1073/pnas.2416070122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2416070122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The origin of sulfur in canary island magmas and its implications for earth’s deep sulfur cycle}, volume = {122}, year = {2025}, }
• (2025). Maintaining cooperation through vertical communication of trust when removing sanctions. PNAS, 122(12), e2415010122. (www)

  @article{ , abstract = {An effective way to foster cooperation is to monitor behavior and sanction freeriding. Yet, previous studies have shown that cooperation quickly declines when sanctioning mechanisms are removed. We test whether explicitly expressing trust in players’ capability to maintain cooperation after the removal of sanctions, i.e., vertical communication of trust, has the potential to alleviate this drop in compliance. Four incentivized public-goods experiments ( N = 2,823) find that the vertical communication of trust maintains cooperation upon the removal of centralized (Study 1), third-party (Study 2a, 2b), and peer punishment (Study 3), and this effect extends beyond single interactions (Study 4). In all studies, vertical trust communication increases mutual trust among players, providing support to the idea that vertically communicating trust can be a self-fulfilling prophecy. Extrapolating our findings to natural environments, they suggest that authorities should carefully consider how they communicate the lifting of rules and sanctions.}, archive = {J_PNAS}, author = {Posten, Ann-Christin and Uğurlar, Pınar and Kube, Sebastian and Lammers, Joris}, doi = {10.1073/pnas.2415010122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2415010122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Maintaining cooperation through vertical communication of trust when removing sanctions}, volume = {122}, year = {2025}, }
• (2025). Isolated steady solutions of the 3D euler equations. PNAS, 122(12), e2414730122. (www)

  @article{ , abstract = {We show that there exist closed three-dimensional Riemannian manifolds where the incompressible Euler equations exhibit smooth steady solutions that are isolated in the C 1 -topology. The proof of this fact combines ideas from dynamical systems, which appear naturally because these isolated states have strongly chaotic dynamics, with techniques from spectral geometry and contact topology, which can be effectively used to analyze the steady Euler equations on carefully chosen Riemannian manifolds. Interestingly, much of this strategy carries over to the Euler equations in Euclidean space, leading to the weaker result that there exist analytic steady solutions on T 3 such that the only analytic steady Euler flows in a C 1 -neighborhood must belong to a certain linear space of dimension six. For comparison, note that in any C k -neighborhood of a shear flow, there are infinitely many linearly independent analytic shears.}, archive = {J_PNAS}, author = {Enciso, Alberto and Kepplinger, Willi and Peralta-Salas, Daniel}, doi = {10.1073/pnas.2414730122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2414730122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Isolated steady solutions of the 3D euler equations}, volume = {122}, year = {2025}, }
• (2025). Staphylococcus aureus uses a GGDEF protein to recruit diacylglycerol kinase to the membrane for lipid recycling. PNAS, 122(12), e2414696122. (www)

  @article{ , abstract = {Staphylococcus aureus is a Gram-positive pathogen responsible for numerous antibiotic-resistant infections. Identifying vulnerabilities in S. aureus is crucial for developing new antibiotics to treat these infections. With this in mind, we probed the function of GdpS, a conserved Staphylococcal membrane protein containing a cytoplasmic GGDEF domain. These domains are canonically involved in cyclic-di-GMP signaling processes, but S. aureus is not known to make cyclic-di-GMP. Using a transposon screen, we found that loss of GdpS is lethal when combined with disruption in synthesis of the glycolipid anchor of a cell surface polymer called lipoteichoic acid (LTA) or with deletion of genes important in cell division. Taking advantage of a small molecule that inhibits LTA glycolipid anchor synthesis, we selected for suppressors of Δ gdpS lethality. The most prevalent suppressors were hypermorphic alleles of dgkB , which encodes a soluble diacylglycerol (DAG) kinase required to recycle DAG to phosphatidylglycerol. By following up on these suppressors, we found that the GGDEF domain of GdpS interacts directly with DgkB, orienting its active site at the membrane to promote DAG recycling. DAG kinase hypermorphs also suppressed the lethality caused by combined loss of gdpS and cell division factors, highlighting the importance of lipid homeostasis for cell division. GdpS’ positive regulation of DAG kinase function was dependent on the GGDEF domain but not its catalytic residues. As the sole conserved GGDEF-domain protein in Staphylococci, GdpS promotes an enzymatic process independent of cyclic-di-GMP signaling, revealing a new function for the ubiquitously conserved GGDEF domain.}, archive = {J_PNAS}, author = {Mychack, Aaron and Evans, Dwayne and Gilles, Tarah and James, Michael J. and Walker, Suzanne}, doi = {10.1073/pnas.2414696122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2414696122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Staphylococcus aureus uses a GGDEF protein to recruit diacylglycerol kinase to the membrane for lipid recycling}, volume = {122}, year = {2025}, }
• (2025). Cryo-EM structures reveal the acetylation process of piccolo NuA4. PNAS, 122(12), e2414490122. (www)

  @article{ , abstract = {NuA4 is the only essential acetyltransferase in yeast that can catalyze the acetylation of the histones H2A, H2A.Z, and H4, thereby affecting gene transcription. However, the acetylation process of NuA4, such as how NuA4 acetylates H4 and H2A.Z differently, remains largely elusive. Here, using cryoelectron microscopy (cryo-EM) single particle analysis, we present seven cryo-EM structures of piccolo NuA4 (pNuA4) in complex with wild-type H2A.Z or H2A.Z-mutant-containing nucleosomes in the absence or presence of acetyl coenzyme A (Ac-CoA). We revealed that, in the absence of Ac-CoA, pNuA4 adopts multiple conformations to search for its substrates. After adding Ac-CoA, the single-molecule Förster resonance energy transfer (smFRET) and cryo-EM data indicated that pNuA4 prefers to bind H4 and undergoes a dynamic conformational change to complete the acetylation. We also obtained previously unseen structures in states associated with the acetylation of H2A.Z. These cryo-EM structures and smFRET results suggest a complex acetylation process on H4 and H2A.Z by pNuA4. The results provide a comprehensive picture of the mechanism by which pNuA4 acetylates its substrates within an H2A.Z-containing nucleosome.}, archive = {J_PNAS}, author = {Wang, Lin and Zhang, Haonan and Jia, Qi and Li, Wenyan and Yang, Chenguang and Ma, Lijuan and Li, Ming and Lu, Ying and Zhu, Hongtao and Zhu, Ping}, doi = {10.1073/pnas.2414490122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2414490122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryo-EM structures reveal the acetylation process of piccolo NuA4}, volume = {122}, year = {2025}, }
• (2025). High-density CRISPRi screens reveal diverse routes to improved acclimation in cyanobacteria. PNAS, 122(12), e2412625122. (www)

  @article{ , abstract = {Cyanobacteria are the oldest form of photosynthetic life on Earth and contribute to primary production in nearly every habitat, from permafrost to hot springs. Despite longstanding interest in the acclimation of these microbes, it remains poorly understood and challenging to rewire. This study uses a high-density, genome-wide CRISPR interference screen to examine the influence of gene-specific transcriptional variation on the growth of Synechococcus sp. PCC 7002 under environmental extremes. Surprisingly, many partial knockdowns enhanced fitness under cold monochromatic conditions. Transcriptional repression of genes for core subunits of the NDH-1 complex, which are important for photosynthesis and carbon uptake, improved growth rates under both red and blue light but at distinct, color-specific optima. Most genes with fitness-improving knockdowns were distinct to each light color, and dual-target transcriptional repression produced nonadditive effects. Findings reveal diverse routes to improved acclimation in cyanobacteria (e.g., attenuation of genes involved in CO 2 uptake, light harvesting, translation, and purine metabolism) and provide an approach for using gradients in sgRNA activity to pinpoint biochemically influential transcriptional changes in cells.}, archive = {J_PNAS}, author = {Hren, Andrew and Lollini, Nicole and Carper, Dana L. and Abraham, Paul E. and Cameron, Jeffrey C. and Fox, Jerome M. and Eckert, Carrie A.}, doi = {10.1073/pnas.2412625122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2412625122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High-density CRISPRi screens reveal diverse routes to improved acclimation in cyanobacteria}, volume = {122}, year = {2025}, }
• (2025). Predicting nature-based coastal protection by mangroves under extreme waves. PNAS, 122(12), e2410883122. (www)

  @article{ , abstract = {Forested wetlands such as mangroves are considered highly valuable for nature-based mitigation of coastal flooding. However, their wave attenuation capacity during extreme storms, when risks are highest, is rarely measured and remains challenging to predict. Here, we compile a unique dataset on the largest incident wave heights (0.39 to 1.44 m) ever recorded in forested wetlands, including our own measurements and literature data. Our analysis reveals that forested wetlands can significantly attenuate storm waves (35% over 3 wavelengths) except in rare near-submerged cases. Notably, 19 of the 20 existing formulations for vegetation drag coefficient, a key parameter for wave attenuation modeling, are inapplicable in storm conditions. Hence, we introduce an new approach to reliably predict wave attenuation during storms, without the need for drag coefficient determination nor modeling expertise. This approach offers coastal practitioners a new user-friendly tool to assess the effectiveness of nature-based solutions for storm hazard mitigation.}, archive = {J_PNAS}, author = {Hu, Zhan and Temmerman, Stijn and Zhu, Qin and Wang, Xinran and Wu, Jinwei and Xu, Tianping and Schoutens, Ken and Suzuki, Tomohiro and Yang, Zhifeng and Bouma, Tjeerd J.}, doi = {10.1073/pnas.2410883122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2410883122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Predicting nature-based coastal protection by mangroves under extreme waves}, volume = {122}, year = {2025}, }
• (2025). Agriculture’s impact on water–energy balance varies across climates. PNAS, 122(12), e2410521122. (www)

  @article{ , abstract = {Agriculture is a cornerstone of global food production, accounting for a substantial portion of water withdrawals worldwide. As the world’s population grows, so does the demand for water in agriculture, leading to alterations in regional water–energy balances. We present an approach to identify the influence of agriculture on the water–energy balance using empirical data. We explore the departure from the Budyko curve for catchments with agricultural expansion and their associations with changes in the water–energy balance using a causal discovery algorithm. Analyzing data from 1,342 catchments across three Köppen-Geiger climate classes—temperate, snowy, and others—from 1980 to 2014, we show that temperate and snowy catchments, which account for over 90% of stations, exhibit distinct patterns. Cropland percentage (CL%) emerges as the dominant factor, explaining 47 and 37% of the variance in deviations from the Budyko curve in temperate and snowy catchments, respectively. In temperate catchments, CL% shows a strong negative correlation with precipitation-streamflow (P-Q) causal strength (Spearman ρ = − 0.75 ), suggesting that cropland exacerbates precipitation-driven deviations. A moderate negative correlation with aridity-streamflow (AR-Q) causal strength ( ρ = − 0.42 ) indicates additional influences of cropland through aridity-driven interactions. In snowy catchments, CL% is similarly influential, with a positive correlation with P-Q causal strength ( ρ = 0.51 ). However, the negative correlation with AR-Q causal strength ( ρ = − 0.45 ) underscores the role of aridity as a secondary driver. While vegetation and precipitation seasonality also contribute to the deviations, their impacts are comparatively lower. These findings underscore the need for inclusion of agricultural activities in changing water–energy balance to secure future water supplies.}, archive = {J_PNAS}, author = {Zaerpour, Masoud and Hatami, Shadi and Ballarin, André S. and Papalexiou, Simon Michael and Pietroniro, Alain and Nazemi, Ali}, doi = {10.1073/pnas.2410521122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2410521122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Agriculture’s impact on water–energy balance varies across climates}, volume = {122}, year = {2025}, }
• (2025). Archaeogenomic insights into commensalism and regional variation in pig management in neolithic northwest europe. PNAS, 122(12), e2410235122. (www)

  @article{ , abstract = {The relationship between humans and pigs has changed dramatically since their domestication in southwest Asia and subsequent human-induced introduction into Europe. Introgression between incoming southwest Asian pigs and European boar resulted in the gradual replacement of southwest Asian ancestry in European pigs. However, we currently lack genomic data required to explore the regional trajectories, nature, and extent of contact between European boar and pigs that led to this turnover, and how this process was facilitated by human activity. We addressed this deficit by sequencing four Mesolithic boar and seven Neolithic pig samples from six archaeological sites in the Netherlands and Britain ranging from the Mesolithic (5500 BCE) to Neolithic (2500 BCE). Our data show that despite continuous gene flow with European boar, Neolithic European pigs show varying levels of southwest Asian ancestry. The low and varying southwest Asian ancestry in pigs from the Early Neolithic Dutch settlement Swifterbant indicates a high contribution of wild ancestry. The genetic profile, enriched δ 15 N values, on-site presence, and wide size distribution of Swifterbant Sus scrofa suggest a commensal relationship. Runs of homozygosity (ROH) imply that both closed-breeding and free-ranging management occurred in Neolithic communities, where the former showed an extreme burden of long segments of ROH. We further show selection signatures, associated with coat color and behavior, in Neolithic herds despite recurrent wild gene flow. Altogether, our results show distinct husbandry practices through space and time in Neolithic Europe, with heavy reliance on boar recruitment via the commensal pathway in northwest Europe.}, archive = {J_PNAS}, author = {Erven, Jolijn A. M. and Mattiangeli, Valeria and Dreshaj, Merita and Mullin, Victoria E. and Rossi, Conor and Daly, Kevin G. and Jackson, Iseult and Parker Pearson, Mike and Bradley, Daniel G. and Frantz, Laurent A. F. and Madsen, Ole and Raemaekers, Daan and Çakirlar, Canan}, doi = {10.1073/pnas.2410235122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2410235122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Archaeogenomic insights into commensalism and regional variation in pig management in neolithic northwest europe}, volume = {122}, year = {2025}, }
• (2025). Dynamics of an algae–bacteria microcosm: Photosynthesis, chemotaxis, and expulsion in inhomogeneous active matter. PNAS, 122(12), e2410225122. (www)

  @article{ , abstract = {In nature, there are significant relationships known between microorganisms from two kingdoms of life, as in the supply of vitamin B 12 by bacteria to algae. Such interactions motivate general investigations into the spatiotemporal dynamics of metabolite exchanges. Here we study by experiment and theory a model system: a coculture of the bacterium Bacillus subtilis , an obligate aerobe that is chemotactic to oxygen, and a nonmotile mutant of the alga Chlamydomonas reinhardtii , which photosynthetically produces oxygen when illuminated. Strikingly, when a shaft of light illuminates a thin, initially uniform suspension of the two, the chemotactic influx of bacteria to the photosynthetically active region leads to expulsion of the algae from that area. We propose that this effect arises from advection by the inhomogeneous bacterial concentration. The resulting generalization of Fick’s law has been proposed in the context of chemotaxis and is mathematically related to the “turbulent pumping” in magnetohydrodynamics.}, archive = {J_PNAS}, author = {Prakash, Praneet and Baig, Yasa and Peaudecerf, François J. and Goldstein, Raymond E.}, doi = {10.1073/pnas.2410225122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2410225122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamics of an algae–bacteria microcosm: Photosynthesis, chemotaxis, and expulsion in inhomogeneous active matter}, volume = {122}, year = {2025}, }
• (2025). Structural assembly of the PAS domain drives the catalytic activation of metazoan PASK. PNAS, 122(12), e2409685122. (www)

  @article{ , abstract = {PAS domains are ubiquitous sensory modules that transduce environmental signals into cellular responses through tandem PAS folds and PAS-associated C-terminal (PAC) motifs. While this conserved architecture underpins their regulatory roles, here we uncover a structural divergence in the metazoan PAS domain–regulated kinase (PASK). By integrating evolutionary-scale domain mapping with deep learning-based structural models, we identified two PAS domains in PASK, namely PAS-B and PAS-C, in addition to the previously known PAS-A domain. Unlike canonical PAS domains, the PAS fold and PAC motif in the PAS-C domain are spatially segregated by an unstructured linker, yet a functional PAS module is assembled through intramolecular interactions. We demonstrate that this assembly is nutrient responsive and serves to remodel the quaternary structure of PASK that positions the PAS-A domain near the kinase activation loop. This nutrient-sensitive spatial arrangement stabilizes the activation loop, enabling catalytic activation of PASK. These findings revealed an alternative mode of regulatory control in PAS sensory proteins, where the structural assembly of PAS domains links environmental sensing to enzymatic activity. By demonstrating that PAS domains integrate signals through dynamic structural rearrangements, this study broadens the understanding of their functional and regulatory roles and highlights potential opportunities for targeting PAS domain–mediated pathways in therapeutic applications.}, archive = {J_PNAS}, author = {Dhungel, Sajina and Xiao, Michael and Pushpabai, Rajesh Rajaian and Kikani, Chintan K.}, doi = {10.1073/pnas.2409685122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2409685122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural assembly of the PAS domain drives the catalytic activation of metazoan PASK}, volume = {122}, year = {2025}, }
• (2025). Trans-synaptic modulation of cholinergic circuits tunes opioid reinforcement. PNAS, 122(12), e2409325122. (www)

  @article{ , abstract = {Opioids trigger structural and functional neural adaptations of the reward circuit that lead to dependence. Synaptic cell adhesion molecules (CAMs) play a pivotal role in circuit organization and present prime candidates for orchestrating remodeling of neural connections in response to drug exposure. However, the contribution of CAMs to opioid-induced rewiring of the reward circuit has not been explored. Here, we used unbiased molecular profiling to identify CAMs in the nucleus accumbens (NAc) modulated by morphine administration. We found that opioid exposure induces the expression of ELFN1, a CAM selectively expressed in cholinergic interneurons in the NAc. We determined that ELFN1 acts trans-synaptically to modulate the strength and plasticity of the glutamatergic inputs onto cholinergic neurons via the recruitment of presynaptic metabotropic glutamate receptor 4 (mGlu4). Disruption of Elfn1 diminished morphine reward and intake in self-administering mice. Together, our findings identify a key molecular factor responsible for adjusting the strength of opioid effects by modulating the configuration of striatal circuitry in an experience-dependent fashion and unveil potential therapeutic target for combating opioid abuse.}, archive = {J_PNAS}, author = {Zucca, Stefano and Brunori, Gloria and Dunn, Henry A. and Lankford, Colten K. and Sutton, Laurie P. and Algibez Flores, Beatriz and Maza, Nycole A. and Sial, Omar and Crynen, Gogce and Luján, Rafael and Martemyanov, Kirill A.}, doi = {10.1073/pnas.2409325122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2409325122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Trans-synaptic modulation of cholinergic circuits tunes opioid reinforcement}, volume = {122}, year = {2025}, }
• (2025). Audible enclaves crafted by nonlinear self-bending ultrasonic beams. PNAS, 122(12), e2408975122. (www)

  @article{ , abstract = {Delivering audible content to a targeted listener without disturbing others is paramount in audio engineering. However, achieving this goal has long been challenging due to the diffraction of low-frequency (long-wavelength) audio waves in linear acoustics. Here, we introduce an approach for creating remote audio spots, dubbed audible enclaves, by harnessing the local nonlinear interaction of two self-bending ultrasonic beams with distinct spectra. The self-bending ultrasonic beams created by acoustic metasurfaces, though inaudible, can bypass obstacles such as human heads. At their intersection behind obstacles, highly localized audible enclaves are formed due to the local nonlinear interactions. Additionally, we demonstrate the ultrabroadband capabilities of our metasurface-based implementation both numerically and experimentally, spanning from 125 Hz to 4 kHz (6 octave bands), covering the majority of the audible frequency range. The practicality of our proposed technique is underscored by its compact implementation size (0.16 m, equivalent to 0.06 wavelengths at 125 Hz), as well as its robust performance under wideband transient audio signal excitation and in a common room with reverberations. Our proposed audible enclaves hold significant potential for various applications in advanced audio engineering, including private speech communications, immersive spatial audio reproduction, and high-resolution sound/quiet zone control.}, archive = {J_PNAS}, author = {Zhong, Jia-Xin and Ji, Jun and Xia, Xiaoxing and Heo, Hyeonu and Jing, Yun}, doi = {10.1073/pnas.2408975122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2408975122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Audible enclaves crafted by nonlinear self-bending ultrasonic beams}, volume = {122}, year = {2025}, }
• (2025). BCFW tilings and cluster adjacency for the amplituhedron. PNAS, 122(12), e2408572122. (www)

  @article{ , abstract = {In 2005, Britto, Cachazo, Feng, and Witten gave a recurrence (now known as the BCFW recurrence) for computing scattering amplitudes in N = 4 super Yang–Mills theory. Arkani-Hamed and Trnka subsequently introduced the amplituhedron to give a geometric interpretation of the BCFW recurrence. Arkani-Hamed and Trnka conjectured that each way of iterating the BCFW recurrence gives a “triangulation” or “tiling” of the m=4 amplituhedron. In this article, we prove the BCFW tiling conjecture of Arkani-Hamed and Trnka. We also prove the cluster adjacency conjecture for BCFW tiles of the amplituhedron, which says that facets of tiles are cut out by collections of compatible cluster variables for the Grassmannian Gr4,n. Moreover we show that each BCFW tile is the subset of the Grassmannian where certain cluster variables have particular signs.}, archive = {J_PNAS}, author = {Even-Zohar, Chaim and Lakrec, Tsviqa and Parisi, Matteo and Sherman-Bennett, Melissa and Tessler, Ran and Williams, Lauren}, doi = {10.1073/pnas.2408572122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2408572122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {BCFW tilings and cluster adjacency for the amplituhedron}, volume = {122}, year = {2025}, }
• (2025). Genomics highlight an underestimation of phenology sensitivity to the urban heat island effect. PNAS, 122(12), e2408564122. (www)

  @article{ , abstract = {The phenological timing of leaf out in temperate forests is a critical transition point each year that alters the global climate system, which in turn, feeds back to plants, driving leaf out to occur nearly 3 d earlier per decade as temperatures rise. To improve predictions of leaf out timing, urban heat islands (UHIs) or densely developed areas that are hotter than surrounding undeveloped regions are often used to approximate warming via space-for-time substitutions (i.e., rural-to-urban temperature gradients). However, more than just environment changes along these gradients—urban regions are highly managed systems with limited-to-no within species diversity. We demonstrate here that recent observations that UHI gradients underpredict leaf out response to temperature when compared to temperature gradients through time is likely because both genetics and environment are changing across rural-to-urban gradients, whereas only environment is changing through time. We tested this hypothesis using genomic, phenological, and temperature data of northern red oak ( Quercus rubra ) over several years between an urban and rural site. Across our gradient, models that included just temperature predicted moderate advancement of leaf out. However, if we account for the genetic diversity of our trees in our model, leaf out phenology is predicted to advance significantly more in response to temperature. We demonstrate that this stronger relationship between phenological timing and climate is because urban trees have reduced genetic diversity as they are planted from limited stock by humans and, moreover, are most closely related to individuals at the rural site that leaf out later on average.}, archive = {J_PNAS}, author = {Blumstein, Meghan and Webster, Sophie and Hopkins, Robin and Basler, David and Yun, Jie and Des Marais, David Lee}, doi = {10.1073/pnas.2408564122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2408564122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genomics highlight an underestimation of phenology sensitivity to the urban heat island effect}, volume = {122}, year = {2025}, }
• (2025). Spatially resolved charge-transfer kinetics at the quantum dot–microbe interface using fluorescence lifetime imaging microscopy. PNAS, 122(12), e2407987122. (www)

  @article{ , abstract = {Integrating the optoelectronic properties of quantum dots (QDs) with biological enzymatic systems to form microbe-semiconductor biohybrids offers promising prospects for both solar-to-chemical conversion and light-modulated biochemical processes. Developing these nano–bio hybrid systems necessitates a deep understanding of charge-transfer dynamics at the nano–bio interface. Photoexcited carrier transfer from QDs to microbes is driven by complex interactions, with emerging insights into the relevant thermodynamic and kinetic factors. The heterogeneities of both microbes and QD ensembles pose significant challenges in mechanistic understanding, which is critical for designing advanced nano–bio hybrids. We used fluorescence lifetime imaging microscopy to analyze charge transfer between a CdSe QD film and Shewanella oneidensis microbes. We correlated the spatiotemporal fluorescence data with an analytical model. Our analysis revealed two distinct distributions of QD de-excitation pathways. The characteristics of these distributions: 1) a faster transfer rate ( k ¯ E T 1 = 1.5 10 9 s - 1 ), with a lower acceptor number ( N ¯ a 1 = 0.03 ) and 2) a slower transfer rate ( k ¯ E T 2 = 4.1 10 8 s - 1 ) with a higher acceptor number ( N ¯ a 2 = 0.18 ). We assign these distributions to the indirect and direct electron transfer mechanisms, respectively. Our findings demonstrate how spectroscopic imaging can uncover fundamental electron transfer mechanisms at complex interfaces, offering valuable design principles for future nano–bio hybrids.}, archive = {J_PNAS}, author = {Suri, Mokshin and Salimi Jazi, Farshid and Crowley, Jack C. and Park, Youngchan and Fu, Bing and Chen, Peng and Zipfel, Warren R. and Barstow, Buz and Hanrath, Tobias}, doi = {10.1073/pnas.2407987122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2407987122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatially resolved charge-transfer kinetics at the quantum dot–microbe interface using fluorescence lifetime imaging microscopy}, volume = {122}, year = {2025}, }
• (2025). Coarse-graining bacterial diffusion in disordered media to surface states. PNAS, 122(12), e2407313122. (www)

  @article{ , abstract = {Bacterial motility in spatially structured environments impacts a variety of natural and engineering processes. Constructing models to predict, control, and design bacterial motility for these processes remains challenging because bacteria and active swimmers have complex interactions with surfaces and because the precise environment geometry is unknown. Here, we present a method for deriving bacterial diffusion coefficients in disordered media in terms of cell and environmental parameters. The approach abstracts the dynamics in the full geometry to “surface states,” which encode how cells interact with surfaces in the environment. Then, a long-time diffusion equation can be derived analytically from the state model. Applying this method to a run-and-tumble particle in a 2D Lorentz gas environment provides analytical predictions that show good agreement with particle simulations. Like past studies, we observe that the diffusivity depends nonmonotonically on the cell’s run length. Using the analytical expressions, we derive the optimal run length, revealing an intuitive dependence on environmental length scales. Furthermore, we find that rescaling length and time by the average distance and time between trap events collapses all of the diffusivities onto a single curve, which we derive analytically. Thus, our approach extracts interpretable, macroscopic diffusive behavior from complex microscopic dynamics, and provides tools and intuitions for understanding bacterial diffusion in disordered media.}, archive = {J_PNAS}, author = {Mattingly, Henry H.}, doi = {10.1073/pnas.2407313122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2407313122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Coarse-graining bacterial diffusion in disordered media to surface states}, volume = {122}, year = {2025}, }
• (2025). US grass-fed beef is as carbon intensive as industrial beef and ≈10-fold more intensive than common protein-dense alternatives. PNAS, 122(12), e2404329122. (www)

  @article{ , abstract = {The high resource intensity of industrial beef in high-income economies has prompted growing interest in alternative, potentially lower environmental impact beef production pathways. Of those, grass feeding is promoted by some as one such alternative, but rigorous quantification of this claim is required. Motivated to bridge this knowledge gap, we integrate empirical evidence with a model based on authoritative equations governing beef cattle performance to quantify the greenhouse gas emissions of producing grass-fed beef. Because geographical specificity and dependence on agricultural intensity are key, we model widely varied herds, from extensive operations on semiarid, marginal rangelands to partially industrial, intensive ones in lusher, more accommodating settings. We find that emissions per kg protein of even the most efficient grass-fed beef are 10 to 25% higher than those of industrial US beef and 3- to over 40-fold higher than a wide range of plant and animal alternatives. Soil sequestration enhancement by rangeland grazing reduces these emissions from 280–390 to 180–290 kg CO 2eq (kg protein) −1 , still somewhat above industrial beef’s 180 to 220 kg CO 2eq (kg protein) −1 , and well above nonbeef alternatives’ 10 to 70 kg CO 2eq (kg protein) −1 . These differences prove robust across a broad set of combinations of grass-fed beef operation types, management practices, and ration qualities. Consequently, even with maximal credit for putative sequestration enhancement, grass-fed beef is still no less carbon intensive than industrial beef, and severalfold more intensive than nonbeef alternatives.}, archive = {J_PNAS}, author = {Eshel, Gidon and Flamholz, Avi I. and Shepon, Alon Alon and Milo, Ron}, doi = {10.1073/pnas.2404329122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2404329122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {US grass-fed beef is as carbon intensive as industrial beef and ≈10-fold more intensive than common protein-dense alternatives}, volume = {122}, year = {2025}, }
• (2025). Reinforcement learning–based adaptive strategies for climate change adaptation: An application for coastal flood risk management. PNAS, 122(12), e2402826122. (www)

  @article{ , abstract = {Conventional computational models of climate adaptation frameworks inadequately consider decision-makers’ capacity to learn, update, and improve decisions. Here, we investigate the potential of reinforcement learning (RL), a machine learning technique that efficaciously acquires knowledge from the environment and systematically optimizes dynamic decisions, in modeling and informing adaptive climate decision-making. We consider coastal flood risk mitigations for Manhattan, New York City, USA (NYC), illustrating the benefit of continuously incorporating observations of sea-level rise into systematic designs of adaptive strategies. We find that when designing adaptive seawalls to protect NYC, the RL-derived strategy significantly reduces the expected net cost by 6 to 36% under the moderate emissions scenario SSP2-4.5 (9 to 77% under the high emissions scenario SSP5-8.5), compared to conventional methods. When considering multiple adaptive policies, including accomodation and retreat as well as protection, the RL approach leads to a further 5% (15%) cost reduction, showing RL’s flexibility in coordinatively addressing complex policy design problems. RL also outperforms conventional methods in controlling tail risk (i.e., low probability, high impact outcomes) and in avoiding losses induced by misinformation about the climate state (e.g., deep uncertainty), demonstrating the importance of systematic learning and updating in addressing extremes and uncertainties related to climate adaptation.}, archive = {J_PNAS}, author = {Feng, Kairui and Lin, Ning and Kopp, Robert E. and Xian, Siyuan and Oppenheimer, Michael}, doi = {10.1073/pnas.2402826122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2402826122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reinforcement learning–based adaptive strategies for climate change adaptation: An application for coastal flood risk management}, volume = {122}, year = {2025}, }
• (2025). Cell–matrix feedback controls stretch-induced cellular memory and fibroblast activation. PNAS, 122(12), e2322762122. (www)

  @article{ , abstract = {Mechanical stretch can activate long-lived changes in fibroblasts, increasing their contractility and initiating phenotypic transformations. This activation, critical to wound healing and procedures such as skin grafting, increases with mechanical stimulus for cells cultured in two-dimensional but is highly variable in cells in three-dimensional (3D) tissue. Here, we show that static mechanical stretch of cells in 3D tissues can either increase or decrease fibroblast activation depending upon recursive cell–extracellular matrix (ECM) feedback and demonstrate control of this activation through integrated in vitro and mathematical models. ECM viscoelasticity, signaling dynamics, and cell mechanics combine to yield a predictable, but nonmonotonic, relationship between mechanical stretch and long-term cell activation. Results demonstrate that feedback between cells and ECM determine how cells retain memory of mechanical stretch and have direct implications for improving outcomes in skin grafting procedures.}, archive = {J_PNAS}, author = {Hong, Yuan and Peng, Xiangjun and Yu, Haomin and Jafari, Mohammad and Shakiba, Delaram and Huang, Yuxuan and Qu, Chengqing and Melika, Ermia E. and Tawadros, Andrew K. and Mujahid, Aliza and Huang, Yin-Yuan and Sandler, Jacob A. and Pryse, Kenneth M. and Sacks, Justin M. and Elson, Elliot L. and Genin, Guy M. and Alisafaei, Farid}, doi = {10.1073/pnas.2322762122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2322762122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cell–matrix feedback controls stretch-induced cellular memory and fibroblast activation}, volume = {122}, year = {2025}, }
• (2025). Iguanas rafted more than 8,000 km from north america to fiji. PNAS, 122(12), e2318622122. (www)

  @article{ , abstract = {Founder-event speciation can occur when one or more organisms colonize a distant, unoccupied area via long-distance dispersal, leading to the evolution of a new species lineage. Species radiations established by long-distance, and especially transoceanic, dispersal can cause substantial shifts in regional biodiversity. Here, we investigate the occurrence and timing of the greatest known long-distance oceanic dispersal event in the history of terrestrial vertebrates—the rafting of iguanas from North America to Fiji. Iguanas are large-bodied herbivores that are well-known overwater dispersers, including species that colonized the Caribbean and the Galápagos islands. However, the origin of Fijian iguanas had not been comprehensively tested. We estimated the phylogenetic relationships and evolutionary timescale of the iguanid lizard radiation using genome-wide exons and ultraconserved elements (UCEs). Those data indicate that the closest living relative of extant Fijian iguanas is the North American desert iguana and that the two taxa likely diverged during the late Paleogene near or after the onset of volcanism that produced the Fijian archipelago. Biogeographic models estimate North America as the most probable ancestral range of Fijian iguanas. Our analyses support the hypothesis that iguanas reached Fiji via an extraordinary oceanic dispersal event from western North America, and which spanned a fifth of the earth’s circumference (>8,000 km). Overwater rafting of iguanas from North America to Fiji strengthens the importance of founder-event speciation in the diversification of iguanids and elucidates the scope of long-distance dispersal across terrestrial vertebrates.}, archive = {J_PNAS}, author = {Scarpetta, Simon G. and Fisher, Robert N. and Karin, Benjamin R. and Niukula, Jone B. and Corl, Ammon and Jackman, Todd R. and McGuire, Jimmy A.}, doi = {10.1073/pnas.2318622122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2318622122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Iguanas rafted more than 8,000 km from north america to fiji}, volume = {122}, year = {2025}, }
• (2025). Constructed languages are processed by the same brain mechanisms as natural languages. PNAS, 122(12), e2313473122. (www)

  @article{ , abstract = {What constitutes a language? Natural languages share features with other domains: from math, to music, to gesture. However, the brain mechanisms that process linguistic input are highly specialized, showing little response to diverse nonlinguistic tasks. Here, we examine constructed languages (conlangs) to ask whether they draw on the same neural mechanisms as natural languages or whether they instead pattern with domains like math and programming languages. Using individual-subject fMRI analyses, we show that understanding conlangs recruits the same brain areas as natural language comprehension. This result holds for Esperanto (n = 19 speakers) and four fictional conlangs [Klingon (n = 10), Na’vi (n = 9), High Valyrian (n = 3), and Dothraki (n = 3)]. These findings suggest that conlangs and natural languages share critical features that allow them to draw on the same representations and computations, implemented in the left-lateralized network of brain areas. The features of conlangs that differentiate them from natural languages—including recent creation by a single individual, often for an esoteric purpose, the small number of speakers, and the fact that these languages are typically learned in adulthood—appear to not be consequential for the reliance on the same cognitive and neural mechanisms. We argue that the critical shared feature of conlangs and natural languages is that they are symbolic systems capable of expressing an open-ended range of meanings about our outer and inner worlds.}, archive = {J_PNAS}, author = {Malik-Moraleda, Saima and Taliaferro, Maya and Shannon, Steve and Jhingan, Niharika and Swords, Sara and Peterson, David J. and Frommer, Paul and Okrand, Marc and Sams, Jessie and Cardwell, Ramsey and Freeman, Cassie and Fedorenko, Evelina}, doi = {10.1073/pnas.2313473122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {12}, pages = {e2313473122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Constructed languages are processed by the same brain mechanisms as natural languages}, volume = {122}, year = {2025}, }
• (2025). Correction for chen et al., live-attenuated virus vaccine defective in RNAi suppression induces rapid protection in neonatal and adult mice lacking mature b and t cells. PNAS, 122(11), e2502986122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502986122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2502986122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for chen et al., live-attenuated virus vaccine defective in RNAi suppression induces rapid protection in neonatal and adult mice lacking mature b and t cells}, volume = {122}, year = {2025}, }
• (2025). Correction for zhang et al., dancr-BRG1 regulates nfatc1 transcription and pgc1β-dependent metabolic shifts in osteoclastogenesis. PNAS, 122(11), e2502976122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502976122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2502976122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for zhang et al., dancr-BRG1 regulates nfatc1 transcription and pgc1β-dependent metabolic shifts in osteoclastogenesis}, volume = {122}, year = {2025}, }
• (2025). Correction for deng et al., the arabidopsis BUB1/MAD3 family protein BMF3 requires BUB3.3 to recruit CDC20 to kinetochores in spindle assembly checkpoint signaling. PNAS, 122(11), e2502783122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502783122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2502783122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for deng et al., the arabidopsis BUB1/MAD3 family protein BMF3 requires BUB3.3 to recruit CDC20 to kinetochores in spindle assembly checkpoint signaling}, volume = {122}, year = {2025}, }
• (2025). Correction for deng et al., a coadapted KNL1 and spindle assembly checkpoint axis orchestrates precise mitosis in arabidopsis. PNAS, 122(11), e2502604122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502604122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2502604122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for deng et al., a coadapted KNL1 and spindle assembly checkpoint axis orchestrates precise mitosis in arabidopsis}, volume = {122}, year = {2025}, }
• (2025). Correction for hogan et al., the genetic regulatory architecture and epigenomic basis for age-related changes in rattlesnake venom. PNAS, 122(11), e2502598122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502598122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2502598122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for hogan et al., the genetic regulatory architecture and epigenomic basis for age-related changes in rattlesnake venom}, volume = {122}, year = {2025}, }
• (2025). Correction for chae et al., vulnerability to natural disasters and sustainable consumption: Unraveling political and regional differences. PNAS, 122(11), e2502585122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502585122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2502585122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for chae et al., vulnerability to natural disasters and sustainable consumption: Unraveling political and regional differences}, volume = {122}, year = {2025}, }
• (2025). Correction for sibille et al., efficient mapping of the thalamocortical monosynaptic connectivity in vivo by tangential insertions of high-density electrodes in the cortex. PNAS, 122(11), e2502365122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502365122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2502365122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for sibille et al., efficient mapping of the thalamocortical monosynaptic connectivity in vivo by tangential insertions of high-density electrodes in the cortex}, volume = {122}, year = {2025}, }
• (2025). Correction for guo et al., targeting amyloid-β in glaucoma treatment. PNAS, 122(11), e2502362122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502362122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2502362122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for guo et al., targeting amyloid-β in glaucoma treatment}, volume = {122}, year = {2025}, }
• (2025). Behold the scale of global zoogeomorphic activity. PNAS, 122(11), e2501894122. (www)

  @article{ , archive = {J_PNAS}, author = {Francis, Robert A.}, doi = {10.1073/pnas.2501894122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2501894122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Behold the scale of global zoogeomorphic activity}, volume = {122}, year = {2025}, }
• (2025). G-quadruplexes and their unexpected ability to fold proteins. PNAS, 122(11), e2501246122. (www)

  @article{ , archive = {J_PNAS}, author = {Schwalbe, Harald and Burkhart, Ines}, doi = {10.1073/pnas.2501246122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2501246122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {G-quadruplexes and their unexpected ability to fold proteins}, volume = {122}, year = {2025}, }
• (2025). How nidoviruses evolved the largest known RNA genomes. PNAS, 122(11), e2501153122. (www)

  @article{ , archive = {J_PNAS}, author = {Dolja, Valerian V.}, doi = {10.1073/pnas.2501153122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2501153122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How nidoviruses evolved the largest known RNA genomes}, volume = {122}, year = {2025}, }
• (2025). A family of bacterial actin homologs forms a three-stranded tubular structure. PNAS, 122(11), e2500913122. (www)

  @article{ , abstract = {The cytoskeleton is crucial for cell organization and movement. In Eukaryotes, it largely consists of the protein actin, that forms a double-stranded linear filamentous structure in the presence of ATP and disassemble upon ATP hydrolysis. Bacteria also possess actin homologs, that drive fundamental cellular processes, including cell division, shape maintenance, and DNA segregation. Like eukaryotic actin, bacterial actins assemble into dynamic polymers upon ATP binding, however variation in interactions between strands gives rise to striking diversity of filament architectures. Here, we report a family of bacterial actins of unknown function, conserved among the Verrucomicrobiota phylum, which assembles into a unique tubular structure in the presence of ATP. A cryo-EM structure of the filaments reveals that it consists of three strands, unlike other described bacterial actin structures. This architecture provides further insights into the organization of actin-like filaments and has implications for understanding the diversity and evolution of the bacterial cytoskeleton.}, archive = {J_PNAS}, author = {Bergeron, Julien R. C. and Lale-Farjat, Shamar L. M. and Lewicka, Hanna M. and Parry, Chloe and Kollman, Justin M.}, doi = {10.1073/pnas.2500913122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2500913122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A family of bacterial actin homologs forms a three-stranded tubular structure}, volume = {122}, year = {2025}, }
• (2025). Fluorescence detection of dopamine signaling to the primate striatum in relation to stimulus–reward associations. PNAS, 122(11), e2426861122. (www)

  @article{ , abstract = {Dopamine (DA) signals to the striatum play critical roles in shaping and sustaining stimulus-reward associations. In primates, however, the dynamics of the DA signals remain unknown since conventional methods are not necessarily appropriate in terms of the spatiotemporal resolution or chemical specificity sufficient for detecting the DA signals. In our study, fiber photometry with a fluorescent DA sensor was employed to identify reward-related DA transients in the monkey striatum. This technique, which directly monitors local DA release, reveals a reward prediction error signal in the anterior putamen originating from midbrain DA neurons. Further, DA transients in the head of the caudate nucleus exhibit a value-based response to reward-predicting stimuli. These signals have been found to arise from two separate groups of DA neurons in the substantia nigra pars compacta. The present results demonstrate that fluorescence DA monitoring is applicable to detect DA signals in the primate striatum for investigating their roles.}, archive = {J_PNAS}, author = {Yan, Gaoge and Amita, Hidetoshi and Nonomura, Satoshi and Inoue, Ken-ichi and Schultz, Wolfram and Takada, Masahiko}, doi = {10.1073/pnas.2426861122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2426861122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fluorescence detection of dopamine signaling to the primate striatum in relation to stimulus–reward associations}, volume = {122}, year = {2025}, }
• (2025). Asymmetric bending boundary layer: The λ-test. PNAS, 122(11), e2426748122. (www)

  @article{ , abstract = {We investigate the mechanics of two asymmetric ribbons bound at one end and pulled apart at the other ends. We characterize the elastic junction near the bonding and conceptualize it as a bending boundary layer. While the size of this junction decreases with the pulling force, we observe the surprising existence of the binding angle as a macroscopic signature of the bending stiffnesses. Our results thus challenge the standard assumption of neglecting bending stiffness of thin shells at large tensile loading. In addition, we show how the rotational response of the structure exhibits a nonlinear and universal behavior regardless of the ratio of asymmetry. Leveraging the independence of the binding angle to the pulling force, we finally introduce the λ -test—a visual measurement technique to characterize membranes through simple mechanical coupling.}, archive = {J_PNAS}, author = {Vani, Nathan and Ibarra, Alejandro and Bico, José and Reyssat, Étienne and Roman, Benoît}, doi = {10.1073/pnas.2426748122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2426748122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Asymmetric bending boundary layer: The λ-test}, volume = {122}, year = {2025}, }
• (2025). Structural mechanisms underlying the modulation of CXCR4 by diverse small-molecule antagonists. PNAS, 122(11), e2425795122. (www)

  @article{ , abstract = {CXCR4 (CXC chemokine receptor type 4), a member of the G protein–coupled receptor superfamily, plays a role in cell migration and functions as a coreceptor for HIV entry. Molecular therapeutics targeting CXCR4 have been under intensive investigation. To date, only two small-molecule antagonist drugs targeting CXCR4, plerixafor (AMD3100) and mavorixafor (AMD070), have been approved. Here, we present the high-resolution structures of CXCR4 complexed with AMD3100 and AMD070, as well as a small-molecule antagonist HF51116 that has very different chemical structure and binding mechanism from AMD3100 and AMD070. The interactions between these antagonists and the receptor are analyzed in details, and the mechanisms of antagonism are elucidated. Both the major and minor subpockets on CXCR4 are found to be involved in binding of these small-molecule antagonists. The distinct conformations of Trp94 2.60 observed in these structures highlight the plasticity of the binding pocket on CXCR4, offering valuable insights into the exploration and refinement of therapeutic strategies targeting this chemokine receptor.}, archive = {J_PNAS}, author = {Sang, Xiaohong and Jiao, Haizhan and Meng, Qian and Fang, Xiong and Pan, Qi and Zhou, Jiao and Qian, Tingli and Zhang, Wanqin and Xu, Yan and An, Jing and Huang, Ziwei and Hu, Hongli}, doi = {10.1073/pnas.2425795122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2425795122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural mechanisms underlying the modulation of CXCR4 by diverse small-molecule antagonists}, volume = {122}, year = {2025}, }
• (2025). Epstein–Barr virus and the immune microenvironment in multiple sclerosis: Insights from high-dimensional brain tissue imaging. PNAS, 122(11), e2425670122. (www)

  @article{ , abstract = {Epstein–Barr virus (EBV) is strongly implicated in the pathogenesis of multiple sclerosis (MS), yet its exact role in disease progression remains unclear. Using high-dimensional CO-detection by indexing, a technology for spatial imaging, this study examines the cellular microenvironment of MS lesions in secondary progressive MS and primary progressive MS. We analyzed immune, glial, neuronal, and endothelial cell interactions within MS lesions and normal-appearing white matter across two independent cohorts. Our findings show the enrichment of EBV markers, particularly EBNA1 and LMP1, within MS lesions. EBV-positive cells interact closely with reactive astrocytes, microglia, and neurons. Image analysis confirmed the presence of EBV-positive staining within neurons and glial cells, suggesting a direct role for EBV in neuronal and glial involvement in MS. Additionally, we observed altered immune cell interactions, including reduced associations with macrophages and memory T cells, and enhanced interactions with glial cells. Disruptions in blood–brain barrier integrity were also noted in regions of the MS brain. These results highlight EBV’s contribution to immune modulation, glial dysfunction, and neuronal damage in MS, particularly in progressive subtypes. The analysis of MS brain tissue suggests potential therapeutic targets, including antivirals and brain penetrant immune modulators, to address EBV’s impact on MS progression.}, archive = {J_PNAS}, author = {Orr, Noga and Steinman, Lawrence}, doi = {10.1073/pnas.2425670122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2425670122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Epstein–Barr virus and the immune microenvironment in multiple sclerosis: Insights from high-dimensional brain tissue imaging}, volume = {122}, year = {2025}, }
• (2025). Initiation of transthyretin aggregation at neutral pH by fluid agitation. PNAS, 122(11), e2425230122. (www)

  @article{ , abstract = {The transthyretin (TTR) tetramer, assembled as a dimer of dimers, transports thyroxine and retinol binding protein in blood plasma and cerebrospinal fluid. Aggregation of wild type (WT) or pathogenic variant TTR leads to transthyretin amyloidosis, which is associated with neurodegenerative and cardiac disease. The trigger for TTR aggregation under physiological conditions is unknown. The tetramer is extremely stable at neutral pH, but aggregation via tetramer dissociation and monomer misfolding can be induced in vitro by lowering the pH. To elucidate factors that may cause TTR aggregation at neutral pH, we examined the effect of shear forces such as those that arise from fluid flow in the vascular system. Fluid shear forces were generated by rapidly stirring TTR solutions in conical microcentrifuge tubes. Under agitation, TTR formed β-rich aggregates and fibrils at a rate that was dependent upon protein concentration. The lag time before the onset of agitation-induced aggregation increases as the total TTR concentration is increased, consistent with a mechanism in which the tetramer first dissociates to form monomer that either partially unfolds to enter the aggregation pathway or reassociates to form tetramer. NMR spectra recorded at various time points during the lag phase revealed growth of an aggregation-prone intermediate trapped as a dynamically perturbed tetramer. Enhanced conformational fluctuations in the weak dimer–dimer interface suggest loosening of critical intersubunit contacts which likely destabilizes the agitated tetramer and predisposes it toward dissociation. These studies provide insights into the mechanism of aggregation of WT human TTR under near-physiological conditions.}, archive = {J_PNAS}, author = {Ritsch, Irina and Dyson, H. Jane and Wright, Peter E.}, doi = {10.1073/pnas.2425230122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2425230122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Initiation of transthyretin aggregation at neutral pH by fluid agitation}, volume = {122}, year = {2025}, }
• (2025). Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls. PNAS, 122(11), e2424986122. (www)

  @article{ , abstract = {Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS), which is linked to Epstein–Barr virus (EBV) infection, preceding the disease. The molecular mechanisms underlying this connection are only partially understood. We previously described molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and three human CNS proteins: anoctamin-2 (ANO2), alpha-B crystallin (CRYAB), and glial cellular adhesion molecule (GlialCAM). Here, we investigated antibody responses against EBNA1 and GlialCAM in a large cohort of 650 MS patients and 661 matched population controls and compared them to responses against CRYAB and ANO2. We confirmed that elevated IgG responses against EBNA1 and all three CNS-mimic antigens associate with increased MS risk. Blocking experiments confirmed the presence of cross-reactive antibodies and molecular mimicry between EBNA1 and GlialCAM, and accompanying antibody responses against adjacent peptide regions of GlialCAM suggest epitope spreading. Antibody responses against EBNA1, GlialCAM, CRYAB, and ANO2 are elevated in MS patients carrying the main risk allele HLA-DRB1*15:01, and combinations of HLA-DRB1*15:01 with anti-EBNA1 and anti-GlialCAM antibodies increase MS risk significantly and in an additive fashion. In addition, antibody reactivities against more than one EBNA1 peptide and more than one CNS-mimic increase the MS risk significantly but modestly. Overall, we show that molecular mimicry between EBNA1 and GlialCAM is likely an important molecular mechanism contributing to MS pathology.}, archive = {J_PNAS}, author = {Sattarnezhad, Neda and Kockum, Ingrid and Thomas, Olivia G. and Liu, Yicong and Ho, Peggy P. and Barrett, Alison K. and Comanescu, Alexandros I. and Wijeratne, Tilini U. and Utz, Paul J. and Alfredsson, Lars and Steinman, Lawrence and Robinson, William H. and Olsson, Tomas and Lanz, Tobias V.}, doi = {10.1073/pnas.2424986122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2424986122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls}, volume = {122}, year = {2025}, }
• (2025). The shortcomings of synthetic census microdata. PNAS, 122(11), e2424655122. (www)

  @article{ , abstract = {U.S. Census Bureau officials recently reaffirmed the Bureau’s ongoing efforts to replace the American Community Survey (ACS) public use microdata sample with “fully synthetic” data to protect respondent confidentiality. With the growth of computing power and expansion of private sector data about the population, the Census Bureau has valid concerns about confidentiality threats to public data. The current plan for fully synthetic data, however, threatens a cornerstone of the nation’s scientific infrastructure. Census microdata samples are among the most frequently used sources in social science research, and they are an essential tool for policy formation and planning from the local to the national level. Synthetic census microdata are not suitable for most research and policy applications. There have been no recent attempts to quantify disclosure risk in the ACS microdata, and the sole existing study failed to establish a credible threat for positive identification of ACS respondents by external intruders. I argue that we need new empirical research to pinpoint specific vulnerabilities that could allow an intruder to determine a particular individual’s confidential census responses. If significant vulnerabilities are uncovered, the Census Bureau in partnership with the research community should develop targeted methods for disclosure risk reduction that minimize damage to data usability.}, archive = {J_PNAS}, author = {Ruggles, Steven}, doi = {10.1073/pnas.2424655122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2424655122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The shortcomings of synthetic census microdata}, volume = {122}, year = {2025}, }
• (2025). EDNA confirms lower trophic interactions help to modulate population outbreaks of the notorious crown-of-thorns sea star. PNAS, 122(11), e2424560122. (www)

  @article{ , abstract = {Variability in predator–prey interactions can modulate population dynamics with impacts scalable to entire ecosystems. As notorious corallivores, crown-of-thorns sea stars (CoTS; Acanthaster spp.) have caused extensive losses of coral habitat during unexplained population outbreaks across the Indo-Pacific. While predation of adult CoTS may help to suppress their outbreaks, it does not sufficiently explain their profound boom-bust dynamics and so remains equivocal. Factors influencing early postsettlement mortality are generally more impactful on population size, thus lower trophic interactions involving juvenile CoTS may better contribute to outbreak prevention. We evaluated the impact of key predatory decapods that interact with juvenile CoTS in their coral rubble nursery before they emerge as destructive corallivores. Decapod density was influenced by habitat complexity and varied regionally, inverse to spatial trends in CoTS outbreaks on the Great Barrier Reef. Using eDNA gut content analysis, we confirmed seven species (~12% of individuals) of wild-caught decapod, collected from two reefs separated by >1,000 km, as CoTS predators. Owing to spatial variation in predator abundance and community structure, we estimated potential (previous aquarium experiments) and realized (eDNA results here) rates of CoTS consumption were ~3-fold and ~1.6-fold lower, respectively, in outbreak hotspots. Through combination of field and molecular techniques, we demonstrated the appreciable impact of cryptic predators on early population success of this nuisance species, which expands our knowledge of CoTS outbreaks, pest species management, and reef conservation. Resolving predator–prey interactions at lower levels of the ecosystem can be crucial to understanding broader ecological outcomes.}, archive = {J_PNAS}, author = {Wolfe, Kennedy and Desbiens, Amelia A. and Patel, Frances and Kwong, Sarah and Fisher, Eric and Mumby, Peter J. and Uthicke, Sven}, doi = {10.1073/pnas.2424560122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2424560122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {EDNA confirms lower trophic interactions help to modulate population outbreaks of the notorious crown-of-thorns sea star}, volume = {122}, year = {2025}, }
• (2025). Protein interactions, calcium, phosphorylation, and cholesterol modulate CFTR cluster formation on membranes. PNAS, 122(11), e2424470122. (www)

  @article{ , abstract = {The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel whose dysfunction leads to intracellular accumulation of chloride ions, dehydration of cell surfaces, and subsequent damage to airway and ductal organs. Beyond its function as a chloride channel, interactions between CFTR, epithelium sodium channel, and solute carrier (SLC) transporter family membrane proteins and cytoplasmic proteins, including calmodulin and Na+/H+ exchanger regulatory factor-1 (NHERF-1), coregulate ion homeostasis. CFTR has also been observed to form mesoscale membrane clusters. However, the contributions of multivalent protein and lipid interactions to cluster formation are not well understood. Using a combination of computational modeling and biochemical reconstitution assays, we demonstrate that multivalent interactions with CFTR protein binding partners, calcium, and membrane cholesterol can induce mesoscale CFTR cluster formation on model membranes. Phosphorylation of the intracellular domains of CFTR also promotes mesoscale cluster formation in the absence of calcium, indicating that multiple mechanisms can contribute to CFTR cluster formation. Our findings reveal that coupling of multivalent protein and lipid interactions promotes CFTR cluster formation consistent with membrane-associated biological phase separation.}, archive = {J_PNAS}, author = {Wan, Yimei and Hudson, Rhea and Smith, Jordyn and Forman-Kay, Julie D. and Ditlev, Jonathon A.}, doi = {10.1073/pnas.2424470122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2424470122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Protein interactions, calcium, phosphorylation, and cholesterol modulate CFTR cluster formation on membranes}, volume = {122}, year = {2025}, }
• (2025). Unintegrated HIV-1 DNA recruits cGAS via its histone-binding domain to escape innate immunity. PNAS, 122(11), e2424465122. (www)

  @article{ , abstract = {To ensure optimal replication and spread, viruses have evolved countermeasures to evade type 1 IFN-mediated antiviral activity. During the early viral replication cycle steps until uncoating, the HIV-1 core protects viral pathogen associated molecular patterns (viral RNA and reverse transcription products) from recognition by innate immune sensors, including cGAS. However, after capsid uncoating, unintegrated viral DNA (uvDNA) becomes accessible. Here, we show that HIV-1 uses chromatin-mediated cGAS inactivation as a mechanism to protect its uvDNA from innate immune activation.}, archive = {J_PNAS}, author = {Jahan, Cyprien and Bonnet-Madin, Lucie and Machida, Shinichi and Sobhian, Bijan and Thenin-Houssier, Suzie and Benkirane, Monsef}, doi = {10.1073/pnas.2424465122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2424465122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unintegrated HIV-1 DNA recruits cGAS via its histone-binding domain to escape innate immunity}, volume = {122}, year = {2025}, }
• (2025). Cold low-latitude ordovician paleotemperatures may be in hot water. PNAS, 122(11), e2424291122. (www)

  @article{ , archive = {J_PNAS}, author = {Grossman, Ethan L. and Barney, Bryce B. and Sun, Zeyang and Henkes, Gregory A. and Gao, Yang and Joachimski, Michael M.}, doi = {10.1073/pnas.2424291122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2424291122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cold low-latitude ordovician paleotemperatures may be in hot water}, volume = {122}, year = {2025}, }
• (2025). Identification of a ligand-binding site on tubulin mediating the tubulin–RB3 interaction. PNAS, 122(11), e2424098122. (www)

  @article{ , abstract = {For decades, microtubules—composed of αβ-tubulin dimers—have been primary targets for cancer chemotherapy. While eight binding sites on the tubulin dimer have been structurally characterized, this study reveals a ninth. We found that the tubulin inhibitor Tumabulin-1 (TM1, a BML284 derivative) binds simultaneously to the well-known colchicine site and a previously unknown site, designated as Tumabulin site. This site resides at the interface of α1-tubulin, β1-tubulin, and RB3 within the tubulin–RB3–tubulintyrosine ligase complex. Remarkably, two TM1 molecules bind cooperatively to this relatively large pocket, interacting with all three proteins. Crucially, this binding is dependent on RB3; it is absent when RB3 is missing or the key residue H71 is mutated (H71Q). We further designed and synthesized Tumabulin-2 (TM2) that selectively binds the Tumabulin site, excluding binding the colchicine site. TM2 acts as a molecular glue, strengthening the interaction between RB3 and the tubulin dimer and consequently enhancing RB3’s tubulin-depolymerizing activity. In conclusion, our findings confirm the existence of a ninth tubulin-binding site and offer a promising foundation for developing Tubulin–RB3 molecular glues as a next generation of anticancer therapeutics.}, archive = {J_PNAS}, author = {Li, Yong and Zhang, Chufeng and Tang, Dongmei and Wang, Tao and Yan, Wei and Yang, Linyu and Bai, Peng and Tang, Minghai and Pei, Heying and Chen, Lijuan and Chen, Qiang and Yang, Jianhong}, doi = {10.1073/pnas.2424098122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2424098122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identification of a ligand-binding site on tubulin mediating the tubulin–RB3 interaction}, volume = {122}, year = {2025}, }
• (2025). A global estimate of multiecosystem photosynthesis losses under microplastic pollution. PNAS, 122(11), e2423957122. (www)

  @article{ , abstract = {Understanding how ecosystems respond to ubiquitous microplastic (MP) pollution is crucial for ensuring global food security. Here, we conduct a multiecosystem meta-analysis of 3,286 data points and reveal that MP exposure leads to a global reduction in photosynthesis of 7.05 to 12.12% in terrestrial plants, marine algae, and freshwater algae. These reductions align with those estimated by a constructed machine learning model using current MP pollution levels, showing that MP exposure reduces the chlorophyll content of photoautotrophs by 10.96 to 12.84%. Model estimates based on the identified MP-photosynthesis nexus indicate annual global losses of 4.11 to 13.52% (109.73 to 360.87 MT·y −1 ) for main crops and 0.31 to 7.24% (147.52 to 3415.11 MT C·y −1 ) for global aquatic net primary productivity induced by MPs. Under scenarios of efficient plastic mitigation, e.g., a ~13% global reduction in environmental MP levels, the MP-induced photosynthesis losses are estimated to decrease by ~30%, avoiding a global loss of 22.15 to 115.73 MT·y −1 in main crop production and 0.32 to 7.39 MT·y −1 in seafood production. These findings underscore the urgency of integrating plastic mitigation into global hunger and sustainability initiatives.}, archive = {J_PNAS}, author = {Zhu, Ruijie and Zhang, Zhaoying and Zhang, Naichi and Zhong, Huan and Zhou, Fanqi and Zhang, Xiao and Liu, Cun and Huang, Yingnan and Yuan, Yuan and Wang, Yujun and Li, Chengjun and Shi, Huahong and Rillig, Matthias C. and Dang, Fei and Ren, Hongqiang and Zhang, Yongguang and Xing, Baoshan}, doi = {10.1073/pnas.2423957122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2423957122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A global estimate of multiecosystem photosynthesis losses under microplastic pollution}, volume = {122}, year = {2025}, }
• (2025). Epitope-directed selection of GPCR nanobody ligands with evolvable function. PNAS, 122(11), e2423931122. (www)

  @article{ , abstract = {Antibodies have the potential to target G protein–coupled receptors (GPCRs) with high receptor, cellular, and tissue selectivity; however, few antibody ligands for GPCRs exist. Here, we describe a generalizable selection method to enrich for GPCR ligands from a synthetic camelid antibody fragment (nanobody) library. Our strategy yielded multiple nanobody ligands for the angiotensin II type I receptor (AT1R), a prototypical GPCR and important drug target. We found that nanobodies readily act as allosteric modulators, encoding selectivity for both the receptor and chemical features of GPCR ligands. We then used structure-guided design to convert two nanobodies from allosteric ligands to competitive AT1R inhibitors through simple mutations. This work demonstrates that nanobodies can encode multiple pharmacological behaviors and have great potential as evolvable scaffolds for the development of next-generation GPCR therapeutics.}, archive = {J_PNAS}, author = {Skiba, Meredith A. and Canavan, Clare and Nemeth, Genevieve R. and Liu, Jinghan and Kanso, Ali and Kruse, Andrew C.}, doi = {10.1073/pnas.2423931122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2423931122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Epitope-directed selection of GPCR nanobody ligands with evolvable function}, volume = {122}, year = {2025}, }
• (2025). Eukaryotic phytoplankton drive a decrease in primary production in response to elevated CO2 in the tropical and subtropical oceans. PNAS, 122(11), e2423680122. (www)

  @article{ , abstract = {Ocean acidification caused by increasing anthropogenic CO 2 is expected to impact marine phytoplankton productivity, yet the extent and even direction of these changes are not well constrained. Here, we investigate the responses of phytoplankton community composition and productivity to acidification across the western North Pacific. Consistent reductions in primary production were observed under acidified conditions in the North Pacific Subtropical Gyre and the northern South China Sea, whereas no significant changes were found at the northern boundary of the subtropical gyre. While prokaryotic phytoplankton showed little or positive responses to high CO 2 , small (<20 µm) eukaryotic phytoplankton which are primarily limited by low ambient nitrogen drove the observed decrease in community primary production. Extrapolating these results to global tropical and subtropical oceans predicts a potential decrease of about 5 Pg C y −1 in primary production in low Chl- a oligotrophic regions, which are anticipated to experience both acidification and stratification in the future.}, archive = {J_PNAS}, author = {Dai, Rongbo and Wen, Zuozhu and Hong, Haizheng and Browning, Thomas J. and Hu, Xiaohua and Chen, Ze and Liu, Xin and Dai, Minhan and Morel, François M. M. and Shi, Dalin}, doi = {10.1073/pnas.2423680122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2423680122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Eukaryotic phytoplankton drive a decrease in primary production in response to elevated CO2 in the tropical and subtropical oceans}, volume = {122}, year = {2025}, }
• (2025). SOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRASG12D inhibitor in KRAS LUAD. PNAS, 122(11), e2422943122. (www)

  @article{ , abstract = {We evaluated the in vivo therapeutic efficacy and tolerability of BI-3406-mediated pharmacological inhibition of SOS1 in comparison to genetic ablation of this universal Ras-GEF in various KRAS-dependent experimental tumor settings. Contrary to the rapid lethality caused by SOS1 genetic ablation in SOS2 KO mice, SOS1 pharmacological inhibition by its specific inhibitor BI-3406 did not significantly affect animal weight/viability nor cause noteworthy systemic toxicity. Allograft assays using different KRAS mut cell lines showed that treatment with BI-3406 impaired RAS activation and RAS downstream signaling and decreased tumor burden and disease progression as a result of both tumor-intrinsic and -extrinsic therapeutic effects of the drug. Consistent with prior genetic evidence and the KRAS mut allografts assays in immunocompromised mice, our analyses using an in vivo model of KRAS G12D -driven lung adenocarcinoma (LUAD) in immunocompetent mice showed that single, systemic BI-3406 treatment impaired tumor growth and downmodulated protumorigenic components of the tumor microenvironment comparably to SOS1 genetic ablation or to treatment with the specific KRAS G12D inhibitor MRTX1133. Furthermore, markedly stronger, synergistic antitumor effects were observed upon concomitant treatment with BI-3406 and MRTX1133 in the same in vivo LUAD mouse model. Our data confirm SOS1 as an actionable therapy target in RAS-dependent cancers and suggest that BI-3406 treatment may yield clinical benefit both as monotherapy or as a potential combination partner for multiple RAS-targeting strategies.}, archive = {J_PNAS}, author = {Baltanás, Fernando C. and Kramer-Drauberg, Maximilian and García-Navas, Rósula and Patrucco, Enrico and Petrini, Ettore and Arnhof, Heribert and Olarte-San Juan, Andrea and Rodríguez-Ramos, Pablo and Borrajo, Javier and Calzada, Nuria and Castellano, Esther and Mair, Barbara and Kostyrko, Kaja and Hofmann, Marco H. and Ambrogio, Chiara and Santos, Eugenio}, doi = {10.1073/pnas.2422943122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2422943122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRASG12D inhibitor in KRAS LUAD}, volume = {122}, year = {2025}, }
• (2025). Sequential evolution of resistance by western corn rootworm to multiple bacillus thuringiensis traits in transgenic maize. PNAS, 122(11), e2422337122. (www)

  @article{ , abstract = {Transgenic crops that produce insecticidal toxins derived from the bacterium Bacillus thuringiensis (Bt) are grown worldwide to manage insect pests. Western corn rootworm is a serious pest of maize in the United States and is managed with Bt maize. In the United States, the commercial cultivation of a Bt crop requires an accompanying resistance-management strategy to delay the evolution of Bt resistance. One of the primary resistance-management strategies consists of non-Bt refuges along with a Bt crop that produces two Bt toxins (i.e., a pyramid) that kill the same pest species. This approach delays resistance because individuals with resistance to one toxin are killed by the second. However, if a pest species is resistant to one toxin in a pyramid, the effectiveness of a pyramid to delay resistance is compromised, potentially leading to the evolution of resistance to both toxins. Here, we apply a meta-analysis to demonstrate the sequential evolution of resistance by western corn rootworm to Bt maize producing Cry3Bb1 followed by resistance to Gpp34/Tpp35Ab1 maize, with resistance to each Bt toxin increasing in a linear manner over time. Additionally, we show that Bt-resistant western corn rootworm imposed substantial feeding injury, in the field, to maize containing a pyramid of Gpp34/Tpp35Ab1 and Cry3Bb1. To minimize the risk of sequential evolution of resistance to multiple transgenic traits, an emphasis should be placed on developing transgenic pyramids not compromised by prior resistance, and in cases where resistance is already present, larger non-Bt refuges and more diversified pest-management approaches should be applied.}, archive = {J_PNAS}, author = {Gassmann, Aaron J. and Brenizer, Ben D. and Kropf, Abigail L. and McCulloch, John B. and Radosevich, Devin L. and Shrestha, Ram B. and Smith, Eliott M. and St. Clair, Coy R.}, doi = {10.1073/pnas.2422337122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2422337122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sequential evolution of resistance by western corn rootworm to multiple bacillus thuringiensis traits in transgenic maize}, volume = {122}, year = {2025}, }
• (2025). NBS1 facilitates preribosomal RNA biogenesis. PNAS, 122(11), e2422029122. (www)

  @article{ , abstract = {Mutations in the NBS1 gene result in Nijmegen breakage syndrome (NBS), and the gene encodes NBS1 that forms a complex with MRE11 and RAD50 and participates in DNA damage repair. However, the molecular mechanism by which NBS1 mutations cause clinical phenotypes of NBS, such as craniofacial dysmorphism, is still unclear. Here, we show that NBS1 localizes at the ribosomal DNA (rDNA) loci in nucleoli and interacts with ribosomal RNA (rRNA) transcription machinery including RNA polymerase I (Pol I) and TCOF1. Loss of NBS1 impairs Pol I-dependent transcription of pre-rRNA and induces nucleolar stress. In particular, lacking Nbs1 in mouse neural crest cells not only leads to the reduction of ribosome biogenesis but also craniofacial abnormalities during prenatal development. Moreover, the C-terminus of NBS1 is associated with pre-rRNA and a number of pre-rRNA processing factors, which may also facilitate pre-rRNA maturation. Taken together, our study reveals the functions of NBS1 in rRNA biogenesis.}, archive = {J_PNAS}, author = {Luo, Man and Yu, Xiaochun}, doi = {10.1073/pnas.2422029122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2422029122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {NBS1 facilitates preribosomal RNA biogenesis}, volume = {122}, year = {2025}, }
• (2025). Topologically reconfigurable nematic emulsions. PNAS, 122(11), e2422026122. (www)

  @article{ , abstract = {In emulsions of multicomponent fluids, the dispersed phase forms tiny droplets in the continuous phase. In situ control and manipulation to achieve diversity in emulsion droplets for emerging applications is challenging. In a liquid crystal-based emulsion, the surface anchoring of the molecules at the isotropic fluid-liquid crystal interface introduces elastic distortions that result in anisotropic interparticle interactions, similar to electrostatic interactions between multipoles, which also lends a naming analogy as elastic dipoles, quadrupoles, and higher. However, controlling the anchoring condition at the interface at will is rarely achieved. Here, we present an emulsion system in which silicone oil droplets in a nematic liquid crystal spontaneously induce conic surface anchoring, forming elastic hexadecapoles without any surfactant. The conic degenerate surface anchoring shows continuous reversible anchoring transition to tangential and homeotropic below and above the ambient temperature, respectively. We introduce a physical design principle and in situ control to achieve three-phase compound droplets with diverse morphologies and topologies by fusing elastic hexadecapoles of oil droplets with elastic dipoles of glycerol droplets. The surrounding director field and the resulting defect structure of the compound droplets are analyzed by numerical simulations. Our approach to forming compound droplets will allow the on-demand design of building blocks for engineered emulsions for reconfigurable composite materials.}, archive = {J_PNAS}, author = {Das, Saikat and Reza, Seyednejad Seyed and Čopar, Simon and Dhara, Surajit}, doi = {10.1073/pnas.2422026122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2422026122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Topologically reconfigurable nematic emulsions}, volume = {122}, year = {2025}, }
• (2025). Populations of large-diameter trees are increasing across the united states. PNAS, 122(11), e2421780122. (www)

  @article{ , abstract = {Large-diameter trees provide vital ecological functions in forested ecosystems. Old, large-diameter trees may also be vulnerable to climate-driven mortality events, but past work on large tree populations has been geographically limited. Here, we characterize the population of large-diameter trees from two size categories, 50 to 100 cm diameter at breast height (DBH) (medium) and >100 cm DBH (big), within the United States using Forest Inventory and Analysis data. Although populations of big trees are concentrated along the west coast, populations of medium trees are more evenly distributed across the nation. In the western United States, trees >50 cm DBH comprise ~75% of the total carbon stored in live trees, while in the eastern United States they comprise ~20%. Plot remeasurement data indicate that populations of big trees are increasing at an annual rate of 0.49% in the west and 2.9% in the east, and populations of medium trees are increasing at an annual rate of 0.5% in the west and 2.4% in the east. One exception is the Sierra Nevada region, where big trees are declining. Additionally, we observed declines for several individual species. While the overall population trend for large-diameter trees is positive, declines in these species could have localized impacts for the environments in which they occur.}, archive = {J_PNAS}, author = {Chisholm, Paul J. and Gray, Andrew N.}, doi = {10.1073/pnas.2421780122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2421780122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Populations of large-diameter trees are increasing across the united states}, volume = {122}, year = {2025}, }
• (2025). Cell type and region-specific transcriptional changes in the endometrium of women with RIF identify potential treatment targets. PNAS, 122(11), e2421254122. (www)

  @article{ , abstract = {Recurrent implantation failure (RIF) is a devastating condition that leaves many undergoing fertility treatment childless. The human endometrium is receptive to a blastocyst for a brief period, the window of implantation. Critical knowledge underpinning biological processes leading to RIF, essential for effective treatment, is lacking. We employed spatial transcriptomics to define region- and cell-type-specific differences in endometrial gene expression in luteinizing hormone timed biopsies between women with RIF (n = 8) and fertile controls (FC) (n = 8). Differentially expressed genes (DEGs) were identified when comparing endometrial regions between FC and RIF (685 luminal epithelium, 293 glandular epithelium, 419 subluminal stroma, 264 functionalis stroma, 1,125 subluminal stromal CD45 + leukocytes, and 1,049 functionalis stromal CD56 + leukocytes). Only 57 DEGs were common to all subregions and cell types, which highlights that multiple DEGs are lost when the endometrium is examined as a single entity. When RIF-specific DEGs were leveraged against knowledge from mouse genetic models, genes associated with aberrant embryo implantation phenotypes were observed, mostly in immune cell populations. Dysregulated pathways in specific endometrial regions included the “WNT signaling pathway,” altered in the functionalis and subluminal stroma. “Response to estradiol” and “ovulation cycle” pathways were dysregulated in the subluminal stroma. In silico drug screening identified potential compounds that can reverse the RIF gene expression profile (e.g., raloxifene, bisoprolol). Our findings, in a well-characterized cohort, highly endorse consideration of each endometrial region and cell type as separate entities. Ignoring individual regions and composite cell populations will overlook important aberrations, forego potential treatment targets, and lead to research waste pursuing clinically irrelevant treatment options.}, archive = {J_PNAS}, author = {Tempest, Nicola and Soul, Jamie and Hill, Christopher J. and Caamaño Gutierrez, Eva and Hapangama, Dharani K.}, doi = {10.1073/pnas.2421254122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2421254122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cell type and region-specific transcriptional changes in the endometrium of women with RIF identify potential treatment targets}, volume = {122}, year = {2025}, }
• (2025). “Kids and girls”: Parents convey a male default in child-directed speech. PNAS, 122(11), e2420810122. (www)

  @article{ , abstract = {Adults tend to view men (more so than women) as default people , with numerous real-world consequences for gender equity. In the United States, the tendency to center men in concepts of people develops across middle childhood, yet the specific mechanisms that contribute to it remain unknown. Here, we investigate one subtle but potentially powerful social mechanism: the category labels that parents use to describe boys/men and girls/women in conversations with their children. Across two studies ( N = 822 parent–child dyads, predominantly from the United States), parents used gender-neutral labels like “kid” or “person” more often to describe boys/men than girls/women and, conversely, used gender-specific labels (e.g., “girl”) more often to describe girls/women than boys/men. These patterns emerged when parents were shown gender-stereotypical girls/women and boys/men (e.g., a girl painting her nails, a boy digging for worms); when parents viewed counterstereotypical stimuli (e.g., a boy painting his nails, a girl digging for worms), the patterns reversed. Our findings illuminate parents’ category label usage as a critical social mechanism that may undergird the development of a male default in a US cultural context, informing efforts to intervene on this process.}, archive = {J_PNAS}, author = {Leshin, Rachel A. and Benitez, Josie and Fu, Serena and Cordeiro, Sophia and Rhodes, Marjorie}, doi = {10.1073/pnas.2420810122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2420810122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {“Kids and girls”: Parents convey a male default in child-directed speech}, volume = {122}, year = {2025}, }
• (2025). Amplification-free, OR-gated CRISPR-cascade reaction for pathogen detection in blood samples. PNAS, 122(11), e2420166122. (www)

  @article{ , abstract = {Rapid and accurate detection of DNA from disease-causing pathogens is essential for controlling the spread of infections and administering timely treatments. While traditional molecular diagnostics techniques like PCR are highly sensitive, they include nucleic acid amplification and many need to be performed in centralized laboratories, limiting their utility in point-of-care settings. Recent advances in CRISPR-based diagnostics (CRISPR-Dx) have demonstrated the potential for highly specific molecular detection, but the sensitivity is often constrained by the slow trans-cleavage activity of Cas enzymes, necessitating preamplification of target nucleic acids. In this study, we present a CRISPR-Cascade assay that overcomes these limitations by integrating a positive feedback loop that enables nucleic acid amplification-free detection of pathogenic DNA at atto-molar levels and achieves a signal-to-noise ratio greater than 1.3 within just 10 min. The versatility of the assay is demonstrated through the detection of bloodstream infection pathogens, including Methicillin-Sensitive Staphylococcus aureus (MSSA), Methicillin-Resistant Staphylococcus aureus (MRSA), Escherichia coli , and Hepatitis B Virus (HBV) spiked in whole blood samples. Additionally, we introduce a multiplexing OR-function logic gate, further enhancing the potential of the CRISPR-Cascade assay for rapid and accurate diagnostics in clinical settings. Our findings highlight the ability of the CRISPR-Cascade assay to provide highly sensitive and specific molecular detection, paving the way for advanced applications in point-of-care diagnostics and beyond.}, archive = {J_PNAS}, author = {Lim, Jongwon and Van, An Bao and Koprowski, Katherine and Wester, Matthew and Valera, Enrique and Bashir, Rashid}, doi = {10.1073/pnas.2420166122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2420166122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Amplification-free, OR-gated CRISPR-cascade reaction for pathogen detection in blood samples}, volume = {122}, year = {2025}, }
• (2025). Proteasomal processing of the viral replicase ORF1 facilitates HEV-induced liver fibrosis. PNAS, 122(11), e2419946122. (www)

  @article{ , abstract = {Chronic infections with hepatitis E virus (HEV), especially those of genotype 3 (G3), frequently lead to liver fibrosis and cirrhosis in patients. However, the causation and mechanism of liver fibrosis triggered by chronic HEV infection remain poorly understood. Here, we found that the viral multiple-domain replicase (ORF1) undergoes unique ubiquitin–proteasomal processing leading to formation of the H EV- D erived S MAD A ctivator (HDSA), a viral polypeptide lacking putative helicase and RNA polymerase domains. The HDSA is stable, non-HSP90-bound, localizes to the nucleus, and is abundant in G3 HEV-infected hepatocytes of various origins. Markedly, the HDSA in hepatocytes potentiates the fibrogenic TGF-β/SMAD pathway by forming compact complexes with SMAD3 to facilitate its promoter binding and coactivator recruitment, leading to significant fibrosis in HEV-susceptible gerbils. Virus infection–induced liver fibrosis in HEV-susceptible gerbils could be prevented by mutating the residues P989C, A990C, and A991C (PAA-3C) within ORF1, which are required for proteasomal processing. Thus, we have identified a viral protein derived from host proteasomal processing, defined its notable role in liver fibrosis and highlighted the nature of an unanticipated host–HEV interaction that facilitates hepatitis E pathogenesis.}, archive = {J_PNAS}, author = {Zhang, Fei and Xu, Ling-Dong and Wu, Shiying and Wu, Qirou and Wang, Ailian and Liu, Shengduo and Zhang, Qian and Yu, Xinyuan and Wang, Bin and Pan, Yinghao and Huang, Fei and Neculai, Dante and Xia, Bing and Feng, Xin-Hua and Shen, Li and Zhang, Qi and Liang, Tingbo and Huang, Yao-Wei and Xu, Pinglong}, doi = {10.1073/pnas.2419946122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2419946122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Proteasomal processing of the viral replicase ORF1 facilitates HEV-induced liver fibrosis}, volume = {122}, year = {2025}, }
• (2025). Machine-learning heat flux closure for multi-moment fluid modeling of nonlinear landau damping. PNAS, 122(11), e2419073122. (www)

  @article{ , abstract = {Nonlinear plasma physics problems are usually simulated through comprehensive modeling of phase space. The extreme computational cost of such simulations has motivated the development of multi-moment fluid models. However, a major challenge has been finding a suitable fluid closure for these fluid models. Recent developments in physics-informed machine learning have led to a renewed interest in constructing accurate fluid closure terms. In this study, we take an approach that integrates kinetic physics from the first-principles Vlasov simulations into a fluid model (through the heat flux closure term) using the Fourier neural operator—a neural network architecture. Without resolving the phase space dynamics, this new fluid model is capable of capturing the nonlinear evolution of the Landau damping process that exactly matches the Vlasov simulation results. This machine learning–assisted new approach provides a computationally affordable framework that surpasses previous fluid models in accurately modeling the kinetic evolution of complex plasma systems.}, archive = {J_PNAS}, author = {Huang, Ziyu and Dong, Chuanfei and Wang, Liang}, doi = {10.1073/pnas.2419073122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2419073122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Machine-learning heat flux closure for multi-moment fluid modeling of nonlinear landau damping}, volume = {122}, year = {2025}, }
• (2025). Results from the inSight mars mission do not require a water-saturated mid crust. PNAS, 122(11), e2418978122. (www)

  @article{ , archive = {J_PNAS}, author = {Jakosky, Bruce M.}, doi = {10.1073/pnas.2418978122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2418978122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Results from the inSight mars mission do not require a water-saturated mid crust}, volume = {122}, year = {2025}, }
• (2025). Reply to crabtree: Market research panels augmenting microtask platforms. PNAS, 122(11), e2418955122. (www)

  @article{ , archive = {J_PNAS}, author = {Gvirtz, Andrés and Sabherwal, Anandita}, doi = {10.1073/pnas.2418955122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2418955122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to crabtree: Market research panels augmenting microtask platforms}, volume = {122}, year = {2025}, }
• (2025). RGMb drives macrophage infiltration to aggravate kidney disease. PNAS, 122(11), e2418739122. (www)

  @article{ , abstract = {The importance of macrophages in kidney diseases has been well established; however, the mechanisms underlying the infiltration of macrophages into injured kidneys are not well understood. RGMb is a member of the repulsive guidance molecule (RGM) family. RGMb can be expressed on the cell surface but a large portion of RGMb is localized intracellularly. Among various immune cell types, macrophages express the highest levels of RGMb, but the biological functions of RGMb in macrophages remain largely unknown. We find that RGMb promoted macrophage migration in vitro and that in vivo, RGMb enhanced infiltration of macrophages into injured kidneys and aggravated kidney inflammation and injury in mice. Mechanistically, RGMb bound to TAB1 inside the cell and facilitated the interaction between TRAF6 ubiquitin ligase and TAB1, thereby promoting TRAF6-mediated K63-linked polyubiquitination and phosphorylation of TAK1, followed by increased αTAT1 phosphorylation and α-tubulin acetylation. The resulting changes in the cytoskeleton promoted macrophage migration in vitro and in vivo. Deletion of Rgmb in macrophages markedly reduced TAK1 phosphorylation, αTAT1 phosphorylation, and α-tubulin acetylation and attenuated macrophage infiltration, renal inflammation, tubular injury, and interstitial fibrosis during kidney injury. Our results suggest that macrophage RGMb promotes kidney disease by increasing macrophage infiltration via the TRAF6-TAB1-TAK1/αTAT1/α-tubulin cascade.}, archive = {J_PNAS}, author = {Kong, Yonglun and Yue, Ming and Xu, Chunhua and Zhang, Jing and Hong, Huiling and Lu, Jiahuan and Wang, Yang and Zhang, Xiaoyi and Chen, Qiuju and Yang, Chen and Liu, Hua-Feng and Qin, Jinzhong and Zhou, Jingying and Lee, Nam Y. and Lin, Bin and Tian, Xiaoyu and Freeman, Gordon J. and Xia, Yin}, doi = {10.1073/pnas.2418739122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2418739122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RGMb drives macrophage infiltration to aggravate kidney disease}, volume = {122}, year = {2025}, }
• (2025). Genetic or therapeutic disruption of the Reelin/Apoer2 signaling pathway improves inflammatory arthritis outcomes. PNAS, 122(11), e2418642122. (www)

  @article{ , abstract = {Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, pannus formation, and progressive joint destruction. The inflammatory milieu in RA drives endothelial cell activation and upregulation of adhesion molecules, thus facilitating leukocyte infiltration into the synovium. Reelin, a circulating glycoprotein previously implicated in endothelial activation and leukocyte recruitment in diseases such as atherosclerosis and multiple sclerosis, has emerged as a potential upstream regulator of these processes. However, its role in RA pathogenesis remains poorly understood. Here, we demonstrate that Reelin levels are markedly elevated in the plasma of both RA patients and mouse models of arthritis, with higher concentrations correlating with greater disease severity. Genetic deletion of the Reelin receptor Apoer2 conferred significant protection against serum transfer arthritis (STA), underscoring the relevance of this pathway in disease progression. Furthermore, therapeutic inhibition of Reelin using the CR-50 antibody yielded robust anti-inflammatory effects in multiple preclinical arthritis models, including STA, K/BxN, and collagen-induced arthritis. Notably, CR-50 treatment not only reduced leukocyte infiltration and synovial inflammation but also mitigated pannus formation. Importantly, these benefits were achieved without the gastrointestinal side effects commonly associated with nonsteroidal anti-inflammatory drugs like diclofenac. Our findings position Reelin as a proinflammatory endothelial biomarker and therapeutic target in RA. By modulating endothelial activation and leukocyte recruitment, anti-Reelin strategies offer an alternative approach to attenuate synovial inflammation and joint damage. These results provide a compelling rationale for further exploration of Reelin-targeted therapies as alternatives to conventional immunosuppressive treatments in RA and other chronic inflammatory diseases.}, archive = {J_PNAS}, author = {Calvier, Laurent and Wasser, Catherine R. and Solow, E. Blair and Wu, Sharon and Evers, Bret M. and Karp, David S. and Kounnas, Maria Z. and Herz, Joachim}, doi = {10.1073/pnas.2418642122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2418642122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genetic or therapeutic disruption of the Reelin/Apoer2 signaling pathway improves inflammatory arthritis outcomes}, volume = {122}, year = {2025}, }
• (2025). Dual mRNA nanoparticles strategy for enhanced pancreatic cancer treatment and β-elemene combination therapy. PNAS, 122(11), e2418306122. (www)

  @article{ , abstract = {Pancreatic ductal adenocarcinoma (PDAC) is notoriously immune-resistant, limiting the clinical efficacy of single-agent immune modulators and thereby necessitating the exploration of multimodal immunotherapy combinations. Traditional approaches combining conventional immune checkpoint inhibitors with neoantigen vaccines have shown some promise in treating PDAC but are often compromised by intratumoral T lymphocyte exhaustion and systemic toxicity. Hence, novel approaches are needed to address these challenges. Herein, we demonstrate that mRNA polymeric nanoparticles encoding anti-PD-1 antibodies in situ at the tumor site enhance the therapeutic efficacy of neoantigen-based mRNA vaccine for PDAC. This mRNA-based, in situ anti-PD-1 antibody production strategy also protects tumor-infiltrating T cells from PD-1 inhibition, potentially reducing the toxicities induced by systemic checkpoint inhibition. Our study may provide an innovative dual mRNA nanoparticle strategy for effective tumor neoantigen immunotherapy, as well as an mRNA cancer combination therapy strategy with other clinically approved drugs (e.g., β-elemene).}, archive = {J_PNAS}, author = {Zhu, Qianru and Yu, Chuao and Chen, Yiquan and Luo, Wei and Li, Meng and Zou, Jianhua and Xiao, Fan and An, Soohwan and Saiding, Qimanguli and Tao, Wei and Kong, Na and Xie, Tian}, doi = {10.1073/pnas.2418306122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2418306122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dual mRNA nanoparticles strategy for enhanced pancreatic cancer treatment and β-elemene combination therapy}, volume = {122}, year = {2025}, }
• (2025). Astrocytes in the mouse brain respond bilaterally to unilateral retinal neurodegeneration. PNAS, 122(11), e2418249122. (www)

  @article{ , abstract = {Glaucomatous optic neuropathy, or glaucoma, is the world’s primary cause of irreversible blindness. Glaucoma is comorbid with other neurodegenerative diseases, but how it might impact the environment of the full central nervous system to increase neurodegenerative vulnerability is unknown. Two neurodegenerative events occur early in the optic nerve, the structural link between the retina and brain: loss of anterograde transport in retinal ganglion cell (RGC) axons and early alterations in astrocyte structure and function. Here, we used whole-mount tissue clearing of full mouse brains to image RGC anterograde transport function and astrocyte responses across retinorecipient regions early in a unilateral microbead occlusion model of glaucoma. Using light sheet imaging, we found that RGC projections terminating specifically in the accessory optic tract are the first to lose transport function. Although degeneration was induced in one retina, astrocytes in both brain hemispheres responded to transport loss in a retinotopic pattern that mirrored the degenerating RGCs. A subpopulation of these astrocytes in contact with large descending blood vessels were immunopositive for LCN2, a marker associated with astrocyte reactivity. Together, these data suggest that even early stages of unilateral glaucoma have broad impacts on the health of astrocytes across both hemispheres of the brain, implying a glial mechanism behind neurodegenerative comorbidity in glaucoma.}, archive = {J_PNAS}, author = {Cooper, Melissa L. and Gildea, Holly K. and Selles, Maria Clara and Katafygiotou, Eleni and Liddelow, Shane A. and Chao, Moses V.}, doi = {10.1073/pnas.2418249122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2418249122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Astrocytes in the mouse brain respond bilaterally to unilateral retinal neurodegeneration}, volume = {122}, year = {2025}, }
• (2025). Yes, you can do global, cross-cultural behavioral science research using existing survey firms. PNAS, 122(11), e2418102122. (www)

  @article{ , archive = {J_PNAS}, author = {Crabtree, Charles}, doi = {10.1073/pnas.2418102122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2418102122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Yes, you can do global, cross-cultural behavioral science research using existing survey firms}, volume = {122}, year = {2025}, }
• (2025). Positive effects of species mixing on biodiversity of understory plant communities and soil health in forest plantations. PNAS, 122(11), e2418090122. (www)

  @article{ , abstract = {Mixed-species plantations are increasingly recognized for their potential to maintain forest biodiversity and soil health; however, a comprehensive assessment of their global effectiveness is lacking. To fill this knowledge gap, we conducted a meta-analysis of 7,045 paired observations between mixed-species and monoculture plantations, derived from 311 studies across diverse forest ecosystems worldwide. Our results show that mixed-species plantations significantly increased understory plant biomass, cover, and species richness by 32.6%, 55.4%, and 32.2%, respectively, compared to monocultures. Furthermore, the Shannon and Pielou diversity indices increased by 28.2% and 8.6%, respectively, and the Simpson index increased by 9.6%. When understory shrub and herbaceous species were considered separately, species mixing had significantly positive effects on shrub diversity but had no effect on herbaceous diversity. Moreover, mixed-species plantations markedly improved soil physical and chemical properties compared to monocultures. These improvements include increases in soil nutrient content (9.6 to 17.8%) and nutrient availability (14.7 to 33.5%), soil microbial biomass (17.2 to 28.8%), and soil carbon sequestration (7.2 to 19.9%). These enhancements were particularly pronounced in plantations that included legumes. Our findings reveal that the benefits of species mixing are influenced by climatic conditions, geographic location, and stand age, with the most substantial effects observed in temperate regions and mature stands. This study underscores the critical role of mixed-species plantations in promoting sustainable forest management and mitigating the ecological limitations of monocultures.}, archive = {J_PNAS}, author = {Guo, Jiahuan and Kneeshaw, Daniel and Peng, Changhui and Wu, Yaoxing and Feng, Lei and Qu, Xinjing and Wang, Weifeng and Pan, Chang and Feng, Huili}, doi = {10.1073/pnas.2418090122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2418090122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Positive effects of species mixing on biodiversity of understory plant communities and soil health in forest plantations}, volume = {122}, year = {2025}, }
• (2025). Characterization of diverse cas9 orthologs for genome and epigenome editing. PNAS, 122(11), e2417674122. (www)

  @article{ , abstract = {CRISPR-Cas9 systems have revolutionized biotechnology, creating diverse new opportunities for biomedical research and therapeutic genome and epigenome editing. Despite the abundance of bacterial CRISPR-Cas9 systems, relatively few are effective in human cells, limiting the overall potential of CRISPR technology. To expand the CRISPR-Cas toolbox, we characterized a set of type II CRISPR-Cas9 systems from select bacterial genera and species encoding diverse Cas9s. Four systems demonstrated robust and specific gene repression in human cells when used as nuclease-null dCas9s fused with a KRAB domain and were also highly active nucleases in human cells. These systems have distinct protospacer adjacent motifs (PAMs), including AT-rich motifs and sgRNA features orthogonal to the commonly used Staphylococcus aureus and Streptococcus pyogenes Cas9s. Additionally, we assessed gene activation when fused with the p300 catalytic domain. Notably, S. uberis Cas9 performed competitively against benchmarks with promising repression, activation, nuclease, and base editing activity. This study expands the CRISPR-Cas9 repertoire, enabling effective genome and epigenome editing for diverse applications.}, archive = {J_PNAS}, author = {Butterfield, Gabriel L. and Rohm, Dahlia and Roberts, Avery and Nethery, Matthew A. and Rizzo, Anthony J. and Morone, Daniel J. and Garnier, Lisa and Iglesias, Nahid and Barrangou, Rodolphe and Gersbach, Charles A.}, doi = {10.1073/pnas.2417674122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2417674122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Characterization of diverse cas9 orthologs for genome and epigenome editing}, volume = {122}, year = {2025}, }
• (2025). DR5 is a restriction factor for human herpesviruses. PNAS, 122(11), e2417372122. (www)

  @article{ , abstract = {Restriction factors are dominant proteins that target different essential steps of the viral life cycle; thus, these proteins provide an early line of defense against viruses. Here, we found that the internalization of DR5, an important receptor of the extrinsic apoptotic pathway, initiates apoptosis to inhibit Kaposi sarcoma–associated herpesvirus (KSHV) lytic replication. An evolutionary analysis of the DR5 sequence demonstrated that three amino acids underwent positive selection in primates. Notably, one of these positive selection sites, A62, is essential for the antiviral function of DR5 and is important for the binding of DR5 to its ligand, TNF-related apoptosis-inducing ligand. Moreover, DR5 exhibits broad antiviral activity against and inhibits various herpesviruses, including Epstein–Barr virus, herpes simplex virus type 1, and herpes simplex virus type 2. As a countermeasure, the KSHV K5 protein interacts with DR5 and promotes DR5 degradation through the lysosomal and proteasomal degradation pathways; lysine 245 of DR5 is essential for K5-induced DR5 degradation. These findings demonstrate that DR5 is a restriction factor for human herpesviruses.}, archive = {J_PNAS}, author = {Han, Chunyan and Gui, Chenwu and Su, Bingbing and Liu, Naizhang and Yan, Haojie and Lan, Ke}, doi = {10.1073/pnas.2417372122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2417372122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {DR5 is a restriction factor for human herpesviruses}, volume = {122}, year = {2025}, }
• (2025). The arabidopsis demethylase REF6 physically interacts with phyB to promote hypocotyl elongation under red light. PNAS, 122(11), e2417253122. (www)

  @article{ , abstract = {The plant photoreceptor phytochrome B (phyB) mediates the responses of plants to red (R) light. Trimethylation of histone H3 at Lys27 (H3K27me3) plays a crucial role in governing gene expression and controlling the response of plants to environmental changes. However, how dynamic H3K27me3 mediates plant response to R light is poorly understood. Here, we report that RELATIVE OF EARLY FLOWERING 6 (REF6), an H3K27me3 demethylase, promotes hypocotyl elongation under R light in Arabidopsis . Upon exposure to R light, REF6 preferentially interacts with the active Pfr form of phyB. Consequently, phyB enhances REF6 accumulation and its binding ability, which are necessary for inducing cell-elongation-related genes from open chromatin, ensuring normal plant growth under prolonged light exposure. Moreover, REF6 acts together with the phyB-PIF4 module to mediate light regulation of hypocotyl growth. These findings provide insights into the understanding of how phytochromes, epigenetic factors, and transcription factors coordinately control plant growth in response to changing light environment.}, archive = {J_PNAS}, author = {Yan, Yan and Zhu, Jiaping and Qiu, Qi and Li, Jigang and Cao, Xiaofeng and Deng, Xian}, doi = {10.1073/pnas.2417253122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2417253122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The arabidopsis demethylase REF6 physically interacts with phyB to promote hypocotyl elongation under red light}, volume = {122}, year = {2025}, }
• (2025). Identifying the interactions conferring functional mechanical rigidity on RNase-resistant RNA from zika virus. PNAS, 122(11), e2417234122. (www)

  @article{ , abstract = {Some viruses counter host-cell efforts to digest invading viral RNA by using special structures resistant to host RNases, known as exoribonuclease-resistant RNAs (xrRNAs). xrRNAs typically form an unusual fold with the 5′-end threaded through a ring consisting of a multihelix junction closed by a pseudoknot. By using single-molecule force spectroscopy (SMFS), we previously showed that a Zika virus xrRNA is extremely rigid mechanically, withstanding very high forces, and that this mechanical resistance—not simply the knot-like fold topology—is essential for RNase resistance. Here, we have determined which interactions are most important for generating mechanical rigidity in the Zika virus xrRNA, by systematically mutating tertiary contacts. We found that removing any of the tertiary contacts involving the threaded 5′ end was sufficient to abrogate mechanical resistance. In contrast, breaking a single pseudoknot base pair was not sufficient to do so: Two broken pairs were needed. This hierarchy of interaction importance for mechanical rigidity was supported by simulations mapping how mechanical tension was distributed within the xrRNA. For all mutants, RNase resistance varied in lock-step with mechanical resistance, confirming the primary role of mechanical rigidity in xrRNA function. This work reveals which interactions are most important for Zika xrRNA function, with implications for targeting the xrRNA therapeutically.}, archive = {J_PNAS}, author = {Zhaguparov, Daniiar and Zhao, Meng and Sekar, Rohith Vedhthaanth and Woodside, Michael T.}, doi = {10.1073/pnas.2417234122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2417234122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identifying the interactions conferring functional mechanical rigidity on RNase-resistant RNA from zika virus}, volume = {122}, year = {2025}, }
• (2025). Negative trend in total solar irradiance over the satellite era. PNAS, 122(11), e2417155122. (www)

  @article{ , abstract = {Linear trends in total solar irradiance (TSI) between different reconstructions of the satellite era, defined as 1978 to 2023, disagree by up to 0.17 W/m 2 per decade. Furthermore, high-quality satellite radiometer observations of the most recent solar cycle, 24, systematically differ from estimates that rely on TSI proxies for reasons that have been unclear. Using a Bayesian Kalman filtering approach to estimate TSI from both satellite-based observations and proxies gives two complementary explanations: recent satellite-based observations of TSI contain unaccounted-for positive linear drifts, and regression-based reconstructions are affected by commonly used solar magnetic proxies becoming less sensitive to TSI variations at low values. After accounting for satellite instrument drifts and reduced sensitivity, direct and proxy observations come into agreement and together indicate a linear trend in overall TSI of −0.15 W/m 2 per decade with a 95% CI of −0.17 to −0.13 W/m 2 per decade between 1980 and 2023.}, archive = {J_PNAS}, author = {Amdur, Ted and Huybers, Peter}, doi = {10.1073/pnas.2417155122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2417155122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Negative trend in total solar irradiance over the satellite era}, volume = {122}, year = {2025}, }
• (2025). Learning reshapes the hippocampal representation hierarchy. PNAS, 122(11), e2417025122. (www)

  @article{ , abstract = {A key feature of biological and artificial neural networks is the progressive refinement of their neural representations with experience. In neuroscience, this fact has inspired several recent studies in sensory and motor systems. However, less is known about how higher associational cortical areas, such as the hippocampus, modify representations throughout the learning of complex tasks. Here, we focus on associative learning, a process that requires forming a connection between the representations of different variables for appropriate behavioral response. We trained rats in a space-context associative task and monitored hippocampal neural activity throughout the entire learning period, over several days. This allowed us to assess changes in the representations of context, movement direction, and position, as well as their relationship to behavior. We identified a hierarchical representational structure in the encoding of these three task variables that was preserved throughout learning. Nevertheless, we also observed changes at the lower levels of the hierarchy where context was encoded. These changes were local in neural activity space and restricted to physical positions where context identification was necessary for correct decision-making, supporting better context decoding and contextual code compression. Our results demonstrate that the hippocampal code not only accommodates hierarchical relationships between different variables but also enables efficient learning through minimal changes in neural activity space. Beyond the hippocampus, our work reveals a representation learning mechanism that might be implemented in other biological and artificial networks performing similar tasks.}, archive = {J_PNAS}, author = {Chiossi, Heloisa S. C. and Nardin, Michele and Tkačik, Gašper and Csicsvari, Jozsef}, doi = {10.1073/pnas.2417025122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2417025122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Learning reshapes the hippocampal representation hierarchy}, volume = {122}, year = {2025}, }
• (2025). Pattern separation and pattern completion in early childhood. PNAS, 122(11), e2416985122. (www)

  @article{ , abstract = {Pattern separation, or distinguishing similar experiences from one another, and pattern completion, in which components of an experience prompt retrieval or forgetting of an event pattern as a unit, are essential components of episodic memory. However, these two components are sometimes described as opposite ends of a continuum and sometimes described as independent processes. Here, we examined the relations between the two processes for the same events in children between 4 and 7 y. Mnemonic discrimination (the behavioral signature of pattern separation) improved with age; holistic recollection (the behavioral signature of pattern completion) did not change in this age range. Crucially, the two behaviors were unrelated, controlling for the effect of age, and even when examining their relations at the fine-grained level of memory for individual events.}, archive = {J_PNAS}, author = {Cohen, Samantha S. and Ngo, Chi T. and Olson, Ingrid R. and Newcombe, Nora S.}, doi = {10.1073/pnas.2416985122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2416985122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pattern separation and pattern completion in early childhood}, volume = {122}, year = {2025}, }
• (2025). Spinal TRPC3 promotes neuropathic pain and coordinates phospholipase c–induced mechanical hypersensitivity. PNAS, 122(11), e2416828122. (www)

  @article{ , abstract = {Neuropathic pain is a debilitating chronic condition mainly caused by peripheral nerve injury. However, the cellular and molecular mechanisms underlying this condition remain unclear. Transient receptor potential canonical 3 (TRPC3), a TRP channel that is activated by downstream of the Gq-phospholipase C (PLC) axis, is expressed in the somatosensory system. Therefore, the present study investigated its pathophysiological role in neuropathic pain following peripheral nerve injury. Here, partial sciatic nerve ligation (pSNL) elicited mechanical and thermal hypersensitivity in wild-type mice, which was suppressed in TRPC3-KO mice. In situ hybridization revealed that TRPC3 is predominantly expressed in neurons in the spinal dorsal horn. Furthermore, spinal dorsal horn neuron-specific downregulation using miRNA attenuated pSNL-induced mechanical hypersensitivity. Spinal TRPC3 activation elicited acute mechanical hypersensitivity. Moreover, its genetic ablation reduced the mechanical hypersensitivity caused by spinal NK 1 R or PLC activation. These findings demonstrate that TRPC3 in spinal dorsal horn neurons facilitates the development of neuropathic pain. Therefore, TRPC3 may be a promising therapeutic target for neuropathic pain caused by peripheral nerve injury.}, archive = {J_PNAS}, author = {Tobori, Shota and Tamada, Kosei and Uemura, Nagi and Sawada, Kyoko and Kakae, Masashi and Nagayasu, Kazuki and Nakagawa, Takayuki and Mori, Yasuo and Kaneko, Shuji and Shirakawa, Hisashi}, doi = {10.1073/pnas.2416828122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2416828122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spinal TRPC3 promotes neuropathic pain and coordinates phospholipase c–induced mechanical hypersensitivity}, volume = {122}, year = {2025}, }
• (2025). The role of excitations in supercooled liquids: Density, geometry, and relaxation dynamics. PNAS, 122(11), e2416800122. (www)

  @article{ , abstract = {Low-energy excitations play a key role in all condensed-matter systems, yet there is limited understanding of their nature in glasses, where they correspond to local rearrangements of groups of particles. Here, we introduce an algorithm to systematically uncover these excitations up to the activation energy scale relevant to structural relaxation. We use it in a model system to measure the density of states on a scale never achieved before, confirming that this quantity shifts to higher energy under cooling, precisely as the activation energy does. Second, we show that the excitations’ energetic and spatial features allow one to predict with great accuracy the dynamic propensity, i.e., the location of future relaxation dynamics. Finally, we find that excitations have a primary field whose properties, including the displacement of the most mobile particle, scale as a power-law of their activation energy and are independent of temperature. Additionally, they exhibit an outer deformation field that depends on the material’s stability and, therefore, on temperature. We build a scaling description of these findings. Overall, our analysis supports that excitations play a crucial role in regulating relaxation dynamics near the glass transition, effectively suppressing the transition to dynamical arrest predicted by mean-field theories while also being strongly influenced by it.}, archive = {J_PNAS}, author = {Ji, Wencheng and Pica Ciamarra, Massimo and Wyart, Matthieu}, doi = {10.1073/pnas.2416800122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2416800122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The role of excitations in supercooled liquids: Density, geometry, and relaxation dynamics}, volume = {122}, year = {2025}, }
• (2025). Cell extrusion drives neural crest cell delamination. PNAS, 122(11), e2416566122. (www)

  @article{ , abstract = {Neural crest cells (NCC) comprise a heterogeneous population of cells with variable potency that contribute to nearly every tissue and organ throughout the body. Considered unique to vertebrates, NCC are transiently generated within the dorsolateral region of the neural plate or neural tube during neurulation. Their delamination and migration are crucial for embryo development as NCC differentiation is influenced by their final resting locations. Previous work in avian and aquatic species revealed that NCC delaminate via an epithelial–mesenchymal transition (EMT), which transforms these progenitor cells from static polarized epithelial cells into migratory mesenchymal cells with fluid front and back polarity. However, the cellular and molecular mechanisms facilitating NCC delamination in mammals are poorly understood. Through time-lapse imaging of NCC delamination in mouse embryos, we identified a subset of cells that exit the neuroepithelium as isolated round cells, which then halt for a short period prior to acquiring the mesenchymal migratory morphology classically associated with delaminating NCC. High-magnification imaging and protein localization analyses of the cytoskeleton, together with measurements of pressure and tension of delaminating NCC and neighboring neuroepithelial cells, revealed that round NCC are extruded from the neuroepithelium prior to completion of EMT. Furthermore, cranial NCC are extruded through activation of the mechanosensitive ion channel, PIEZO1. Our results support a model in which cell density, pressure, and tension in the neuroepithelium result in activation of the live cell extrusion pathway and delamination of a subpopulation of NCC in parallel with EMT, which has implications for cell delamination in development and disease.}, archive = {J_PNAS}, author = {Moore Zajic, Emma L. and Zhao, Ruonan and McKinney, Mary C. and Yi, Kexi and Wood, Christopher and Trainor, Paul A.}, doi = {10.1073/pnas.2416566122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2416566122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cell extrusion drives neural crest cell delamination}, volume = {122}, year = {2025}, }
• (2025). Activation of proresolving macrophages in dorsal root ganglia attenuates persistent arthritis pain. PNAS, 122(11), e2416343122. (www)

  @article{ , abstract = {Pain independent of disease activity is frequently reported by rheumatoid arthritis patients and remains undertreated. Preclinical evidence suggests that imbalance of neuroimmune proresolving interactions within dorsal root ganglia (DRG) rather than at the site of inflammation plays mechanistic roles in persistent arthritis pain. Here, we inhibited production of proresolving lipid mediators by silencing 12/15-lipoxygenase expression in CX3CR1 + monocyte/macrophages conditional knockout (cKO) mice. In an arthritis model, hind paw mechanical hypersensitivity is exacerbated in male and female cKO mice in association with DRG infiltration of neutrophils, which migrate in response to leukotriene B 4 released by macrophages through 5-lipoxygenase conversion of arachidonic acid provided by neuron-derived vesicles. Neutrophils apoptosis promotes primary macrophage efferocytosis which is defective in cKO macrophages. In wild-type (WT) and cKO mice, intrathecal injection of MerTK activating antibody, attenuates persistent hypersensitivity and polarizes DRG macrophages toward a proresolving phenotype with production of antinociceptive lipoxin A 4 . Thus, we delineate a neuron–macrophage–neutrophil bidirectional circuit that can be exploited to reduce persistent arthritis pain.}, archive = {J_PNAS}, author = {Oggero, Silvia and Voisin, Mathieu-Benoit and Picco, Francesca and Huerta, Miguel Á. and Cecconello, Chiara and Burgoyne, Thomas and Perretti, Mauro and Malcangio, Marzia}, doi = {10.1073/pnas.2416343122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2416343122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Activation of proresolving macrophages in dorsal root ganglia attenuates persistent arthritis pain}, volume = {122}, year = {2025}, }
• (2025). Dual-filament regulation of relaxation in mammalian fast skeletal muscle. PNAS, 122(11), e2416324122. (www)

  @article{ , abstract = {Muscle contraction is driven by myosin motors from the thick filaments pulling on the actin-containing thin filaments of the sarcomere, and it is regulated by structural changes in both filaments. Thin filaments are activated by an increase in intracellular calcium concentration [Ca 2+ ] i and by myosin binding to actin. Thick filaments are activated by direct sensing of the filament load. However, these mechanisms cannot explain muscle relaxation when [Ca 2+ ] i decreases at high load and myosin motors are attached to actin. There is, therefore, a fundamental gap in our understanding of muscle relaxation, despite its importance for muscle function in vivo, for example, for rapid eye movements or, on slower timescales, for the efficient control of posture. Here, we used time-resolved small-angle X-ray diffraction (SAXD) to determine how muscle thin and thick filaments switch OFF in extensor digitorum longus (EDL) muscles of the mouse in response to decreases in either [Ca 2+ ] i or muscle load and to describe the distribution of muscle sarcomere lengths (SLs) during relaxation. We show that reducing load at high [Ca 2+ ] i is more effective in switching OFF both the thick and thin filaments than reducing [Ca 2+ ] i at high load in normal relaxation. In the latter case, the thick filaments initially remain fully ON, although the number of myosin motors bound to actin decreases and the force per attached motor increases. That initial slow phase of relaxation is abruptly terminated by yielding of one population of sarcomeres, triggering a redistribution of SLs that leads to the rapid completion of mechanical relaxation.}, archive = {J_PNAS}, author = {Hill, Cameron and Kalakoutis, Michaeljohn and Arcidiacono, Alice and Paradine Cullup, Flair and Wang, Yanhong and Fukutani, Atsuki and Narayanan, Theyencheri and Brunello, Elisabetta and Fusi, Luca and Irving, Malcolm}, doi = {10.1073/pnas.2416324122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2416324122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dual-filament regulation of relaxation in mammalian fast skeletal muscle}, volume = {122}, year = {2025}, }
• (2025). A mechanistic basis for genetic assimilation in natural fly populations. PNAS, 122(11), e2415982122. (www)

  @article{ , abstract = {Genetic assimilation is a process by which a trait originally driven by the environment becomes independent of the initial cue and is expressed constitutively in a population. More than seven decades have passed since Waddington’s pioneering demonstration of the acquisition of morphological traits through genetic assimilation, but the underlying mechanism remains unknown. Here, we address this gap by performing combined genomic analyses of Waddington’s genetic assimilation experiments using the ectopic veins (EV) phenocopy in Drosophila as a model. Our study reveals the assimilation of EV in both outbred and inbred fly natural populations, despite their limited genetic diversity. We identified key changes in the expression of developmental genes and pinpointed selected alleles involved in EV assimilation. The assimilation of EV is mainly driven by the selection of regulatory alleles already present in the ancestral populations, including the downregulation of the receptor tyrosine kinase gene Cad96Ca by the insertion of a transposable element in its 3′ untranslated region. The genetic variation at this locus in the inbred population is maintained by a large chromosomal inversion. In outbred populations, the evolution of EV results from a polygenic response shaped by the selective environment. Our results support a model in which selection for multiple preexisting alleles in the ancestral population, rather than stress-induced genetic or epigenetic variation, drives the evolution of EV in natural fly populations.}, archive = {J_PNAS}, author = {Sabarís, Gonzalo and Schuettengruber, Bernd and Papadopoulos, Giorgio L. and Coronado-Zamora, Marta and Fitz-James, Maximilian H. and González, Josefa and Cavalli, Giacomo}, doi = {10.1073/pnas.2415982122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2415982122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A mechanistic basis for genetic assimilation in natural fly populations}, volume = {122}, year = {2025}, }
• (2025). P53 activates circASCC3 to repress R-loops and enhance resistance to chemotherapy. PNAS, 122(11), e2415869122. (www)

  @article{ , abstract = {The tumor suppressor p53 can trigger tumor resistance to chemotherapy by facilitating DNA damage repair and maintaining genomic integrity. Here, we report that a p53-induced circular RNA circASCC3 promotes chemotherapeutic resistance by resolving R-loops. Our results reveal that p53 directly activates the transcription of ASCC3 , the host gene of circASCC3. In addition, the RNA-binding protein SFPQ is identified to inhibit the formation of circASCC3 by associating with its flanking regions. Importantly, p53 facilitates the formation of circASCC3 by repressing the expression of SFPQ. CircASCC3 has a marginal effect on the survival and growth of cancer cells under normal growing conditions but surprisingly boosts their survival and growth in response to DNA damage stress. Mechanistic analysis reveals that circASCC3 binds to the DEAD-box RNA helicase DDX5 to inhibit its proteasomal degradation. This results in the prevention of R-loop accumulation due to DNA damage, thereby conferring tumor resistance to chemotherapy. Together, our study uncovers that p53 activates circASCC3 to promote R-loop resolution, which maintains genomic stability and potentially contributes to chemoresistance.}, archive = {J_PNAS}, author = {Cao, Mingming and Gan, Yu and Huang, Yingdan and Tong, Jing and Xiong, Chen and Chen, Yajie and Chen, Bing and Huang, Ruixuan and Xie, Bangxiang and Deng, Jun and Huang, Shenglin and He, Xianghuo and Hao, Qian and Zhou, Xiang}, doi = {10.1073/pnas.2415869122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2415869122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {P53 activates circASCC3 to repress R-loops and enhance resistance to chemotherapy}, volume = {122}, year = {2025}, }
• (2025). The SUbventral-gland regulator (SUGR-1) of nematode virulence. PNAS, 122(11), e2415861122. (www)

  @article{ , abstract = {Pathogens must precisely tailor their gene expression to cause infection. However, a signaling cascade from host signal to effector production has remained elusive for metazoan pathogens. Here, we show that plants contain molecular signals, termed effectostimulins, that activate the first identified regulator of plant-parasitic nematode effectors. SUGR-1 directly binds effector promoters, and is central to a transcriptional network that activates 58 effector genes. Importantly, we demonstrate that downregulation of sugr-1 inhibits parasitism, underlining SUGR-1 signaling as a valuable target for crop protection and food security. This, in the wider context of nematodes as parasites of humans and other animals, has scope for potentially broader impact: Disrupting effector production could, in principle, be applied to any pathogen that secrets effectors.}, archive = {J_PNAS}, author = {Pellegrin, Clement and Damm, Anika and Sperling, Alexis L. and Molloy, Beth and Shin, Dio S. and Long, Jonathan and Brett, Paul and Iguh, Tochukwu Chisom and Kranse, Olaf P. and Bravo, Andrea Díaz-Tendero and Lynch, Sarah Jane and Senatori, Beatrice and Vieira, Paulo and Mejias, Joffrey and Kumar, Anil and Masonbrink, Rick E. and Maier, Tom R. and Baum, Thomas J. and Eves-van den Akker, Sebastian}, doi = {10.1073/pnas.2415861122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2415861122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The SUbventral-gland regulator (SUGR-1) of nematode virulence}, volume = {122}, year = {2025}, }
• (2025). GSDMD-mediated mitochondrial dysfunction in marginal cells: A potential driver of inflammation and stria vascularis damage in CIHL. PNAS, 122(11), e2415805122. (www)

  @article{ , abstract = {Inflammation is among the known causes of cisplatin-induced hearing loss (CIHL), but its exact pathophysiological mechanisms remain unclear. Herein, we demonstrated that pyroptosis—a recently identified inflammatory type of regulated cell death dependent on gasdermin D (GSDMD)—was activated in the cochleae of cisplatin-treated mice, causing CIHL. Meanwhile, treatment with the GSDMD inhibitor necrosulfonamide alleviated CIHL in these mice. To further examine the role of GSDMD-mediated pyroptosis in CIHL, we conducted experiments in Gsdmd- deficient mice . Gsdmd −/− mice demonstrated significantly lower cisplatin-induced cochlear damage than control mice and appeared to be invulnerable to CIHL. Furthermore, GSDMD-mediated pyroptosis in the stria vascularis (SV), but not in the hair cells (HCs), played a dominant role in CIHL. In marginal cells (MCs) of SV, cisplatin induced caspase-dependent GSDMD cleavage, and the pore-forming N-terminal of GSDMD rapidly localized to the mitochondria, leading to abnormal mitochondrial aggregation and oxidative stress. The consequent mitochondrial dysfunction in MCs might result in the severe progression of inflammation, SV damage, and HC loss. Notably, the pharmacological inhibition of pyroptosis using the FDA-approved drug disulfiram effectively alleviated the symptoms of CIHL. Collectively, these findings offer a broad avenue for inhibiting pyroptosis-induced cisplatin ototoxicity and provide valuable theoretical insights for the clinical management of CIHL.}, archive = {J_PNAS}, author = {Xiao, Yu and Zhang, Xiaohan and Guo, Siwei and Liu, Ziyi and Zhao, Xiaoxu and Dong, Fengyue and Bi, Xiuli and Hong, Guodong and Chang, Miao and Qiao, Ruifeng and Cao, Shengda and Liu, Ying and Xia, Ming and Yuan, Wei and Zhang, Jing and Li, Wen and Zhu, Liya and Chai, Renjie and Gao, Jiangang and Fu, Xiaolong}, doi = {10.1073/pnas.2415805122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2415805122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {GSDMD-mediated mitochondrial dysfunction in marginal cells: A potential driver of inflammation and stria vascularis damage in CIHL}, volume = {122}, year = {2025}, }
• (2025). Brain-wide dynamic coactivation states code for hand movements in the resting state. PNAS, 122(11), e2415508122. (www)

  @article{ , abstract = {Resting brain activity, in the absence of explicit tasks, appears as distributed spatiotemporal patterns that reflect structural connectivity and correlate with behavioral traits. However, its role in shaping behavior remains unclear. Recent evidence shows that resting-state spatial patterns not only align with task-evoked topographies but also encode distinct visual (e.g., lines, contours, faces, places) and motor (e.g., hand postures) features, suggesting mechanisms for long-term storage and predictive coding. While prior research focused on static, time-averaged task activations, we examine whether dynamic, time-varying motor states seen during active hand movements are also present at rest. Three distinct motor activation states, engaging the motor cortex alongside sensory and association areas, were identified. These states appeared both at rest and during task execution but underwent temporal reorganization from rest to task. Thus, resting-state dynamics serve as strong spatiotemporal priors for task-based activation. Critically, resting-state patterns more closely resembled those associated with frequent ecological hand movements than with an unfamiliar movement, indicating a structured repertoire of movement patterns that is replayed at rest and reorganized during action. This suggests that spontaneous neural activity provides priors for future movements and contributes to long-term memory storage, reinforcing the functional interplay between resting and task-driven brain activity.}, archive = {J_PNAS}, author = {Zhang, Lu and Pini, Lorenzo and Shulman, Gordon L. and Corbetta, Maurizio}, doi = {10.1073/pnas.2415508122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2415508122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Brain-wide dynamic coactivation states code for hand movements in the resting state}, volume = {122}, year = {2025}, }
• (2025). Comparing color qualia structures through a similarity task in young children versus adults. PNAS, 122(11), e2415346122. (www)

  @article{ , abstract = {Examination of the subjective qualitative aspects of an experience, or “qualia” in short, is a fundamental and core aspect of consciousness research. How can we characterize the particular quality of redness, i.e. a red quale? Based on a recent proposal of the structural characterization of qualia, which did not rely on verbal descriptions, we developed a task that obtained pairwise similarity judgments at four graded levels, with easy and intuitive visual interfaces designed to engage young children. We examined color qualia structures in children (3 to 12-y-old in Japan and 6 to 8-y-old in China) and compared these with those of Japanese adults. Approximately half of the assessed 3-y-old children completed the experiment via our touch panel device version of the task and had reliable responses. Despite known developmental and/or cultural effects of color term usage, we found that color qualia structures were quite similar across the age groups and cultures. Our finding supports the view that color qualia structures emerge early. We also observed age-related differences in the evaluations of some color pairs, which implied subtle changes in the structures behind color experience.}, archive = {J_PNAS}, author = {Moriguchi, Yusuke and Watanabe, Ryoichi and Sakata, Chifumi and Zeleznikow-Johnston, Ariel and Wang, Jue and Saji, Noburo and Tsuchiya, Naotsugu}, doi = {10.1073/pnas.2415346122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2415346122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Comparing color qualia structures through a similarity task in young children versus adults}, volume = {122}, year = {2025}, }
• (2025). Cryo-ET reveals the in situ architecture of the polar tube invasion apparatus from microsporidian parasites. PNAS, 122(11), e2415233122. (www)

  @article{ , abstract = {Microsporidia are divergent fungal pathogens that employ a unique harpoon-like apparatus called the polar tube (PT) to invade host cells. The long PT is fired out of the microsporidian spore over the course of just a few hundred milliseconds. Once fired, the PT is thought to pierce the plasma membrane of a target cell and act as a conduit for the transfer of the parasite into the host cell, which initiates infection. The PT architecture and its association with neighboring organelles within the parasite cell remain poorly understood. Here, we use cryoelectron tomography to investigate the structural cell biology of the PT in dormant spores from the human-infecting microsporidian species, Encephalitozoon intestinalis . Segmentation and subtomogram averaging of the PT reveal at least four layers: two protein-based layers surrounded by a membrane layer and filled with a dense core. Regularly spaced protein filaments form the structural skeleton of the PT. Combining cryoelectron tomography with cellular modeling, we propose a model for the three-dimensional organization of the polaroplast, an organelle that surrounds the PT and is continuous with the outermost, membranous layer of the PT. Our results reveal the ultrastructure of the microsporidian invasion apparatus in situ, laying the foundation for understanding infection mechanisms.}, archive = {J_PNAS}, author = {Usmani, Mahrukh and Coudray, Nicolas and Riggi, Margot and Raghu, Rishwanth and Ramchandani, Harshita and Bobe, Daija and Kopylov, Mykhailo and Zhong, Ellen D. and Iwasa, Janet H. and Ekiert, Damian C. and Bhabha, Gira}, doi = {10.1073/pnas.2415233122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2415233122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryo-ET reveals the in situ architecture of the polar tube invasion apparatus from microsporidian parasites}, volume = {122}, year = {2025}, }
• (2025). The impact of political assassinations on turnout: Evidence from colombia. PNAS, 122(11), e2414767122. (www)

  @article{ , abstract = {Although a growing literature has investigated the effects of various types of civil war violence on political behavior, no study has examined the impact of assassinations targeting politicians. This is a critical omission, as violence against local politicians is prevalent across civil war contexts and may be the most consequential form of violence for political participation by affecting both candidate supply and voter demand. Using an original dataset of nearly 2,000 killings of Colombian local politicians between 1980 and 2023, we estimate the impact of this violence on voter turnout. Taking municipalities where assassination attempts failed as a comparison group, we find that political assassinations significantly decrease voter turnout in both the short and medium terms, with effects persisting in various elections even after the signing of a peace agreement. These findings contrast with many studies suggesting that other forms of civil war violence enhance political participation during the postconflict period or after a truce or peace agreement. Our results suggest that different forms of violence can have distinct effects on political behavior, underscoring the need to theorize how the targeting, nature, and context of violence condition its effects. This echoes calls for more nuanced studies on the behavioral impacts of violence. Our findings also have implications for understanding democracy amid rising violence against political leaders in countries affected by organized crime, such as Mexico and Brazil; polarized contexts, such as the United States; and weakly institutionalized democracies, such as South Africa, Indonesia, and the Philippines.}, archive = {J_PNAS}, author = {Arjona, Ana and Chacón, Mario and García-Montoya, Laura}, doi = {10.1073/pnas.2414767122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2414767122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The impact of political assassinations on turnout: Evidence from colombia}, volume = {122}, year = {2025}, }
• (2025). Real-life intense fear is communicated through context, not facial expressions. PNAS, 122(11), e2414677122. (www)

  @article{ , abstract = {Central emotion theories assume that during threatening and dangerous events the human face signals a prototypical, distinct, and universally recognized expression of fear which can be accurately decoded by conspecific perceivers. Due to the importance of fear expressions, an unusually large body of research has been dedicated to exploring their evolutionary origins, neurobiological mechanisms, and clinical significance. However, these studies typically utilize highly recognizable posed actor portrayals presumed to closely resemble the diagnostic physical appearance of real-life fearful faces. Here, we challenge this diagnosticity assumption. Following context-dependent frameworks (Barrett, 2017), we hypothesized that extrafacial context (e.g., situational information, body posture, etc.) plays a far greater role in fear communication than the signal of the isolated face. In 12 preregistered experiments (N = 4,180), we examined the perception of authentic, real-life videos documenting a diverse range of intense fear-inducing situations (e.g., height jumping, physical attacks, exposure to phobia triggers). Participants viewed the face alone, the context with no face, or the full video while various response methods of emotion perception were tested (forced choice, open-ended, multiple emotion scales, valence-arousal ratings). Across experiments, videos of the faces alone failed to communicate fear in a reliable manner. In sharp contrast, context with no faces, and faces with context were clearly and robustly perceived as fearful, with medium to large effect sizes. These findings suggest that despite the undisputed importance of perceiving fear reactions, facial expressions alone bear minimal diagnostic value, while context plays a critical role in real-life fear perception.}, archive = {J_PNAS}, author = {Lecker, Maya and Hallock, Scott and Danielson, Axel and Van Aertrickc, Maximilien and Kindt, Merel and Aviezer, Hillel}, doi = {10.1073/pnas.2414677122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2414677122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Real-life intense fear is communicated through context, not facial expressions}, volume = {122}, year = {2025}, }
• (2025). Infant EEG microstate dynamics relate to fine-grained patterns of infant attention during naturalistic play with caregivers. PNAS, 122(11), e2414636122. (www)

  @article{ , abstract = {As infants grow, they develop greater attentional control during interactions with others, shifting from patterns of attention primarily driven by caregivers (exogenous) to those that are also self-directed (endogenous). The ability to endogenously control attention during infancy is thought to reflect ongoing brain development and is influenced by patterns of joint attention between infant and caregiver. However, whether measures of infant attentional control and caregiver behavior during infant–caregiver interactions relate to patterns of infant brain activity is unknown and key for informing developmental models of attentional control. Using data from 43 infant–caregiver dyads, we quantified patterns of visual attention with dyadic, head-mounted eye tracking during infant–caregiver play and associated them with the duration of infant EEG microstate D/4 measured during rest. Importantly, microstate D/4 is a scalp potential topography thought to reflect the organization and function of attention-related brain networks. We found that microstate D/4 associated positively with infant-led joint attention rate but did not associate with caregiver-led joint attention rate, suggesting that infant-led coordination of joint attention during play may be critical for the neurobiological development of attentional control, or vice versa. Further, we found that microstate D/4 associated negatively with infant attention shift rate and positively with infant sustained attention duration, suggesting that increased stability of microstate D/4 may reflect maturation of attentional control and its underlying neural substrates. Together, our findings provide insights into how infant attentional control abilities and infant–caregiver visual behavior during play are associated with the spatial and temporal dynamics of infant brain activity.}, archive = {J_PNAS}, author = {Bagdasarov, Armen and Markert, Sarah and Gaffrey, Michael S.}, doi = {10.1073/pnas.2414636122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2414636122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Infant EEG microstate dynamics relate to fine-grained patterns of infant attention during naturalistic play with caregivers}, volume = {122}, year = {2025}, }
• (2025). Bacterial motility depends on a critical flagellum length and energy-optimized assembly. PNAS, 122(11), e2413488122. (www)

  @article{ , abstract = {The flagellum is the most complex macromolecular structure known in bacteria and is composed of around two dozen distinct proteins. The main building block of the long, external flagellar filament, flagellin, is secreted through the flagellar type-III secretion system at a remarkable rate of several tens of thousands of amino acids per second, significantly surpassing the rates achieved by other pore-based protein secretion systems. The evolutionary implications and potential benefits of this high secretion rate for flagellum assembly and function, however, have remained elusive. In this study, we provide both experimental and theoretical evidence that the flagellar secretion rate has been evolutionarily optimized to facilitate rapid and efficient construction of a functional flagellum. By synchronizing flagellar assembly, we found that a minimal filament length of 2.5 μm was required for swimming motility. Biophysical modeling revealed that this minimal filament length threshold resulted from an elasto-hydrodynamic instability of the whole swimming cell, dependent on the filament length. Furthermore, we developed a stepwise filament labeling method combined with electron microscopy visualization to validate predicted flagellin secretion rates of up to 10,000 amino acids per second. A biophysical model of flagellum growth demonstrates that the observed high flagellin secretion rate efficiently balances filament elongation and energy consumption, thereby enabling motility in the shortest amount of time. Taken together, these insights underscore the evolutionary pressures that have shaped the development and optimization of the flagellum and type-III secretion system, illuminating the intricate interplay and cost-benefit tradeoff between functionality and efficiency in assembly of large macromolecular structures.}, archive = {J_PNAS}, author = {Halte, Manuel and Popp, Philipp F. and Hathcock, David and Severn, John and Fischer, Svenja and Goosmann, Christian and Ducret, Adrien and Charpentier, Emmanuelle and Tu, Yuhai and Lauga, Eric and Erhardt, Marc and Renault, Thibaud T.}, doi = {10.1073/pnas.2413488122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2413488122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bacterial motility depends on a critical flagellum length and energy-optimized assembly}, volume = {122}, year = {2025}, }
• (2025). A unified neural representation model for spatial and conceptual computations. PNAS, 122(11), e2413449122. (www)

  @article{ , abstract = {The hippocampus and entorhinal cortex encode spaces by spatially local and hexagonal grid activity patterns (place cells and grid cells), respectively. In addition, the same brain regions also implicate neural representations for nonspatial, semantic concepts (concept cells). These observations suggest that neurocomputational mechanisms for spatial knowledge and semantic concepts are related in the brain. However, the exact relationship remains to be understood. Here, we show a mathematical correspondence between a value function for goal-directed spatial navigation and an information measure for word embedding models in natural language processing. Based on this relationship, we integrate spatial and semantic computations into a neural representation model called “disentangled successor information” (DSI). DSI generates biologically plausible neural representations: spatial representations like place cells and grid cells, and concept-specific word representations which resemble concept cells. Furthermore, with DSI representations, we can perform inferences of spatial contexts and words by a common computational framework based on simple arithmetic operations. This computation can be biologically interpreted by partial modulations of cell assemblies of nongrid cells and concept cells. Our model offers a theoretical connection of spatial and semantic computations and suggests possible computational roles of hippocampal and entorhinal neural representations.}, archive = {J_PNAS}, author = {Haga, Tatsuya and Oseki, Yohei and Fukai, Tomoki}, doi = {10.1073/pnas.2413449122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2413449122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A unified neural representation model for spatial and conceptual computations}, volume = {122}, year = {2025}, }
• (2025). IPSCs engrafted in allogeneic hosts without immunosuppression induce donor-specific tolerance to secondary allografts. PNAS, 122(11), e2413398122. (www)

  @article{ , abstract = {Currently, most cell or tissue transplantations using induced pluripotent stem cells (iPSCs) are anticipated to involve allogeneic iPSCs. However, the immunological properties of iPSCs in an allogeneic setting are not well understood. We previously established a mouse transplantation model of MHC-compatible/minor antigen-mismatched combinations, assuming a hypoimmunogenic iPSC-setting. Here, we found that iPSCs subcutaneously inoculated into MHC-compatible allogeneic host mice resisted rejection and formed teratomas without immunosuppressant administration. Notably, when skin grafts were transplanted onto hosts more than 40 d after the initial iPSCs inoculation, only the skin of the same strain as the initial iPSCs was engrafted. Therefore, donor-specific immune tolerance was induced by a single iPSC inoculation. Diverse analyses, including single-cell RNA-sequencing after transplantation, revealed an increase in regulatory T cell (Treg) population, particularly CD25 + CD103 + effector Tregs within the teratoma and skin grafts. The removal of CD25 + or Foxp3 + cells suppressed the increase in effector Tregs and disrupted graft acceptance, indicating the importance of these cells in the establishment of immune tolerance. Within the teratoma, we observed an increase in TGF-β2 levels, suggesting an association with the increase in effector Tregs. Our results provide important insights for future applications of allogeneic iPSC-based cell or tissue transplantation.}, archive = {J_PNAS}, author = {Kamatani, Tomoki and Kimura, Reiko and Ikeda, Satoshi and Inoue, Makoto and Seino, Ken-ichiro}, doi = {10.1073/pnas.2413398122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2413398122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {IPSCs engrafted in allogeneic hosts without immunosuppression induce donor-specific tolerance to secondary allografts}, volume = {122}, year = {2025}, }
• (2025). Quantifying compositional variability in microbial communities with FAVA. PNAS, 122(11), e2413211122. (www)

  @article{ , abstract = {Microbial communities vary across space, time, and individual hosts, generating a need for statistical methods capable of quantifying variability across multiple microbiome samples at once. To understand heterogeneity across microbiome samples from different host individuals, sampling times, spatial locations, or experimental replicates, we present FAVA ( F ST -based Assessment of Variability across vectors of relative Abundances), a framework for characterizing compositional variability across two or more microbiome samples. FAVA quantifies variability across many samples of taxonomic or functional relative abundances in a single index ranging between 0 and 1, equaling 0 when all samples are identical and 1 when each sample is entirely composed of a single taxon (and at least two distinct taxa are present across samples). Its definition relies on the population-genetic statistic F ST , with samples playing the role of “populations” and taxa playing the role of “alleles.” Its mathematical properties allow users to compare datasets with different numbers of samples and taxonomic categories. We introduce extensions that incorporate phylogenetic similarity among taxa and spatial or temporal distances between samples. We demonstrate FAVA in two examples. First, we use FAVA to measure how the taxonomic and functional variability of gastrointestinal microbiomes across individuals from seven ruminant species changes along the gastrointestinal tract. Second, we use FAVA to quantify the increase in temporal variability of gut microbiomes in healthy humans following an antibiotic course and to measure the duration of the antibiotic’s influence on temporal microbiome variability. We have implemented this tool in an R package, FAVA , for use in pipelines for the analysis of microbial relative abundances.}, archive = {J_PNAS}, author = {Morrison, Maike L. and Xue, Katherine S. and Rosenberg, Noah A.}, doi = {10.1073/pnas.2413211122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2413211122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantifying compositional variability in microbial communities with FAVA}, volume = {122}, year = {2025}, }
• (2025). Insulation between adjacent TADs is controlled by the width of their boundaries through distinct mechanisms. PNAS, 122(11), e2413112122. (www)

  @article{ , abstract = {Topologically associating domains (TADs) are sub-Megabase regions in vertebrate genomes with enriched intradomain interactions that restrict enhancer–promoter contacts across their boundaries. However, the mechanisms that separate TADs remain incompletely understood. Most boundaries between TADs contain CTCF binding sites (CBSs), which individually contribute to the blocking of Cohesin-mediated loop extrusion. Using genome-wide classification, here we show that the width of TAD boundaries forms a continuum from narrow to highly extended and correlates with CBSs distribution, chromatin features, and gene regulatory elements. To investigate how these boundary widths emerge, we modified the random crosslinker polymer model to incorporate specific boundary configurations, enabling us to evaluate the differential impact of boundary composition on TAD insulation. Our analysis, using three generic boundary categories, identifies differential influence on TAD insulation, with varying local and distal effects on neighboring domains. Notably, we find that increasing boundary width reduces long-range inter-TAD contacts, as confirmed by Hi-C data. While blocking loop extrusion at boundaries indirectly promotes spurious intermingling of neighboring TADs, extended boundaries counteract this effect, emphasizing their role in establishing genome organization. In conclusion, TAD boundary width not only enhances the efficiency of loop extrusion blocking but may also modulate enhancer–promoter contacts over long distances across TAD boundaries, providing a further mechanism for transcriptional regulation.}, archive = {J_PNAS}, author = {Papale, Andrea and Segueni, Julie and El Maroufi, Hanae and Noordermeer, Daan and Holcman, David}, doi = {10.1073/pnas.2413112122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2413112122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Insulation between adjacent TADs is controlled by the width of their boundaries through distinct mechanisms}, volume = {122}, year = {2025}, }
• (2025). Human stem cells with in vivo high plasticity generated by cell–cell communication. PNAS, 122(11), e2413043122. (www)

  @article{ , abstract = {Stem cells possess inherent properties of self-renewal and differentiation, and thus hold significant promise for regenerating damaged tissues or replacing lost cells. Unless their therapeutic effects are solely mediated by paracrine, transplanted stem cells need to be highly plastic to adapt to the host tissue environment and differentiate into constituent tissue-specific cells for tissue repair. Stem cells used in current cell-based therapies either have limited differentiation potential or are pluripotent but must be strictly restricted to avoid tumorigenicity risk in vivo. Here, we describe the derivation of human adult high-plasticity stem cells, which we call guide-integrated adult stem cells (giaSCs), from the interaction of blood-derived guide cells and umbilical cord tissue–derived mesenchymal stromal cells (UC-MSCs). The guide cells are a cell population derived from the peripheral blood of human adults. Unidirectional transfer through nanotube-like structures of granular substances from the guide cells into the recipient UC-MSCs gave rise to giaSCs. Topical application of human giaSCs into full-layer excisional wounds of wild-type mice led to reconstitution of skin tissue. Systemically administered human giaSCs migrated to and reside in mouse small intestinal tissue damaged by lipopolysaccharides and then differentiated into small intestinal epithelial cells for tissue repair. These transplantation experiments demonstrated that giaSCs have in vivo high plasticity. Additional in vivo and in vitro data showed that giaSCs have low immunogenicity and are nontumorigenic. These data indicate that giaSCs offer a highly promising approach to stem cell therapy.}, archive = {J_PNAS}, author = {Li, Shaowei and Chen, Xi and Xin, Jingxue and Liu, Bowen and Liu, Bo and Hu, Min and Wong, Wing Hung}, doi = {10.1073/pnas.2413043122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2413043122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Human stem cells with in vivo high plasticity generated by cell–cell communication}, volume = {122}, year = {2025}, }
• (2025). How spatiotemporal dynamics can enhance ecosystem resilience. PNAS, 122(11), e2412522122. (www)

  @article{ , abstract = {We study how self-organization in systems showing complex spatiotemporal dynamics can increase ecosystem resilience. We consider a general simple model that includes positive feedback as well as negative feedback mediated by an inhibitor. We apply this model to Posidonia oceanica meadows, where positive and negative feedbacks are well documented, and there is empirical evidence of the role of sulfide accumulation, toxic for the plant, in driving complex spatiotemporal dynamics. We describe a progressive transition from homogeneous meadows to extinction through dynamical regimes that allow the ecosystem to avoid the typical ecological tipping points of homogeneous vegetation covers. A predictable sequence of distinct dynamical regimes is observed as mortality is continuously increased: turbulent regimes, formation of spirals and wave trains, and isolated traveling pulses or expanding rings, the latter being a harbinger of ecosystem collapse, however far beyond the tipping point of the homogeneous cover. The model used in this paper is general, and the results can be applied to other plant–soil spatially extended systems, regardless of the mechanisms behind negative and positive feedbacks.}, archive = {J_PNAS}, author = {Moreno-Spiegelberg, Pablo and Rietkerk, Max and Gomila, Damià}, doi = {10.1073/pnas.2412522122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2412522122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How spatiotemporal dynamics can enhance ecosystem resilience}, volume = {122}, year = {2025}, }
• (2025). Sinorhizobium meliloti FcrX coordinates cell cycle and division during free-living growth and symbiosis by a ClpXP-dependent mechanism. PNAS, 122(11), e2412367122. (www)

  @article{ , abstract = {Sinorhizobium meliloti is a soil bacterium that establishes a nitrogen-fixing symbiosis within root nodules of legumes. In this symbiosis, S. meliloti undergoes a drastic cellular change leading to a terminally differentiated form, called bacteroid, characterized by genome endoreduplication, increased cell size, and high membrane permeability. Bacterial cell cycle (mis)regulation is at the heart of this differentiation process. In free-living cells, the master regulator CtrA ensures the progression of cell cycle by activating cell division (controlled by FtsZ) and inhibiting DNA replication, while on the other hand the so far poorly unknown downregulation of CtrA and FtsZ is essential for bacteroid differentiation. Here, we combine cell biology, biochemistry, and bacterial genetics to understand the functions of FcrX, a factor that controls both CtrA and FtsZ in free-living growth and in symbiosis. Depletion of the essential gene fcrX led to abnormally high levels of FtsZ and CtrA and minicell formation. Using multiple complementary techniques, we showed that FcrX may interact with FtsZ and CtrA. Moreover, fcrX transcription is directly controlled by CtrA itself and the FcrX protein displays a cell cycle-dependent pattern. We showed further that FcrX also binds the degradosome complex ClpXP and its adaptors CpdR1 and RcdA, and that CtrA degradation efficiency depends on FcrX. We further showed that, despite weak homology with FliJ-like proteins, only FcrX proteins from closely related species are able to complement S. meliloti fcrX function. Finally, deregulation of FcrX showed abnormal symbiotic behaviors in plants suggesting a putative role of this factor during bacteroid differentiation.}, archive = {J_PNAS}, author = {Dendene, Sara and Xue, Shuanghong and Mohammedi, Roza and Vieillard, Adam and Nicoud, Quentin and Valette, Odile and Frascella, Angela and Bonnardel, Anna and Le Bars, Romain and Bourge, Mickaël and Mergaert, Peter and Brilli, Matteo and Alunni, Benoît and Biondi, Emanuele G.}, doi = {10.1073/pnas.2412367122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2412367122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sinorhizobium meliloti FcrX coordinates cell cycle and division during free-living growth and symbiosis by a ClpXP-dependent mechanism}, volume = {122}, year = {2025}, }
• (2025). Physical proximity drives gay discrimination in the gig economy. PNAS, 122(11), e2412362122. (www)

  @article{ , abstract = {Despite legal protections, discrimination based on sexual orientation remains difficult to detect and measure in labor markets. We present evidence from a field experiment ( N = 1,128) conducted in Australia on a major gig economy platform that allows users to outsource everyday tasks. By manipulating both the sexual orientation of job posters (gay vs. straight male) and physical proximity requirements of tasks (inside vs. outside the home), we identify discrimination against gay profiles and demonstrate a specific mechanism for its emergence: physical proximity. Gay profiles received fewer offers and less engagement, and attracted workers with significantly lower quality ratings, but only for tasks requiring close physical proximity. Additional exploratory analysis further suggests that the results are driven by an anti-gay bias rather than an anti-men or pro-women bias and that discrimination is stronger for tasks with a higher degree of interaction between worker and job poster. Our findings demonstrate how digital labor platforms can perpetuate traditional forms of discrimination, while shedding light on physical proximity as one important mechanism. These results have important implications for users of the gig economy, a sector of increasing importance due to its rapid growth and comparatively lax regulatory frameworks.}, archive = {J_PNAS}, author = {Smerdon, David and Pearson, Samuel and Albrecht, Sabina}, doi = {10.1073/pnas.2412362122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2412362122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Physical proximity drives gay discrimination in the gig economy}, volume = {122}, year = {2025}, }
• (2025). Periarteriolar niches become inflamed in aging bone marrow, remodeling the stromal microenvironment and depleting lymphoid progenitors. PNAS, 122(11), e2412317122. (www)

  @article{ , abstract = {In early postnatal and young adult bone marrow, Leptin receptor–expressing (LepR + ) stromal cells and endothelial cells synthesize factors required for hematopoietic stem cell (HSC) maintenance, including Stem Cell Factor (SCF) and Cxcl12. However, little is known about how these stromal cells change during aging. We performed single-cell RNA sequencing of mouse bone marrow stromal cells at 2, 12, and 24 mo of age. We identified five transcriptionally distinct subsets of LepR + cells, all of which expressed the highest levels of Scf and Cxcl12 in bone marrow throughout adult life. In aging bone marrow, SCF from LepR + cells, but not endothelial cells, continued to be necessary for the maintenance of HSCs and early restricted progenitors. However, arteriolar endothelial cells and other periarteriolar cells expressed increasing levels of interferon during aging. This increased the numbers of periarteriolar Sca1 + Cxcl9 + LepR + cells with an inflammatory gene signature and depleted lymphoid progenitors, at least some of which are also periarteriolar. The periarteriolar environment thus became particularly inflamed during aging, remodeling the stromal microenvironment and depleting lymphoid progenitors in an interferon-dependent manner.}, archive = {J_PNAS}, author = {Du, Liming and Freitas-Cortez, Maria Angelica and Zhang, Jingzhu and Xue, Yuanyuan and Veettil, Reshma T. and Zhao, Zhiyu and Morrison, Sean J.}, doi = {10.1073/pnas.2412317122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2412317122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Periarteriolar niches become inflamed in aging bone marrow, remodeling the stromal microenvironment and depleting lymphoid progenitors}, volume = {122}, year = {2025}, }
• (2025). N6-methyladnosine of vRNA facilitates influenza a virus replication by promoting the interaction of vRNA with polymerase proteins. PNAS, 122(11), e2411554122. (www)

  @article{ , abstract = {N 6-methyladnosine (m 6 A) modification is present in both positive- and negative-strand RNA of influenza A virus (IAV) and affects the replication and pathogenicity of IAV. However, little is known about the regulatory mechanism of m 6 A in IAV RNA. In the present study, we identified the m 6 A methylation of the viral RNA of different IAV subtypes and confirmed that m 6 A modification promotes the polymerase activity and replication of IAV. By mutating m 6 A motifs on the multiple viral RNAs (vRNAs) of IAV, we revealed that m 6 A deficiency in vRNA suppresses the expression of viral genes and the replication of the virus in vitro. In addition, m 6 A deficiency in vRNA reduced the pathogenicity of IAV in a mouse model. Mechanistically, m 6 A deficiency in vRNA suppresses the assembly of the viral ribonucleoprotein (vRNP) complex by impairing the interaction between vRNA and vRNP proteins in an m 6 A methyltransferase-dependent manner, but not the m 6 A reader proteins. Together, our findings reveal an important role for m 6 A on viral RNAs in facilitating the activity of the polymerase complex and the replication and pathogenicity of IAV, which provides insights for the development of novel anti-influenza strategies.}, archive = {J_PNAS}, author = {Wang, Qian and Xu, Shuai and Shen, Wentao and Wei, Yanli and Han, Lu and Wang, Zhengxiang and Yu, Yingying and Liu, Minxuan and Liu, Junwen and Deng, Guohua and Chen, Hualan and Zhu, Qiyun}, doi = {10.1073/pnas.2411554122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2411554122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {N6-methyladnosine of vRNA facilitates influenza a virus replication by promoting the interaction of vRNA with polymerase proteins}, volume = {122}, year = {2025}, }
• (2025). Large increases in public R&D investment are needed to avoid declines of US agricultural productivity. PNAS, 122(11), e2411010122. (www)

  @article{ , abstract = {Increasing agricultural productivity is a gradual process with significant time lags between research and development (R&D) investment and the resulting gains. We estimate the response of US agricultural Total Factor Productivity to both R&D investment and weather and quantify the public R&D spending required to offset the emerging impacts of climate change. We find that offsetting the climate-induced productivity slowdown by 2050 will require R&D spending over 2021 to 2050 to grow at 5.2 to 7.8% per year under a fixed spending growth scenario or by an additional $2.2 to $3.8B per year under a fixed supplement spending scenario (in addition to the current spending of ~$5B per year). This amounts to an additional $208 to $434B or $65 to $113B over the period, respectively, and would be comparable in ambition to the public R&D spending growth that followed the two World Wars.}, archive = {J_PNAS}, author = {Ortiz-Bobea, Ariel and Chambers, Robert G. and He, Yurou and Lobell, David B.}, doi = {10.1073/pnas.2411010122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2411010122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Large increases in public R&D investment are needed to avoid declines of US agricultural productivity}, volume = {122}, year = {2025}, }
• (2025). Earth greening and climate change reshaping the patterns of terrestrial water sinks and sources. PNAS, 122(11), e2410881122. (www)

  @article{ , abstract = {While vegetation brings positive benefits for climate mitigation and adaptation, the impact of ongoing global greening remains controversial due to its uncertain effects on hydrological cycle. Here, we quantitatively assess the impact of vegetation dynamics on global water availability by proposing a comprehensive framework to quantify the terrestrial water sink and source scores associated with vegetation dynamics. These scores serve as indicators of whether large alterations in water resources have occurred in the lands due to either the greening or degradation of surface vegetation. We use multisource datasets from climate model projections, remote sensing, and local measurements to examine the impact of vegetation dynamics on water availability over the periods of 1982 to 2019 and 2015 to 2100. During historical observation periods, regions such as India and northern China experienced large depletion of water resources as a result of vegetation greening, leading to water scarcity. In the future, a shift is projected for India and northern China, transforming them into regions capable of meeting water demands arising from vegetation greening. This transition is largely attributed to wetting and warming climates. It indicates that trade-off effects between climate and underlying vegetation dynamics may result in strengthening regional hydrological resilience and ensuring the stable status of local water resources. Furthermore, tropical rainforests (except for the Amazon Rainforest) are experiencing greening with minimal impact on local water resources consistently. These insights are valuable for globally identifying optimal locations to implement ecological restoration, facilitating the balance of sustainable water resources and vegetation greening.}, archive = {J_PNAS}, author = {Yan, Yu and Liu, Zhiyong and Chen, Lei and Chen, Xiaohong and Lin, Kairong and Zeng, Zhenzhong and Lan, Xin and Huang, Liyan and Wang, Yajun and Yao, Lili and Cheng, Linyin and Ma, Zhimin}, doi = {10.1073/pnas.2410881122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2410881122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Earth greening and climate change reshaping the patterns of terrestrial water sinks and sources}, volume = {122}, year = {2025}, }
• (2025). Variable DPP4 expression in multiciliated cells of the human nasal epithelium as a determinant for MERS-CoV tropism. PNAS, 122(11), e2410630122. (www)

  @article{ , abstract = {Transmissibility of respiratory viruses is a complex viral trait that is intricately linked to tropism. Several highly transmissible viruses, including severe acute respiratory syndrome coronavirus 2 and Influenza viruses, specifically target multiciliated cells in the upper respiratory tract to facilitate efficient human-to-human transmission. In contrast, the zoonotic Middle East respiratory syndrome coronavirus (MERS-CoV) generally transmits poorly between humans, which is largely attributed to the absence of its receptor dipeptidyl peptidase 4 (DPP4) in the upper respiratory tract. At the same time, MERS-CoV epidemiology is characterized by occasional superspreading events, suggesting that some individuals can disseminate this virus effectively. Here, we utilized well-differentiated human pulmonary and nasal airway organoid-derived cultures to further delineate the respiratory tropism of MERS-CoV. We find that MERS-CoV replicated to high titers in both pulmonary and nasal airway cultures. Using single-cell messenger-RNA sequencing, immunofluorescence, and immunohistochemistry, we show that MERS-CoV preferentially targeted multiciliated cells, leading to loss of ciliary coverage. MERS-CoV cellular tropism was dependent on the differentiation of the organoid-derived cultures, and replication efficiency varied considerably between donors. Similarly, variable and focal expression of DPP4 was revealed in human nose tissues. This study indicates that the upper respiratory tract tropism of MERS-CoV may vary between individuals due to differences in DPP4 expression, providing an explanation for the unpredictable transmission pattern of MERS-CoV.}, archive = {J_PNAS}, author = {Breugem, Tim I. and Riesebosch, Samra and Zhang, Jingshu and Mykytyn, Anna Z. and Krabbendam, Lisette and Groen, Nathalie and Baptista Varela, Sivana and Schipper, Debby and van den Doel, Petra B. and van Acker, Romy and Stadhouders, Ralph and Lamers, Mart M. and Haagmans, Bart L.}, doi = {10.1073/pnas.2410630122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2410630122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Variable DPP4 expression in multiciliated cells of the human nasal epithelium as a determinant for MERS-CoV tropism}, volume = {122}, year = {2025}, }
• (2025). Expansion and pathogenic activation of skeletal muscle–resident macrophages in mdx5cv/Ccr2−/− mice. PNAS, 122(11), e2410095122. (www)

  @article{ , abstract = {Infiltrating macrophages contribute to muscle dystrophic changes in Duchenne muscular dystrophy (DMD). In a DMD mouse model, mdx 5cv mice, CC chemokine receptor type 2 (CCR2) deficiency diminishes Ly6C hi macrophage infiltration by blocking blood Ly6C hi inflammatory monocyte recruitment. This is accompanied by transient improvement of muscle damage, fibrosis, and regeneration. The benefit, however, is lost after the expansion of intramuscular Ly6C lo macrophages. To address the mechanisms underlying the Ly6C lo macrophage expansion, we compared mdx 5cv /Nur77 −/− and mdx 5cv /Ccr2 −/− /Nur7 −/− mice with mdx 5cv and mdx 5cv /Ccr2 −/− mice, respectively, and found no evidence to suggest Ly6C lo monocyte recruitment by dystrophic muscles. Single-cell RNA sequencing analysis and Flt3 cre /Rosa26 LSL-YFP -based lineage tracing of macrophage origins demonstrated the expansion and pathogenic activation of muscle resident macrophages in CCR2-deficient mdx 5cv mice. The expansion was associated with increased cell proliferation, which appeared induced by colony-stimulating factor-1 (CSF-1) derived from fibro/adipogenic progenitors (FAPs). Our study establishes a pathogenic role for skeletal muscle resident macrophages and supports a regulatory role of FAPs in stimulating the expansion of resident macrophages in the DMD mouse model when the inflammatory macrophage infiltration is inhibited.}, archive = {J_PNAS}, author = {Wang, Yinhang and Wang, Xingyu and Alabdullatif, Salam and Homma, Sachiko T. and Alekseyev, Yuriy O. and Zhou, Lan}, doi = {10.1073/pnas.2410095122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2410095122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Expansion and pathogenic activation of skeletal muscle–resident macrophages in mdx5cv/Ccr2−/− mice}, volume = {122}, year = {2025}, }
• (2025). The decade-long growth of government-authored news media in china under xi jinping. PNAS, 122(11), e2408260122. (www)

  @article{ , abstract = {Autocratic governments around the world use clandestine propaganda campaigns to influence the media. We document a decade-long trend in China toward the planting of government-authored articles in party and commercial newspapers. To examine this phenomenon, we develop an approach to identifying scripted propaganda—the coerced reprinting of lightly adapted government-authored articles in newspapers—that leverages the footprints left by the government when making media interventions. We show that in China, scripted propaganda is a daily phenomenon—on 90% of days from 2012 to 2022, the vast majority of party newspapers include at least some scripted propaganda at the direction of a central directive. On particular sensitive days, the amount of scripted propaganda can spike to 30% of the articles appearing in major newspapers. We show that scripted propaganda has strengthened under President Xi Jinping. In the last decade, the front page of party newspapers has evolved from 5% scripted articles to approximately 20% scripted. This government-authored content throughout the paper is increasingly homogeneous—fewer and fewer adaptations are done by individual newspapers. In contrast to popular speculation, we show that scripted content is not only on ideological topics (although it is increasingly ideological) and is also very prevalent in commercial papers. Using a case study of domestic coverage of COVID-19, we demonstrate how the regime uses scripting to shape, constrain, and delay information during crises. Our findings reveal the wide-ranging influence of government-authored propaganda in China’s media ecosystem.}, archive = {J_PNAS}, author = {Waight, Hannah and Yuan, Yin and Roberts, Margaret E. and Stewart, Brandon M.}, doi = {10.1073/pnas.2408260122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2408260122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The decade-long growth of government-authored news media in china under xi jinping}, volume = {122}, year = {2025}, }
• (2025). Planets larger than neptune have elevated eccentricities. PNAS, 122(11), e2405295122. (www)

  @article{ , abstract = {NASA’s Kepler mission identified over 4,000 extrasolar planets that transit (cross in front of) their host stars. This sample has revealed detailed features in the demographics of planet sizes and orbital spacings. However, knowledge of their orbital shapes—a key tracer of planetary formation and evolution—remains far more limited. We present measurements of eccentricities for 1,646 Kepler planets, 92% of which are smaller than Neptune. For all planet sizes, the eccentricity distribution peaks at e = 0 and falls monotonically toward zero at e = 1. As planet size increases, mean population eccentricity rises from ⟨ e ⟩ = 0.05 ± 0.01 for small planets to ⟨ e ⟩ = 0.20 ± 0.03 for planets larger than ∼3.5 Earth-radii R ⊕ . The overall planet occurrence rate and planet-metallicity correlation also change abruptly at this size. Taken together, these patterns indicate distinct formation channels for planets above and below ∼3.5 R ⊕ . We also find size-dependent associations between eccentricity, host star metallicity, and orbital period. While smaller planets generally have low eccentricities, there are hints of a noteworthy exception: eccentricities are slightly elevated in the “radius valley,” a narrow band of low occurrence rate density which separates rocky “super-Earths” (1.0 to 1.5 R ⊕ ) from gas-rich “sub-Neptunes” (2.0 to 3.0 R ⊕ ). We detect this feature at 2.1σ significance. Planets in single- and multitransiting systems exhibit the same size–eccentricity relationship, suggesting they are drawn from the same parent population.}, archive = {J_PNAS}, author = {Gilbert, Gregory J. and Petigura, Erik A. and Entrican, Paige M.}, doi = {10.1073/pnas.2405295122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2405295122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Planets larger than neptune have elevated eccentricities}, volume = {122}, year = {2025}, }
• (2025). Neanderthal adaptive introgression shaped LCT enhancer region diversity without linking to lactase persistence in east asian populations. PNAS, 122(11), e2404393122. (www)

  @article{ , abstract = {Positive selection at the 2q21.3 enhancer region for lactase gene ( LCT ) expression in Europeans and Africans has long been attributed to selection for lactase persistence (LP), the capacity of adults to digest lactose in milk, presumably because of the benefits associated with milk consumption. While considered a classic example of gene–culture coevolution, recently doubts have been raised about the link between selection at 2q21.3 and LP. Analysis of additional populations could shed further light; here, we demonstrate that a haplotype spanning ~467 kb at the 2q21.3 locus has risen to high frequency in East Asians (~25%) but is absent from Africans and Europeans. This haplotype likely derived from Neanderthals and has been under positive selection in East Asians. The East Asian–specific haplotype is associated with alterations in LCT expression and promoter methylation in certain cell types, similar to what is observed with LP-associated haplotypes in Europeans. Moreover, its frequency is comparable to that of LP in East Asians, suggesting a potential association with LP in East Asians. However, it is highly unlikely that selection in East Asians was related to milk-drinking habits. We find that this haplotype impacts the expression of UBXN4 , DARS1, and DARS1-AS1 in immune cells and is associated with neutrophil and white blood cell counts. Hence, the selection might be linked to certain aspects of immune function. This implies that selection on 2q21.3 has thus either occurred for different reasons in different populations or the selection observed in other populations is also not due to LP.}, archive = {J_PNAS}, author = {Ma, Xixian and Lu, Yan and Stoneking, Mark and Xu, Shuhua}, doi = {10.1073/pnas.2404393122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2404393122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neanderthal adaptive introgression shaped LCT enhancer region diversity without linking to lactase persistence in east asian populations}, volume = {122}, year = {2025}, }
• (2025). For geological carbon sequestration to work, we need a geospatial planning policy. PNAS, 122(11), e2403020122. (www)

  @article{ , archive = {J_PNAS}, author = {Menefee, Anne and Wiseman, Hannah and Blumsack, Seth and Helbing, Michael}, doi = {10.1073/pnas.2403020122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2403020122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {For geological carbon sequestration to work, we need a geospatial planning policy}, volume = {122}, year = {2025}, }
• (2025). Enhancement of mitochondrial calcium uptake is cardioprotective against maladaptive hypertrophy by retrograde signaling uptuning akt. PNAS, 122(11), e2402639122. (www)

  @article{ , abstract = {Regulation of mitochondrial Ca 2+ uptake is critical in cardiac adaptation to chronic stressors. Abnormalities in Ca 2+ handling, including mitochondrial uptake mechanisms, have been implicated in pathological heart hypertrophy. Enhancing mitochondrial Ca 2+ uniporter (MCU) expression has been suggested to interfere with maladaptive development of heart failure. Here, we addressed whether MCU modulation affects the cardiac response to pressure overload. MCU content was quantified in human and murine hearts at different phases of myocardial hypertrophy. Cardiac function/structure were analyzed after Transverse Aortic Constriction (TAC) in mice undergone viral-assisted overexpression or downregulation of MCU. In vitro and ex vivo assays determined the effect of MCU modulation on mitochondrial Ca 2+ uptake, cellular phenotype and hypertrophic signaling. In human and murine hearts MCU levels increased in the adaptive phase of myocardial hypertrophy and declined in the failing stage. Consistently, modulation of MCU had a cell-autonomous effect in cardiomyocyte/heart adaptation to chronic overload. Indeed, upon TAC MCU-downregulation accelerated development of contractile dysfunction, interstitial fibrosis and heart failure. Conversely, MCU-overexpression prolonged the adaptive phase of hypertrophic response, as, in advanced stages upon TAC, hearts showed preserved contractility, absence of fibrosis and intact vascularization. In vitro and ex vivo analyses indicated that enhancement in mitochondrial Ca 2+ uptake in cardiomyocytes entails “mitochondrion-to-cytoplasm” signals leading to ROS-mediated activation of Akt, which may explain the protective effects towards heart response to TAC. Enhanced mitochondrial Ca 2+ uptake affects the compensatory response to pressure overload via retrograde mitochondrial-Ca 2+ /ROS/Akt signaling, thus uncovering a potentially targetable mechanism against maladaptive myocardial hypertrophy.}, archive = {J_PNAS}, author = {Zaglia, Tania and Campo, Antonio and Moro, Nicola and Di Mauro, Vittoria and Borile, Giulia and Menabò, Roberta and Antonucci, Salvatore and Poli, Laura and Campesan, Marika and Carullo, Pierluigi and Martinazzi, Sara and Luciani, Giovanni B. and Hammer, Karin and Pesce, Paola and Bariani, Riccardo and Faggian, Giuseppe and Maier, Lars and Ventura, Laura and De Stefani, Diego and Mammucari, Cristina and Rizzuto, Rosario and Catalucci, Daniele and Di Lisa, Fabio and Mongillo, Marco}, doi = {10.1073/pnas.2402639122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2402639122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Enhancement of mitochondrial calcium uptake is cardioprotective against maladaptive hypertrophy by retrograde signaling uptuning akt}, volume = {122}, year = {2025}, }
• (2025). Competition for shared resources increases dependence on initial population size during coalescence of gut microbial communities. PNAS, 122(11), e2322440122. (www)

  @article{ , abstract = {The long-term success of introduced populations depends on both their initial size and ability to compete against existing residents, but it remains unclear how these factors collectively shape colonization dynamics. Here, we investigate how initial population (propagule) size shapes the outcome of community coalescence by systematically mixing eight pairs of in vitro microbial communities at ratios that vary over six orders of magnitude, and we compare our results to neutral ecological theory. Although the composition of the resulting cocultures deviated substantially from neutral expectations, each coculture contained species whose relative abundance depended on propagule size even after ~40 generations of growth. Using a consumer–resource model, we show that this dose-dependent colonization can arise when resident and introduced species have high niche overlap and consume shared resources at similar rates. Strain isolates displayed longer-lasting dose dependence when introduced into diverse communities than in pairwise cocultures, consistent with our model’s prediction that propagule size should have larger, more persistent effects in diverse communities. Our model also successfully predicted that species with similar resource-utilization profiles, as inferred from growth in spent media and untargeted metabolomics, would show stronger dose dependence in pairwise coculture. This work demonstrates that transient, dose-dependent colonization dynamics can emerge from resource competition and exert long-term effects on the outcomes of community coalescence.}, archive = {J_PNAS}, author = {Goldman, Doran A. and Xue, Katherine S. and Parrott, Autumn B. and Lopez, Jamie A. and Vila, Jean C. C. and Jeeda, Rashi R. and Franzese, Lauryn R. and Porter, Rachel L. and Gray, Ira J. and DeFelice, Brian C. and Petrov, Dmitri A. and Good, Benjamin H. and Relman, David A. and Huang, Kerwyn Casey}, doi = {10.1073/pnas.2322440122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {11}, pages = {e2322440122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Competition for shared resources increases dependence on initial population size during coalescence of gut microbial communities}, volume = {122}, year = {2025}, }
• (2025). Correction for huseby et al., antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in gram-negative bacteria. PNAS, 122(10), e2502871122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502871122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2502871122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for huseby et al., antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in gram-negative bacteria}, volume = {122}, year = {2025}, }
• (2025). Correction for mayo et al., band asymmetry–driven nonreciprocal electronic transport in a helimagnetic semimetal α-EuP3. PNAS, 122(10), e2502291122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502291122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2502291122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for mayo et al., band asymmetry–driven nonreciprocal electronic transport in a helimagnetic semimetal α-EuP3}, volume = {122}, year = {2025}, }
• (2025). Correction for qin et al., a signaling molecule from intratumor bacteria promotes trastuzumab resistance in breast cancer cells. PNAS, 122(10), e2502214122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502214122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2502214122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for qin et al., a signaling molecule from intratumor bacteria promotes trastuzumab resistance in breast cancer cells}, volume = {122}, year = {2025}, }
• (2025). Correction for manik et al., structural basis for TIR domain–mediated innate immune signaling by toll-like receptor adaptors TRIF and TRAM. PNAS, 122(10), e2502122122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502122122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2502122122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for manik et al., structural basis for TIR domain–mediated innate immune signaling by toll-like receptor adaptors TRIF and TRAM}, volume = {122}, year = {2025}, }
• (2025). Correction for ganley et al., iron limitation triggers roseoceramide biosynthesis and membrane remodeling in marine roseobacter. PNAS, 122(10), e2502118122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502118122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2502118122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for ganley et al., iron limitation triggers roseoceramide biosynthesis and membrane remodeling in marine roseobacter}, volume = {122}, year = {2025}, }
• (2025). Correction for patel et al., aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory. PNAS, 122(10), e2502115122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502115122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2502115122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for patel et al., aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory}, volume = {122}, year = {2025}, }
• (2025). Correction for liu et al., cytoskeleton remodeling mediated by circRNA-YBX1 phase separation suppresses the metastasis of liver cancer. PNAS, 122(10), e2501920122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2501920122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2501920122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for liu et al., cytoskeleton remodeling mediated by circRNA-YBX1 phase separation suppresses the metastasis of liver cancer}, volume = {122}, year = {2025}, }
• (2025). Correction for qian et al., chemoptogenetic damage to mitochondria causes rapid telomere dysfunction. PNAS, 122(10), e2501913122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2501913122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2501913122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for qian et al., chemoptogenetic damage to mitochondria causes rapid telomere dysfunction}, volume = {122}, year = {2025}, }
• (2025). Nanoscale distribution of bioactive ligands on biomaterials regulates cell mechanosensing through translocation of actin into the nucleus. PNAS, 122(10), e2501264122. (www)

  @article{ , abstract = {Cells respond to adhesive ligands such as arginine-glycine-aspartate (RGD) through integrins, which regulates cellular activities via influencing cytoskeleton assembly. Herein, we report that the nanoscale distribution of active ligands on biomaterials regulates cells through not only cytoplasmic tension but also nuclear tension. This is particularly related to translocation of actin into nucleus and highlighted in our interpretation of an “abnormal” phenomenon that large RGD nanospacing (>70 nm) disassembles integrin clusters, inhibits cell adhesion, but promotes osteogenic differentiation of mesenchymal stem cells. Our studies reveal that the unstable adhesion at the 150 nm RGD distance increases actin dynamics, resulting in the nuclear translocation of globular (G) actin. The compartment polymerization of more G-actins to filamentous actins in nucleus increases nuclear tension, facilitating transcription activity and releasing calcium ions from the endoplasmic reticulum. This noncanonical mechanotransduction process sheds insight into mechanotransduction pertinent to cell–material interactions.}, archive = {J_PNAS}, author = {Liu, Xiaojing and Zhang, Man and Wang, Peng and Zheng, Kaikai and Wang, Xinlei and Xie, Wenyan and Pan, Xiaokai and Shen, Runjia and Liu, Ruili and Ding, Jiandong and Wei, Qiang}, doi = {10.1073/pnas.2501264122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2501264122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nanoscale distribution of bioactive ligands on biomaterials regulates cell mechanosensing through translocation of actin into the nucleus}, volume = {122}, year = {2025}, }
• (2025). Sex ratio drive in mice: A binding competition between sex-linked genes. PNAS, 122(10), e2501248122. (www)

  @article{ , archive = {J_PNAS}, author = {Campbell, Polly and Heitzmann, Louise D.}, doi = {10.1073/pnas.2501248122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2501248122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Sex ratio drive in mice: A binding competition between sex-linked genes}, volume = {122}, year = {2025}, }
• (2025). Archaeology and traversing america’s pre-columbian fault line. PNAS, 122(10), e2501227122. (www)

  @article{ , archive = {J_PNAS}, author = {Thomas, David Hurst}, doi = {10.1073/pnas.2501227122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2501227122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Archaeology and traversing america’s pre-columbian fault line}, volume = {122}, year = {2025}, }
• (2025). Calcineurin goes to sleep. PNAS, 122(10), e2500910122. (www)

  @article{ , archive = {J_PNAS}, author = {Ye, Michael and Diering, Graham H.}, doi = {10.1073/pnas.2500910122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2500910122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Calcineurin goes to sleep}, volume = {122}, year = {2025}, }
• (2025). Reply to ye: Parallel progress in funder practices and expansion of academic incentives to support engaged research. PNAS, 122(10), e2500539122. (www)

  @article{ , archive = {J_PNAS}, author = {Bednarek, Angela T. and Miyamoto, Ben}, doi = {10.1073/pnas.2500539122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2500539122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to ye: Parallel progress in funder practices and expansion of academic incentives to support engaged research}, volume = {122}, year = {2025}, }
• (2025). Potential limiting factor on engaged research: Academic evaluation systems. PNAS, 122(10), e2500271122. (www)

  @article{ , archive = {J_PNAS}, author = {Ye, Hongnan}, doi = {10.1073/pnas.2500271122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2500271122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Potential limiting factor on engaged research: Academic evaluation systems}, volume = {122}, year = {2025}, }
• (2025). State-dependent motion of a genetically encoded fluorescent biosensor. PNAS, 122(10), e2426324122. (www)

  @article{ , abstract = {Genetically encoded biosensors can measure biochemical properties such as small-molecule concentrations with single-cell resolution, even in vivo. Despite their utility, these sensors are “black boxes”: Very little is known about the structures of their low- and high-fluorescence states or what features are required to transition between them. We used LiLac, a lactate biosensor with a quantitative fluorescence-lifetime readout, as a model system to address these questions. X-ray crystal structures and engineered high-affinity metal bridges demonstrate that LiLac exhibits a large interdomain twist motion that pulls the fluorescent protein away from a “sealed,” high-lifetime state in the absence of lactate to a “cracked,” low-lifetime state in its presence. Understanding the structures and dynamics of LiLac will help to think about and engineer other fluorescent biosensors.}, archive = {J_PNAS}, author = {Rosen, Paul C. and Horwitz, Samantha M. and Brooks, Daniel J. and Kim, Erica and Ambarian, Joseph A. and Waidmann, Lidia and Davis, Katherine M. and Yellen, Gary}, doi = {10.1073/pnas.2426324122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2426324122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {State-dependent motion of a genetically encoded fluorescent biosensor}, volume = {122}, year = {2025}, }
• (2025). Candidate transmission survival genome of mycobacterium tuberculosis. PNAS, 122(10), e2425981122. (www)

  @article{ , abstract = {Mycobacterium tuberculosis (Mtb), a leading cause of death from infection, completes its life cycle entirely in humans except for transmission through the air. To begin to understand how Mtb survives aerosolization, we mimicked liquid and atmospheric conditions experienced by Mtb before and after exhalation using a model aerosol fluid (MAF) based on the water-soluble, lipidic, and cellular constituents of necrotic tuberculosis lesions. MAF induced drug tolerance in Mtb, remodeled its transcriptome, and protected Mtb from dying in microdroplets desiccating in air. Yet survival was not passive: Mtb appeared to rely on hundreds of genes to survive conditions associated with transmission. Essential genes subserving proteostasis offered most protection. A large number of conventionally nonessential genes appeared to contribute as well, including genes encoding proteins that resemble antidesiccants. The candidate transmission survival genome of Mtb may offer opportunities to reduce transmission of tuberculosis.}, archive = {J_PNAS}, author = {Mishra, Saurabh and Singh, Prabhat Ranjan and Hu, Xiaoyi and Lopez-Quezada, Landys and Jinich, Adrian and Jahn, Robin and Geurts, Luc and Shen, Naijian and DeJesus, Michael A. and Hartman, Travis and Rhee, Kyu and Zimmerman, Matthew and Dartois, Veronique and Jones, Richard M. and Jiang, Xiuju and Almada-Monter, Ricardo and Bourouiba, Lydia and Nathan, Carl}, doi = {10.1073/pnas.2425981122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2425981122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Candidate transmission survival genome of mycobacterium tuberculosis}, volume = {122}, year = {2025}, }
• (2025). Allosteric inhibition of the IZUMO1–JUNO fertilization complex by the naturally occurring antisperm antibody OBF13. PNAS, 122(10), e2425952122. (www)

  @article{ , abstract = {Sperm IZUMO1 binds to egg JUNO, and this interaction is essential for mammalian fertilization. Isolated from a female mouse immunized with syngeneic sperm, the antisperm antibody OBF13 recognizes IZUMO1 and inhibits murine fertilization. How OBF13 interferes with sperm–egg interactions was unknown. Here, we present the X-ray crystal structure of IZUMO1 in complex with OBF13. OBF13 binds to the apex of the four-helix domain of IZUMO1, distant from the JUNO-binding site. Our crystal structure of OBF13-bound IZUMO1 resembles apo-IZUMO1 and differs from the structure of IZUMO1 in complex with JUNO. We identify that OBF13 carries a low level of somatic hypermutation, and through deep mutational scanning, we engineer an affinity-enhanced OBF13 variant. This OBF13 variant single-chain fragment variable decreases the apparent affinity of IZUMO1 for membrane-bound murine JUNO and blocks the binding of acrosome-reacted sperm to eggs, thereby preventing fertilization. We propose allostery between the OBF13 epitope and the JUNO-binding site. OBF13 inhibits a conformational change in IZUMO1, preventing fusion-competent sperm from adhering to murine eggs during fertilization. Surprisingly, murine IZUMO1 binds to hamster JUNO with an affinity ~20-fold higher than to murine JUNO. The decreased affinity caused by OBF13 of murine IZUMO1 for hamster JUNO is sufficient for murine sperm to bind to and fuse with hamster eggs. Our studies provide a structural and mechanistic framework for species-specific, allosteric inhibition of IZUMO1 by a naturally occurring antisperm antibody and offer insights into the development of immunocontraceptives.}, archive = {J_PNAS}, author = {Lu, Yonggang and Ikawa, Masahito and Tang, Shaogeng}, doi = {10.1073/pnas.2425952122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2425952122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Allosteric inhibition of the IZUMO1–JUNO fertilization complex by the naturally occurring antisperm antibody OBF13}, volume = {122}, year = {2025}, }
• (2025). The NAE1-mediated neddylation operates as an essential post-translational modification checkpoint for effector CD8+ t cells. PNAS, 122(10), e2424061122. (www)

  @article{ , abstract = {Optimal activation of CD8+ T cells is crucial for immunity-mediated destruction of cancer, requiring a substantial amount of proteins involved in metabolism, proliferation, and effector function. Despite extensive studies emphasizing the role of transcriptional regulation in this process, paired transcriptomic and proteomic analyses reveal that the RNA profile is poorly correlated with protein levels. This discrepancy underscores the importance of post-translational modifications (PTMs) in controlling protein abundance during activation. However, the impact of PTMs on the CD8+ T cell protein dynamic remains underexplored. We identify that neddylation, a recently discovered PTM, is activated in response to T cell receptor (TCR) stimulation and enriched in effector CD8+ T cells from colon cancer patients. Mechanistically, we found the rate-limiting enzyme of neddylation, neural precursor cell expressed developmentally down-regulated protein 8 activating enzyme E1 (NAE1), is induced by the NFATc1, a critical transcription factor downstream of TCR signaling. Our observation revealed that genetic ablation of NAE1 significantly disturbed the proteomic landscape related to activation and mitochondrial function. As a result, CD8+ T cells lacking NAE1 exhibited severely compromised activation, proliferation, and survival, which was accompanied by impaired mitochondrial function. Consistently, deletion of NAE1 in CD8+ T cells abolished their antitumor function and promoted tumor progression. By contrast, the overexpression of NAE1 significantly improved the function of tumor-infiltrating CD8+ T cells. Overall, we uncovered neddylation, a previously underappreciated PTM, as a proteomic checkpoint for CD8+ T cell activation. Enforced expression of NAE1 offers promising therapeutic potential for boosting the antitumor CD8+ T cell responses.}, archive = {J_PNAS}, author = {Jin, Jiacheng and Zhang, Ruohan and Li, Jianying and Gao, Fengxia and Liao, Zhiwei and Yu, Yanbao and Wang, Yi and Bucci, Donna and Xiao, Min and Ma, Ruilin and Ma, Qin and Gao, Shuaixin and Lio, Jerry and Novais, Fernanda and Huang, Stanley Ching-Cheng and Zhu, Jiangjiang and Ghoneim, Hazem and Wen, Haitao and Li, Zihai and Sun, Nuo and Xin, Gang}, doi = {10.1073/pnas.2424061122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2424061122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The NAE1-mediated neddylation operates as an essential post-translational modification checkpoint for effector CD8+ t cells}, volume = {122}, year = {2025}, }
• (2025). Systematic identification of allosteric effectors in escherichia coli metabolism. PNAS, 122(10), e2423767122. (www)

  @article{ , abstract = {Recent physical binding screens suggest that protein–metabolite interactions are more extensive than previously recognized. To elucidate the functional relevance of these interactions, we developed a mass spectrometry–based screening method for higher throughput in vitro enzyme assays. By systematically quantifying the effects of 79 metabolites on the activity of 20 central Escherichia coli enzymes, we not only assess functional relevance but also gauge the depth of the current understanding of regulatory interactions within one of the best-characterized networks. Our identification of 50 inhibitors and 14 activators not only expands the range of known input signals but also uncovers novel regulatory logic. For instance, we observed that AMP inhibits malic enzyme to safeguard the cyclic operation of the tricarboxylic acid cycle, and erythrose-4-phosphate inhibits 6-phosphogluconate dehydrogenase to redirect flux from the pentose phosphate pathway into the Entner–Doudoroff pathway. Discrepancies between our standardized assays and existing database entries suggest that many previously reported interactions might occur only under specific, often nonphysiological conditions. Our dataset represents a systematically determined functional protein–metabolite interaction network, establishing a baseline for allosteric regulation in central metabolism. These results enhance our understanding of the regulatory logic governing metabolic processes and underscore its significance in cellular adaptation and growth.}, archive = {J_PNAS}, author = {Gruber, Christoph Heinrich and Noor, Elad and Buffing, Marieke Francisca and Sauer, Uwe}, doi = {10.1073/pnas.2423767122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2423767122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Systematic identification of allosteric effectors in escherichia coli metabolism}, volume = {122}, year = {2025}, }
• (2025). Stereospecific control of microbial growth by a combinatoric suite of chiral siderophores. PNAS, 122(10), e2423730122. (www)

  @article{ , abstract = {Bacteria compete for iron by producing small-molecule chelators known as siderophores. The triscatechol siderophores trivanchrobactin and ruckerbactin, produced by Vibrio campbellii DS40M4 and Yersinia ruckeri YRB, respectively, are naturally occurring diastereomers that form chiral ferric complexes in opposing enantiomeric configurations. Chiral recognition is a hallmark of specificity in biological systems, yet the biological consequences of chiral coordination compounds are relatively unexplored. We demonstrate stereoselective discrimination of microbial growth and iron uptake by chiral Fe(III)–siderophores. The siderophore utilization pathway in V. campbellii DS40M4 is stereoselective for Λ-Fe(III)–trivanchrobactin, but not the mismatched Δ-Fe(III)–ruckerbactin diastereomer. Chiral recognition is likely conferred by the stereospecificity of both the outer membrane receptor (OMR) protein FvtA and the periplasmic binding protein (PBP) FvtB, both of which must interact preferentially with the Λ-configured Fe(III)-coordination complexes.}, archive = {J_PNAS}, author = {Stow, Parker R. and Forsch, Kiefer O. and Thomsen, Emil and Naka, Hiroaki and Haygood, Margo G. and Barbeau, Katherine A. and Butler, Alison}, doi = {10.1073/pnas.2423730122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2423730122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stereospecific control of microbial growth by a combinatoric suite of chiral siderophores}, volume = {122}, year = {2025}, }
• (2025). Evidence for a possible quantum effect on the formation of lithium-doped amorphous calcium phosphate from solution. PNAS, 122(10), e2423211122. (www)

  @article{ , abstract = {Differential isotope effects are an emerging tool for discovering possible nontrivial quantum mechanical effects within biological systems. However, it is often nearly impossible to elucidate the exact mechanisms by which a biological isotope effect manifests due to the complexity of these systems. As such, one proposed in vitro system of study for a quantum isotope effect is calcium phosphate aggregation, where symmetric calcium phosphate molecular species, known as Posner molecules, have been theorized to have phosphorus nuclear spin–dependent self-binding rates, which could be differently modulated by doping with stable lithium isotopes. Here, we present in vitro evidence for such a differential lithium isotope effect on the formation and aggregation of amorphous calcium phosphate from solution under certain conditions. Experiments confirm that lithium incorporates into amorphous calcium phosphate, with 7 Li found to promote a greater abundance of observable calcium phosphate particles than 6 Li under identical solution preparations. These in vitro results offer a potential explanation for in vivo biological studies that have shown differential lithium isotope effects. Given the importance of calcium phosphate in biological systems—ranging from mitochondrial signaling pathways to key biomineralization processes, as well as the proposed role of Posner molecules as a “neural qutrit”—these results present an important step in understanding calcium phosphate nucleation as well as the potential role of calcium phosphate for quantum biology and processing.}, archive = {J_PNAS}, author = {Straub, Joshua S. and Patel, Manisha L. and Nowotarski, Mesopotamia S. and Rao, Lokeswara and Turiansky, Mark E. and Fisher, Matthew P. A. and Helgeson, Matthew E.}, doi = {10.1073/pnas.2423211122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2423211122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evidence for a possible quantum effect on the formation of lithium-doped amorphous calcium phosphate from solution}, volume = {122}, year = {2025}, }
• (2025). Cryo-EM meets crystallography: A model-independent view of the heteronuclear Mn4Ca cluster structure of photosystem II. PNAS, 122(10), e2423012122. (www)

  @article{ , abstract = {Photosynthesis converts solar energy to chemical energy by splitting water molecules and carbon dioxide to produce oxygen and carbohydrates with an efficiency that engineers working on solar energy device can only dream of. Photosystem II (PSII) is the enzyme that catalyzes the light-driven oxidation of water that occurs during photosynthesis. This oxygen-producing reaction occurs in the Mn 4 Ca cluster found inside the enzyme’s oxygen-evolving center (OEC). Even though the structure and mechanism of action of the OEC have been intensively investigated for many decades, questions still remain about both. The Mn 4 Ca cluster stores the high-energy oxidizing equivalents required for water oxidation so that its own oxidation state depends on its chemical composition, i.e., the number of its oxygen ligands. The issue addressed here is the number of oxygen ligands associated with the Mn 4 Ca cluster after PSII has been exposed to two of the four flashes of light necessary for it to produce an oxygen molecule, PSII 2F. Comparisons of recently published cryo-EM maps and crystallographic OEC-omit maps described here reveal the OEC structure of PSII 2F contains only five internal oxygen ligands, and that the sixth O ligand identified earlier in PSII 2F crystal structures is an artifact caused by model bias. This finding should have a significant impact on our understanding of the mechanism of water oxidation that is catalyzed by PSII because it is incompatible with prevailing high valence paradigm (HVP) models for this process.}, archive = {J_PNAS}, author = {Wang, Jimin}, doi = {10.1073/pnas.2423012122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2423012122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryo-EM meets crystallography: A model-independent view of the heteronuclear Mn4Ca cluster structure of photosystem II}, volume = {122}, year = {2025}, }
• (2025). Bacterial estrogenesis without oxygen: Wood–Ljungdahl pathway likely contributed to the emergence of estrogens in the biosphere. PNAS, 122(10), e2422930122. (www)

  @article{ , abstract = {Androgen and estrogen, key sex hormones, were long thought to be exclusively produced by vertebrates. The O 2 -dependent aromatase that converts androgen to estrogen (estrogenesis) has never been identified in any prokaryotes. Here, we report the finding of anaerobic estrogenesis in a Peptococcaceae bacterium ( Phosphitispora sp. strain TUW77) isolated from the gut of the great blue-spotted mudskipper ( Boleophthalmus pectinirostris ). This strain exhibits testosterone fermentation pathways, transforming testosterone into estrogens and androstanediol under anaerobic conditions. Physiological experiments revealed that strain TUW77 grows exclusively on testosterone, utilizing the androgenic C-19 methyl group as both the carbon source and electron donor. The genomic analysis identified three copies of a polycistronic gene cluster, abeABC (anaerobic bacterial estrogenesis), encoding components of a classic cobalamin-dependent methyltransferase system. These genes, highly expressed under testosterone-fed conditions, show up to 57% protein identity to the characterized EmtAB from denitrifying Denitratisoma spp., known for methylating estrogen into androgen (the reverse reaction). Tiered transcriptomic and proteomic analyses suggest that the removed C-19 methyl group is completely oxidized to CO 2 via the oxidative Wood–Ljungdahl pathway (WLP), while the reducing equivalents (NADH) fully reduce remaining testosterone to androstanediol. Consistently, the addition of anthraquinone-2,6-disulfonate, an extracellular electron acceptor, to testosterone-fed TUW77 cultures enabled complete testosterone conversion into estrogen without androstanediol accumulation (anaerobic testosterone oxidation). This finding of aromatase-independent estrogenesis in anaerobic bacteria suggests that the ancient WLP may have contributed to the emergence of estrogens in the early biosphere.}, archive = {J_PNAS}, author = {Wang, Po-Hsiang and Wu, Tien-Yu and Chen, Yi-Lung and Gicana, Ronnie G. and Lee, Tzong-Huei and Chen, Mei-Jou and Hsiao, Tsun-Hsien and Lu, Mei-Yeh Jade and Lai, Yi-Li and Wang, Tzi-Yuan and Li, Jeng-Yi and Chiang, Yin-Ru}, doi = {10.1073/pnas.2422930122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2422930122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bacterial estrogenesis without oxygen: Wood–Ljungdahl pathway likely contributed to the emergence of estrogens in the biosphere}, volume = {122}, year = {2025}, }
• (2025). Photoreduction of mercuric bromides in polar ice. PNAS, 122(10), e2422885122. (www)

  @article{ , abstract = {In the polar regions, which are vulnerable receptors of mercury pollution, atmospheric mercury depletion events (AMDEs) efficiently convert elemental mercury (Hg(0)) into oxidized mercury (Hg(II)) via bromine oxidation. Hg(II) subsequently deposits onto snow and sea ice. While field observations have shown that a large percentage of deposited mercury is re-emitted from the ice to the atmosphere by a photoinduced process, the fundamental photochemistry that drives the re-emission process remains unknown. Here, using multiconfigurational quantum chemistry, we find that the photoreduction of HgBr 2 , HgBr 3 − , and HgBr 4 2− in ice is more efficient than in the gas phase. This results from the influence of water molecules on the molecular geometry and electronic structure of mercuric bromides in ice, which enhances the absorption intensities at wavelengths relevant in the troposphere (λ > 290 nm), as compared to gas phase. Kinetic modeling shows that ~30 to 60% of deposited mercury in AMDEs can be reemitted due to the photoreduction of mercuric bromides in ice, in agreement with field observations. Our results reveal a photoreduction mechanism of sunlight-induced excited state chemistry of mercuric bromides on ice. These findings strongly suggest that this chemistry should be incorporated into atmospheric models to account for ice-atmosphere mercury cycling in the polar environments, currently not considered.}, archive = {J_PNAS}, author = {Carmona-García, Javier and Saiz-Lopez, Alfonso and Mahajan, Anoop S. and Wang, Feiyue and Borrego-Sánchez, Ana and Acuña, A. Ulises and Cuevas, Carlos A. and Dávalos, Juan Z. and Feinberg, Aryeh and Spolaor, Andrea and Ruiz-López, Manuel F. and Francisco, Joseph S. and Roca-Sanjuán, Daniel}, doi = {10.1073/pnas.2422885122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2422885122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Photoreduction of mercuric bromides in polar ice}, volume = {122}, year = {2025}, }
• (2025). Structural basis for dimerization and activation of UvrD-family helicases. PNAS, 122(10), e2422330122. (www)

  @article{ , abstract = {UvrD-family helicases are superfamily 1A motor proteins that function during DNA replication, recombination, repair, and transcription. UvrD family monomers translocate along single-stranded (ss) DNA but need to be activated by dimerization to unwind DNA in the absence of force or accessory factors. However, prior structural studies have only revealed monomeric complexes. Here, we report the first structures of a dimeric UvrD-family helicase, Mycobacterium tuberculosis UvrD1, both free and bound to a DNA junction. In each structure, the dimer interface occurs between the 2B subdomains of each subunit. The apo UvrD1 dimer is observed in symmetric compact and extended forms indicating substantial flexibility. This symmetry is broken in the DNA-bound dimer complex with leading and trailing subunits adopting distinct conformations. Biochemical experiments reveal that the Escherichia coli UvrD dimer shares the same 2B–2B interface. In contrast to the dimeric structures, an inactive, autoinhibited UvrD1 DNA-bound monomer structure reveals 2B subdomain–DNA contacts that are likely inhibitory. The major reorientation of the 2B subdomains that occurs upon UvrD1 dimerization prevents these duplex DNA interactions, thus relieving the autoinhibition. These structures reveal that the 2B subdomain serves a major regulatory role rather than participating directly in DNA unwinding.}, archive = {J_PNAS}, author = {Chadda, Ankita and Nguyen, Binh and Lohman, Timothy M. and Galburt, Eric A.}, doi = {10.1073/pnas.2422330122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2422330122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis for dimerization and activation of UvrD-family helicases}, volume = {122}, year = {2025}, }
• (2025). A horizontally transferred bacterial gene aids the freezing tolerance of antarctic bdelloid rotifers. PNAS, 122(10), e2421910122. (www)

  @article{ , abstract = {Bdelloid rotifers are well known for their abilities to survive long periods of freezing as well as acquire foreign genes. Recently sequenced genomes of some bdelloid rotifers in England were found to encode several proteins similar to ice-binding proteins (IBPs) that are usually associated with freeze–thaw tolerance. Here, I describe bdelloid rotifers inhabiting an algal patch in Antarctica that have multiple homologs of these genes. Structures of the proteins predicted by AlphaFold show that they are well designed for ice-binding and a recombinant protein made for one of them showed strong ice-binding activity. The existence of multiple copies of these proteins is another characteristic of IBPs. Furthermore, multiple bdelloid rotifers in the algal patch were revived in less than an hour after storage at −25 °C for 24 y, an apparent record for laboratory-controlled studies. Several characteristics of these genes point to bacteria as their source: sequence homology, absence of introns, and a structural peculiarity so far found only in bacteria. The remarkable freezing tolerance of bdelloid rotifers can thus be at least partially attributed to horizontally acquired bacterial genes encoding IBPs.}, archive = {J_PNAS}, author = {Raymond, James A.}, doi = {10.1073/pnas.2421910122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2421910122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A horizontally transferred bacterial gene aids the freezing tolerance of antarctic bdelloid rotifers}, volume = {122}, year = {2025}, }
• (2025). Dux cluster duplication ensures full activation of totipotent genes. PNAS, 122(10), e2421594122. (www)

  @article{ , abstract = {Zygotic genome activation (ZGA) confers to the mouse two-cell (2C) embryo a unique transcriptional profile characterized by transient up-regulation of many totipotency-related genes and MERVL retrotransposons. Intriguingly, those genes are duplicated and clustered in the genome during evolution, including Dux cluster, Obox, and Zscan4 family members in mice. However, the contribution and biological significance of the totipotency-related gene duplication events in early embryo development remain poorly understood. Here, we focus on Dux cluster, the master regulator of ZGA that is necessary and sufficient for the induction of 2C-like cells and activation of totipotency-related genes in mouse embryonic stem cells (mESCs). By reducing Dux gene copies from 31 to 0 or 1 through CRISPR-Cas9 technology, we generate Dux -KO and Dux (n = 1) mESC lines, respectively. We uncover that the totipotency-related gene transcriptional profile is awakened to a much lesser extent in Dux (n = 1) mESCs compared to wild type mESCs following global DNA demethylation reprogramming or induction of DNA damage, mimicking the intrinsic events in preimplantation development. Together, Dux cluster duplication is critically required for full activation of ZGA transcripts.}, archive = {J_PNAS}, author = {Lin, Meiqi and Du, Zeling and Guo, Dan and Zhang, Yiran and Dan, Jiameng}, doi = {10.1073/pnas.2421594122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2421594122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dux cluster duplication ensures full activation of totipotent genes}, volume = {122}, year = {2025}, }
• (2025). Fluidization and anomalous density fluctuations in 2D voronoi cell tissues with pulsating activity. PNAS, 122(10), e2421518122. (www)

  @article{ , abstract = {Cells not only can be motile by crawling but are also capable of nonmotility active motions like periodic contraction or pulsation. In this work, based on a Voronoi cell model, we show how this nonmotility activity affects the structure, dynamic, and density fluctuations of cellular monolayers. Our model shows that random cell pulsation fluidizes solid epithelial tissues into a hyperuniform fluid state, while pulsation synchronization inhibits the fluidity and causes a reverse solidification. Our results indicate this solidification is a Berezinskii–Kosterlitz–Thouless-type transition, characterized by strong density/dynamic heterogeneity arising from the annihilation of topological defects in the pulsating phase space. The magnitude and length scale of density heterogeneity diverge with the pulsating period, resulting in an opposite giant density fluctuation or anti-hyperuniformity. We propose a fluctuating hydrodynamic theory that can unify the two opposite anomalous fluctuation phenomena. Our findings can help to understand recent experimental observations in Madin-Darby canine kidney monolayers.}, archive = {J_PNAS}, author = {Li, Zhu-Qin and Lei, Qun-Li and Ma, Yu-Qiang}, doi = {10.1073/pnas.2421518122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2421518122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fluidization and anomalous density fluctuations in 2D voronoi cell tissues with pulsating activity}, volume = {122}, year = {2025}, }
• (2025). Independent and combined effects of long-term air pollution exposure and genetic predisposition on COVID-19 severity: A population-based cohort study. PNAS, 122(10), e2421513122. (www)

  @article{ , abstract = {The relationships between air pollution, genetic susceptibility, and COVID-19-related outcomes, as well as the potential interplays between air pollution and genetic susceptibility, remain largely unexplored. The Cox proportional hazards model was used to assess associations between long-term exposure to air pollutants and the risk of COVID-19 outcomes (infection, hospitalization, and death) in a COVID-19-naive cohort (n = 458,396). Additionally, associations between air pollutants and the risk of COVID-19 severity (hospitalization and death) were evaluated in a COVID-19 infection cohort (n = 110,216). Furthermore, this study investigated the role of host genetic susceptibility in the relationships between exposure to air pollutants and the development of COVID-19-related outcomes. Long-term exposure to air pollutants was significantly associated with an increased risk of COVID-19-related outcomes in the COVID-19 naive cohort. Similarly, in COVID-19 infection cohort, hazard ratios (HRs) for COVID-19 hospital admission were 1.23 (1.19, 1.27) for PM 2.5 and 1.22 (1.17, 1.26) for PM 10 , whereas HRs for COVID-19 death were 1.28 (1.18, 1.39) for PM 2.5 and 1.25 (1.16, 1.36) for PM 10 . Notably, significant interactions were found between PM 2.5 /PM 10 and genetic susceptibility in COVID-19 death. In COVID-19 infection cohort, participants with both high genetic risk and high air pollutants exposure had 1.86- to 1.97-fold and 1.91- to 2.14-fold higher risk of COVID-19 hospitalization and death compared to those with both low genetic risk and low air pollutants exposure. Exposure to air pollution is significantly associated with an increased burden of severe COVID-19, and air pollution–gene interactions may play a crucial role in the development of COVID-19-related outcomes.}, archive = {J_PNAS}, author = {Ma, Yudiyang and Wang, Jianing and Cui, Feipeng and Tang, Linxi and Khalid, Sara and Tian, Yaohua and Xie, Junqin}, doi = {10.1073/pnas.2421513122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2421513122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Independent and combined effects of long-term air pollution exposure and genetic predisposition on COVID-19 severity: A population-based cohort study}, volume = {122}, year = {2025}, }
• (2025). Molecular mechanism of arp2/3 complex activation by nucleation-promoting factors and an actin monomer. PNAS, 122(10), e2421467122. (www)

  @article{ , abstract = {Arp (actin-related protein) 2/3 complex nucleates actin filament branches on the sides of preexisting actin filaments during cell and organelle movements. We used computer simulations of mammalian Arp2/3 complex to address fundamental questions about the mechanism. Metadynamics and umbrella free energy sampling simulations of the pathway revealed that a clash between the D-loop of Arp2 and Arp3 produces an energy barrier of 20 ± 6 kcal/mol between the inactive splayed and active short-pitch conformations of Arp2/3 complex. Atomistic molecular dynamics simulations showed that binding the CA motif of the nucleation-promoting factor Neuronal Wiskott-Aldrich Syndrome Protein (N-WASp) to inactive, splayed Arp2/3 complex shifts it toward the short-pitch active conformation and opens a binding site for an actin monomer on Arp3. Other simulations showed that this actin monomer stabilizes a transition state of Arp2/3 complex. These observations together with prior experimental work provide insights required to propose a physically grounded pathway for actin filament branch formation.}, archive = {J_PNAS}, author = {Sridharan Iyer, Sahithya and Wu, Jiangbo and Pollard, Thomas D. and Voth, Gregory A.}, doi = {10.1073/pnas.2421467122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2421467122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular mechanism of arp2/3 complex activation by nucleation-promoting factors and an actin monomer}, volume = {122}, year = {2025}, }
• (2025). Adeno-associated viruses for efficient gene expression in the axolotl nervous system. PNAS, 122(10), e2421373122. (www)

  @article{ , abstract = {Axolotls are amphibian models for studying nervous system evolution, development, and regeneration. Tools to visualize and manipulate cells of the axolotl nervous system with high-efficiency, spatial and temporal precision are therefore greatly required. Recombinant adeno-associated viruses (AAVs) are frequently used for in vivo gene transfer of the nervous system but virus-mediated gene delivery to the axolotl nervous system has not yet been described. Here, we demonstrate the use of AAVs for efficient gene transfer within the axolotl brain, the spinal cord, and the retina. We show that serotypes AAV8, AAV9, and AAVPHP.eB are suitable viral vectors to infect both excitatory and inhibitory neuronal populations of the axolotl brain. We further use AAV9 to trace retrograde and anterograde projections between the retina and the brain and identify a cell population projecting from the brain to the retina. Together, our work establishes AAVs as a powerful tool to interrogate neuronal organization in the axolotl.}, archive = {J_PNAS}, author = {Lust, Katharina and Tanaka, Elly M.}, doi = {10.1073/pnas.2421373122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2421373122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Adeno-associated viruses for efficient gene expression in the axolotl nervous system}, volume = {122}, year = {2025}, }
• (2025). RNA-targeted proteomics identifies YBX1 as critical for efficient HCMV mRNA translation. PNAS, 122(10), e2421155122. (www)

  @article{ , abstract = {Viruses have evolved unique strategies to circumvent host control of protein synthesis and enable viral protein synthesis in the face of the host response. Defining the factors that regulate viral messenger RNA (mRNA) translation is thus critical to understand how viruses replicate and cause disease. To identify factors that might regulate viral mRNA translation, we developed a technique for identifying proteins associated with a native RNA expressed from its endogenous promoter and genomic locus. This approach uses a guide RNA to target dCas13b fused to a biotin ligase domain to a specific RNA, where it covalently labels proteins in close proximity. Using this approach, we identified multiple proteins associated with transcripts encoding the human cytomegalovirus (HCMV) IE1 and IE2 proteins and found that several associated proteins positively or negatively regulate HCMV replication. We confirmed that one such protein, the cellular Y-box binding protein 1 (YBX1), binds to HCMV immediate early mRNAs and is required for efficient viral protein expression and virus replication. Ablating YBX1 expression reduced the association of HCMV immediate early mRNAs with polysomes, demonstrating a role for YBX1 as a positive regulator of viral RNA translation. These results provide a powerful tool for unraveling RNA–protein interactions that can be used in a wide range of biological processes and reveal a role for YBX1 as a critical regulator of HCMV immediate early gene expression.}, archive = {J_PNAS}, author = {Dickmander, Rebekah J. and Lenarcic, Erik M. and Sears, John D. and Hale, Andrew E. and Moorman, Nathaniel J.}, doi = {10.1073/pnas.2421155122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2421155122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RNA-targeted proteomics identifies YBX1 as critical for efficient HCMV mRNA translation}, volume = {122}, year = {2025}, }
• (2025). Monitoring chalcogenide ions–guided in situ transform active sites of tailored bismuth electrocatalysts for CO2 reduction to formate. PNAS, 122(10), e2420922122. (www)

  @article{ , abstract = {Although bismuth catalysts enable accelerated electrochemical CO 2 -to-formate conversion, the intrinsic active sites and forming mechanisms under operating conditions remain elusive. Herein, we prepared Bi 2 O 2 NCN, Bi 2 O 3 , and Bi 2 O 2 S as precatalysts. Among them, Bi 2 O 2 NCN-derived catalyst possesses optimum performance of electrochemical CO 2 -to-formate, exhibiting an upsurge of Faradaic efficiency to 98.3% at –0.6 V vs. reversible hydrogen electrodes. In-situ infrared and electrochemical impedance spectra trace and interpret the superior performance. Multimodal structural analyses utilizing quasi-in-situ X-ray diffraction, in-situ X-ray absorption near edge structure and in-situ Raman spectra provide powerful support to monitoring the catalysts’ in-situ transforms to metallic Bi, identifying the formation of the active sites influenced by the chalcogenide ions-guided: Carbodiimide promotes to form of the dominant Bi(003) facet exposure, which distinguishes from sulfide- and oxide-preferred dominant Bi(012) facets exposure. Concurrently, theoretical insights garnered from multiscale/multilevel computational analyses harmoniously corroborate the experimental findings. These findings show the pivotal role of chalcogenide in tailoring bismuth electrocatalysts for selective CO 2 reduction to formate, illuminating the significance of controlling structural chemistry in designing catalysts toward high-efficiency renewable energy conversion.}, archive = {J_PNAS}, author = {Chen, Zheng and Xiao, Yi and Qiao, Xianji and Ou, Honghui and Lee, Chi-Feng and Wang, Hsiao-Tsu and Shao, Yu-Cheng and Han, Lili}, doi = {10.1073/pnas.2420922122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2420922122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Monitoring chalcogenide ions–guided in situ transform active sites of tailored bismuth electrocatalysts for CO2 reduction to formate}, volume = {122}, year = {2025}, }
• (2025). Logic-based machine learning predicts how escitalopram attenuates cardiomyocyte hypertrophy. PNAS, 122(10), e2420499122. (www)

  @article{ , abstract = {Cardiomyocyte hypertrophy is a key clinical predictor of heart failure. High-throughput and AI-driven screens have the potential to identify drugs and downstream pathways that modulate cardiomyocyte hypertrophy. Here, we developed LogiRx, a logic-based mechanistic machine learning method that predicts drug-induced pathways. We applied LogiRx to discover how drugs discovered in a previous compound screen attenuate cardiomyocyte hypertrophy. We experimentally validated LogiRx predictions in neonatal cardiomyocytes, adult mice, and two patient databases. Using LogiRx, we predicted antihypertrophic pathways for seven drugs currently used to treat noncardiac disease. We experimentally validated that escitalopram (Lexapro) and mifepristone inhibit hypertrophy of cultured cardiomyocytes in two contexts. The LogiRx model predicted that escitalopram prevents hypertrophy through an “off-target” serotonin receptor/PI3Kγ pathway, mechanistically validated using additional investigational drugs. Further, escitalopram reduced cardiomyocyte hypertrophy in a mouse model of hypertrophy and fibrosis. Finally, mining of both FDA and University of Virginia databases showed that patients with depression on escitalopram have a lower incidence of cardiac hypertrophy than those prescribed other serotonin reuptake inhibitors that do not target the serotonin receptor. Mechanistic machine learning by LogiRx discovers drug pathways that perturb cell states, which may enable repurposing of escitalopram and other drugs to limit cardiac remodeling through off-target pathways.}, archive = {J_PNAS}, author = {Eggertsen, Taylor G. and Travers, Joshua G. and Hardy, Elizabeth J. and Wolf, Matthew J. and McKinsey, Timothy A. and Saucerman, Jeffrey J.}, doi = {10.1073/pnas.2420499122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2420499122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Logic-based machine learning predicts how escitalopram attenuates cardiomyocyte hypertrophy}, volume = {122}, year = {2025}, }
• (2025). Genetic ablation of the TET family in retinal progenitor cells impairs photoreceptor development and leads to blindness. PNAS, 122(10), e2420091122. (www)

  @article{ , abstract = {The retina is responsible for converting light into electrical signals that, when transmitted to the brain, create the sensation of vision. The mammalian retina is epigenetically unique since the differentiation of retinal progenitor cells (RPCs) into retinal cells is accompanied by a decrease in DNA methylation in the promoters of many genes important for retinal development and function. However, the pathway responsible for DNA demethylation and its role in retinal development and function were unknown. We hypothesized that the Ten-Eleven Translocation (TET) family of dioxygenases plays a key role in this pathway. To this end, we knocked out the TET family in RPCs and characterized the TET-deficient and control retinas using various approaches including electron microscopy, electroretinogram tests, TUNEL, RNA-seq, WGBS, and 5hmC-Seal. We found that while the TET-dependent DNA demethylation pathway contributes to the development of many retinal cell types, it is the most significant contributor to rod and cone photoreceptor development and function. We found that genetic ablation of TET enzymes in RPCs prevents demethylation and the activity of genes essential for rod specification and for rod and cone maturation. Reduced activity of genes responsible for rod specification results in the TET-deficient retina being depleted of these neurons. Meanwhile, reduced activity of genes responsible for rod and cone maturation leads to the underdevelopment or complete absence of outer segments and synaptic termini in the TET-deficient photoreceptors, which results in loss of their function and leads to blindness. These function-deprived, underdeveloped photoreceptors die over time, leading to retinal dystrophy.}, archive = {J_PNAS}, author = {Dvoriantchikova, Galina and Moulin, Chloe and Fleishaker, Michelle and Almeida, Vania and Pelaez, Daniel and Lam, Byron L. and Ivanov, Dmitry}, doi = {10.1073/pnas.2420091122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2420091122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genetic ablation of the TET family in retinal progenitor cells impairs photoreceptor development and leads to blindness}, volume = {122}, year = {2025}, }
• (2025). Recessive genetic contribution to congenital heart disease in 5,424 probands. PNAS, 122(10), e2419992122. (www)

  @article{ , abstract = {Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands. Rare damaging RGs were estimated to contribute to at least 2.2% of CHD, with greater enrichment among laterality phenotypes (5.4%) versus other subsets (1.4%). Among 108 curated human recessive CHD genes, there were 66 RGs, with 54 in 11 genes with >1 RG, 12 genes with 1 RG, and 85 genes with zero. RGs were more prevalent among offspring of consanguineous union (4.7%, 32/675) than among nonconsanguineous probands (0.7%, 34/4749). Founder variants in GDF1 and PLD1 accounted for 74% of the contribution of RGs among 410 Ashkenazi Jewish probands. We identified genome-wide significant enrichment of RGs in C1orf127 , encoding a likely secreted protein expressed in embryonic mouse notochord and associated with laterality defects. Single-cell transcriptomes from gastrulation-stage mouse embryos revealed enrichment of RGs in genes highly expressed in the cardiomyocyte lineage, including contractility-related genes MYH6, UNC45B , MYO18B , and MYBPC3 in probands with left-sided CHD, consistent with abnormal contractile function contributing to these malformations. Genes with significant RG burden account for 1.3% of probands, more than half the inferred total. These results reveal the recessive contribution to CHD, and indicate that many genes remain to be discovered, with each likely accounting for a very small fraction of the total.}, archive = {J_PNAS}, author = {Dong, Weilai and Jin, Sheng Chih and Sierant, Michael C. and Lu, Ziyu and Li, Boyang and Lu, Qiongshi and Morton, Sarah U. and Zhang, Junhui and López-Giráldez, Francesc and Nelson-Williams, Carol and Knight, James R. and Zhao, Hongyu and Cao, Junyue and Mane, Shrikant and Gruber, Peter J. and Lek, Monkol and Goldmuntz, Elizabeth and Deanfield, John and Giardini, Alessandro and Mital, Seema and Russell, Mark and Gaynor, J. William and Cnota, James F. and Wagner, Michael and Srivastava, Deepak and Bernstein, Daniel and Porter, George A. and Newburger, Jane and Roberts, Amy E. and Yandell, Mark and Yost, H. Joseph and Tristani-Firouzi, Martin and Kim, Richard and Seidman, Jonathan and Chung, Wendy K. and Gelb, Bruce D. and Seidman, Christine E. and Lifton, Richard P. and Brueckner, Martina}, doi = {10.1073/pnas.2419992122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2419992122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Recessive genetic contribution to congenital heart disease in 5,424 probands}, volume = {122}, year = {2025}, }
• (2025). Structural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr. PNAS, 122(10), e2419854122. (www)

  @article{ , abstract = {Targeting the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 with small molecules is a promising therapeutic strategy against COVID-19, but potent and safe inhibitors are lacking. HeE1-2Tyr, a nonnucleoside inhibitor of Dengue virus RdRp, was also shown to inhibit SARS-CoV-2 RdRp in vitro and to have antiviral activity in cells, but the underlying mechanism remains unclear. Here, we elucidate the molecular mechanism of HeE1-2Tyr-mediated SARS-CoV-2 RdRp inhibition. Biochemical assays confirm that HeE1-2Tyr inhibits RdRp with an IC 50 of 5 µM and show that it competes with RNA binding to RdRp in vitro. Structural analysis using cryo-EM reveals that a stack of three HeE1-2Tyr molecules binds to the RNA binding site of RdRp. The identification of the conserved HeE1-2Tyr binding site and its intriguing inhibition mechanism of three stacked molecules that outcompete RNA may facilitate further development of pan-corona nonnucleoside inhibitors.}, archive = {J_PNAS}, author = {Kabinger, Florian and Doze, Valerie and Schmitzová, Jana and Lidschreiber, Michael and Dienemann, Christian and Cramer, Patrick}, doi = {10.1073/pnas.2419854122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2419854122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr}, volume = {122}, year = {2025}, }
• (2025). The neural bases of the reach–grasp movement in humans: Quantitative evidence from brain lesions. PNAS, 122(10), e2419801122. (www)

  @article{ , abstract = {Visually guided grasping is a fundamental building block of animal behavior, the specific neural mechanisms of which remain poorly documented in the human brain. We have mapped the causal contribution of different brain parts to grasping behavior by studying the kinematic parameters of 33 patients with brain tumors, engaged in actions directed toward objects of different sizes. Using motion capture techniques, we analyzed the dynamics of grip aperture and wrist transport. Voxel-based lesion-symptom mapping analysis was applied to correlate lesion volumes with specific behavioral deficits. Results showed that lesions in the anterior and lateral bank of the intraparietal sulcus produced impaired finger scaling related to object size. Conversely, impaired velocity of finger aperture was associated with lesions in the dorsal premotor cortex (PMd). Grip aperture deficits following dominant hemisphere lesions were bilateral and were unilateral when following nondominant hemisphere lesions. Impaired wrist transport during reaching was associated with lesions in the first segment of the superior longitudinal fasciculus. Our work highlights an architecture of the grasping network in humans, with unique species-specific features. We hypothesize a model of human neural architecture in which object geometry for hand preshaping is first coded in the left anterior intraparietal cortex and then shared with the right hemisphere. Execution of the motor program of hand preshaping is then performed by the PMd on the corresponding side.}, archive = {J_PNAS}, author = {Di Caro, Valeria and Cesari, Paola and Sala, Francesco and Cattaneo, Luigi}, doi = {10.1073/pnas.2419801122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2419801122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The neural bases of the reach–grasp movement in humans: Quantitative evidence from brain lesions}, volume = {122}, year = {2025}, }
• (2025). MUC5AC filaments illuminate the structural diversification of respiratory and intestinal mucins. PNAS, 122(10), e2419717122. (www)

  @article{ , abstract = {Secreted mucins are multimegadalton glycoprotein polymers that share the function of protecting mucosal tissues but diversified for activities in different organs of the body. Structural studies of secreted mucins are complicated by the enormous sizes, flexibility, and complex supramolecular assembly modes of these glycoproteins. The two major respiratory mucins are MUC5AC and MUC5B. Here, we present structures of a large amino-terminal segment of MUC5AC in the form of helical filaments. These filaments differ from filamentous and tubular structures observed previously for the intestinal mucin MUC2 and the partial mucin homolog VWF. Nevertheless, the MUC5AC helical filaments support the proposed mechanism, based on MUC2 and VWF, for how noncovalent interactions between mucin monomers guide disulfide crosslinking to form polymers. The high-resolution MUC5AC structures show how local and limited changes in amino acid sequence can profoundly affect higher-order assembly while preserving the overall folds and polymerization activity of mucin glycoproteins. Differences in supramolecular assembly are likely to be functionally significant considering the divergence of mechanical properties and physiological requirements between respiratory and intestinal mucins. Determining the high-resolution structures of respiratory mucins provides a foundation for understanding the mechanisms by which they clean and protect the lungs. Moreover, the MUC5AC structure enables visualization of the sites of human amino acid sequence variation and disease-associated mutations.}, archive = {J_PNAS}, author = {Haberman, Meital and Kamyshinsky, Roman and Reznik, Nava and Yeshaya, Noa and Khmelnitsky, Lev and Plender, Elizabeth G. and Eichler, Evan E. and Fass, Deborah}, doi = {10.1073/pnas.2419717122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2419717122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MUC5AC filaments illuminate the structural diversification of respiratory and intestinal mucins}, volume = {122}, year = {2025}, }
• (2025). The effect of salt additives on the glycine crystallization pathway revealed by studying one crystal nucleation at a time. PNAS, 122(10), e2419638122. (www)

  @article{ , abstract = {Molecular-level understanding of the early stage of crystallization remains a significant challenge. For a wide range of fundamental research and applications, it is of great importance to understand the mechanism of crystal polymorph selections in different solvents or in the presence of additives. We studied glycine crystallization in aqueous solution with or without the addition of sodium chloride (NaCl), one crystal nucleation at a time, using the recently developed single-crystal nucleation spectroscopy (SCNS). It has been reported that glycine forms γ-glycine when salt is added to aqueous solution, and the mechanism has been considered as a classical nucleation where γ-glycine forms directly as a crystal nucleus. Our study shows that metastable polymorph β-glycine forms first in aqueous solution both with or without NaCl through a nonclassical nucleation pathway. NaCl can stabilize the metastable β-glycine over several hours and also prevent it from converting to α-glycine. Eventually γ-glycine nucleates on the surface of β-glycine and then grows while dissolving the mother β-glycine. The crystal habit of β-glycine suggests that the stabilization by NaCl occurs at its polar face. SCNS provides crucial information to accelerate the investigation of the early stage of crystallization toward the rational control of polymorphisms.}, archive = {J_PNAS}, author = {Cotting, Gabriel and Urquidi, Oscar and Besnard, Céline and Brazard, Johanna and Adachi, Takuji B. M.}, doi = {10.1073/pnas.2419638122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2419638122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The effect of salt additives on the glycine crystallization pathway revealed by studying one crystal nucleation at a time}, volume = {122}, year = {2025}, }
• (2025). HCV NS3/4A protease relocalizes CCTα to viral replication sites, enhancing phosphatidylcholine synthesis and viral replication. PNAS, 122(10), e2419632122. (www)

  @article{ , abstract = {Positive-sense single-stranded RNA [(+)RNA] viruses constitute more than one-third of all virus genera, including numerous pathogens of clinical significance. All (+)RNA viruses reorganize cellular membranes from organelles to establish replication compartments (RCs). These RCs are thought to form a platform for membrane-associated replicases, in addition to protecting the viral RNAs from cytosolic innate immune signaling and RNA-degradation machinery. Previous work demonstrated that three families of (+)RNA viruses, namely Bromoviridae , Picornaviridae , and Flaviviridae , commonly induce the accumulation of phosphatidylcholine (PC) at their RCs. This phenomenon suggests a potential avenue for a broad-spectrum antiviral strategy targeting PC metabolism. Our study elucidates three key observations: i) hepatitis C virus (HCV) infection prompts the relocalization of CCTα, the rate-limiting enzyme in PC synthesis, to the RCs; ii) the enhancement of PC synthesis is contingent upon the protease activity of the NS3/4A protein; and iii) utilizing click chemistry, we demonstrate that HCV infection stimulates de novo PC synthesis at the viral replication site through the Kennedy pathway. These findings provide significant insights into the manipulation of lipid metabolism by HCV during RC formation, a mechanism likely conserved across various (+)RNA virus families.}, archive = {J_PNAS}, author = {Sarwar, Shamila and Randall, Glenn}, doi = {10.1073/pnas.2419632122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2419632122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {HCV NS3/4A protease relocalizes CCTα to viral replication sites, enhancing phosphatidylcholine synthesis and viral replication}, volume = {122}, year = {2025}, }
• (2025). Coronavirus endoribonuclease antagonizes ZBP1-mediated necroptosis and delays multiple cell death pathways. PNAS, 122(10), e2419620122. (www)

  @article{ , abstract = {Identifying conserved mechanisms used by viruses to delay host innate responses can reveal potential targets for antiviral therapeutics. Here, we investigated coronavirus nonstructural protein 15 (nsp15), which encodes a highly conserved endoribonuclease (EndoU). EndoU functions as an immune antagonist by limiting the accumulation of viral replication intermediates that would otherwise be sensed by the host. Despite being a promising antiviral target, it has been difficult to develop small-molecule inhibitors that target the EndoU active site. We generated nsp15 mutants of the coronaviruses severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mouse hepatitis virus (MHV)-A59 and identified conserved residues within the amino-terminal domain that are required for EndoU activity. Loss of EndoU activity caused the activation of host sensors, which limited viral replication in interferon-responsive cells and attenuated disease in MHV-infected mice. Using transcriptional profiling, we found that MHV EndoU mutant viruses upregulate multiple host sensors, including Z-form nucleic acid-binding protein 1 (ZBP1). We found that nsp15 mutants induced early, robust ZBP1-mediated necroptosis. EndoU mutant viruses also induced ZBP1-independent apoptosis and pyroptosis pathways, causing early, robust cell death that limits virus replication and pathogenesis. Overall, we document the importance of the amino-terminal domain for EndoU function. We also highlight the importance of nsp15/EndoU activity for evading host sensors, delaying cell death, and promoting pathogenesis.}, archive = {J_PNAS}, author = {Evdokimova, Monika and Feng, Shuchen and Caobi, Allen and Moreira, Fernando R. and Jones, Dakota and Alysandratos, Konstantinos-Dionysios and Tully, Ena S. and Kotton, Darrell N. and Boyd, David F. and Banach, Bridget S. and Kirchdoerfer, Robert N. and Saeed, Mohsan and Baker, Susan C.}, doi = {10.1073/pnas.2419620122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2419620122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Coronavirus endoribonuclease antagonizes ZBP1-mediated necroptosis and delays multiple cell death pathways}, volume = {122}, year = {2025}, }
• (2025). Cluster dynamical mean-field study of intra-unit-cell charge nematicity in hole-doped cuprates. PNAS, 122(10), e2419534122. (www)

  @article{ , abstract = {Recent scanning-tunneling microscopy on hole-doped Bi 2 Sr 2 CaCu 2 O 8 , one of the materials of the cuprate family, finds a long-range ordered spontaneous splitting of the energy levels of oxygen orbitals inside the CuO 2 unit cells [S. Wang et al ., Nat. Mat. 23, 492–498 (2024)]. This spontaneous intra-unit-cell orbital ordering, also known as electronic nematicity, breaks C 4 symmetry and is thought to arise from the Coulomb interaction (denoted by V pp ) between oxygen p x and p y electrons. In this work, we study the spontaneous emergence of electronic nematicity within the three-band Hubbard [aka the Emery-VSA (Varma-Schmitt-Rink-Abrahams) model], using cluster dynamical mean-field theory. This method incorporates short-range electronic correlations and gives us access to the density of states, a quantity that is directly probed in experiments. We argue that there is a delicate competition between V pp and V pd (the latter being the Coulomb interaction between copper d x 2 − y 2 and oxygen p x , y electrons) that must be taken into account in order to find a Zhang-Rice singlet band well-resolved from the upper Hubbard band, and a splitting of the charge-transfer band (one of the signatures of charge nematicity) by roughly 50 meV, as observed recently.}, archive = {J_PNAS}, author = {Kumar, Abhishek and Sénéchal, David and Tremblay, A.-M. S.}, doi = {10.1073/pnas.2419534122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2419534122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cluster dynamical mean-field study of intra-unit-cell charge nematicity in hole-doped cuprates}, volume = {122}, year = {2025}, }
• (2025). Mechanical ventilation energy analysis: Recruitment focuses injurious power in the ventilated lung. PNAS, 122(10), e2419374122. (www)

  @article{ , abstract = {The progression of acute respiratory distress syndrome (ARDS) from its onset due to disease or trauma to either recovery or death is poorly understood. Currently, there are no generally accepted treatments aside from supportive care using mechanical ventilation. However, this can lead to ventilator-induced lung injury (VILI), which contributes to a 30 to 40% mortality rate. In this study, we develop and demonstrate a technique to quantify forms of energy transport and dissipation during mechanical ventilation to directly evaluate their relationship to VILI. A porcine ARDS model was used, with ventilation parameters independently controlling lung overdistension and alveolar/airway recruitment/derecruitment (RD). Hourly measurements of airflow, tracheal and esophageal pressures, respiratory system impedance, and oxygen transport were taken for six hours following lung injury to track energy transfer and lung function. The final degree of injury was assessed histologically. Total and dissipated energies were quantified from lung pressure–volume relationships and subdivided into contributions from airflow, tissue viscoelasticity, and RD. Only RD correlated with physiologic recovery. Despite accounting for a very small fraction (2 to 5%) of the total energy dissipation, RD is damaging because it occurs quickly over a very small area. We estimate power intensity of RD energy dissipation to be 100 W/m 2 , equivalent to 10% of the Sun’s luminance at the Earth’s surface. Minimizing repetitive RD events may thus be crucial for mitigating VILI.}, archive = {J_PNAS}, author = {Gaver, Donald P. and Kollisch-Singule, Michaela and Nieman, Gary and Satalin, Joshua and Habashi, Nader and Bates, Jason H. T.}, doi = {10.1073/pnas.2419374122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2419374122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mechanical ventilation energy analysis: Recruitment focuses injurious power in the ventilated lung}, volume = {122}, year = {2025}, }
• (2025). BIN1 reduction ameliorates DNM2-related Charcot–Marie–Tooth neuropathy. PNAS, 122(10), e2419244122. (www)

  @article{ , abstract = {Charcot–Marie–Tooth (CMT) disease, the most common inherited neuromuscular disorder, manifests as progressive muscle weakness and peripheral nerve defects. Dominant mutations in DNM2 , encoding the large GTPase dynamin 2, result in CMT without any suggested therapeutic strategy. Different dominant mutations in DNM2 also cause centronuclear myopathy (CNM), and increasing BIN1 (amphiphysin 2), an endogenous modulator of DNM2, rescued CNM in mice. Here, we found that increasing BIN1 level exacerbated the phenotypes of the Dnm2 K562E/+ mouse carrying the most common DNM2 -CMT mutation. Conversely, whole-body reduction of Bin1 expression level, through the generation of Dnm2 K562E/+ mice with heterozygous loss of BIN1, restored motor performance and ameliorated muscle organization and structural defects of peripheral nerves. The rescue of motor defects was maintained at least up to 1 y of age. BIN1 inhibited the GTPase activity of DNM2, and the rescue was driven by an increased activity of the K562E DNM2 -CMT mutant, and a normalization of integrin localization in muscle. Overall, this study highlights BIN1 as a modifier of DNM2 -CMT, and its reduction as a potential therapeutic strategy. It also revealed an opposite pathological mechanism and inverse therapeutic concepts for DNM2 -CMT peripheral neuropathy versus DNM2 -CNM myopathy.}, archive = {J_PNAS}, author = {Goret, Marie and Thomas, Morgane and Edelweiss, Evelina and Messaddeq, Nadia and Laporte, Jocelyn}, doi = {10.1073/pnas.2419244122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2419244122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {BIN1 reduction ameliorates DNM2-related Charcot–Marie–Tooth neuropathy}, volume = {122}, year = {2025}, }
• (2025). Input-driven circuit reconfiguration in critical recurrent neural networks. PNAS, 122(10), e2418818122. (www)

  @article{ , abstract = {Changing a circuit dynamically, without actually changing the hardware itself, is called reconfiguration, and is of great importance due to its manifold technological applications. Circuit reconfiguration appears to be a feature of the cerebral cortex, so understanding the dynamical principles underlying self-reconfiguration may prove of import to elucidate brain function. We present a very simple example of dynamical reconfiguration: a family of networks whose signal pathways can be switched on the fly, only through use of their inputs, with no changes to their synaptic weights. These are single-layer convolutional recurrent network with local unitary synaptic weights and a smooth sigmoidal activation function. We generate traveling waves using the high spatiotemporal frequencies of the input, and we use the low spatiotemporal frequencies of the input to landscape the ongoing activity, channeling said traveling waves through an input-specified spatial pattern. This mechanism uses inherent properties of marginally stable, dynamically critical systems, which are a direct consequence of their unitary convolution kernels: every network in the family can do this. We show these networks solve the classical connectedness detection problem, by allowing signal propagation only along the regions to be evaluated for connectedness, and forbidding it elsewhere.}, archive = {J_PNAS}, author = {Magnasco, Marcelo O.}, doi = {10.1073/pnas.2418818122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2418818122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Input-driven circuit reconfiguration in critical recurrent neural networks}, volume = {122}, year = {2025}, }
• (2025). Vimentin undergoes liquid–liquid phase separation to form droplets which wet and stabilize actin fibers. PNAS, 122(10), e2418624122. (www)

  @article{ , abstract = {The cytoskeleton is composed of F-actin, microtubules, and intermediate filaments (IFs). Vimentin is one of the most ubiquitous and well-studied IFs. It is involved in many activities including wound healing, tissue fibrosis, and cancer metastasis, all of which require rapid vimentin IF assembly. In this paper, we report that vimentin forms liquid condensates which appear to enable rapid filament growth. Given the transient nature of these droplets, we focus on properties of vimentin-Y117L, which has a point mutation that leads to formation of condensates but not IFs, enabling us to study these droplets in detail. The droplets dissolve under 1,6-Hexanediol treatment and under decreasing concentration, confirming that they are liquid, and phase separated. These condensates extensively wet actin stress fibers, rendering them resistant to actin-binding drugs and protecting them from depolymerization. We show similar behavior occurs in wild-type vimentin during its assembly into filaments.}, archive = {J_PNAS}, author = {Basu, Arkaprabha and Krug, Tommy and du Pont, Benjamin and Huang, Qiaoling and Sun, Sijie and Adam, Stephen A. and Goldman, Robert D. and Weitz, David A.}, doi = {10.1073/pnas.2418624122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2418624122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Vimentin undergoes liquid–liquid phase separation to form droplets which wet and stabilize actin fibers}, volume = {122}, year = {2025}, }
• (2025). Visualizing agonist-induced m2 receptor activation regulated by aromatic ring dynamics. PNAS, 122(10), e2418559122. (www)

  @article{ , abstract = {Despite the growing number of G protein–coupled receptor (GPCR) structures being resolved, the dynamic process of how GPCRs transit from the inactive toward the active state remains unclear. In this study, comprehensive molecular dynamics simulations were performed to explore how ligand binding modulates the conformational dynamics of the M2 muscarinic acetylcholine receptor (M2R). We observed a sequential occurrence of structural changes in the inactive-to-active transition of M2R induced by a superagonist iperoxo, which includes the orthosteric binding site contraction, the TM6 opening into an intermediate conformation, and a further structural change toward full activation upon binding to G protein or a G protein mimetic nanobody. Two activation intermediates were identified, which show structural features different from those reported for apo-GPCRs. Moreover, our results suggest that stabilization of a specific W400 6.48 conformation and enhanced F396 6.44 dynamics are crucial for activation, whereas distinct side-chain rotamer equilibriums of Y206 5.58 in the cytoplasmic cavity are correlated with agonist efficacies. Our work provides atomic-level structural insights into the agonist-induced M2R activation pathway and highlights a mechanism by which ligand efficacy can be encoded and transduced in the form of aromatic ring dynamics.}, archive = {J_PNAS}, author = {Gong, Zhou and Zhang, Xu and Liu, Maili and Jin, Changwen and Hu, Yunfei}, doi = {10.1073/pnas.2418559122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2418559122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Visualizing agonist-induced m2 receptor activation regulated by aromatic ring dynamics}, volume = {122}, year = {2025}, }
• (2025). Atomic ionization: Sd energy imbalance and Perdew–Zunger self-interaction correction energy penalty in 3d atoms. PNAS, 122(10), e2418305122. (www)

  @article{ , abstract = {To accurately describe the energetics of transition metal systems, density functional approximations (DFAs) must provide a balanced description of s- and d- electrons. One measure of this is the sd transfer error, which has previously been defined as E ( 3 d n − 1 4 s 1 ) − E ( 3 d n − 2 4 s 2 ) . Theoretical concerns have been raised about this definition due to its evaluation of excited-state energies using ground-state DFAs. A more serious concern appears to be strong correlation in the 4s 2 configuration. Here, we define a ground-state measure of the sd energy imbalance, based on the errors of s- and d-electron second ionization energies of the 3d atoms, that effectively circumvents the aforementioned problems. We find an improved performance as we move from the local spin density approximation (LSDA) to the Perdew-Burke-Ernzerhof (PBE) generalized gradient approximation (GGA) to the regularized and restored Strongly Constrained and Appropriately Normed (r 2 SCAN) meta-GGA for first-row transition metal atoms. However, we find large (∼2 eV) ground-state sd energy imbalances when applying a Perdew–Zunger 1981 self-interaction correction. This is attributed to an “energy penalty” associated with the noded 3d orbitals. A local scaling of the self-interaction correction to LSDA results in a balance of s- and d-errors.}, archive = {J_PNAS}, author = {Maniar, Rohan and Shukla, Priyanka B. and Johnson, J. Karl and Jackson, Koblar A. and Perdew, John P.}, doi = {10.1073/pnas.2418305122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2418305122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Atomic ionization: Sd energy imbalance and Perdew–Zunger self-interaction correction energy penalty in 3d atoms}, volume = {122}, year = {2025}, }
• (2025). TEX38 localizes ZDHHC19 to the plasma membrane and regulates sperm head morphogenesis in mice. PNAS, 122(10), e2417943122. (www)

  @article{ , abstract = {Sperm morphogenesis is a tightly regulated differentiation process, disruption of which leads to sperm malfunction and male infertility. Here, we show that Tex38 knockout (KO) male mice are infertile. Tex38 KO spermatids exhibit excess retention of residual cytoplasm around the head, resulting in abnormal sperm morphology with backward head bending. TEX38 interacts and colocalizes with ZDHHC19, a testis-enriched acyltransferase catalyzing protein S-palmitoylation, at the plasma membrane of spermatids. ZDHHC19 and TEX38 are each downregulated in mouse testes lacking the other protein. TEX38 stabilizes and localizes ZDHHC19 to the plasma membrane of cultured cells and vice versa, consolidating their interdependence. Mice deficient in ZDHHC19 or harboring a C142S mutation that disables the palmitoyltransferase activity of ZDHHC19 display phenotypes resembling those of Tex38 KO mice. Strikingly, ZDHHC19 palmitoylates ARRDC5, an arrestin family protein regulating sperm differentiation. Overall, our findings indicate that TEX38 forms a stable complex with ZDHHC19 at the plasma membrane of spermatids, which governs downstream S-palmitoylation of proteins essential for morphological transformation of spermatids.}, archive = {J_PNAS}, author = {Kaneda, Yuki and Lu, Yonggang and Sun, Jiang and Shimada, Keisuke and Emori, Chihiro and Noda, Taichi and Koyano, Takayuki and Matsuyama, Makoto and Miyata, Haruhiko and Ikawa, Masahito}, doi = {10.1073/pnas.2417943122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2417943122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TEX38 localizes ZDHHC19 to the plasma membrane and regulates sperm head morphogenesis in mice}, volume = {122}, year = {2025}, }
• (2025). Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH). PNAS, 122(10), e2417682122. (www)

  @article{ , abstract = {The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by undesirable drug-like properties of lead compounds. Prodrug approaches temporarily mask undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin (Fsm), exhibit significantly higher antimalarial potency than their parent compounds [R.L. Edwards et al. , Sci. Rep. 7 , 8400 (2017)]. However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH), is the major activating enzyme of multiple lipophilic ester prodrugs. Surprisingly, this enzyme is taken up by the malaria parasite, Plasmodium falciparum , where it localizes to the parasite cytoplasm and retains enzymatic activity. Using a fluorogenic ester library, we characterize the structure–activity relationship of APEH and compare it to that of P. falciparum esterases. We show that parasite-internalized APEH plays an important role in the activation of substrates with branching at the alpha carbon, in keeping with its exopeptidase activity. Our findings highlight a mechanism for antimicrobial prodrug activation, relying on a host-derived enzyme to yield activation at a microbial target. Mutations in prodrug-activating enzymes are a common mechanism for antimicrobial drug resistance [E. S. Istvan et al. , Nat. Commun. 8 , 14240 (2017); K. M. V. Sindhe et al. , mBio 11 , e02640-19 (2020); J. H. Butler et al. , Acs Infect Dis. 6 , 2994–3003 (2020)]. Leveraging an internalized host enzyme would circumvent this, enabling the design of prodrugs with higher barriers to drug resistance.}, archive = {J_PNAS}, author = {Sundararaman, Sesh A. and Miller, Justin J. and Daley, Ellora C. and O’Brien, Kelsey A. and Kasak, Paulina and Daniels, Abigail M. and Edwards, Rachel L. and Heidel, Kenneth M. and Bague, Darean A. and Wilson, Madeleine A. and Koelper, Andrew J. and Kourtoglou, Elexi C. and White, Alex D. and August, Sloan A. and Apple, Georgia A. and Rouamba, Regis W. and Durand, Anthony J. and Esteb, John J. and Muller, Florian L. and Johnson, R. Jeremy and Hoops, Geoffrey C. and Dowd, Cynthia S. and Odom John, Audrey R.}, doi = {10.1073/pnas.2417682122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2417682122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH)}, volume = {122}, year = {2025}, }
• (2025). Hypercholesterolemia-induced LXR signaling in smooth muscle cells contributes to vascular lesion remodeling and visceral function. PNAS, 122(10), e2417512122. (www)

  @article{ , abstract = {Vascular smooth muscle cells (VSMC) are the most abundant cell type in the artery’s media layer and regulate vascular tone and lesion remodeling during atherogenesis. Like monocyte-derived macrophages, VSMCs accumulate excess lipids and contribute to the total intimal foam cell population in human coronary plaques and mouse aortic atheroma. While there are extensive studies characterizing the contribution of lipid metabolism in macrophage immunometabolic responses in atherosclerotic plaques, the role of VSMC lipid metabolism in regulating vascular function and lesion remodeling in vivo remains poorly understood. Here, we report that the liver X receptor (LXR) signaling pathway in VSMC is continuously activated during atherogenesis. Notably, we found that LXR deficiency in SMCs under hypercholesterolemic conditions influenced lesion remodeling by altering the fate of dedifferentiated SMCs and promoting the accumulation of VSMC-derived transitional cells. This phenotypic switching was accompanied by reduced indices of plaque stability, characterized by a larger necrotic core area and reduced fibrous cap thickness. Moreover, SMC-specific LXR deficiency impaired vascular function and caused visceral myopathy characterized by maladaptive bladder remodeling and gut lipid malabsorption. Mechanistically, we found that the expression of several genes involved in cholesterol efflux and FA synthesis including Abca1 , Srebf1 , Scd1 , Scd2 , Acsl3, and Mid1ip1 was downregulated in mice lacking LXRαβ in SMCs, likely contributing to the phenotypic switching of VSMC in the atherosclerotic lesions.}, archive = {J_PNAS}, author = {Zhang, Hanming and Sáenz de Urturi, Diego and Fernández-Tussy, Pablo and Huang, Yan and Jovin, Daniel G. and Zhang, Xinbo and Huang, Shushu and Lek, Monkol and da Silva Catarino, Jonatas and Sternak, Magdalena and Citrin, Kathryn M. and Swirski, Fillip K. and Gustafsson, Jan-Åke and Greif, Daniel M. and Esplugues, Enric and Biwer, Lauren A. and Suárez, Yajaira and Fernández-Hernando, Carlos}, doi = {10.1073/pnas.2417512122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2417512122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hypercholesterolemia-induced LXR signaling in smooth muscle cells contributes to vascular lesion remodeling and visceral function}, volume = {122}, year = {2025}, }
• (2025). Core dimensions of human material perception. PNAS, 122(10), e2417202122. (www)

  @article{ , abstract = {Visually categorizing and comparing materials is crucial for everyday behavior, but what organizational principles underlie our mental representation of materials? Here, we used a large-scale data-driven approach to uncover core latent dimensions of material representations from behavior. First, we created an image dataset of 200 systematically sampled materials and 600 photographs (STUFF dataset, https://osf.io/myutc/ ). Using these images, we next collected 1.87 million triplet similarity judgments and used a computational model to derive a set of sparse, positive dimensions underlying these judgments. The resulting multidimensional embedding space predicted independent material similarity judgments and the similarity matrix of all images close to the human intersubject consistency. We found that representations of individual images were captured by a combination of 36 material dimensions that were highly reproducible and interpretable, comprising perceptual (e.g., grainy, blue) as well as conceptual (e.g., mineral, viscous) dimensions. These results provide the foundation for a comprehensive understanding of how humans make sense of materials.}, archive = {J_PNAS}, author = {Schmidt, Filipp and Hebart, Martin N. and Schmid, Alexandra C. and Fleming, Roland W.}, doi = {10.1073/pnas.2417202122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2417202122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Core dimensions of human material perception}, volume = {122}, year = {2025}, }
• (2025). Phase transitions in the rolling of irregular cylinders and spheres. PNAS, 122(10), e2417161122. (www)

  @article{ , abstract = {When placed on an inclined plane, a perfect 2D disk or 3D sphere simply rolls down in a straight line under gravity. But how is the rolling affected if these shapes are irregular or random? Treating the terminal rolling speed as an order parameter, we show that there are qualitative transitions in the speed as a function of the dimension of the state space and inertia. We calculate the scaling exponents and the macroscopic lag time associated with the presence of first- and second-order transitions and describe the regimes of coexistence of stable states and the accompanying hysteresis. Experiments with rolling cylinders corroborate our theoretical results on the scaling of the lag time. Experiments with spheres reveal closed orbits and their period-doubling in the overdamped and inertial limits, respectively, providing visible manifestations of the hairy ball theorem and the doubly connected nature of S O ( 3 ) , the space of 3D rotations. Going beyond simple curiosity, our study might shed light on a number of natural and artificial systems that involve the rolling of irregular objects, ranging from nanoscale cellular transport to robotics.}, archive = {J_PNAS}, author = {Qian, Daoyuan and Jung, Yeonsu and Mahadevan, L.}, doi = {10.1073/pnas.2417161122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2417161122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phase transitions in the rolling of irregular cylinders and spheres}, volume = {122}, year = {2025}, }
• (2025). Early evidence of avocado domestication from el gigante rockshelter, honduras. PNAS, 122(10), e2417072122. (www)

  @article{ , abstract = {Molecular research suggests that avocados ( Persea americana Mill.) were domesticated multiple times in the Americas. Seed exchange, hybridization, and cloning have played an essential role across their wild distribution from Mexico to South America to create the modern varieties of today. Archaeological sites with well-preserved and directly radiocarbon-dated botanical assemblages are rare, however, so we know very little about the complexities of the domestication process. Here, we define an early locus of avocado domestication using well-dated desiccated and carbonized avocado remains from El Gigante rockshelter in western Honduras spanning the last 11,000 y. Measurements of avocado seeds and rinds show evidence for long-term management resulting in selection for larger, more robust fruits through time that culminated by 2,250 to 2,080 calendar B.P. (cal. B.P.). However, human-directed selection for larger fruits with thicker rinds is evident as early as 7,565 to 7,265 cal. B.P. Seed morphology is similar to P. americana var. guatemalensis and is congruent with genetic data for the development of this variety in both the highlands of Guatemala and Honduras. Increases in seed size and rind thickness through time are consistent with genetic evidence for the enrichment of putative candidate genes for fruit development and ripening in this variety.}, archive = {J_PNAS}, author = {VanDerwarker, Amber M. and Thakar, Heather B. and Hirth, Kenneth and Domic, Alejandra I. and Harper, Thomas K. and George, Richard J. and Johnson, Emily S. and Newhall, Victoria and Scheffler, Timothy E. and McCool, Weston C. and Wann, Kevin and Gaut, Brandon S. and Kistler, Logan and Kennett, Douglas J.}, doi = {10.1073/pnas.2417072122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2417072122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Early evidence of avocado domestication from el gigante rockshelter, honduras}, volume = {122}, year = {2025}, }
• (2025). Bioinspired ion-shuttling memristor with both neuromorphic functions and ion selectivity. PNAS, 122(10), e2417040122. (www)

  @article{ , abstract = {The fluidic memristor has attracted growing attention as a promising candidate for neuromorphic computing and brain–computer interfaces. However, a fluidic memristor with ion selectivity as that of natural ion channels remains a key challenge. Herein, inspired by the structure of natural biomembranes, we developed an ion-shuttling memristor (ISM) by utilizing organic solvents and artificial carriers to emulate ion channels embedded in biomembranes, which exhibited both neuromorphic functions and ion selectivity. Pinched hysteresis I-V loop curve, scan rate dependency, and distinctive impedance spectra confirmed the memristive characteristics of the as-prepared device. Moreover, the memory mechanism was discussed theoretically and validated by finite-element modeling. The ISM features multiple neuromorphic functions, such as paired-pulse facilitation, paired-pulse depression, and learning–experience behavior. More importantly, the ion selectivity of the ISM was observed, which allowed further emulation of ion-selective neural functions like resting membrane potential. Benefiting from the structural similarity to membrane-embedded ion channels, the ISM opens the door for ion-based neuromorphic computing and sophisticated chemical regulation by manipulating multifarious ions with neuromorphic functions.}, archive = {J_PNAS}, author = {Xie, Boyang and Xiong, Tianyi and Guo, Guangguo and Pan, Cong and Ma, Wenjie and Yu, Ping}, doi = {10.1073/pnas.2417040122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2417040122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bioinspired ion-shuttling memristor with both neuromorphic functions and ion selectivity}, volume = {122}, year = {2025}, }
• (2025). Evolution of the JULGI–SMXL4/5 module for phloem development in angiosperms. PNAS, 122(10), e2416674122. (www)

  @article{ , abstract = {Bifacial cambium, which produces xylem and phloem, and monopodial architecture, characterized by apical dominance and lateral branching from axillary buds, are key developmental features of seed plants, consisting of angiosperms and gymnosperms. These allow seed plants to adapt to diverse environments by optimizing resource allocation and structural integrity. In seed plants, SUPPRESSOR OF MAX2-LIKE ( SMXL ) family members function in phloem development and strigolactone-induced inhibition of axillary bud outgrowth. Although strigolactone signaling regulates most SMXL family members, the only known regulator of SMXL4 and SMXL5 is the RNA-binding protein JULGI. We demonstrate that in angiosperms, by directly regulating SMXL4/5 expression, JULGI uncouples SMXL4/5 activity from strigolactone signaling. JULGI and ancestral SMXL s from seedless vascular plants or SMXL4/5 from seed plants are coexpressed in the phloem tissues of vascular plants, from lycophytes to angiosperms. Core angiosperm SMXL4/5 mRNAs contain a G-rich element in the 5′ untranslated region (UTR) that serves as a target sequence for JULGI to negatively regulate SMXL4/5 expression. Heterologous expression of JULGI s from various angiosperms rescued the Arabidopsis jul1 jul2 mutant. Expressing SMXL4/5 s from seed plants and ancestral SMXL s rescued Arabidopsis smxl4 smxl5 . Angiosperm SMXL4/5s lack an RGKT motif for proteasomal degradation. Indeed, treatment with the synthetic strigolactone analog rac -GR24 induced proteasomal degradation of SMXL from ferns and SMXL5a from gymnosperms, but not SMXL4/5 from angiosperms. These findings suggest that in ancestral angiosperms, the 5′ UTR of SMXL4/5 gained G-rich elements, creating a regulatory module with JULGI that allows the phloem development pathway to act independently of strigolactone signaling.}, archive = {J_PNAS}, author = {Park, Chanyoung and Cho, Hyun Seob and Lim, Yookyung and Cho, Chung Hyun and Nam, Hoyoung and Choi, Sangkyu and Lim, Hojun and Kim, Young-Dong and Yoon, Hwan Su and Cho, Hyunwoo and Hwang, Ildoo}, doi = {10.1073/pnas.2416674122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2416674122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolution of the JULGI–SMXL4/5 module for phloem development in angiosperms}, volume = {122}, year = {2025}, }
• (2025). Brain aging shows nonlinear transitions, suggesting a midlife “critical window” for metabolic intervention. PNAS, 122(10), e2416433122. (www)

  @article{ , abstract = {Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal “landmarks” of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain’s regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons’ energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife “critical window” for early metabolic intervention.}, archive = {J_PNAS}, author = {Antal, Botond B. and van Nieuwenhuizen, Helena and Chesebro, Anthony G. and Strey, Helmut H. and Jones, David T. and Clarke, Kieran and Weistuch, Corey and Ratai, Eva-Maria and Dill, Ken A. and Mujica-Parodi, Lilianne R.}, doi = {10.1073/pnas.2416433122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2416433122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Brain aging shows nonlinear transitions, suggesting a midlife “critical window” for metabolic intervention}, volume = {122}, year = {2025}, }
• (2025). Conformational free energy landscape of a glutamate transporter and microscopic details of its transport mechanism. PNAS, 122(10), e2416381122. (www)

  @article{ , abstract = {Removing glutamate from the synaptic cleft is vital for proper function of the brain. Excitatory amino acid transporters mediate this process by uptaking the neurotransmitter from the synaptic cleft back to the cell after its release. The archaeal homolog, Glt Ph , an aspartate transporter from Pyrococcus horikoshii , presents the best structurally characterized model for this family of transporters. In order to transport, Glt Ph undergoes elevator-like conformational changes between inward-facing (IF) and outward-facing (OF) states. Here, we characterize, at an atomic level, the OF⇌IF transition of Glt Ph in different apo /bound states using a combination of ensemble-based enhanced sampling techniques, employing more than two thousand of coupled simulation replicas of membrane-embedded Glt Ph . The resulting free-energy profiles portray the transition of apo /bound states as a complex four-stage process, while sodium binding alone locks the structure in one of its states. Along the transition, the transport domain (TD) disengages from the scaffold domain (SD), allowing it to move as a piston sliding vertically with respect to the membrane during the elevator-like motion of TD. Lipid interactions with residues comprising the SD–TD interface directly influence the large-scale conformational changes and, consequently, the energetics of transport. Structural intermediates formed during the transition leak water molecules and may correlate to the uncoupled Cl − ion conductance observed experimentally in both prokaryotic and mammalian glutamate transporters. Mechanistic insights obtained from our study provide a structural framework for better development of therapeutic for neurological disorders.}, archive = {J_PNAS}, author = {Thangapandian, Sundar and Fakharzadeh, Ashkan and Moradi, Mahmoud and Tajkhorshid, Emad}, doi = {10.1073/pnas.2416381122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2416381122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Conformational free energy landscape of a glutamate transporter and microscopic details of its transport mechanism}, volume = {122}, year = {2025}, }
• (2025). A simple, statistically robust test of discrimination. PNAS, 122(10), e2416348122. (www)

  @article{ , abstract = {In observational studies of discrimination, the most common statistical approaches consider either the rate at which decisions are made (benchmark tests) or the success rate of those decisions (outcome tests). Both tests, however, have well-known statistical limitations, sometimes suggesting discrimination even when there is none. Despite the fallibility of the benchmark and outcome tests individually, here we prove a surprisingly strong statistical guarantee: Under a common nonparametric assumption, at least one of the two tests must be correct; consequently, when both tests agree, they are guaranteed to yield correct conclusions. We present empirical evidence that the underlying assumption holds approximately in several important domains, including lending, education, and criminal justice—and that our hybrid test is robust to the moderate violations of the assumption that we observe in practice. Applying this approach to 2.8 million police stops across California, we find evidence of widespread racial discrimination.}, archive = {J_PNAS}, author = {Gaebler, Johann D. and Goel, Sharad}, doi = {10.1073/pnas.2416348122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2416348122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A simple, statistically robust test of discrimination}, volume = {122}, year = {2025}, }
• (2025). Direct observation of cholesterol monohydrate crystallization. PNAS, 122(10), e2415719122. (www)

  @article{ , abstract = {Cholesterol crystallization is integral to the pathology of diseases such as atherosclerosis and gallstones, yet the relevant mechanisms of crystal growth have remained elusive. Here, we use a variety of in situ techniques to examine cholesterol monohydrate crystallization over multiple length scales. In this study, we first identified a biomimetic solvent to generate triclinic monohydrate crystals, while avoiding the formation of nonphysiological solvates and enabling crystallization at rates where the dynamics of surface growth could be captured in real time. Using a binary mixture of water and isopropanol, with the latter serving as a surrogate for lipids in physiological environments, we show that cholesterol monohydrate crystals grow classically by the nucleation and spreading of crystal layers. Time-resolved imaging confirms that layers are generated by dislocations and monomers incorporate into advancing steps after diffusion along the crystal surface and not directly from the solution. In situ atomic force microscopy (AFM) and microfluidics measurements concertedly reveal abundant macrosteps, which engender a self-inhibition mechanism that reduces the rate of crystal growth. This finding stands in contrast to numerous other systems, in which classical mechanisms lead to unhindered growth by spreading of single layers.}, archive = {J_PNAS}, author = {Chakraborty, Dipayan and Ma, Wenchuan and Wang, Xiqu and Chu, Zheting and Yang, Taimin and Warzecha, Monika and Vekilov, Peter G. and Rimer, Jeffrey D.}, doi = {10.1073/pnas.2415719122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2415719122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Direct observation of cholesterol monohydrate crystallization}, volume = {122}, year = {2025}, }
• (2025). EGFR-induced lncRNA TRIDENT promotes drug resistance in non–small cell lung cancer via phospho-TRIM28-mediated DNA damage repair. PNAS, 122(10), e2415389122. (www)

  @article{ , abstract = {Long noncoding RNAs (lncRNAs) play numerous roles in cellular biology and alterations in lncRNA expression profiles have been implicated in a variety of cancers. Here, we identify and characterize a lncRNA, TRIM28 Interacting DNA damage repair Enhancing Noncoding Transcript ( TRIDENT ), whose expression is induced upon epithelial growth factor receptor (EGFR) activation, and which exerts pro-oncogenic functions in EGFR-driven non–small cell lung cancer. Knocking down TRIDENT leads to decreased tumor-cell proliferation in both in vitro and in vivo model systems and induces sensitization to chemotherapeutic drugs. Using ChIRP-MS analysis we identified TRIM28 as a protein interactor of TRIDENT . TRIDENT promotes phosphorylation of TRIM28 and knocking down TRIDENT leads to accumulation of DNA damage in cancer cells via decreased TRIM28 phosphorylation. Altogether, our results reveal a molecular pathway in which TRIDENT regulates TRIM28 phosphorylation to promote tumor cell growth and drug resistance. Our findings suggest that TRIDENT can be developed as a biomarker or therapeutic target for EGFR mutant non–small cell lung cancer.}, archive = {J_PNAS}, author = {Saxena, Tanvi and Quan, Anan and Chan, Erica and Kozlova, Nina and Matai, Latika and Lee, Jonathan D. and Rupaimoole, Rajesha and Beca, Francisco and Muranen, Taru and Slack, Frank J.}, doi = {10.1073/pnas.2415389122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2415389122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {EGFR-induced lncRNA TRIDENT promotes drug resistance in non–small cell lung cancer via phospho-TRIM28-mediated DNA damage repair}, volume = {122}, year = {2025}, }
• (2025). Reply to johnson: Holistic evaluation of ecological models in paleobiology. PNAS, 122(10), e2415303122. (www)

  @article{ , archive = {J_PNAS}, author = {Saulsbury, James G. and Parins-Fukuchi, C. Tomomi and Wilson, Connor J. and Reitan, Trond and Liow, Lee Hsiang}, doi = {10.1073/pnas.2415303122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2415303122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to johnson: Holistic evaluation of ecological models in paleobiology}, volume = {122}, year = {2025}, }
• (2025). Cas9-mediated gene-editing frequency in microalgae is doubled by harnessing the interaction between importin α and phytopathogenic NLSs. PNAS, 122(10), e2415072122. (www)

  @article{ , abstract = {Pathogen-derived nuclear localization signals (NLSs) enable vigorous nuclear invasion in the host by the virulence proteins harboring them. Herein, inspired by the robust nuclear import mechanism, we show that NLSs originating from the plant infection–associated Agrobacterium proteins VirD2 and VirE2 can be incorporated into the Cas9 system as efficient nuclear delivery enhancers, thereby improving the low gene-editing frequency in a model microalga, Chlamydomonas reinhardtii , caused by poor nuclear localization of the bulky nuclease. Prior to evaluation of the NLSs, IPA1 (Cre04.g215850) was first defined in the alga as the nuclear import-related importin alpha (Impα) that serves as a counterpart adaptor protein of the NLSs, based on extensive in silico analyses considering the protein’s sequence, tertiary folding behavior, and structural basis when interacting with a well-studied SV40TAg NLS. Through precursive affinity explorations, we reproducibly found that the NLSs mediated the binding between the Cas9 and Impα with nM affinities and visually confirmed that the fusion of the NLSs strictly localized the peptide-bearing cargoes in the microalgal nucleus without compensating for their cleavage ability. When employed in a real-world application, the VirD2 NLS increases the mutation frequency (~1.12 × 10 −5 ) over 2.4-fold compared to an archetypal SV40TAg NLS (~0.46 × 10 −5 ) when fused with Cas9. We demonstrate the cross-species versatility of the Impα-dependent strategy by successfully applying it to an industrial alga, Chlorella Sp. HS2. This work, focused on affinity augmentation, provides insights into increasing the frequency of gene editing, which can be advantageously used in programmable mutagenesis with broad applicability.}, archive = {J_PNAS}, author = {Le, Trang Thi and Choi, Hong Il and Kim, Ji Won and Yun, Jin-Ho and Lee, Yoon Hyeok and Jeon, Eun Jung and Kwon, Kil Koang and Cho, Dae-Hyun and Choi, Dong-Yun and Park, Su-Bin and Yoon, Hyang Ran and Lee, Jeongmi and Sim, Eun Jeong and Lee, Yong Jae and Kim, Hee-Sik}, doi = {10.1073/pnas.2415072122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2415072122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cas9-mediated gene-editing frequency in microalgae is doubled by harnessing the interaction between importin α and phytopathogenic NLSs}, volume = {122}, year = {2025}, }
• (2025). Prediction of carbon nanostructure mechanical properties and the role of defects using machine learning. PNAS, 122(10), e2415068122. (www)

  @article{ , abstract = {Graphene-based nanostructures hold immense potential as strong and lightweight materials, however, their mechanical properties such as modulus and strength are difficult to fully exploit due to challenges in atomic-scale engineering. This study presents a database of over 2,000 pristine and defective nanoscale CNT bundles and other graphitic assemblies, inspired by microscopy, with associated stress–strain curves from reactive molecular dynamics (MD) simulations using the reactive INTERFACE force field (IFF-R). These 3D structures, containing up to 80,000 atoms, enable detailed analyses of structure-stiffness-failure relationships. By leveraging the database and physics- and chemistry-informed machine learning (ML), accurate predictions of elastic moduli and tensile strength are demonstrated at speeds 1,000 to 10,000 times faster than efficient MD simulations. Hierarchical Graph Neural Networks with Spatial Information (HS-GNNs) are introduced, which integrate chemistry knowledge. HS-GNNs as well as extreme gradient boosted trees (XGBoost) achieve forecasts of mechanical properties of arbitrary carbon nanostructures with only 3 to 6% mean relative error. The reliability equals experimental accuracy and is up to 20 times higher than other ML methods. Predictions maintain 8 to 18% accuracy for large CNT bundles, CNT junctions, and carbon fiber cross-sections outside the training distribution. The physics- and chemistry-informed HS-GNN works remarkably well for data outside the training range while XGBoost works well with limited training data inside the training range. The carbon nanostructure database is designed for integration with multimodal experimental and simulation data, scalable beyond 100 nm size, and extendable to chemically similar compounds and broader property ranges. The ML approaches have potential for applications in structural materials, nanoelectronics, and carbon-based catalysts.}, archive = {J_PNAS}, author = {Winetrout, Jordan J. and Li, Zilu and Zhao, Qi and Gaber, Landon and Unnikrishnan, Vinu and Varshney, Vikas and Xu, Yanxun and Wang, Yusu and Heinz, Hendrik}, doi = {10.1073/pnas.2415068122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2415068122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prediction of carbon nanostructure mechanical properties and the role of defects using machine learning}, volume = {122}, year = {2025}, }
• (2025). On the shape of air bubbles trapped in ice. PNAS, 122(10), e2415027122. (www)

  @article{ , abstract = {Water usually contains dissolved gases, and because freezing is a purifying process these gases must be expelled for ice to form. Bubbles appear at the freezing front and are then trapped in ice, making pores. These pores come in a range of sizes from microns to millimeters and their shapes are peculiar; never spherical but elongated, and usually fore-aft asymmetric. We show that these remarkable shapes result of a delicate balance between freezing, capillarity, and mass diffusion. A nonlinear ordinary differential equation suffices to describe the bubbles, which features two nondimensional numbers representing the supersaturation and the freezing rate, and two additional parameters representing simultaneous freezing and nucleation treated as the initial condition. Our experiments provide us with a large variety of pictures of bubble shapes. We show that all of these bubbles have their rounded tip well described by an asymptotic regime of the differential equation and that most bubbles can have their full shape quantitatively matched by a full solution. This method enables the measurement of the freezing conditions of ice samples, and the design of freeze-cast porous materials. Furthermore, the equation exhibits a bifurcation that explains why some bubbles grow indefinitely and make long cylindrical “ice worms,” well known to glaciologists.}, archive = {J_PNAS}, author = {Thiévenaz, Virgile and Meijer, Jochem G. and Lohse, Detlef and Sauret, Alban}, doi = {10.1073/pnas.2415027122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2415027122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {On the shape of air bubbles trapped in ice}, volume = {122}, year = {2025}, }
• (2025). Effects of binding partners on thermal reversion rates of photoswitchable molecules. PNAS, 122(10), e2414748122. (www)

  @article{ , abstract = {The binding of photoswitchable molecules to partners forms the basis of many naturally occurring light-dependent signaling pathways and various photopharmacological and optogenetic tools. A critical parameter affecting the function of these molecules is the thermal half-life of the light state. Reports in the literature indicate that, in some cases, a binding partner can significantly influence the thermal half-life, while in other cases it has no effect. Here, we present a unifying framework for quantitatively analyzing the effects of binding partners on thermal reversion rates. We focus on photoswitchable protein/binder interactions involving LOV domains, photoactive yellow protein, and CBCR GAF domains with partners that bind either the light or the dark state of the photoswitchable domain. We show that the effect of a binding partner depends on the extent to which the transition state for reversion resembles the dark state or the light state. We quantify this resemblance with a ϕ switching value, where ϕ switching = 1 if the conformation of the part of the photoswitchable molecule that interacts with the binding partner closely resembles its dark state conformation and ϕ switching = 0 if it resembles its light state. In addition to providing information on the transition state for switching, this analysis can guide the design of photoswitchable systems that retain useful thermal half-lives in practice. The analysis also provides a basis for the use of simple kinetic measurements to determine effective changes in affinity even in complex milieu.}, archive = {J_PNAS}, author = {Reed, P. Maximilian M. and Jang, Jaewan and Woloschuk, Ryan M. and Reis, Jakeb and Hille, Jacques I. C. and Uppalapati, Maruti and Woolley, G. Andrew}, doi = {10.1073/pnas.2414748122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2414748122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Effects of binding partners on thermal reversion rates of photoswitchable molecules}, volume = {122}, year = {2025}, }
• (2025). Immobile lipopolysaccharides and outer membrane proteins differentially segregate in growing escherichia coli. PNAS, 122(10), e2414725122. (www)

  @article{ , abstract = {The outer membrane (OM) of gram-negative bacteria is a robust, impermeable barrier that excludes many classes of antibiotics. Contrary to the classical model of an asymmetric lipid bilayer, recent evidence suggests the OM is predominantly an asymmetric proteolipid membrane (APLM). Outer leaflet lipopolysaccharides (LPS) that surround integral β-barrel outer membrane proteins (OMPs) are shared with other OMPs to form a supramolecular network in which the levels of OMPs approach those of LPS. Some of the most abundant OMPs in the Escherichia coli OM are trimeric porins. How porins and LPS are incorporated into the OM of growing bacteria is poorly understood. Here, we use live-cell imaging and microfluidics to investigate how LPS, labeled using click chemistry, and the porin OmpF, labeled using the bacteriocin colicin N, are incorporated into the E. coli OM. Diffraction-limited fluorescence microscopy shows OmpF and LPS to be uniformly distributed and immobile. However, clustering of both macromolecules becomes evident by superresolution microscopy, which is also the case for their biogenesis proteins, BamA and LptD, respectively. Notwithstanding these common organizational features, OmpF insertion into the OM is cell-cycle-dependent leading to binary partitioning and strong polar accumulation of old OmpF. Old LPS on the other hand is diluted ~50% at each division cycle by new LPS, resulting in only mild polar accumulation of preexisting LPS. We conclude that although LPS and OMPs are destined to form the APLM their insertion dynamics are fundamentally different, which has major implications for understanding how the OM is assembled.}, archive = {J_PNAS}, author = {Kumar, Sandip and Inns, Patrick G. and Ward, Scott and Lagage, Valentine and Wang, Jingyu and Kaminska, Renata and Booth, Martin J. and Uphoff, Stephan and Cohen, Edward A. K. and Mamou, Gideon and Kleanthous, Colin}, doi = {10.1073/pnas.2414725122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2414725122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Immobile lipopolysaccharides and outer membrane proteins differentially segregate in growing escherichia coli}, volume = {122}, year = {2025}, }
• (2025). The mechanism of electrical conduction in glassy semiconductors. PNAS, 122(10), e2414650122. (www)

  @article{ , abstract = {We argue that the dominant charge carrier in glassy semiconducting alloys is a compound particle in the form of an electron or hole bound to an intimate pair of topological lattice defects; the particle is similar to the polaron solution of the Su–Schrieffer–Heeger Hamiltonian. The spatial component of the density of states for these special polarons is determined by the length scale of spatial modulation of electronegativity caused by a separate set of standalone topological defects. The latter length scale is fixed by the cooperativity size for structural relaxation; the size is largely independent of temperature in the glass but above melting, it decreases with temperature. Thus we predict that the temperature dependence of the electrical conductivity should exhibit a jump in the slope near the glass transition; the size of the jump is predicted to increase with the fragility of the melt. The predicted values of the jump and of the conductivity itself are consistent with experiment.}, archive = {J_PNAS}, author = {Kurnosov, Arkady and Lubchenko, Vassiliy}, doi = {10.1073/pnas.2414650122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2414650122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The mechanism of electrical conduction in glassy semiconductors}, volume = {122}, year = {2025}, }
• (2025). In the activation of HPV-specific human b cells HPV-VLP vaccines mimic membrane-associated antigens. PNAS, 122(10), e2414514122. (www)

  @article{ , abstract = {B cell responses to membrane-presented antigens appear to be strongly favored over soluble antigens in vivo suggesting that vaccines that mimic membrane-presented antigens may be highly efficacious. We recently demonstrated that human B cell responses to membrane-associated but not to soluble antigens in vitro depended on the expression and activity of the plasma membrane mechanosensitive ion channel, Piezo1. Here, we provide evidence that the efficacy of the current human papillomavirus virus-like particle (HPV VLP) vaccines may be due in part to their inherent ability to mimic Piezo1-dependent membrane presentation of antigens to B cells. We compared HPV-specific human B cell responses to HPV VLPs versus soluble HPV pentameric capsomeres and showed that although both induced calcium responses, only HPV VLP-induced responses were blocked by Piezo1 inhibitors. The kinetics of internalization of HPV-VLP and capsomeres into HPV-specific B cells were similar and neither required Piezo1 function as shown by small interfering RNA (siRNA)-mediated knockdown of Piezo. However, trafficking of HPV-VLPs into intracellular major histocompatibility complex (MHC) class II, lysosomal associated membrane protein 1 (LAMP1) + antigen-processing compartments was Piezo1-dependent, whereas trafficking of capsomeres was not. In addition, a time course of intracellular trafficking suggested that colocalization of HPV-VLP with MHC classII was more stable over time as compared to capsomeres. Taken together these findings suggest that the ability of HPV-VLP vaccines to mimic Piezo1-dependent membrane antigen presentation may be exploited in the design of highly effective human vaccines.}, archive = {J_PNAS}, author = {Torgbor, Charles and Sohn, Haewon and Dizon, Brian L. P. and Mutic, Evan C. and George, Rachel and Kwak, Kihyuck and Akkaya, Munir and Ulker, Esin Bayrali and Traver, Maria and Brzostowski, Joseph and Galloway, Denise A. and Thompson, Cynthia D. and Çuburu, Nicolas and Schiller, John T. and Pierce, Susan K.}, doi = {10.1073/pnas.2414514122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2414514122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In the activation of HPV-specific human b cells HPV-VLP vaccines mimic membrane-associated antigens}, volume = {122}, year = {2025}, }
• (2025). Specific microbial ratio in the gut microbiome is associated with multiple sclerosis. PNAS, 122(10), e2413953122. (www)

  @article{ , abstract = {Gut microbiota dysbiosis is associated with multiple sclerosis (MS), but the causal relationship between specific gut bacteria and MS pathogenesis remains poorly understood. Therefore, we profiled the stool microbiome of people with MS (PwMS) and healthy controls (HC) using shotgun metagenomic sequencing. PwMS showed a distinct microbiome compared to HC, with Prevotella copri ( PC ) and Blautia species as drivers of microbial communities in HC and PwMS, respectively. Administration of MS-driving Blautia species ( Blautia wexlerae; BW ) to mice resulted in increased levels of gut inflammatory markers and altered microbiota with increased capacity to induce proinflammatory cytokines. Utilizing experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we identified a lower gut Bifidobacterium to Akkermansia ratio as a hallmark of the disease. BW -administered mice also showed a lower Bifidobacterium to Akkermansia ratio pre-EAE induction which correlated with increased disease severity post-EAE induction. The importance of the Bifidobacterium to Akkermansia ratio at the species level, lower Bifidobacterium adolescentis to Akkermansia muciniphila ( BA:AM ), was validated in our MS cohort and a large International Multiple Sclerosis Microbiome Study. Thus, our findings highlight the BA:AM ratio as a potential gut microbial marker in PwMS, opening avenues for microbiome-based diagnosis, prognosis, and therapy in MS.}, archive = {J_PNAS}, author = {Ghimire, Sudeep and Lehman, Peter C. and Aguilar Meza, Leeann S. and Shahi, Shailesh K. and Hoang, Jemmie and Olalde, Heena and Paullus, Mishelle and Cherwin, Catherine and Wang, Kai and Gill, Christine and Cho, Tracey and Mangalam, Ashutosh K.}, doi = {10.1073/pnas.2413953122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2413953122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Specific microbial ratio in the gut microbiome is associated with multiple sclerosis}, volume = {122}, year = {2025}, }
• (2025). Copy number variation contributes to parallel local adaptation in an invasive plant. PNAS, 122(10), e2413587122. (www)

  @article{ , abstract = {Adaptation is a critical determinant of the diversification, persistence, and geographic range limits of species. Yet the genetic basis of adaptation is often unknown and potentially underpinned by a wide range of mutational types—from single nucleotide changes to large-scale alterations of chromosome structure. Copy number variation (CNV) is thought to be an important source of adaptive genetic variation, as indicated by decades of candidate gene studies that point to CNVs underlying rapid adaptation to strong selective pressures. Nevertheless, population-genomic studies of CNVs face unique logistical challenges not encountered by other forms of genetic variation. Consequently, few studies have systematically investigated the contributions of CNVs to adaptation at a genome-wide scale. We present a genome-wide analysis of CNV contributing to the adaptation of an invasive weed, Ambrosia artemisiifolia . CNVs show clear signatures of parallel local adaptation between North American (native) and European (invaded) ranges, implying widespread reuse of CNVs during adaptation to shared heterogeneous patterns of selection. We used a local principal component analysis (PCA) to genotype CNV regions in whole-genome sequences of samples collected over the last two centuries. We identified 16 large CNV regions of up to 11.85 megabases in length, eight of which show signals of rapid evolutionary change, with pronounced frequency shifts between historic and modern populations. Our results provide compelling genome-wide evidence that CNV underlies rapid adaptation over contemporary timescales of natural populations.}, archive = {J_PNAS}, author = {Wilson, Jonathan and Bieker, Vanessa C. and Boheemen, Lotte van and Connallon, Tim and Martin, Michael D. and Battlay, Paul and Hodgins, Kathryn A.}, doi = {10.1073/pnas.2413587122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2413587122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Copy number variation contributes to parallel local adaptation in an invasive plant}, volume = {122}, year = {2025}, }
• (2025). Scaling language model size yields diminishing returns for single-message political persuasion. PNAS, 122(10), e2413443122. (www)

  @article{ , abstract = {Large language models can now generate political messages as persuasive as those written by humans, raising concerns about how far this persuasiveness may continue to increase with model size. Here, we generate 720 persuasive messages on 10 US political issues from 24 language models spanning several orders of magnitude in size. We then deploy these messages in a large-scale randomized survey experiment ( N = 25,982) to estimate the persuasive capability of each model. Our findings are twofold. First, we find evidence that model persuasiveness is characterized by sharply diminishing returns, such that current frontier models are only slightly more persuasive than models smaller in size by an order of magnitude or more. Second, we find that the association between language model size and persuasiveness shrinks toward zero and is no longer statistically significant once we adjust for mere task completion (coherence, staying on topic), a pattern that highlights task completion as a potential mediator of larger models’ persuasive advantage. Given that current frontier models are already at ceiling on this task completion metric in our setting, taken together, our results suggest that further scaling model size may not much increase the persuasiveness of static LLM-generated political messages.}, archive = {J_PNAS}, author = {Hackenburg, Kobi and Tappin, Ben M. and Röttger, Paul and Hale, Scott A. and Bright, Jonathan and Margetts, Helen}, doi = {10.1073/pnas.2413443122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2413443122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Scaling language model size yields diminishing returns for single-message political persuasion}, volume = {122}, year = {2025}, }
• (2025). Deep learning to quantify the pace of brain aging in relation to neurocognitive changes. PNAS, 122(10), e2413442122. (www)

  @article{ , abstract = {Brain age (BA), distinct from chronological age (CA), can be estimated from MRIs to evaluate neuroanatomic aging in cognitively normal (CN) individuals. BA, however, is a cross-sectional measure that summarizes cumulative neuroanatomic aging since birth. Thus, it conveys poorly recent or contemporaneous aging trends, which can be better quantified by the (temporal) pace P of brain aging. Many approaches to map P , however, rely on quantifying DNA methylation in whole-blood cells, which the blood–brain barrier separates from neural brain cells. We introduce a three-dimensional convolutional neural network (3D-CNN) to estimate P noninvasively from longitudinal MRI. Our longitudinal model (LM) is trained on MRIs from 2,055 CN adults, validated in 1,304 CN adults, and further applied to an independent cohort of 104 CN adults and 140 patients with Alzheimer’s disease (AD). In its test set, the LM computes P with a mean absolute error (MAE) of 0.16 y (7% mean error). This significantly outperforms the most accurate cross-sectional model, whose MAE of 1.85 y has 83% error. By synergizing the LM with an interpretable CNN saliency approach, we map anatomic variations in regional brain aging rates that differ according to sex, decade of life, and neurocognitive status. LM estimates of P are significantly associated with changes in cognitive functioning across domains. This underscores the LM’s ability to estimate P in a way that captures the relationship between neuroanatomic and neurocognitive aging. This research complements existing strategies for AD risk assessment that estimate individuals’ rates of adverse cognitive change with age.}, archive = {J_PNAS}, author = {Yin, Chenzhong and Imms, Phoebe and Chowdhury, Nahian F. and Chaudhari, Nikhil N. and Ping, Heng and Wang, Haoqing and Bogdan, Paul and Irimia, Andrei and null, null and Weiner, Michael and Aisen, Paul and Petersen, Ronald and Jack, Clifford R. and Jagust, William and Landau, Susan and Rivera-Mindt, Monica and Okonkwo, Ozioma and Shaw, Leslie M. and Lee, Edward B. and Toga, Arthur W. and Beckett, Laurel and Harvey, Danielle and Green, Robert C. and Saykin, Andrew J. and Nho, Kwangsik and Perrin, Richard J. and Tosun, Duygu and Sachdev, Pallavi and Drake, Erin and Montine, Tom and Conti, Cat and Weiner, Michael W. and Nosheny, Rachel and Truran Sacrey, Diana and Fockler, Juliet and Miller, Melanie J. and Conti, Catherine and Kwang, Winnie and Jin, Chengshi and Diaz, Adam and Ashford, Miriam and Flenniken, Derek and Kormos, Adrienne and Rafii, Michael and Raman, Rema and Jimenez, Gustavo and Donohue, Michael and Salazar, Jennifer and Fidell, Andrea and Boatwright, Virginia and Robison, Justin and Zimmerman, Caileigh and Cabrera, Yuliana and Walter, Sarah and Clanton, Taylor and Shaffer, Elizabeth and Webb, Caitlin and Hergesheimer, Lindsey and Smith, Stephanie and Ogwang, Sheila and Adegoke, Olusegun and Mahboubi, Payam and Pizzola, Jeremy and Jenkins, Cecily and Saito, Naomi and Hussen, Kedir Adem and Amaza, Hannatu and Thao, Mai Seng and Parkins, Shaniya and Ayo, Omobolanle and Glittenberg, Matt and Hoang, Isabella and Germano, Kaori Kubo and Strong, Joe and Weisensel, Trinity and Magana, Fabiola and Thomas, Lisa and Guzman, Vanessa and Ajayi, Adeyinka and Di Benedetto, Joseph and Talavera, Sandra and Felmlee, Joel and Fox, Nick C. and Thompson, Paul and DeCarli, Charles and Forghanian-Arani, Arvin and Borowski, Bret and Reyes, Calvin and Hedberg, Caitie and Ward, Chad and Schwarz, Christopher and Reyes, Denise and Gunter, Jeff and Moore-Weiss, John and Kantarci, Kejal and Matoush, Leonard and Senjem, Matthew and Vemuri, Prashanthi and Reid, Robert and Malone, Ian and Thomopoulos, Sophia I. and Nir, Talia M. and Jahanshad, Neda and Knaack, Alexander and Fletcher, Evan and Tosun-Turgut, Duygu and Rossi Chen, Stephanie and Choe, Mark and Crawford, Karen and Yushkevich, Paul A. and Das, Sandhitsu and Koeppe, Robert A. and Rabinovici, Gil and Villemagne, Victor and LoPresti, Brian and Morris, John and Franklin, Erin and Bernhardt, Haley and Cairns, Nigel J. and Taylor-Reinwald, Lisa and Shaw, Leslie and Lee, Virginia M.Y. and Korecka, Magdalena and Brylska, Magdalena and Wan, Yang and Trojanowki, J.Q. and Neu, Scott and Foroud, Tatiana M. and Jo, Taeho and Risacher, Shannon L. and Craft, Hannah and Apostolova, Liana G. and Nudelman, Kelly and Faber, Kelley and Potter, Zoë and Lacy, Kaci and Kaddurah-Daouk, Rima and Shen, Li and Karlawish, Jason and Erickson, Claire and Grill, Joshua and Largent, Emily and Harkins, Kristin and Thal, Leon and Kachaturian, Zaven and Frank, Richard and Snyder, Peter J. and Buckholtz, Neil and Hsiao, John K. and Ryan, Laurie and Molchan, Susan and Khachaturian, Zaven and Carrillo, Maria and Potter, William and Barnes, Lisa and Bernard, Marie and González, Hector and Ho, Carole and Jackson, Jonathan and Masliah, Eliezer and Masterman, Donna and Perrin, Richard and Silverberg, Nina and Silbert, Lisa and Kaye, Jeffrey and White, Sylvia and Pierce, Aimee and Thomas, Amy and Clay, Tera and Schwartz, Daniel and Devereux, Gillian and Taylor, Janet and Ryan, Jennifer and Nguyen, Mike and DeCapo, Madison and Shang, Yanan and Schneider, Lon and Munoz, Cynthia and Ferman, Diana and Conant, Carlota and Martin, Katherin and Oleary, Kristin and Pawluczyk, Sonia and Trejo, Elizabeth and Dagerman, Karen and Teodoro, Liberty and Becerra, Mauricio and Fairooz, Madiha and Garrison, Sonia and Boudreau, Julia and Avila, Yair and Brewer, James and Jacobson, Aaron and Gama, Antonio and Kim, Chi and Little, Emily and Frascino, Jennifer and Ferng, Nichol and Trujillo, Socorro and Heidebrink, Judith and Koeppe, Robert and MacDonald, Steven and Malyarenko, Dariya and Ziolkowski, Jaimie and O’Connor, James and Robert, Nicole and Lowe, Suzan and Rogers, Virginia and Hackenmiller, Barbara and Boeve, Bradley and Albers, Colleen and Kreuger, Connie and Jones, David and Knopman, David and Botha, Hugo and Magnuson, Jessica and Graff-Radford, Jonathan and Crawley, Kerry and Schumacher, Michael and McKinzie, Sanna and Smith, Steven and Helland, Tascha and Lowe, Val and Ramanan, Vijay and Pavlik, Valory and Faircloth, Jacob and Bishop, Jeffrey and Nath, Jessica and Chaudhary, Maria and Kataki, Maria and Yu, Melissa and Pacini, Nathiel and Barker, Randall and Brooks, Regan and Aggarwal, Ruchi and Honig, Lawrence and Stern, Yaakov and Mintz, Akiva and Cordona, Jonathan and Hernandez, Michelle and Long, Justin and Arnold, Abbey and Groves, Alex and Middleton, Anna and Vogler, Blake and McCurry, Cierra and Mayo, Connie and Raji, Cyrus and Amtashar, Fatima S. and Klemp, Heather and Elmore, Heather Nicole and Ruszkiewicz, James and Kusuran, Jasmina and Stewart, Jasmine and Horenkamp, Jennifer and Greeson, Julia and Wever, Kara and Vo, Katie and Larkin, Kelly and Rao, Lesley and Schoolcraft, Lisa and Gallagher, Lora and Paczynski, Madeline and McMillan, Maureen and Holt, Michael and Gagliano, Nicole and Henson, Rachel and LaBarge, Renee and Swarm, Robert and Munie, Sarah and Cepeda, Serena and Winterton, Stacey and Hegedus, Stephen and Wilson, TaNisha and Harte, Tanya and Bonacorsi, Zach and Geldmacher, David and Watkins, Amber and Barger, Brandi and Smelser, Bryan and Bates, Charna and Stover, Cynthia and McKinley, Emily and Ikner, Gregory and Hendrix, Haley and Cooper, Harold Matthew and Mahaffey, Jennifer and Booth Robbins, Lindsey and Brown Ashley, Loren and Natelson-Love, Marissa and Carter, Princess and Solomon, Veronika and Grossman, Hillel and Groome, Alexandra and Ardolino, Allison and Kaplan, Anthony and Sheppard, Faye and Burgos-Rivera, Genesis and Garcia-Camilo, Gina and Lim, Joanne and Neugroschl, Judith and Jackson, Kimberly and Evans, Kirsten and Soleimani, Laili and Sano, Mary and Ghesani, Nasrin and Binder, Sarah and Apuango, Xiomara Mendoza and Sood, Ajay and Troutman, Amelia and Blanchard, Kimberly and Richards, Arlene and Nelson, Grace and Hendrickson, Kirsten and Yurko, Erin and Plenge, Jamie and Rufo, Victoria and Shah, Raj and Duara, Ranjan and Lynch, Brendan and Chirinos, Cesar and Dittrich, Christine and Campbell, Debbie and Mejia, Diego and Perez, Gilberto and Colvee, Helena and Gonzalez, Joanna and Gondrez, Josalen and Knaack, Joshua and Acevedo, Mara and Cereijo, Maria and Greig-Custo, Maria and Villar, Michelle and Wishnia, Morris and Detling, Sheryl and Barker, Warren and Albert, Marilyn and Moghekar, Abhay and Rodzon, Barbara and Demsky, Corey and Pontone, Gregory and Pekar, Jim and Farrington, Leonie and Pomper, Martin and Johnson, Nicole and Alo, Tolulope and Sadowski, Martin and Ulysse, Anaztasia and Masurkar, Arjun and Marti, Brittany and Mossa, David and Geesey, Emilie and Petrocca, Emily and Schulze, Evan and Wong, Jennifer and Boonsiri, Joseph and Kenowsky, Sunnie and Martinez, Tatianne and Briglall, Veronica and Doraiswamy, P. Murali and Nwosu, Adaora and Adhikari, Alisa and Hellegers, Cammie and Petrella, Jeffrey and James, Olga and Wong, Terence and Hawk, Thomas and Vaishnavi, Sanjeev and McCoubrey, Hannah and Nasrallah, Ilya and Rovere, Rachel and Maneval, Jeffrey and Robinson, Elizabeth and Rivera, Francisco and Uffelman, Jade and Combs, Martha and O’Donnell, Patricia and Manning, Sara and King, Richard and Nieto, Alayne and Glueck, Amanda and Mandal, Anjana and Swain, Audrie and Gamble, Bethanie and Meacham, Beverly and Forenback, Denece and Ross, Dorothy and Cheatham, Elizabeth and Hartman, Ellen and Cornell, Gary and Harp, Jordan and Ashe, Laura and Goins, Laura and Watts, Linda and Yazell, Morgan and Mandal, Prabin and Buckler, Regan and Vincent, Sylvia and Rudd, Triana and Lopez, Oscar and Malia, Ann Arlene and Chiado, Caitlin and Zik, Cary and Savage, Kathleen and Fenice, Linda and Oakley, MaryAnn and Tacey, Paige C. and Berman, Sarah and Bowser, Sarah and Saganis, Xanthia and Porsteinsson, Anton and Mathewson, Abigail and Widman, Asa and Holvey, Bridget and Clark, Emily and Morales, Esmeralda and Young, Iris and Hopkins, Kevin and Martin, Kimberly and Kowalski, Nancy and Hunt, Rebecca and Calzavara, Roberta and Kurvach, Russell and D’Ambrosio, Stephen and Thai, Gaby and Vides, Beatriz and Lieb, Brigit and McAdams-Ortiz, Catherine and Toso, Cyndy and Mares, Ivan and Moorlach, Kathryn and Liu, Luter and Corona, Maria and Nguyen, Mary and Tallakson, Melanie and McDonnell, Michelle and Rangel, Milagros and Basheer, Neetha and Place, Patricia and Romero, Romina and Tam, Steven and Nguyen, Trung and Thomas, Abey and Frolov, Alexander and Khera, Alka and Browning, Amy and Kelley, Brendan and Dawson, Courtney and Mathews, Dana and Most, Elaine and Phillips, Elizeva and Nguyen, Lynn and Nunez, Maribel and Miller, Matalin and Jones, Matthew R. and Martinez, Natalie and Logan, Rebecca and McColl, Roderick and Pham, Sari and Fox, Tiffani and Moore, Tracey and Levey, Allan and Brown, Abby and Kippels, Andrea and Ellison, Ashton and Lyons, Casie and Hales, Chadwick and Parry, Cindy and Williams, Courtney and McCorkle, Elizabeth and Harris, Guy and Rose, Heather and Jooma, Inara and Al-Amin, Jahmila and Lah, James and Webster, James and Swiniarski, Jessica and Chapman, Latasha and Donnelly, Laura and Mariotti, Lauren and Locke, Mary and Vaughn, Phyllis and Penn, Rachael and Carpentier, Sallie and Yeboah, Samira and Basadre, Sarah and Malakauskas, Sarah and Lyron, Stefka and Villinger, Tara and Burney, Terra and Burns, Jeffrey and Abusalim, Ala and Dahlgren, Alexandra and Montero, Alexandria and Arthur, Anne and Dooly, Heather and Kreszyn, Katelynn and Berner, Katherine and Gillen, Lindsey and Scanlan, Maria and Madison, Mercedes and Mathis, Nicole and Switzer, Phyllis and Townley, Ryan and Fikru, Samantha and Sullivan, Samantha and Wright, Ella and Beigi, Maryam and Daley, Anthony and Ko, Ashley and Luong, Brittney and Nyborg, Glen and Morales, Jessica and Durbin, Kelly and Garcia, Lauren and Parand, Leila and Macias, Lorena and Monserratt, Lorena and Farchi, Maya and Wu, Pauline and Hernandez, Robert and Rodriguez, Thao and Graff-Radford, Neill and Marolt, A’llana and Thomas, Anton and Aloszka, Deborah and Moncayo, Ercilia and Westerhold, Erin and Day, Gregory and Chrestensen, Kandise and Imhansiemhonehi, Mary and Stephens, Sochenda and Grant, Sylvia and Brosch, Jared and Perkins, Amy and Saunders, Aubree and Kovac, Debra Silberberg and Polson, Heather and Mwaura, Isabell and Mejia, Kassandra and Britt, Katherine and King, Kathy and Nichols, Kayla and Lawrence, Kayley and Rankin, Lisa and Farlow, Martin and Wiesenauer, Patricia and Bryant, Robert and Herring, Scott and Lynch, Sheryl and Wilson, Skylar and Day, Traci and Korst, William and van Dyck, Christopher and Mecca, Adam and Miller, Alyssa and Brennan, Amanda and Khan, Amber and Ruan, Audrey and Gunnoud, Carol and Mendonca, Chelsea and Raynes-Goldfinger, Danielle and Salardini, Elaheh and Hidalgo, Elisa and Cooper, Emma and Singh, Erawadi and Murphy, Erin and May, Jeanine and Stanhope, Jesse and Lam, Jessica and Waszak, Julia and Nelsen, Kimberly and Sacaza, Kimberly and Hasbani, Mayer Joshua and Donahue, Meghan and Chen, Ming-Kai and Barcelos, Nicole and Eigenberger, Paul and Bonomi, Robin and O’Dell, Ryan and Jefferson, Sarah and Khasnavis, Siddharth and Smilowitz, Stephen and DeStefano, Susan and Good, Susan and Camarro, Terry and Clayton, Vanessa and Cavrel, Yanis and Lu, YuQuan and Chertkow, Howard and Bergman, Howard and Hosein, Chris and Black, Sandra and Kapadia, Anish and Bhan, Aparna and Lam, Benjamin and Scott, Christopher and Gabriel, Gillian and Bray, Jennifer and Zotovic, Ljubica and Gutierrez, Maria Samira and Masellis, Mario and Farshadi, Marjan and Gui, Maurylette and Mitchell, Meghan and Taylor, Rebecca and Endre, Ruby and Taghi-Zada, Zhala and Hsiung, Robin and English, Carolyn and Kim, Ellen and Yau, Eugene and Tong, Haley and Barlow, Laura and Jennings, Lauren and Assaly, Michele and Nunes, Paula and Marian, Tahlee and Kertesz, Andrew and Rogers, John and Trost, Dick and Wint, Dylan and Bernick, Charles and Munic, Donna and Grant, Ian and Korkoyah, Aaliyah and Raja, Ali and Lapins, Allison and Ryan, Caila and Pejic, Jelena and Basham, Kailey and Lukose, Leena and Haddad, Loreece and Quinlan, Lucas and Houghtaling, Nathaniel and Sadowsky, Carl and Martinez, Walter and Villena, Teresa and Reynolds, Brigid and Forero, Angelica and Ward, Carolyn and Brennan, Emma and Figueroa, Esteban and Esposito, Giuseppe and Mallory, Jessica and Johnson, Kathleen and Turner, Kathryn and Seidenberg, Katie and McCann, Kelly and Bassett, Margaret and Chadwick, Melanie and Turner, Raymond Scott and Bean, Robin and Sharma, Saurabh and Marshall, Gad and Haviari, Aferdita and Pietras, Alison and Wallace, Bradley and Munro, Catherine and Rivera-Delpin, Gladiliz and Hustead, Hadley and Levesque, Isabella and Ramirez, Jennifer and Nolan, Karen and Glennon, Kirsten and Palou, Mariana and Erkkinen, Michael and DaSilva, Nicole and Friedman, Pamela and Silver, Regina M. and Salazar, Ricardo and Polleys, Roxxanne and McGinnis, Scott and Gale, Seth and Hall, Tia and Luu, Tuan and Chao, Steven and Lin, Emmeline and Coleman, Jaila and Epperson, Kevin and Vasanawala, Minal and Atri, Alireza and Rangel, Amy and Evans, Brittani and Monarrez, Candy and Cline, Carol and Liebsack, Carolyn and Bandy, Daniel and Goldfarb, Danielle and Intorcia, Debbie and Olgin, Jennifer and Clark, Kelly and King, Kelsey and York, Kylee and Reade, Marina and Callan, Michael and Glass, Michael and Johnson, Michaela and Gutierrez, Michele and Goddard, Molly and Trncic, Nadira and Choudhury, Parichita and Reyes, Priscilla and Lowery, Serena and Hall, Shaundra and Olgin, Sonia and de Santiago, Stephanie and Alosco, Michael and Ton, Alyssa and Jimenez, Amanda and Ellison, Andrew and Tran, Anh and Anderson, Brandon and Carter, Della and Veronelli, Donna and Lenio, Steven and Steinberg, Eric and Mez, Jesse and Weller, Jason and Johns, Jennifer and Harkins, Jessica and Puleio, Alexa and Hoti, Ina and Mwicigi, Jane and Schultz, Olivia and Lauture, Mona and Denis, Ridiane and Killiany, Ronald and Singh, Sarab and Qiu, Wendy and Devis, Ycar and Obisesan, Thomas and Stone, Andrew and Ordor, Debra and Udodong, Ifreke and Okonkwo, Immaculata and Khan, Javed and Turner, Jillian and Hughes, Kyliah and Kadiri, Oshoze and Duffy, Charles and Moss, Ariana and Stapleton, Katherine and Toth, Maria and Sanders, Marianne and Ayres, Martin and Hamski, Melissa and Fatica, Parianne and Ogrocki, Paula and Ash, Sarah and Pot, Stacy and Chen, Doris and Soto, Andres and Tanase, Costin and Bissig, David and Vanya, Hafsanoor and Russell, Heather and Patel, Hitesh and Zhang, Hongzheng and Wallace, Kelly and Ayers, Kristi and Gallegos, Maria and Forloines, Martha and Sinn, Meghan and Kahulugan, Queennie Majorie S. and Isip, Richard and Calderon, Sandra and Hamm, Talia and Borrie, Michael and Lee, T-Y and Bartha, Rob and Johnson, Sterling and Asthana, Sanjay and Carlsson, Cynthia M. and Perrin, Allison and Tariot, Pierre and Fleisher, Adam and Reeder, Stephanie and Capote, Horacio and Emborsky, Allison and Mattle, Anna and Ajtai, Bela and Wagner, Benjamin and Myers, Bennett and Slazyk, Daryn and Fragale, Delaney and Fransen, Erin and Macnamara, Heather and Falletta, Jonathan and Hirtreiter, Joseph and Mechtler, Laszlo and King, Megan and Asbach, Michael and Rainka, Michelle and Zawislak, Richard and Wisniewski, Scott and O’Malley, Stephanie and Jimenez-Knight, Tatiana and Peehler, Todd and Aladeen, Traci and Bates, Vernice and Wenner, Violet and Elmalik, Wisam and Scharre, Douglas W. and Ramamurthy, Arun and Bouchachi, Soumya and Tarawneh, Rawan and Celmins, Dzintra and Leader, Alicia and Figueroa, Chris and Bauerle, Heather and Patterson, Katlynn and Reposa, Michael and Presto, Steven and Ahmed, Tuba and Stewart, Wendy and Pearlson, Godfrey D. and Blank, Karen and Anderson, Karen and Santulli, Robert B. and Schwartz, Eben S. and Williamson, Jeff and Jessup, Alicia and Williams, Andrea and Duncan, Crystal and O’Connell, Abigail and Gagnon, Karen and Zamora, Ezequiel and Bateman, James and Crawford, Freda and Thompson, Deb and Walker, Eboni and Rowell, Jennifer and White, Mikell and Ledford, Phillip and Bohlman, Sarah and Henkle, Susan and Bottoms, Joseph and Moretz, Lena and Hoover, Bevan and Shannon, Michael and Rogers, Samantha and Baker, Wendy and Harrison, William and Wu, Chuang-Kuo and DeMarco, Alexis and Stipanovich, Ava and Arcuri, Daniel and Clark, Jan and Davis, Jennifer and Doyon, Kerstin and Amoyaw, Marie and Acosta, Mauro Veras and Bailey, Ronald and Warren, Scott and Fogerty, Terry and Sanborn, Victoria and Riddle, Meghan and Salloway, Stephen and Malloy, Paul and Correia, Stephen and Windon, Charles and Blackburn, Morgan and Rosen, Howard J. and Miller, Bruce L. and Smith, Amanda and Mba, Ijeoma and Echevarria, Jenny and Janavs, Juris and Roglaski, Emily and Yong, Meagan and Devine, Rebecca and Okhravi, Hamid and Rivera, Edgardo and Kalowsky, Teresa and Smith, Caroline and Rosario, Christina and Masdeu, Joseph and Le, Richard and Gurung, Maushami and Sabbagh, Marwan and Garcia, Angelica and Ellis Slaughter, Micah and Elayan, Nadeen and Acothley, Skieff and Pomara, Nunzio and Hernando, Raymundo and Pomara, Vita and Reichert, Chelsea and Brawman-Mintzer, Olga and Acree, Allison and Williams, Arthur and Long, Campbell and Long, Rebecca and Newhouse, Paul and Hill, Sydni Jenee and Boegel, Amy and Seshadri, Sudha and Saklad, Amy and Jones, Floyd and Hu, William and Sotelo, V. and Gonazalez Rojas, Yaneicy and Mintzer, Jacobo and Flynn Longmire, Crystal and Spicer, Kenneth}, doi = {10.1073/pnas.2413442122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2413442122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deep learning to quantify the pace of brain aging in relation to neurocognitive changes}, volume = {122}, year = {2025}, }
• (2025). Dynamic and context-dependent keystone species effects in kelp forests. PNAS, 122(10), e2413360122. (www)

  @article{ , abstract = {Sea otters are an iconic keystone predator that can maintain kelp forests by preying on grazing invertebrates such as sea urchins. However, the effects of sea otters on kelp forests vary over their geographic range. Here, we analyze two 30-y datasets on kelp forest communities during the reintroduction of sea otters along the west coast of Vancouver Island, BC, Canada, and around San Nicolas Island, CA. We developed a community model to estimate species interactions as dynamic rates, varying with community state. We find evidence of a classic trophic cascade off Vancouver Island; the arrival of otters quickly led to depletion of urchins and recovery of kelp. However, this cascade was muted around San Nicolas Island, with otters, urchins, and kelp all coexisting at intermediate densities for multiple years. Our models show that this difference came from a pulse of strong otter impacts on urchins following recolonization off Vancouver Island, but not off San Nicolas Island. The mean effects of otters on urchins and urchins on kelp were not stronger in the north, indicating that interaction dynamics and not average interaction strength are key to explaining differences in community trajectories. We also find stronger multistep interaction chains in the south, arising from competitive interactions that indirectly buffered otter effects. These findings shed light on long-standing hypotheses about how interspecific interactions can alter the function of keystone species across community contexts. More broadly, we show how community change can be more accurately predicted by considering dynamic interaction strengths.}, archive = {J_PNAS}, author = {Langendorf, Ryan E. and Estes, James A. and Watson, Jane C. and Kenner, Michael C. and Hatfield, Brian B. and Tinker, M. Tim and Waddle, Ellen and DeMarche, Megan L. and Doak, Daniel F.}, doi = {10.1073/pnas.2413360122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2413360122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic and context-dependent keystone species effects in kelp forests}, volume = {122}, year = {2025}, }
• (2025). A cosmopolitan calcifying benthic foraminifera in agglutinated disguise as a geochemical recorder of coastal environments. PNAS, 122(10), e2413054122. (www)

  @article{ , abstract = {Calcifying foraminifera from the orders Rotaliida and Miliolida are widely used as geochemical proxies for recording paleoceanographic conditions, while agglutinated foraminifera are often overlooked since their tests are mostly composed of foreign particles. This study investigated the geochemical properties of Textularia agglutinans, a cosmopolitan agglutinated benthic species from the order Textulariida which has an exceptional inner calcareous test and is evolutionarily basal to Rotaliida. This study confirms the evolutionary link between textulariids and rotaliids based on their geochemistry and establishes T. agglutinans as a geochemical recorder of marine environments. Specimens from the Mediterranean coast of Israel were analyzed using laser ablation ICP-MS and compared to whole-test ICP-MS measurements of rotaliid and miliolid taxa from the same location. An Mg/Ca temperature calibration was established by LA-ICP-MS analyses of cultured specimens at 15, 17, 20, and 25 °C. Results show that T. agglutinans is a mid-Mg species (~19 to ~60 mmol/mol), with an Mg/Ca temperature correlation similar to high-Mg species. Its Pb, Zn, and Mn/Ca ratios are variable, generally overlapping with rotaliids and significantly lower than miliolids. Notably, T. agglutinans exhibits significantly higher Sr/Ca ratios (3.2 to 4.7 mmol/mol) compared to most foraminifera. Raman analyses reveal that the inner wall comprises a mix of aragonite and calcite, explaining these elevated Sr/Ca ratios. Rotaliida are the most prolific group of calcifying foraminifera. Our findings suggest that rotaliid tests evolved from an agglutinated textulariid ancestor with an inner aragonitic wall, a hypothesis that is further supported by the close phylogenetic relationship of the two groups.}, archive = {J_PNAS}, author = {Sosnitsky, Tamara and Krekova, Vasilisa and Elisha, Bar and Sadekov, Aleksey and Torfstein, Adi and Holzmann, Maria and Li, Hua and Abramovich, Sigal and Ashckenazi-Polivoda, Sarit}, doi = {10.1073/pnas.2413054122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2413054122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A cosmopolitan calcifying benthic foraminifera in agglutinated disguise as a geochemical recorder of coastal environments}, volume = {122}, year = {2025}, }
• (2025). Curve-fitting alone cannot validate neutral theory. PNAS, 122(10), e2412160122. (www)

  @article{ , archive = {J_PNAS}, author = {Johnson, Evan C.}, doi = {10.1073/pnas.2412160122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2412160122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Curve-fitting alone cannot validate neutral theory}, volume = {122}, year = {2025}, }
• (2025). Decoding planetary surfaces by counting cracks. PNAS, 122(10), e2411738122. (www)

  @article{ , abstract = {Planets are often covered with thin cracked shells. From mud films to lithospheres of rock or ice, fracture networks form two-dimensional (2D) tessellations of convex polygons whose geometry encodes their genesis. Here, we chart the geometry of 2D fracture mosaics across the solar system, and decode their formative conditions using a new dynamical crack model. We show that mosaics can be projected onto a Symbolic Ternary Diagram, where the relative proportions of “T,” “X,” and “Y” junctions are uniquely related to contributions from distinct modes of fracture. Most planetary mosaics cluster in a region associated with hierarchical fracture networks, where sequential cracking favors formation of T junctions. Exceptions to this rule may betray the presence of water. Europa’s fracture networks stand apart due to the predominance of X junctions; this is a special feature of ice, where healing of cracks by refreezing of water allows new fractures to overprint older ones. Several fracture networks on Mars appear as outliers due to the high proportion of Y junctions. These patterns—previously interpreted as ancient mudcracks and frozen polar terrain, based on geological evidence—are consistent with the twisting of crack junctions by cyclic volume change. Our findings suggest that counting cracks could aid in the identification of other water-influenced planetary environments.}, archive = {J_PNAS}, author = {Silver, S. and Regős, K. and Jerolmack, D. J. and Domokos, G.}, doi = {10.1073/pnas.2411738122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2411738122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Decoding planetary surfaces by counting cracks}, volume = {122}, year = {2025}, }
• (2025). Structural basis of DNA replication fidelity of the mpox virus. PNAS, 122(10), e2411686122. (www)

  @article{ , abstract = {The Mpox virus (MPXV) is an orthopoxvirus that caused a global outbreak in 2022. The poxvirus DNA polymerase complex is responsible for the replication and integrity of the viral genome; however, the molecular mechanisms underlying DNA replication fidelity are still unclear. In this study, we determined the cryoelectron microscopy (cryo-EM) structures of the MPXV F8–A22–E4 polymerase holoenzyme in its editing state, in complex with mismatched primer–template DNA and DNA containing uracil deoxynucleotide. We showed that the MPXV polymerase has a similar replication-to-edit transition mechanism to proofread the mismatched nucleotides like the B-family DNA polymerases of other species. The unique processivity cofactor A22–E4 undergoes conformational changes in different working states and might affect the proofreading process. Moreover, we elucidated the base excision repair (BER) function of E4 as a uracil-DNA glycosylase and the coupling mechanism of genome replication and BER, characteristic of poxviruses. Our findings greatly enhance our molecular understanding of DNA replication fidelity of orthopoxviruses and will stimulate the development of broad-spectrum antiviral drugs.}, archive = {J_PNAS}, author = {Xie, Yufeng and Kuai, Lu and Peng, Qi and Wang, Qian and Wang, Han and Li, Xiaomei and Qi, Jianxun and Ding, Qiang and Shi, Yi and Gao, George F.}, doi = {10.1073/pnas.2411686122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2411686122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis of DNA replication fidelity of the mpox virus}, volume = {122}, year = {2025}, }
• (2025). Characterizing sliding and rolling contacts between single particles. PNAS, 122(10), e2411414122. (www)

  @article{ , abstract = {Contacts between particles in dense, sheared suspensions are believed to underpin much of their rheology. Roughness and adhesion are known to constrain the relative motion of particles, and thus globally affect the shear response, but an experimental description of how they microscopically influence the transmission of forces and relative displacements within contacts is lacking. Here, we show that an innovative colloidal-probe atomic force microscopy technique allows the simultaneous measurement of normal and tangential forces exchanged between tailored surfaces and microparticles while tracking their relative sliding and rolling, unlocking the direct measurement of coefficients of rolling friction, as well as of sliding friction. We demonstrate that, in the presence of sufficient traction, particles spontaneously roll, reducing dissipation and promoting longer-lasting contacts. Conversely, when rolling is prevented, friction is greatly enhanced for rough and adhesive surfaces, while smooth particles coated by polymer brushes maintain well-lubricated contacts. We find that surface roughness induces rolling due to load-dependent asperity interlocking, leading to large off-axis particle rotations. In contrast, smooth, adhesive surfaces promote rolling along the principal axis of motion. Our results offer direct values of friction coefficients for numerical studies and an interpretation of the onset of discontinuous shear thickening based on them, opening up ways to tailor rheology via contact engineering.}, archive = {J_PNAS}, author = {Scherrer, Simon and Ramakrishna, Shivaprakash N. and Niggel, Vincent and Hsu, Chiao-Peng and Style, Robert W. and Spencer, Nicholas D. and Isa, Lucio}, doi = {10.1073/pnas.2411414122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2411414122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Characterizing sliding and rolling contacts between single particles}, volume = {122}, year = {2025}, }
• (2025). A WRKY transcription factor confers broad-spectrum resistance to biotic stresses and yield stability in rice. PNAS, 122(10), e2411164122. (www)

  @article{ , abstract = {Plants are subject to attack by diverse pests and pathogens. Few genes conferring broad-spectrum resistance to both insects and pathogens have been identified. Because of the growth–defense tradeoff, it is often challenging to balance biotic stress resistance and yield for crops. Here, we report that OsWRKY36 suppresses the resistance to insects and pathogens via transcriptional repression of Phenylalanine Ammonia Lyases ( PALs ), a key enzyme in phenylpropanoid pathway in rice. Knocking out OsWRKY36 causes elevated lignin biosynthesis and increased sclerenchyma thickness of leaf sheath, leading to enhanced resistance to multiple pests and pathogens. Additionally, loss of OsWRKY36 also derepresses the transcription of Ideal Plant Architecture 1 ( IPA1 ) and MONOCULM2 ( MOC2 ), resulting in increased spikelet number per panicle and tiller number. These findings provide mechanistic insights into biotic stress tolerance in rice and offer a promising strategy to breed rice cultivars with broad-spectrum resistance to insects and pathogens while maintaining stable yield.}, archive = {J_PNAS}, author = {Liu, Daoming and He, Jun and Li, Qi and Zhang, Xiao and Wang, Yongsheng and Sun, Quanguang and Wang, Wenhui and Zhang, Menglong and Wang, Yunlong and Xu, Haosen and Fang, Liang and Jiang, Ling and Liu, Shijia and Chen, Liangming and Tian, Yunlu and Liu, Xi and Wang, Ruyi and Zhang, Zhengguang and Chern, Mawsheng and Dong, Xiaoou and Wang, Haiyang and Liu, Yuqiang and Ronald, Pamela C. and Wan, Jianmin}, doi = {10.1073/pnas.2411164122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2411164122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A WRKY transcription factor confers broad-spectrum resistance to biotic stresses and yield stability in rice}, volume = {122}, year = {2025}, }
• (2025). Broken time-reversal symmetry in visual motion detection. PNAS, 122(10), e2410768122. (www)

  @article{ , abstract = {Our intuition suggests that when a movie is played in reverse, our perception of motion at each location in the reversed movie will be perfectly inverted compared to the original. This intuition is also reflected in classical theoretical and practical models of motion estimation, in which velocity flow fields invert when inputs are reversed in time. However, here we report that this symmetry of motion perception upon time reversal is broken in real visual systems. We designed a set of visual stimuli to investigate time reversal symmetry breaking in the fruit fly Drosophila ’s well-studied optomotor rotation behavior. We identified a suite of stimuli with a wide variety of properties that can uncover broken time reversal symmetry in fly behavioral responses. We then trained neural network models to predict the velocity of scenes with both natural and artificial contrast distributions. Training with naturalistic contrast distributions yielded models that broke time reversal symmetry, even when the training data themselves were time reversal symmetric. We show analytically and numerically that the breaking of time reversal symmetry in the model responses can arise from contrast asymmetry in the training data, but can also arise from other features of the contrast distribution. Furthermore, shallower neural network models can exhibit stronger symmetry breaking than deeper ones, suggesting that less flexible neural networks may be more prone to time reversal symmetry breaking. Overall, these results reveal a surprising feature of biological motion detectors and suggest that it could arise from constrained optimization in natural environments.}, archive = {J_PNAS}, author = {Wu, Nathan and Zhou, Baohua and Agrochao, Margarida and Clark, Damon A.}, doi = {10.1073/pnas.2410768122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2410768122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Broken time-reversal symmetry in visual motion detection}, volume = {122}, year = {2025}, }
• (2025). Phased ERK responsiveness and developmental robustness regulate teleost skin morphogenesis. PNAS, 122(10), e2410430122. (www)

  @article{ , abstract = {Elongation of the vertebrate embryonic axis necessitates rapid expansion of the epidermis to accommodate the growth of underlying tissues. Here, we generated a toolkit to visualize and quantify signaling in entire cell populations of the periderm, the outermost layer of the epidermis, in live developing zebrafish. We find that oriented cell divisions facilitate growth of the early periderm during axial elongation rather than cell addition from the basal layer. Activity levels of Extracellular signal-regulated kinase (ERK), a downstream effector of the MAPK pathway, gauged by a live biosensor, predict cell cycle entry, and optogenetic ERK activation regulates cell cycling dynamics. As development proceeds, rates of peridermal cell proliferation decrease, and ERK activity becomes more pulsatile and functionally transitions to promote hypertrophic cell growth. Targeted genetic blockade of cell division generates animals with oversized periderm cells, yet, unexpectedly, development to adulthood is not impaired. Our findings reveal stage-dependent differential responsiveness to ERK signaling and marked developmental robustness in growing teleost skin.}, archive = {J_PNAS}, author = {Ramkumar, Nitya and Richardson, Christian and O'Brien, Makinnon and Butt, Faraz Ahmed and Park, Jieun and Chao, Anna T. and Bagnat, Michel and Poss, Kenneth D. and Di Talia, Stefano}, doi = {10.1073/pnas.2410430122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2410430122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Phased ERK responsiveness and developmental robustness regulate teleost skin morphogenesis}, volume = {122}, year = {2025}, }
• (2025). Urban highways are barriers to social ties. PNAS, 122(10), e2408937122. (www)

  @article{ , abstract = {Urban highways are common, especially in the United States, making cities more car-centric. They promise the annihilation of distance but obstruct pedestrian mobility, thus playing a key role in limiting social interactions locally. Although this limiting role is widely acknowledged in urban studies, the quantitative relationship between urban highways and social ties is barely tested. Here, we define a Barrier Score that relates massive, geolocated online social network data to highways in the 50 largest US cities. At the granularity of individual social ties, we show that urban highways are associated with decreased social connectivity. This barrier effect is especially strong for short distances and consistent with historical cases of highways that were built to purposefully disrupt or isolate Black neighborhoods. By combining spatial infrastructure with social tie data, our method adds a dimension to demographic studies of social segregation. Our study can inform reparative planning for an evidence-based reduction of spatial inequality, and more generally, support a better integration of the social fabric in urban planning.}, archive = {J_PNAS}, author = {Aiello, Luca Maria and Vybornova, Anastassia and Juhász, Sándor and Szell, Michael and Bokányi, Eszter}, doi = {10.1073/pnas.2408937122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2408937122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Urban highways are barriers to social ties}, volume = {122}, year = {2025}, }
• (2025). Multilevel irreversibility reveals higher-order organization of nonequilibrium interactions in human brain dynamics. PNAS, 122(10), e2408791122. (www)

  @article{ , abstract = {Information processing in the human brain can be modeled as a complex dynamical system operating out of equilibrium with multiple regions interacting nonlinearly. Yet, despite extensive study of the global level of nonequilibrium in the brain, quantifying the irreversibility of interactions among brain regions at multiple levels remains an unresolved challenge. Here, we present the Directed Multiplex Visibility Graph Irreversibility framework, a method for analyzing neural recordings using network analysis of time-series. Our approach constructs directed multilayer graphs from multivariate time-series where information about irreversibility can be decoded from the marginal degree distributions across the layers, which each represents a variable. This framework is able to quantify the irreversibility of every interaction in the complex system. Applying the method to magnetoencephalography recordings during a long-term memory recognition task, we quantify the multivariate irreversibility of interactions between brain regions and identify the combinations of regions which showed higher levels of nonequilibrium in their interactions. For individual regions, we find higher irreversibility in cognitive versus sensorial brain regions while for pairs, strong relationships are uncovered between cognitive and sensorial pairs in the same hemisphere. For triplets and quadruplets, the most nonequilibrium interactions are between cognitive–sensorial pairs alongside medial regions. Combining these results, we show that multilevel irreversibility offers unique insights into the higher-order, hierarchical organization of neural dynamics from the perspective of brain network dynamics.}, archive = {J_PNAS}, author = {Nartallo-Kaluarachchi, Ramón and Bonetti, Leonardo and Fernández-Rubio, Gemma and Vuust, Peter and Deco, Gustavo and Kringelbach, Morten L. and Lambiotte, Renaud and Goriely, Alain}, doi = {10.1073/pnas.2408791122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2408791122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multilevel irreversibility reveals higher-order organization of nonequilibrium interactions in human brain dynamics}, volume = {122}, year = {2025}, }
• (2025). Giant quantum oscillations in thermal transport in low-density metals via electron absorption of phonons. PNAS, 122(10), e2408546122. (www)

  @article{ , abstract = {Oscillations of conductance observed in strong magnetic fields are a striking manifestation of the quantum dynamics of charge carriers in solids. The large charge carrier density in typical metals sets the scale of oscillations in both electrical and thermal conductivity, which characterize the Fermi surface. In semimetals, thermal transport at low-charge carrier density is expected to be phonon dominated, yet several experiments observe giant quantum oscillations in thermal transport. This raises the question of whether there is an overarching mechanism leading to sizable oscillations that survives in phonon-dominated semimetals. In this work, we show that such a mechanism exists. It relies on the peculiar phase-space allowed for phonon scattering by electrons when only a few Landau levels are filled. Our measurements on the Dirac semimetal ZrTe 5 support this counterintuitive mechanism through observation of pronounced thermal quantum oscillations, since they occur in similar magnitude and phase in directions parallel and transverse to the magnetic field. Our phase-space argument applies to all low-density semimetals, topological or not, including graphene and bismuth. Our work illustrates that phonon absorption can be leveraged to reveal degrees of freedom through their imprint on longitudinal thermal transport.}, archive = {J_PNAS}, author = {Bermond, Baptiste and Wawrzyńczak, Rafał and Zherlitsyn, Sergei and Kotte, Tommy and Helm, Toni and Gorbunov, Denis and Gu, Genda and Li, Qiang and Janasz, Filip and Meng, Tobias and Menges, Fabian and Felser, Claudia and Wosnitza, Joachim and Grushin, Adolfo and Carpentier, David and Gooth, Johannes and Gałeski, Stanisław}, doi = {10.1073/pnas.2408546122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2408546122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Giant quantum oscillations in thermal transport in low-density metals via electron absorption of phonons}, volume = {122}, year = {2025}, }
• (2025). Record of paleo water divide locations reveals intermittent divide migration and links to paleoclimate proxies. PNAS, 122(10), e2408426122. (www)

  @article{ , abstract = {Drainage divide migration alters the geometry of drainage basins, influencing the distribution of water, erosion, sediments, and ecosystems across Earth’s surface. The rate of divide migration is governed by differences in erosion rates across the divide and is thus sensitive to spatiotemporal variations in tectonics and climate. However, established approaches for quantifying divide migration rates offer only indirect evidence for the motion of the divide and provide only migration rate averages. Consequently, transience in divide migration cannot be resolved, hindering the ability to explore environmental changes that drive the dynamics of such potential transience. Here, we study a set of datable terraces identified as markers of paleo-divide locations, which provide direct evidence for the paleo motion of the divide. The location and age of the terraces reveal intermittent divide migration at timescales of 10 4 to 10 5 y, with phases of rapid migration—at rates more than twice the average—which coincide with documented regional paleoclimate fluctuations. These findings highlight the intermittent nature of divide migration dynamics over geomorphic timescales and its potential sensitivity to climate changes, underscoring the impact of such changes on the planform evolution of drainage basins.}, archive = {J_PNAS}, author = {Harel, Elhanan and Goren, Liran and Crouvi, Onn and Porat, Naomi and Qu, Tianyue and Ginat, Hanan and Shelef, Eitan}, doi = {10.1073/pnas.2408426122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2408426122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Record of paleo water divide locations reveals intermittent divide migration and links to paleoclimate proxies}, volume = {122}, year = {2025}, }
• (2025). A general framework for interpretable neural learning based on local information-theoretic goal functions. PNAS, 122(10), e2408125122. (www)

  @article{ , abstract = {Despite the impressive performance of biological and artificial networks, an intuitive understanding of how their local learning dynamics contribute to network-level task solutions remains a challenge to this date. Efforts to bring learning to a more local scale indeed lead to valuable insights, however, a general constructive approach to describe local learning goals that is both interpretable and adaptable across diverse tasks is still missing. We have previously formulated a local information processing goal that is highly adaptable and interpretable for a model neuron with compartmental structure. Building on recent advances in Partial Information Decomposition (PID), we here derive a corresponding parametric local learning rule, which allows us to introduce “infomorphic” neural networks. We demonstrate the versatility of these networks to perform tasks from supervised, unsupervised, and memory learning. By leveraging the interpretable nature of the PID framework, infomorphic networks represent a valuable tool to advance our understanding of the intricate structure of local learning.}, archive = {J_PNAS}, author = {Makkeh, Abdullah and Graetz, Marcel and Schneider, Andreas C. and Ehrlich, David A. and Priesemann, Viola and Wibral, Michael}, doi = {10.1073/pnas.2408125122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2408125122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A general framework for interpretable neural learning based on local information-theoretic goal functions}, volume = {122}, year = {2025}, }
• (2025). Environmental justice beyond race: Skin tone and exposure to air pollution. PNAS, 122(10), e2407064122. (www)

  @article{ , abstract = {Recent research, focused mostly on the United States and Western Europe, shows that marginalized communities often face greater environmental degradation. However, the ethnoracial categories used in these studies may not fully capture environmental inequality in the Global South. Moving beyond conventional ethnoracial variables, this study presents findings exploring the link between skin tone and fine particulate matter (PM 2.5 ) exposure in Colombia. By matching household geolocations from a large-scale longitudinal survey with satellite-based PM 2.5 estimates, we find that skin tone predicts both initial pollution exposure levels and their changes over time. Although average exposure levels remained stable during our study period, the environmental justice (EJ) landscape in Colombia contemporaneously underwent a complete transformation. In 2010, lighter-skinned individuals faced higher PM 2.5 exposure, but darker-skinned individuals experienced steeper increases in the following years. By 2016, the EJ gap had reversed, with people with the darkest skin tones exposed to PM 2.5 levels nearly one SD higher than those faced by people with the lightest skin tones. These patterns remain robust when controlling for a comprehensive set of theoretically relevant covariates, including ethnoracial self-identification and income. Disproportionate exposure to pollution from fires partially explains the observed disparities. Decomposition analysis shows that this variable, local collective action, and economic marginalization account for a sizeable share of the EJ gap. However, one-third of the gap remains unexplained by observable characteristics. With climate change intensifying fire incidence, the disproportionate disease burdens that vulnerable groups face might deepen unless policy measures are taken to reverse this trend.}, archive = {J_PNAS}, author = {Aguilar-Gomez, Sandra and Cardenas, Juan Camilo and Salas Diaz, Ricardo}, doi = {10.1073/pnas.2407064122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2407064122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Environmental justice beyond race: Skin tone and exposure to air pollution}, volume = {122}, year = {2025}, }
• (2025). Dynamic investigation of hypoxia-induced L-lactylation. PNAS, 122(10), e2404899122. (www)

  @article{ , abstract = {The recently identified histone modification lysine lactylation can be stimulated by L-lactate and glycolysis. Although the chemical group added upon lysine lactylation was originally proposed to be the L-enantiomer of lactate (K L-la ), two isomeric modifications, lysine D-lactylation (K D-la ) and N-ε-(carboxyethyl) lysine (K ce ), also exist in cells, with their precursors being metabolites of glycolysis. The dynamic regulation and differences among these three modifications in response to hypoxia remain poorly understood. In this study, we demonstrate that intracellular K L-la , but not K D-la or K ce , is up-regulated in response to hypoxia. Depletion of glyoxalase enzymes, GLO1 and GLO2, had minimal impact on K D-la , K ce , or hypoxia-induced K L-la . Conversely, blocking glycolytic flux to L-lactate under hypoxic conditions by knocking out lactate dehydrogenase A/B completely abolished the induction of K L-la but increased K D-la and K ce . We further observed a correlation between the level of K L-la and hypoxia-inducible factor 1 alpha (HIF-1α) expression under hypoxic conditions and when small molecules were used to stabilize HIF-1α in the normoxia condition. Our result demonstrated that there is a strong correlation between HIF-1α and K L-la in lung cancer tissues and that patient samples with higher grade tend to have higher K L-la levels. Using a proteomics approach, we quantified 66 K L-la sites that were up-regulated by hypoxia and demonstrated that p300/CBP contributes to hypoxia-induced K L-la . Collectively, our study demonstrates that K L-la , rather than K D-la or K ce , is the prevailing lysine lactylation in response to hypoxia. Our results therefore demonstrate a link between K L-la and the hypoxia-induced adaptation of tumor cells.}, archive = {J_PNAS}, author = {Gao, Jinjun and Liu, Ruilong and Huang, Kevin and Li, Ziyuan and Sheng, Xinlei and Chakraborty, Kasturi and Han, Chang and Zhang, Di and Becker, Lev and Zhao, Yingming}, doi = {10.1073/pnas.2404899122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2404899122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic investigation of hypoxia-induced L-lactylation}, volume = {122}, year = {2025}, }
• (2025). S-nitrosylation-triggered secretion of mycobacterial PknG leads to phosphorylation of SODD to prevent apoptosis of infected macrophages. PNAS, 122(10), e2404106122. (www)

  @article{ , abstract = {The tuberculosis-causing agent Mycobacterium tuberculosis (M.tb) establishes its niche inside macrophages by secretion of several virulence factors and engaging many host factors. Mycobacterial infection of macrophages results in a proinflammatory trigger–mediated secretion of TNFα. Protein kinase G (PknG), a Serine/Threonine kinase, is essential for mycobacterial survival within the macrophage. Pathogenic mycobacteria, upon infection, can trigger the secretion of proinflammatory cytokine TNFα, but whether secreted PknG plays any role in TNFα secretion at early stages of infection remains undeciphered. Moreover, at early infection stages, prevention of macrophage apoptosis is vital to successful mycobacterial pathogenesis. Our studies show that mycobacteria-secreted PknG can dampen the expression and concomitant secretion of proinflammatory TNFα. During early infection, M.tb infection–induced generation of reactive nitrogen intermediates (RNI) leads to S-nitrosylation of PknG on Cys109, thereby enabling its secretion into macrophages. Upon M.tb infection, secreted S-nitrosylated PknG phosphorylates macrophage Silencer of Death Domains (SODD) at Thr405, as identified through our phosphoproteomic studies. Thereafter, phosphorylated SODD, through an irreversible binding with the TNFR1 death domain, prevents Caspase8 activation and concomitant extrinsic apoptotic trigger. Moreover, alveolar macrophages from mice infected with PknG-knockout M.tb also exhibited SODD phosphorylation and hindered Caspase8 activation to prevent extrinsic macrophage apoptosis. Therefore, this work exhibits S-nitrosylation-mediated secretion of PknG to induce phosphorylation of macrophage SODD, which, through irreversible interaction with TNFR1, prevented extrinsic macrophage apoptosis at the early stages of infection.}, archive = {J_PNAS}, author = {Saha, Saradindu and Roy, Sadhana and Hazra, Arnab and Das, Debayan and Kumar, Vimal and Singh, Amit Kumar and Singh, Ajay Vir and Mondal, Rajesh and Bose Dasgupta, Somdeb}, doi = {10.1073/pnas.2404106122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2404106122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {S-nitrosylation-triggered secretion of mycobacterial PknG leads to phosphorylation of SODD to prevent apoptosis of infected macrophages}, volume = {122}, year = {2025}, }
• (2025). Structure of activity in multiregion recurrent neural networks. PNAS, 122(10), e2404039122. (www)

  @article{ , abstract = {Neural circuits comprise multiple interconnected regions, each with complex dynamics. The interplay between local and global activity is thought to underlie computational flexibility, yet the structure of multiregion neural activity and its origins in synaptic connectivity remain poorly understood. We investigate recurrent neural networks with multiple regions, each containing neurons with random and structured connections. Inspired by experimental evidence of communication subspaces, we use low-rank connectivity between regions to enable selective activity routing. These networks exhibit high-dimensional fluctuations within regions and low-dimensional signal transmission between them. Using dynamical mean-field theory, with cross-region currents as order parameters, we show that regions act as both generators and transmitters of activity—roles that are often in tension. Taming within-region activity can be crucial for effective signal routing. Unlike previous models that suppressed neural activity to control signal flow, our model achieves routing by exciting different high-dimensional activity patterns through connectivity structure and nonlinear dynamics. Our analysis of this disordered system offers insights into multiregion neural data and trained neural networks.}, archive = {J_PNAS}, author = {Clark, David G. and Beiran, Manuel}, doi = {10.1073/pnas.2404039122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2404039122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure of activity in multiregion recurrent neural networks}, volume = {122}, year = {2025}, }
• (2025). Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases. PNAS, 122(10), e2402117122. (www)

  @article{ , abstract = {Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11 , e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer’s disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22 , 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.}, archive = {J_PNAS}, author = {Johnson, Elizabeth A. and Nowar, Raghad and Viola, Kirsten L. and Huang, Weijian and Zhou, Sihang and Bicca, Maíra A. and Zhu, Wei and Kranz, Daniel L. and Klein, William L. and Silverman, Richard B.}, doi = {10.1073/pnas.2402117122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2402117122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases}, volume = {122}, year = {2025}, }
• (2025). Environmental drivers of spatial variation in tropical forest canopy height: Insights from NASA’s GEDI spaceborne LiDAR. PNAS, 122(10), e2401755122. (www)

  @article{ , abstract = {Forest canopy height is a fundamental ecosystem property—influencing patterns of forest carbon storage and forest ecosystem responses to climate variability and change. Previous studies have analyzed environmental drivers influencing spatial variation in canopy height at landscape-to-regional scales; however, far less is known about the environmental determinants underlying regional and global scale variation in forest canopy height. Using the canopy height metrics products from Global Ecosystem Dynamics Investigation (GEDI), a space-borne Light Detection and Ranging (LiDAR) instrument specifically designed to characterize forest structure, we analyze the environmental correlates of spatial variation of global tropical forest canopy height. Our study demonstrates that climate, topography, and soil properties account for 75% of the variation in tropical forest canopy height. Elevation, dry season length, and solar radiation are the most important drivers in determining canopy height both locally and regionally. These results emphasize the vulnerability of tropical forest structure to ongoing changes in the earth’s climate and provide a valuable empirical baseline for tropical forest management.}, archive = {J_PNAS}, author = {Liu, Shaoqing and Csillik, Ovidiu and Ordway, Elsa M. and Chang, Li-Ling and Longo, Marcos and Keller, Michael and Moorcroft, Paul R.}, doi = {10.1073/pnas.2401755122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2401755122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Environmental drivers of spatial variation in tropical forest canopy height: Insights from NASA’s GEDI spaceborne LiDAR}, volume = {122}, year = {2025}, }
• (2025). Resilient tree-planting strategies for carbon dioxide removal under compounding climate and economic uncertainties. PNAS, 122(10), e2320961122. (www)

  @article{ , abstract = {To meet decarbonization targets, nations around the globe have made ambitious commitments to expand forested land. Operationalizing these commitments requires choosing a planting strategy: How many trees should be planted, of which species, and where? Given those choices must be made now but have long-term consequences, such decisions are plagued by uncertainty. For example, species that are well suited to present conditions may perform poorly under future climates, yet those future climates are themselves highly uncertain. Using the exemplar of the United Kingdom, a nation committed to achieving net zero emissions by midcentury, we quantify key uncertainties pertaining to coevolving climate and economic conditions and examine how modern methods of decision-making under uncertainty can advise on planting choices. Our analysis reveals that the best planting strategy assuming a “high-emissions” future is radically different to that for a future that remains on a “near-historic” path. Planting for the former while experiencing the latter results in substantial net costs to UK society. Assimilating uncertainty into decision-making identifies planting strategies that diversify risk and significantly reduce the probability of high-cost outcomes. Importantly, our research reveals that the scope for mitigating risk through choice of planting strategy is relatively limited. Despite this persistent risk, we find that tree planting remains a highly cost-effective carbon removal solution when compared to alternative technologies, even when those alternatives are assumed to be riskless.}, archive = {J_PNAS}, author = {Cho, Frankie H. T. and Aglonucci, Paolo and Bateman, Ian J. and Lee, Christopher F. and Lovett, Andrew and Mancini, Mattia C. and Rapti, Chrysanthi and Day, Brett H.}, doi = {10.1073/pnas.2320961122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2320961122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Resilient tree-planting strategies for carbon dioxide removal under compounding climate and economic uncertainties}, volume = {122}, year = {2025}, }
• (2025). Genomic divergence across the tree of life. PNAS, 122(10), e2319389122. (www)

  @article{ , abstract = {Nucleotide sequence data are being harnessed to identify species, even in cases in which organisms themselves are neither in hand nor witnessed. But how genome-wide sequence divergence maps to species status is far from clear. While gene sequence divergence is commonly used to delineate bacterial species, its correspondence to established species boundaries has yet to be explored across eukaryotic taxa. Because the processes underlying gene flow differ fundamentally between prokaryotes and eukaryotes, these domains are likely to differ in the relationship between reproductive isolation and genome-wide sequence divergence. In prokaryotes, homologous recombination, the basis of gene flow, depends directly on the degree of genomic sequence divergence, whereas in sexually reproducing eukaryotes, reproductive incompatibility can stem from changes in very few genes. Guided by measures of genome-wide sequence divergence in bacteria, we gauge how genomic criteria correspond to species boundaries in eukaryotes. In recognized species of eukaryotes, levels of gene sequence divergence within species are typically very small, averaging <1% across protein-coding regions in most animals, plants, and fungi. There are even instances in which divergence between sister species is the same or less than that among conspecifics. In contrast, bacterial species, defined as populations exchanging homologous genes, show levels of divergence both within and between species that are considerably higher. Although no single threshold delineates species, eukaryotic populations with >1% genome-wide sequence divergence are likely separate species, whereas prokaryotic populations with 1% divergence are still able to recombine and thus can be considered the same species.}, archive = {J_PNAS}, author = {Hart, Rowan and Moran, Nancy A. and Ochman, Howard}, doi = {10.1073/pnas.2319389122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {10}, pages = {e2319389122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genomic divergence across the tree of life}, volume = {122}, year = {2025}, }
• (2025). Correction for atlas et al., turbulence in the tropical stratosphere, equatorial kelvin waves, and the quasi-biennial oscillation. PNAS, 122(9), e2501726122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2501726122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2501726122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for atlas et al., turbulence in the tropical stratosphere, equatorial kelvin waves, and the quasi-biennial oscillation}, volume = {122}, year = {2025}, }
• (2025). Correction for schmidt et al., conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2. PNAS, 122(9), e2501339122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2501339122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2501339122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for schmidt et al., conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for melo et al., small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing. PNAS, 122(9), e2501333122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2501333122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2501333122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for melo et al., small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing}, volume = {122}, year = {2025}, }
• (2025). Correction for ahituv et al., starch-rich plant foods 780,000 y ago: Evidence from acheulian percussive stone tools. PNAS, 122(9), e2501154122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2501154122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2501154122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for ahituv et al., starch-rich plant foods 780,000 y ago: Evidence from acheulian percussive stone tools}, volume = {122}, year = {2025}, }
• (2025). Component mechanisms of gaia: Biogeochemical cycles are special. PNAS, 122(9), e2500741122. (www)

  @article{ , archive = {J_PNAS}, author = {Szathmáry, Eörs}, doi = {10.1073/pnas.2500741122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2500741122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Component mechanisms of gaia: Biogeochemical cycles are special}, volume = {122}, year = {2025}, }
• (2025). Correction for jenewein et al., concomitant formation of protocells and prebiotic compounds under a plausible early earth atmosphere. PNAS, 122(9), e2500712122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2500712122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2500712122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for jenewein et al., concomitant formation of protocells and prebiotic compounds under a plausible early earth atmosphere}, volume = {122}, year = {2025}, }
• (2025). Correction for wu et al., hapalindole q suppresses autophagosome−lysosome fusion by promoting YAP1 degradation via chaperon-mediated autophagy. PNAS, 122(9), e2500709122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2500709122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2500709122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for wu et al., hapalindole q suppresses autophagosome−lysosome fusion by promoting YAP1 degradation via chaperon-mediated autophagy}, volume = {122}, year = {2025}, }
• (2025). Rethinking postdoc careers through the science of science. PNAS, 122(9), e2500344122. (www)

  @article{ , archive = {J_PNAS}, author = {Youyou, Wu and Feng, Kaiyun}, doi = {10.1073/pnas.2500344122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2500344122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rethinking postdoc careers through the science of science}, volume = {122}, year = {2025}, }
• (2025). 3A or not 3A: Cytidine deaminases in the etiology of the CAG-repeat expansion diseases. PNAS, 122(9), e2426776122. (www)

  @article{ , archive = {J_PNAS}, author = {Usdin, Karen}, doi = {10.1073/pnas.2426776122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2426776122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {3A or not 3A: Cytidine deaminases in the etiology of the CAG-repeat expansion diseases}, volume = {122}, year = {2025}, }
• (2025). Reply to trollmann et al.: Perspective on LNP structure and simulation. PNAS, 122(9), e2423433122. (www)

  @article{ , archive = {J_PNAS}, author = {Garaizar, Adiran and Díaz-Oviedo, David and Zablowsky, Nina and Rissanen, Sami and Köbberling, Johannes and Sun, Jiawei and Steiger, Christoph and Steigemann, Patrick and Mann, Florian A. and Meier, Katharina}, doi = {10.1073/pnas.2423433122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2423433122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to trollmann et al.: Perspective on LNP structure and simulation}, volume = {122}, year = {2025}, }
• (2025). Thiopurine therapy enhances immune checkpoint inhibitor efficacy in low-mutational burden melanoma: A promising anticancer approach. PNAS, 122(9), e2423246122. (www)

  @article{ , abstract = {A key limitation of immune checkpoint inhibitors (ICI) therapy is their reduced efficacy toward cancers with a low tumor mutational burden (TMB). Since low-TMB tumors express fewer neoantigens, they are less responsive to ICI therapy like anti-PD-1 and anti-CTLA-4. In preclinical immunocompetent mouse models of low-TMB melanoma, we recently demonstrated that exposure to 6-thioguanine (6TG) significantly improved tumor control by increasing TMB and creating a proinflammatory tumor microenvironment. The combination of 6TG with anti-PD-1 further improved tumor control, although it did not fully inhibit tumor growth. We here investigated additional ICI combinations, assessing anti-CTLA-4 with anti-PD-1 to improve efficacy. ICI eliminated tumors in 6TG-exposed mice when ICI treatment was initiated at tumor volumes of 20 mm 3 , stopped tumor growth at volumes of 120 mm 3 , and had no effect at volumes of 300 mm 3 . Finally, we showed that mice achieving complete tumor regression with 6TG and ICI treatment exhibited lasting immune memory, which effectively suppressed tumor growth at relapse upon re-exposure to tumor cells. These findings may pave the way to effective application of ICI to low-TMB cancers, when initiated at low tumor volume.}, archive = {J_PNAS}, author = {Nazerai, Loulieta and Tsiavou, Christina and Vardouli, Lina and Schmiegelow, Kjeld and De Zio, Daniela}, doi = {10.1073/pnas.2423246122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2423246122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Thiopurine therapy enhances immune checkpoint inhibitor efficacy in low-mutational burden melanoma: A promising anticancer approach}, volume = {122}, year = {2025}, }
• (2025). Boosted recovery of rare earth elements from mining wastes and discarded NdFeB magnets by tributyl phosphate–grafted ZIF-8. PNAS, 122(9), e2423217122. (www)

  @article{ , abstract = {The escalating demand for rare earth elements (REEs) highlights the necessity for their sustainable recovery from waste streams and secondary resources. However, this process requires materials with exceptional selectivity and capacity for REEs due to their low concentration and high presence of interfering ions. Herein, we synthesized zeolitic imidazolate framework-8 (ZIF-8) and subsequently modified it with tributyl phosphate (TBP) to enhance its affinity and selectivity for the recovery of REEs. The distribution coefficients ( K d ) of ZIF-8-TBP for REEs (neodymium, Nd, and dysprosium, Dy) were orders of magnitude higher than the K d of main interfering ions (e.g., Mg, Ni Al, and Fe). Particularly, the maximum sorption capacities ( q m ) for Nd and Dy were 475 and 529 mg g −1 , respectively. In addition, the separation factor between Dy (a representative of heavy REE) and Nd (a representative of light REE) reached 24, greatly exceeding the figures reported previously. Importantly, the outstanding ability of ZIF-8-TBP for selective separation and recovery of REEs was demonstrated via its application to real samples including mining wastewater, and leaching solutions from REE filter cakes and discarded NdFeB magnets. Multiscale simulations reveal that ZIF-8-TBP possessed a stronger binding strength and greater sorption energy for REE ions. These results indicate that ZIF-8-TBP could effectively harvest REEs from wastes and offers an efficient alternative for industrial applications in REE recovery.}, archive = {J_PNAS}, author = {Wan, Shun and Liu, Wu-Jun and Tan, Guangcai and Yu, Han-Qing}, doi = {10.1073/pnas.2423217122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2423217122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Boosted recovery of rare earth elements from mining wastes and discarded NdFeB magnets by tributyl phosphate–grafted ZIF-8}, volume = {122}, year = {2025}, }
• (2025). Reply to smith and siegel: Most lithium hops in paddlewheel-claimed conductors occur without spatially and temporally correlated anion-group rotations. PNAS, 122(9), e2423194122. (www)

  @article{ , archive = {J_PNAS}, author = {Jun, KyuJung and Ceder, Gerbrand}, doi = {10.1073/pnas.2423194122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2423194122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to smith and siegel: Most lithium hops in paddlewheel-claimed conductors occur without spatially and temporally correlated anion-group rotations}, volume = {122}, year = {2025}, }
• (2025). Revisiting lipid nanoparticle composition and structure: A critical take on simulation approaches. PNAS, 122(9), e2422995122. (www)

  @article{ , archive = {J_PNAS}, author = {Trollmann, Marius F. W. and Rossetti, Paolo and Böckmann, Rainer A.}, doi = {10.1073/pnas.2422995122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2422995122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Revisiting lipid nanoparticle composition and structure: A critical take on simulation approaches}, volume = {122}, year = {2025}, }
• (2025). No evidence for peto’s paradox in terrestrial vertebrates. PNAS, 122(9), e2422861122. (www)

  @article{ , abstract = {Larger, longer-lived species are expected to have a higher cancer prevalence compared to smaller, shorter-lived species owing to the greater number of cell divisions that occur during their lifespan. Yet, to date, no evidence has been found to support this expectation, and no association has been found between cancer prevalence and body size across species—a phenomenon known as Peto’s paradox. Specifically, while anticancer mechanisms have been identified for individual species, wider phylogenetic evidence has remained elusive. Here, we show that there is no evidence for Peto’s paradox across amphibians, birds, mammals, and squamate reptiles: Larger species do in fact have a higher cancer prevalence compared to smaller species. Moreover, we demonstrate that the accumulation of repeated instances of accelerated body size evolution in mammals and birds is associated with a reduction in the prevalence of neoplasia and malignancy, suggesting that increased rates of body size evolution are associated with the evolution of improved cellular growth control. These results represent empirical evidence showing that larger body size is related to higher cancer prevalence, thus rejecting Peto’s paradox, and demonstrating the importance of heterogenous routes of body size evolution in shaping anticancer defenses.}, archive = {J_PNAS}, author = {Butler, George and Baker, Joanna and Amend, Sarah R. and Pienta, Kenneth J. and Venditti, Chris}, doi = {10.1073/pnas.2422861122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2422861122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {No evidence for peto’s paradox in terrestrial vertebrates}, volume = {122}, year = {2025}, }
• (2025). Climate change is leading to an ecological trap in a migratory insect. PNAS, 122(9), e2422595122. (www)

  @article{ , abstract = {Many insect migrants rely on favorable seasonal winds to carry out long-range latitudinal migrations. In East China, the annual advance and retreat of the East Asian summer monsoon produces ideal conditions for seasonal range expansion and contraction of many migratory crop pests. However, climate-induced changes in the strength, timing, and location of the monsoon are impacting wind systems which may, in turn, affect migration patterns. We investigated these questions in the rice leafroller (RLR) moth, a severe pest of rice that annually invades the Lower Yangtze River Valley (LYRV) of China from winter-breeding areas further south. Using a 24-y dataset of RLR population dynamics from 31 monitoring stations across Southeast China, we investigated the impact of changes in monsoon wind regimes on fall migration patterns of the pest. Historically, RLR emigrated from the LYRV to South China on the favorably directed winds produced by the retreat of the monsoon at the end of the outbreak season (from mid-August onward). We show that in the recent 12-y period, prevailing late-season winds remain northward for longer than previously, preventing locally produced moths from emigrating southward. Additionally, winds now facilitate mass late-season immigrations into the LYRV, creating an ecological trap, as immigrants do not have time to produce another generation. As a consequence of the changing wind patterns, pest pressure is declining, and climate-induced changes to the East Asian summer monsoon result in seasonal migration becoming a riskier strategy. Such changes in insect migration patterns have severe implications for the population dynamics of windborne migrants, ecosystem functioning, and pest management strategies.}, archive = {J_PNAS}, author = {Zhang, Shi-Yan and Zhang, Yi-Yang and Yang, Fan and Zhou, Chen and Shen, Hui-Mei and Wang, Bei-Bei and Zeng, Juan and Reynolds, Don R. and Chapman, Jason W. and Hu, Gao}, doi = {10.1073/pnas.2422595122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2422595122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Climate change is leading to an ecological trap in a migratory insect}, volume = {122}, year = {2025}, }
• (2025). Ancient ocean coastal deposits imaged on mars. PNAS, 122(9), e2422213122. (www)

  @article{ , abstract = {The northern lowlands of early Mars could have contained a significant quantity of liquid water. However, the ocean hypothesis remains controversial due to the lack of conclusive evidence from the Martian subsurface. We use data from the Zhurong Rover Penetrating Radar on the southern Utopia Planitia to identify subsurface dipping reflectors indicative of an ancient prograding shoreline. The reflectors dip unidirectionally with inclinations in the range 6° to 20° and are imaged to a thickness of 10 to 35 m along an uninterrupted 1.3 km northward shoreline-perpendicular traverse. The consistent dip inclinations, absence of dissection by fluvial channels along the extended traverse, and low permittivity of the sediments are consistent with terrestrial coastal deposits—and discount fluvial, aeolian, or magmatic origins favored elsewhere on Mars. The structure, thickness, and length of the section support voluminous supply of onshore sediments into a large body of water, rather than a merely localized and short-lived melt event. Our findings not only provide support for the existence of an ancient Martian ocean in the northern plains but also offer crucial insights into the evolution of the ancient Martian environment.}, archive = {J_PNAS}, author = {Li, Jianhui and Liu, Hai and Meng, Xu and Duan, Diwen and Lu, Haijing and Zhang, Jinhai and Zhang, Fengshou and Elsworth, Derek and Cardenas, Benjamin T. and Manga, Michael and Zhou, Bin and Fang, Guangyou}, doi = {10.1073/pnas.2422213122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2422213122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ancient ocean coastal deposits imaged on mars}, volume = {122}, year = {2025}, }
• (2025). Directed evolution of a sequence-specific covalent protein tag for RNA labeling. PNAS, 122(9), e2422085122. (www)

  @article{ , abstract = {Efficient methods for conjugating proteins to RNA are needed for RNA delivery, imaging, editing, interactome mapping, and barcoding applications. Noncovalent coupling strategies using viral RNA binding proteins such as MS2/MCP have been widely applied but are limited by tag size, sensitivity, and dissociation over time. We took inspiration from a sequence-specific, covalent protein–DNA conjugation method based on the Rep nickase of a porcine circovirus called “HUH tag”. Though wild-type HUH protein has no detectable activity toward an RNA probe, we engineered an RNA-reactive variant, called “rHUH”, through 7 generations of yeast display–based directed evolution. Our 13.4 kD rHUH has 12 mutations relative to HUH and forms a covalent tyrosine-phosphate ester linkage with a 10-nucleotide RNA recognition sequence (“rRS”) within minutes. We engineered the sensitivity down to 1 nM of target RNA, shifted the metal ion requirement from Mn 2+ toward Mg 2+ , and demonstrated efficient labeling in mammalian cell lysate. This work paves the way toward a potentially powerful methodology for sequence-specific covalent protein–RNA conjugation in biological systems.}, archive = {J_PNAS}, author = {Huang, Rongbing and Ting, Alice Y.}, doi = {10.1073/pnas.2422085122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2422085122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Directed evolution of a sequence-specific covalent protein tag for RNA labeling}, volume = {122}, year = {2025}, }
• (2025). Multiomics analysis unveils the cellular ecosystem with clinical relevance in aldosterone-producing adenomas with KCNJ5 mutations. PNAS, 122(9), e2421489122. (www)

  @article{ , abstract = {Aldosterone-producing adenomas (APA), a major endocrine tumor and leading subtype of primary aldosteronism, cause secondary hypertension with high cardiometabolic risks. Despite potentially producing multiple steroid hormones, detailed cellular mechanisms in APA remain insufficiently studied. Our multiomics analysis focusing on APA with KCNJ5 mutations, which represent the most common genetic form, revealed marked cellular heterogeneity. Tumor cell reprogramming initiated from stress-responsive cells to aldosterone-producing or cortisol-producing cells, with the latter progressing to proliferative stromal-like cells. These cell subtypes showed spatial segregation, and APA exhibited genomic intratumor heterogeneity. Among the nonparenchymal cells, lipid-associated macrophages, which were abundant in APA, might promote the progression of cortisol-producing and stromal-like cells, suggesting their role in the tumor microenvironment. Intratumor cortisol synthesis was correlated with increased blood cortisol levels, which were associated with the development of vertebral fractures, a hallmark of osteoporosis. This study unveils the complex cellular ecosystem with clinical relevance in APA with KCNJ5 mutations, providing insights into tumor biology that could inform future clinical approaches.}, archive = {J_PNAS}, author = {Yokomoto-Umakoshi, Maki and Fujita, Masamichi and Umakoshi, Hironobu and Ogasawara, Tatsuki and Iwahashi, Norifusa and Nakatani, Kohta and Kaneko, Hiroki and Fukumoto, Tazuru and Nakao, Hiroshi and Haji, Shojiro and Kawamura, Namiko and Shimma, Shuichi and Seki, Masahide and Suzuki, Yutaka and Izumi, Yoshihiro and Oda, Yoshinao and Eto, Masatoshi and Ogawa, Seishi and Bamba, Takeshi and Ogawa, Yoshihiro}, doi = {10.1073/pnas.2421489122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2421489122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multiomics analysis unveils the cellular ecosystem with clinical relevance in aldosterone-producing adenomas with KCNJ5 mutations}, volume = {122}, year = {2025}, }
• (2025). A bipartite interaction with the processivity clamp potentiates pol IV-mediated TLS. PNAS, 122(9), e2421471122. (www)

  @article{ , abstract = {Processivity clamps mediate polymerase switching for translesion synthesis (TLS). All three Escherichia coli TLS polymerases interact with the β 2 processivity clamp through a conserved clamp-binding motif (CBM), which is indispensable for TLS. Notably, Pol IV also interacts weakly with the rim of the clamp through non-CBM residues. Ablating this “rim contact” in cells results in selective sensitivity to DNA-damaging agents, raising the question how the rim contact contributes to TLS. Here, we show that the rim contact is critical for TLS past a strong replication block but barely necessary for a weak blocking lesion. Within the in vitro reconstituted E. coli replisome, the rim mutation compromises Pol IV-mediated TLS past 3-deaza-methyl dA, a strong block, whereas barely affecting TLS past N 2 -furfuryl dG, a weak block. Similar observations are also made in E. coli cells bearing a single copy of these lesions in the genome. At lesion-stalled replication forks, single-stranded DNA binding protein locally enriches Pol IV, enabling it to bind the low-affinity rim site. This interaction poises Pol IV to better compete with Pol III, the replicative polymerase, which competitively inhibits Pol IV from interacting with the clamp through its CBM. We propose that this bipartite clamp interaction enables Pol IV to rapidly resolve lesion-stalled replication at a strong block through TLS, which reduces damage-induced mutagenesis.}, archive = {J_PNAS}, author = {Chang, Seungwoo and Laureti, Luisa and Thrall, Elizabeth S. and Kay, Marguerite S. and Philippin, Gaëlle and Jergic, Slobodan and Pagès, Vincent and Loparo, Joseph J.}, doi = {10.1073/pnas.2421471122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2421471122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A bipartite interaction with the processivity clamp potentiates pol IV-mediated TLS}, volume = {122}, year = {2025}, }
• (2025). Bipartite binding of the intrinsically disordered scaffold protein JIP1 to the kinase JNK1. PNAS, 122(9), e2419915122. (www)

  @article{ , abstract = {Scaffold proteins are key players in many signaling pathways where they ensure spatial and temporal control of molecular interactions by simultaneous tethering of multiple signaling components. The protein JIP1 acts as a scaffold within the c-Jun N-terminal kinase (JNK) signaling pathway by assembling three kinases, MLK3, MKK7, and JNK, into a macromolecular complex that enables their specific activation. The recruitment of these kinases depends on the 450-amino acid intrinsically disordered tail of JIP1, however, the structural details of this tail and the molecular mechanisms by which it binds kinases have remained elusive. Here, we provide an atomic resolution structural description of the JIP1 tail, and we study its interaction with the kinase JNK1. Using NMR spectroscopy, we show that JNK1 not only engages with the well-known docking site motif (D-motif) of JIP1, but also interacts with a noncanonical F-motif. We determine the crystal structure of the JIP1–JNK1 complex at 2.35 Å resolution revealing a bipartite binding mode of JIP1. Our work provides insights into the sequence determinants of F-motifs suggesting that these motifs may be more prevalent in JNK substrates than previously recognized. More broadly, our study highlights the power of NMR spectroscopy in uncovering kinase interaction motifs within disordered scaffold proteins, and it paves the way for atomic-resolution interaction studies of JIP1 with its multitude of interaction partners.}, archive = {J_PNAS}, author = {Orand, Thibault and Delaforge, Elise and Lee, Alexandra and Kragelj, Jaka and Tengo, Maud and Tengo, Laura and Blackledge, Martin and Boeri Erba, Elisabetta and Davis, Roger J. and Palencia, Andrés and Jensen, Malene Ringkjøbing}, doi = {10.1073/pnas.2419915122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2419915122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bipartite binding of the intrinsically disordered scaffold protein JIP1 to the kinase JNK1}, volume = {122}, year = {2025}, }
• (2025). A proper definition of the paddlewheel effect affirms its existence. PNAS, 122(9), e2419892122. (www)

  @article{ , archive = {J_PNAS}, author = {Smith, Jeffrey G. and Siegel, Donald J.}, doi = {10.1073/pnas.2419892122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2419892122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A proper definition of the paddlewheel effect affirms its existence}, volume = {122}, year = {2025}, }
• (2025). PTDP-43 levels correlate with cell type–specific molecular alterations in the prefrontal cortex of c9orf72 ALS/FTD patients. PNAS, 122(9), e2419818122. (www)

  @article{ , abstract = {Repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with C9orf72 ALS/FTD, we compared healthy controls with C9orf72 ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during FTD development. Loss of neurosurveillance microglia and activation of the complement cascade take place early, when pTDP-43 aggregates are absent or very low, and become more pronounced in late stages, suggesting an initial involvement of microglia in disease progression. Reduction of layer 2-3 cortical projection neurons with high expression of CUX2/LAMP5 also occurs early, and the reduction becomes more pronounced as pTDP-43 accumulates. Several unique features were observed only in samples with high levels of pTDP-43, including global alteration of chromatin accessibility in oligodendrocytes, microglia, and astrocytes; higher ratios of premature oligodendrocytes; increased levels of the noncoding RNA NEAT1 in astrocytes and neurons, and higher amount of phosphorylated ribosomal protein S6. Our findings reveal progressive functional changes in major cell types found in the prefrontal cortex of C9orf72 ALS/FTD patients that shed light on the mechanisms underlying the pathology of this disease.}, archive = {J_PNAS}, author = {Wang, Hsiao-Lin V. and Xiang, Jian-Feng and Yuan, Chenyang and Veire, Austin M. and Gendron, Tania F. and Murray, Melissa E. and Tansey, Malú G. and Hu, Jian and Gearing, Marla and Glass, Jonathan D. and Jin, Peng and Corces, Victor G. and McEachin, Zachary T.}, doi = {10.1073/pnas.2419818122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2419818122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PTDP-43 levels correlate with cell type–specific molecular alterations in the prefrontal cortex of c9orf72 ALS/FTD patients}, volume = {122}, year = {2025}, }
• (2025). Empowering genome-wide association studies via a visualizable test based on the regional association score. PNAS, 122(9), e2419721122. (www)

  @article{ , abstract = {The genome-wide association studies identified genes associated with many diseases, but the identification and verification of disease variants are still challenging due to small effects and large number of individual variants. In this paper, we propose a powerful method that first quantifies the strength of regional associations at each single nucleotide polymorphism and converts these measures into time series data before using a change point detection algorithm to identify significant regions. In our extensive simulation study, the proposed method consistently demonstrates greater power than existing alternatives, achieving a relative increase of over 20% in challenging scenarios where true causal variants are sparse and multiple association regions exist at the same time, while maintaining a lower false positive rate.}, archive = {J_PNAS}, author = {Jiang, Yiran and Zhang, Heping}, doi = {10.1073/pnas.2419721122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2419721122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Empowering genome-wide association studies via a visualizable test based on the regional association score}, volume = {122}, year = {2025}, }
• (2025). Weakening AMOC reduces ocean carbon uptake and increases the social cost of carbon. PNAS, 122(9), e2419543122. (www)

  @article{ , abstract = {A weakening of the Atlantic Meridional Overturning Circulation (AMOC) has been found to be globally beneficial by economic assessments. This result emerges because AMOC weakening would cool the Northern Hemisphere, thereby reducing expected climate damages and decreasing estimates of the global social cost of carbon dioxide (SCC). There are, however, many other impacts of AMOC weakening that are not yet taken into account. Here, we add a second impact channel by quantifying the effects of AMOC weakening on ocean carbon uptake, using biogeochemically-only coupled freshwater hosing simulations in the Max Planck Institute Earth System Model. Our simulations reveal an approximately linear relationship between AMOC strength and carbon uptake reductions, constituting a carbon cycle feedback that leads to higher atmospheric CO 2 concentrations and stronger global warming. This AMOC carbon feedback, when incorporated into an integrated climate-economy model, leads to additional economic damages of several trillion US dollars and raises the SCC by about 1%. The SCC increase is similar in magnitude, but of opposite sign, to the SCC effect of Northern Hemisphere cooling. While there are many other potentially relevant economic impact channels, the AMOC carbon feedback alone could thus flip the consequences of AMOC weakening into a net cost to society.}, archive = {J_PNAS}, author = {Schaumann, Felix and Alastrué de Asenjo, Eduardo}, doi = {10.1073/pnas.2419543122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2419543122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Weakening AMOC reduces ocean carbon uptake and increases the social cost of carbon}, volume = {122}, year = {2025}, }
• (2025). Cryo-EM heterogeneity analysis using regularized covariance estimation and kernel regression. PNAS, 122(9), e2419140122. (www)

  @article{ , abstract = {Proteins and the complexes they form are central to nearly all cellular processes. Their flexibility, expressed through a continuum of states, provides a window into their biological functions. Cryogenic electron microscopy (cryo-EM) is an ideal tool to study these dynamic states as it captures specimens in noncrystalline conditions and enables high-resolution reconstructions. However, analyzing the heterogeneous distributions of conformations from cryo-EM data is challenging. We present RECOVAR, a method for analyzing these distributions based on principal component analysis (PCA) computed using a REgularized COVARiance estimator. RECOVAR is fast, robust, interpretable, expressive, and competitive with state-of-the-art neural network methods on heterogeneous cryo-EM datasets. The regularized covariance method efficiently computes a large number of high-resolution principal components that can encode rich heterogeneous distributions of conformations and does so robustly thanks to an automatic regularization scheme. The reconstruction method based on adaptive kernel regression resolves conformational states to a higher resolution than all other tested methods on extensive independent benchmarks while remaining highly interpretable. Additionally, we exploit favorable properties of the PCA embedding to estimate the conformational density accurately. This density allows for better interpretability of the latent space by identifying stable states and low free-energy motions. Finally, we present a scheme to navigate the high-dimensional latent space by automatically identifying these low free-energy trajectories. We make the code freely available at https://github.com/ma-gilles/recovar .}, archive = {J_PNAS}, author = {Gilles, Marc Aurèle and Singer, Amit}, doi = {10.1073/pnas.2419140122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2419140122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryo-EM heterogeneity analysis using regularized covariance estimation and kernel regression}, volume = {122}, year = {2025}, }
• (2025). Chiral structural color from microdomes. PNAS, 122(9), e2419113122. (www)

  @article{ , abstract = {Artificial chiral-structural-color materials can carry high-dimensional information based on multiple optical degrees of freedom, providing possibilities for advanced optical security and information storage. However, current artificial chiral-structural-color materials are hindered by their specific compositions, fine nanostructures, and single polarization modulation. Here, we found that microdomes made from common polymers have chiral structural colors with broadband tunability and multiple polarization-modulated chirality. The microdome patterns are easily fabricated by ordinary printing techniques and have inhomogeneous spatial distributions of full polarization states and customizable colors. Our chiral-structural-color microdomes (CSCMs) provide a promising roadmap for high-capacity information encryption and high-security anti-counterfeiting. We developed multidimensional tunable structural color displays and achieved encryption with high information capacity. To further highlight the application potential, we constructed contact lenses integrated with CSCMs for identity authentication with 2 32 distinctive cryptograms.}, archive = {J_PNAS}, author = {Lai, Xintao and Li, Tongyu and Hou, Xiaoyu and Vogelbacher, Florian and Wang, Jiajun and Song, Yanlin and Shi, Lei and Li, Mingzhu}, doi = {10.1073/pnas.2419113122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2419113122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chiral structural color from microdomes}, volume = {122}, year = {2025}, }
• (2025). O-GalNAc glycans are enriched in neuronal tracts and regulate nodes of ranvier. PNAS, 122(9), e2418949122. (www)

  @article{ , abstract = {Protein O-glycosylation is a critical modification in the brain, as genetic variants in the pathway are associated with common and severe neuropsychiatric phenotypes. However, little is known about the most abundant O-glycans in the mammalian brain, which are N-acetylgalactosamine (O-GalNAc) linked. Here, we determined the spatial localization, protein carriers, and cellular function of O-GalNAc glycans in the mouse brain. We observed striking spatial enrichment of O-GalNAc glycans in neuronal tracts, and specifically at nodes of Ranvier, specialized structures involved in signal propagation in the brain. Glycoproteomic analysis revealed that more than half of the identified O-GalNAc glycans were present on chondroitin sulfate proteoglycans termed lecticans, and display both domain enrichment and regional heterogeneity. Inhibition of O-GalNAc synthesis in neurons reduced binding of Siglec-4, a known regulator of neurite growth, and shortened the length of nodes of Ranvier. This work establishes a function of O-GalNAc glycans in the brain and will inform future studies on their role in development and disease.}, archive = {J_PNAS}, author = {Noel, Maxence and Suttapitugsakul, Suttipong and Cummings, Richard D. and Mealer, Robert G.}, doi = {10.1073/pnas.2418949122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2418949122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {O-GalNAc glycans are enriched in neuronal tracts and regulate nodes of ranvier}, volume = {122}, year = {2025}, }
• (2025). Measuring criticism of the police in the local news media using large language models. PNAS, 122(9), e2418821122. (www)

  @article{ , abstract = {High-profile incidents of police violence against Black citizens over the past decade have spawned contentious debates in the United States on the role of police. This debate has played out prominently in the news media, leading to a perception that media outlets have become more critical of the police. There is currently, however, little empirical evidence supporting this perceived shift. We construct a large dataset of local news reporting on the police from 2013 to 2023 in 10 politically diverse U.S. cities. Leveraging advanced language models, we measure criticism by analyzing whether reporting supports or is critical of two contentions: 1) that the police protect citizens and 2) that the police are racist. To validate this approach, we collect labels from members of different political parties. We find that contrary to public perceptions, local media criticism of the police has remained relatively stable along these two dimensions over the past decade. While criticism spiked in the aftermath of high-profile police killings, such as George Floyd’s murder, these events did not produce sustained increases in negative police news. In fact, reporting supportive of police effectiveness has increased slightly since Floyd’s death. We find only small differences in coverage trends in more conservative and more liberal cities, undermining the idea that local outlets cater to the politics of their audiences. Last, although Republicans are more likely to view a piece of news as supportive of the police than Democrats, readers across parties see reporting as no more critical than it was a decade ago.}, archive = {J_PNAS}, author = {Crowl, Logan and Dutta, Sujan and KhudaBukhsh, Ashiqur R. and Severnini, Edson and Nagin, Daniel S.}, doi = {10.1073/pnas.2418821122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2418821122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Measuring criticism of the police in the local news media using large language models}, volume = {122}, year = {2025}, }
• (2025). Policy options for the drug pricing conundrum. PNAS, 122(9), e2418540122. (www)

  @article{ , abstract = {Current proposals aimed at reducing U.S. pharmaceutical prices would have immediate benefits (particularly for low-income and elderly populations), but could dramatically reduce firms’ investment in potentially highly welfare-improving Research and Development (R&D). The United States subsidizes the worldwide pharmaceutical market: U.S. drug prices are more than 250% of those in other Organization for Economic Co-operation and Development (OECD) countries. If each drug had a single international price across the highest-income OECD countries and total pharmaceutical firm profits were held fixed: U.S. prices would fall by half; every other country’s prices would increase (by 28 to over 300%); and R&D incentives would be maintained. We propose a potential lever for the U.S. government to influence worldwide drug pricing: access to the Medicare market.}, archive = {J_PNAS}, author = {Ho, Kate and Pakes, Ariel}, doi = {10.1073/pnas.2418540122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2418540122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Policy options for the drug pricing conundrum}, volume = {122}, year = {2025}, }
• (2025). Ancient genomes reveal trans-eurasian connections between the european huns and the xiongnu empire. PNAS, 122(9), e2418485122. (www)

  @article{ , abstract = {The Huns appeared in Europe in the 370s, establishing an Empire that reshaped West Eurasian history. Yet until today their origins remain a matter of extensive debate. Traditional theories link them to the Xiongnu, the founders of the first nomadic empire of the Mongolian steppe. The Xiongnu empire dissolved, however, ~300 y before the Huns appeared in Europe, and there is little archaeological and historical evidence of Huns in the steppe during this time gap. Furthermore, despite the rich 5th to 6th centuries current era (CE) archaeological record of the Carpathian Basin, the cultural elements of connections with the steppe are limited to few findings and even fewer solitary eastern-type burials. In this study, we coanalyze archaeological evidence with 35 newly sequenced and published genomic data for a total of 370 individuals—from 5th to 6th century CE contexts in the Carpathian Basin including 10 Hun-period eastern-type burials, 2nd to 5th century sites across Central Asia and 2nd c. before current era (BCE) to 1st c. CE Xiongnu period sites across the Mongolian steppe. We find no evidence for the presence of a large eastern/steppe descent community among the Hun- and post-Hun-period Carpathian Basin population. We also observe a high genetic diversity among the eastern-type burials that recapitulates the variability observed across the Eurasian Steppe. This suggests a mixed origin of the incoming steppe conquerors. Nevertheless, long-shared genomic tracts provide compelling evidence of genetic lineages directly connecting some individuals of the highest Xiongnu-period elite with 5th to 6th century CE Carpathian Basin individuals, showing that some European Huns descended from them.}, archive = {J_PNAS}, author = {Gnecchi-Ruscone, Guido Alberto and Rácz, Zsófia and Liccardo, Salvatore and Lee, Juhyeon and Huang, Yilei and Traverso, Luca and Radzevičiūtė, Rita and Hajnal, Zsuzsanna and Szécsényi-Nagy, Anna and Gyuris, Balázs and Mateovics-László, Orsolya and Bernert, Zsolt and Szeniczey, Tamás and Hajdu, Tamás and Mészáros, Boglárka and Bálint, Marianna and Mende, Balázs Gusztáv and Miller, Bryan and Samashev, Zainolla and Childebayeva, Ainash and Djansugurova, Leyla and Geary, Patrick and Ringbauer, Harald and Vida, Tivadar and Jeong, Choongwon and Pohl, Walter and Krause, Johannes and Hofmanová, Zuzana}, doi = {10.1073/pnas.2418485122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2418485122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ancient genomes reveal trans-eurasian connections between the european huns and the xiongnu empire}, volume = {122}, year = {2025}, }
• (2025). Linking DNA-packing density distribution and TAD boundary locations. PNAS, 122(9), e2418456122. (www)

  @article{ , abstract = {DNA is heterogeneously packaged into chromatin, which is further organized into topologically associating domains (TADs) with sharp boundaries. These boundary locations are critical for genome regulation. Here, we explore how the distribution of DNA-packing density across chromatin affects the TAD boundary locations. We develop a polymer-physics-based model that utilizes DNA accessibility data to parameterize DNA-packing density along chromosomes, treating them as heteropolymers, and simulates the stochastic folding of these heteropolymers within a nucleus to yield a conformation ensemble. Such an ensemble reproduces a subset (over 60%) of TAD boundaries across the human genome, as confirmed by Hi-C data. Additionally, it reproduces the spatial distance matrices of 2-Mb genomic regions provided by FISH experiments. Furthermore, our model suggests that utilizing DNA accessibility data alone as input is sufficient to predict the emergence and disappearance of key TADs during early T cell differentiation. We show that stochastic folding of heteropolymers in a confined space can replicate both the prevalence of chromatin domain structures and the cell-to-cell variation in domain boundary positions observed in single-cell experiments. Furthermore, regions of lower DNA-packing density preferentially form domain boundaries, and this preference drives the emergence of TAD boundaries observed in ensemble-averaged Hi-C maps. The enrichment of TAD boundaries at CTCF binding sites can be attributed to the influence of CTCF binding on local DNA-packing density in our model. Collectively, our findings establish a strong link between TAD boundaries and regions of lower DNA-packing density, providing insights into the mechanisms underlying TAD formation.}, archive = {J_PNAS}, author = {Meng, Luming and Sheong, Fu Kit and Luo, Qiong}, doi = {10.1073/pnas.2418456122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2418456122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Linking DNA-packing density distribution and TAD boundary locations}, volume = {122}, year = {2025}, }
• (2025). Van der waals quantum dots on layered hexagonal boron nitride. PNAS, 122(9), e2417859122. (www)

  @article{ , abstract = {Semiconductor quantum dots (QD) promise unique electronic, optical, and chemical properties, which can be exquisitely tuned by controlling the composition, size, and morphology. Semiconductor QDs have been synthesized primarily via two approaches, namely, epitaxial growth and wet-chemical synthesis. However, the properties of epitaxial QDs (eQDs) are susceptible to wetting layer formation and substrate dislocations, while colloidal QDs (cQDs) face fluorescence intermittency issues. Here, we report on the synthesis of a class of QDs that can overcome the fundamental limitations of eQDs and cQDs. By exploiting the sp 2 bonding of layered hexagonal boron nitride (hBN), we show that GaN QDs can be epitaxially grown through a weak van der Waals (vdW) interaction without two-dimensional wetting layer formation. The photoluminescence intensity of GaN van der Waals quantum dots (vQDs) is more than six times stronger than that of conventional GaN eQDs and no optical blinking was observed from vQDs. We show that the interadatom bond strength is about one order of magnitude stronger compared with that between the adatoms and the hBN substrate. This work shows that vQDs have unique properties that are difficult to achieve using existing QDs synthesis methods and thus can potentially enable new classes of high-performance optoelectronic and quantum devices.}, archive = {J_PNAS}, author = {Wu, Yuanpeng and Xiao, Yixin and Zhao, Ying and Shen, Yifan and Sun, Kai and Wang, Boyu and Wang, Ping and Wang, Ding and Zhou, Peng and Wang, Danhao and Liu, Jiangnan and Hu, Mingtao and B. Norris, Theodore and Song, Jun and Mi, Zetian}, doi = {10.1073/pnas.2417859122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2417859122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Van der waals quantum dots on layered hexagonal boron nitride}, volume = {122}, year = {2025}, }
• (2025). Leaky ribosomal scanning enables tunable translation of bicistronic ORFs in green algae. PNAS, 122(9), e2417695122. (www)

  @article{ , abstract = {Advances in sequencing technology have unveiled examples of nucleus-encoded polycistrons, once considered rare. Exclusively polycistronic transcripts are prevalent in green algae, although the mechanism by which multiple polypeptides are translated from a single transcript is unknown. Here, we used bioinformatic and in vivo mutational analyses to evaluate competing mechanistic models for translation of bicistronic mRNAs in green algae. High-confidence manually curated datasets of bicistronic loci from two divergent green algae, Chlamydomonas reinhardtii and Auxenochlorella protothecoides , revealed a preference for weak Kozak-like sequences for ORF 1 and an underrepresentation of potential initiation codons before the ORF 2 start codon, which are suitable conditions for leaky ribosome scanning to allow ORF 2 translation. We used mutational analysis in A. protothecoides to test the mechanism. In vivo manipulation of the ORF 1 Kozak-like sequence and start codon altered reporter expression at ORF 2, with a weaker Kozak-like sequence enhancing expression and a stronger one diminishing it. A synthetic bicistronic dual reporter demonstrated inversely adjustable activity of green fluorescent protein expressed from ORF 1 and luciferase from ORF 2, depending on the strength of the ORF 1 Kozak-like sequence. Our findings demonstrate that translation of multiple ORFs in green algal bicistronic transcripts is consistent with episodic leaky scanning of ORF 1 to allow translation at ORF 2. This work has implications for the potential functionality of upstream open reading frames (uORFs) found across eukaryotic genomes and for transgene expression in synthetic biology applications.}, archive = {J_PNAS}, author = {Dueñas, Marco A. and Craig, Rory J. and Gallaher, Sean D. and Moseley, Jeffrey L. and Merchant, Sabeeha S.}, doi = {10.1073/pnas.2417695122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2417695122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Leaky ribosomal scanning enables tunable translation of bicistronic ORFs in green algae}, volume = {122}, year = {2025}, }
• (2025). Chemical genetic interactions elucidate pathways controlling tuberculosis antibiotic efficacy during infection. PNAS, 122(9), e2417525122. (www)

  @article{ , abstract = {Successful tuberculosis therapy requires treatment with an unwieldy multidrug combination for several months. Thus, there is a growing need to identify novel genetic vulnerabilities that can be leveraged to develop new, more effective antitubercular drugs. Consequently, recent efforts to optimize tuberculosis (TB) therapy have exploited Mycobacterium tuberculosis (Mtb) chemical genetics to identify pathways influencing antibiotic efficacy, novel mechanisms of antibiotic action, and new targets for TB drug discovery. However, the influence of the complex host environment on these interactions remains largely unknown, leaving the therapeutic potential of the identified targets unclear. In this study, we leveraged a library of conditional mutants targeting 467 essential Mtb genes to characterize the chemical–genetic interactions (CGIs) with TB drugs directly in the mouse infection model. We found that these in vivo CGIs differ significantly from those identified in vitro. Both drug-specific and drug-agnostic effects were identified, and many were preserved during treatment with a multidrug combination, suggesting numerous strategies for enhancing therapy. This work also elucidated the complex effects of pyrazinamide (PZA), a drug that relies on aspects of the infection environment for efficacy. Specifically, our work supports the importance of coenzyme A synthesis- inhibition during infection, as well as the antagonistic effect of iron limitation on PZA activity. In addition, we found that inhibition of thiamine and purine synthesis increases PZA efficacy, suggesting additional therapeutically exploitable metabolic dependencies. Our findings present a map of the unique in vivo CGIs, characterizing the mechanism of PZA activity in vivo and identifying potential targets for TB drug development.}, archive = {J_PNAS}, author = {Oluoch, Peter O. and Koh, Eun-Ik and Proulx, Megan K. and Reames, Charlotte J. and Papavinasasundaram, Kadamba G. and Murphy, Kenan C. and Zimmerman, Matthew D. and Dartois, Véronique and Sassetti, Christopher M.}, doi = {10.1073/pnas.2417525122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2417525122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chemical genetic interactions elucidate pathways controlling tuberculosis antibiotic efficacy during infection}, volume = {122}, year = {2025}, }
• (2025). Computational biology predicts metabolic engineering targets for increased production of 103 valuable chemicals in yeast. PNAS, 122(9), e2417322122. (www)

  @article{ , abstract = {Development of efficient cell factories that can compete with traditional chemical production processes is complex and generally driven by case-specific strategies, based on the product and microbial host of interest. Despite major advancements in the field of metabolic modeling in recent years, prediction of genetic modifications for increased production remains challenging. Here, we present a computational pipeline that leverages the concept of protein limitations in metabolism for prediction of optimal combinations of gene engineering targets for enhanced chemical bioproduction. We used our pipeline for prediction of engineering targets for 103 different chemicals using Saccharomyces cerevisiae as a host. Furthermore, we identified sets of gene targets predicted for groups of multiple chemicals, suggesting the possibility of rational model-driven design of platform strains for diversified chemical production.}, archive = {J_PNAS}, author = {Domenzain, Iván and Lu, Yao and Wang, Haoyu and Shi, Junling and Lu, Hongzhong and Nielsen, Jens}, doi = {10.1073/pnas.2417322122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2417322122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Computational biology predicts metabolic engineering targets for increased production of 103 valuable chemicals in yeast}, volume = {122}, year = {2025}, }
• (2025). RORγt-expressing dendritic cells are functionally versatile and evolutionarily conserved antigen-presenting cells. PNAS, 122(9), e2417308122. (www)

  @article{ , abstract = {Conventional dendritic cells (cDCs) are potent antigen-presenting cells (APCs) that integrate signals from their environment allowing them to direct situation-adapted immunity. Thereby they harbor great potential for being targeted in vaccination, autoimmunity, and cancer. Here, we use fate mapping, functional analyses, and comparative cross-species transcriptomics to show that RORγt + DCs are a conserved, functionally versatile, and transcriptionally distinct type of DCs. RORγt + DCs entail various populations described in different contexts including Janus cells/RORγt-expressing extrathymic Aire-expressing cells (eTACs), subtypes of Thetis cells, RORγt + -DC (R-DC) like cells, cDC2C and ACY3 + DCs. We show that in response to inflammatory triggers, RORγt + DCs can migrate to lymph nodes and in the spleen can activate naïve CD4 + T cells. These findings expand the functional repertoire of RORγt + DCs beyond the known role of eTACs and Thetis cells in inducing T cell tolerance to self-antigens and intestinal microbes in mice. We further show that RORγt + DCs with proinflammatory features accumulate in autoimmune neuroinflammation in mice and men. Thus, our work establishes RORγt + DCs as immune sentinel cells that exhibit a broad functional spectrum ranging from inducing peripheral T cell tolerance to T cell activation depending on signals they integrate from their environment.}, archive = {J_PNAS}, author = {Narasimhan, Hamsa and Richter, Maria L. and Shakiba, Ramin and Papaioannou, Nikos E. and Stehle, Christina and Ravi Rengarajan, Kaushikk and Ulmert, Isabel and Kendirli, Arek and de la Rosa, Clara and Kuo, Pin-Yu and Altman, Abigail and Münch, Philipp and Mahboubi, Saba and Küntzel, Vanessa and Sayed, Amina and Stange, Eva-Lena and Pes, Jonas and Ulezko Antonova, Alina and Pereira, Carlos-Filipe and Klein, Ludger and Dudziak, Diana and Colonna, Marco and Torow, Natalia and Hornef, Mathias W. and Clausen, Björn E. and Kerschensteiner, Martin and Lahl, Katharina and Romagnani, Chiara and Colomé-Tatché, Maria and Schraml, Barbara U.}, doi = {10.1073/pnas.2417308122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2417308122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RORγt-expressing dendritic cells are functionally versatile and evolutionarily conserved antigen-presenting cells}, volume = {122}, year = {2025}, }
• (2025). NOTCH, ERK, and SHH signaling respectively control the fate determination of cortical glia and olfactory bulb interneurons. PNAS, 122(9), e2416757122. (www)

  @article{ , abstract = {During cortical development, radial glial cells (neural stem cells) initially are neurogenic, generating intermediate progenitor cells that exclusively produce glutamatergic pyramidal neurons. Next, radial glial cells generate tripotential intermediate progenitor cells (Tri-IPCs) that give rise to cortical astrocytes and oligodendrocytes, and olfactory bulb interneurons. The molecular mechanisms underlying the transition from cortical neurogenesis to gliogenesis, and the subsequent fate determination of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons, remain unclear. Here, we report that extracellular signal-regulated kinase (ERK) signaling plays a fundamental role in promoting cortical gliogenesis and the generation of Tri-IPCs. Additionally, sonic hedgehog-smoothened-glioma-associated oncogene homolog (SHH-SMO-GLI) activator signaling has an auxiliary function to ERK during these processes. We further demonstrate that, from Tri-IPCs, NOTCH signaling is crucial for the fate determination of astrocytes, while ERK signaling plays a prominent role in oligodendrocyte fate specification, and SHH signaling is required for the fate determination of olfactory bulb interneurons. We provide evidence suggesting that this mechanism is conserved in both mice and humans. Finally, we propose a unifying principle of mammalian cortical gliogenesis.}, archive = {J_PNAS}, author = {Gao, Yanjing and Sun, Mengge and Fu, Tongye and Wang, Ziwu and Jiang, Xin and Yang, Lin and Liang, Xiaoyi G. and Liu, Guoping and Tian, Yu and Yang, Feihong and Li, Jialin and Li, Zhenmeiyu and Li, Xiaosu and You, Yan and Ding, Chaoqiong and Wang, Yuan and Ma, Tong and Zhang, Zhuangzhi and Xu, Zhejun and Chen, Bin and Yang, Zhengang}, doi = {10.1073/pnas.2416757122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2416757122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {NOTCH, ERK, and SHH signaling respectively control the fate determination of cortical glia and olfactory bulb interneurons}, volume = {122}, year = {2025}, }
• (2025). CTCF regulates global chromatin accessibility and transcription during rod photoreceptor development. PNAS, 122(9), e2416384122. (www)

  @article{ , abstract = {Chromatin architecture facilitates accurate transcription at a number of loci, but it remains unclear how much chromatin architecture is involved in global transcriptional regulation. Previous work has shown that rapid depletion of the architectural protein CTCF in cell culture alters global chromatin organization but results in surprisingly limited gene expression changes. This discrepancy has also been observed when other architectural proteins are depleted, and one possible explanation is that full transcriptional changes are masked by cellular heterogeneity. We tested this idea by performing multiomics analyses with sorted juvenile postmitotic mouse rods, which undergo synchronized development, and we identified CTCF-dependent regulation of global chromatin accessibility and gene expression. CTCF depletion leads to dysregulation of ~20% of the entire transcriptome (>3,000 genes) and ~41% of genome accessibility (>27,000 sites) before any prominent cellular or physiological phenotypes arise. Importantly, these changes are highly enriched for CTCF occupancy at euchromatin, suggesting direct CTCF binding and transcriptional regulation at these active loci. CTCF mainly promotes chromatin accessibility and frequently inhibits expression of these direct binding targets, which are enriched for binding motifs of transcription repressors. These findings provide different and sometimes opposite conclusions from previous studies, emphasizing the need to consider cellular heterogeneity and cell-type specificity when performing multiomics analyses. CTCF knockout rods undergo complete degeneration by adulthood, indicating an essential role for their viability. We conclude that the architectural protein CTCF binds chromatin and regulates global chromatin accessibility and transcription during rod development.}, archive = {J_PNAS}, author = {Chen, Dahong and Keremane, Saumya and Wang, Silu and Lei, Elissa P.}, doi = {10.1073/pnas.2416384122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2416384122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CTCF regulates global chromatin accessibility and transcription during rod photoreceptor development}, volume = {122}, year = {2025}, }
• (2025). Abrupt changes in algal biomass of thousands of US lakes are related to climate and are more likely in low-disturbance watersheds. PNAS, 122(9), e2416172122. (www)

  @article{ , abstract = {Climate change is predicted to intensify lake algal blooms globally and result in regime shifts. However, observed increases in algal biomass do not consistently correlate with air temperature or precipitation, and evidence is lacking for a causal effect of climate or the nonlinear dynamics needed to demonstrate regime shifts. We modeled the causal effects of climate on annual lake chlorophyll (a measure of algal biomass) over 34 y for 24,452 lakes across broad ecoclimatic zones of the United States and evaluated the potential for regime shifts. We found that algal biomass was causally related to climate in 34% of lakes. In these cases, 71% exhibited abrupt but mostly temporary shifts as opposed to persistent changes, 13% had the potential for regime shifts. Climate was causally related to algal biomass in lakes experiencing all levels of human disturbance, but with different likelihood. Climate causality was most likely to be observed in lakes with minimal human disturbance and cooler summer temperatures that have increased over the 34 y studied. Climate causality was variable in lakes with low to moderate human disturbance, and least likely in lakes with high human disturbance, which may mask climate causality. Our results explain some of the previously observed heterogeneous climate responses of lake algal biomass globally and they can be used to predict future climate effects on lakes.}, archive = {J_PNAS}, author = {Soranno, Patricia A. and Hanly, Patrick J. and Webster, Katherine E. and Wagner, Tyler and McDonald, Andrew and Shuvo, Arnab and Schliep, Erin M. and Reinl, Kaitlin L. and McCullough, Ian M. and Tan, Pang-Ning and Lottig, Noah R. and Spence Cheruvelil, Kendra}, doi = {10.1073/pnas.2416172122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2416172122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Abrupt changes in algal biomass of thousands of US lakes are related to climate and are more likely in low-disturbance watersheds}, volume = {122}, year = {2025}, }
• (2025). A spectral machine learning approach to derive central aortic pressure waveforms from a brachial cuff. PNAS, 122(9), e2416006122. (www)

  @article{ , abstract = {Analyzing cardiac pulse waveforms offers valuable insights into heart health and cardiovascular disease risk, although obtaining the more informative measurements from the central aorta remains challenging due to their invasive nature and limited noninvasive options. To address this, we employed a laboratory-developed cuff device for high-resolution pulse waveform acquisition and constructed a spectral machine learning model to nonlinearly map the brachial wave components to the aortic site. Simultaneous invasive aortic catheter and brachial cuff waveforms were acquired in 115 subjects to evaluate the clinical performance of the developed wave-based approach. Magnitude, shape, and pulse waveform analysis on the measured and reconstructed aortic waveforms were correlated on a beat-to-beat basis. The proposed cuff-based method reconstructed aortic waveform contours with high fidelity (mean normalized-RMS error = 11.3%). Furthermore, continuous signal reconstruction captured dynamic aortic systolic blood pressure (BP) oscillations (r = 0.76, P < 0.05). Method-derived central pressures showed strong correlation with the independent invasive measurement for systolic BP (R 2 = 0.83; B [LOA] = −0.3 [−17.0, 16.4] mmHg) and diastolic BP (R 2 = 0.58; B [LOA] = −0.7 [−13.1, 11.6] mmHg). Shape-based features are effectively captured by the spectral machine learning method, showing strong correlations and no systemic bias for systolic pressure–time integral (r = 0.91, P < 0.05), diastolic pressure–time integral (r = 0.95, P < 0.05), and subendocardial viability ratio (r = 0.86, P < 0.05). These results suggest that the nonlinear transformation of wave components from the distal to the central site predicts the morphological waveform changes resulting from complex wave propagation and reflection within the cardiovascular network. The proposed wave-based approach holds promise for future applications of noninvasive devices in clinical cardiology.}, archive = {J_PNAS}, author = {Tamborini, Alessio and Aghilinejad, Arian and Gharib, Morteza}, doi = {10.1073/pnas.2416006122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2416006122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A spectral machine learning approach to derive central aortic pressure waveforms from a brachial cuff}, volume = {122}, year = {2025}, }
• (2025). The RNA-binding protein RBPMS inhibits smooth muscle cell–driven vascular remodeling in atherosclerosis and vascular injury. PNAS, 122(9), e2415933122. (www)

  @article{ , abstract = {Atherosclerosis and vessel wall trauma induce vascular smooth muscle cell (VSMC) phenotypic modulation, leading to plaque cap growth and postintervention restenosis. Our systems biology approach identified RNA binding protein, mRNA processing factor ( RBPMS ) as a conserved, VSMC-specific gene associated with VSMC modulation in atherosclerosis. RBPMS gene expression positively correlates with VSMC contractile markers in human and murine atherosclerotic arteries as well as in two vascular injury models during the postinjury intimal hyperplasia phase. RBPMS promotes contractile VSMC differentiation, reduces plaque cap development in high-fat diet-fed apolipoprotein E-null ( ApoE −/− ) murine atherosclerotic arteries, and inhibits intimal hyperplasia. Mechanistically, the RBPMS protein interacts with the myocardin ( MYOCD ) pre-mRNA and enhances MYOCD_v3 / MYOCD_v1 transcript balance through alternative exon 2a splicing. RBPMS promotes the VSMC contractile phenotype and reduces their fibroproliferative activity in a MYOCD_v3a-dependent manner. RBPMS enhances Myocd_v3 / Myocd_v1 transcript balance in both atherosclerotic and injured vessels. RBPMS may inhibit VSMC-driven plaque cap development and intervention-induced restenosis.}, archive = {J_PNAS}, author = {Du, Jianlin and Yuan, Xin and Wang, Jiajia and Zhang, Lujun and Tan, Fangyan and Hu, Tianyang and Li, Xingsheng and Liu, Fan and Ran, Haitao and Wang, Zhigang and Li, Yongyong and Feng, Yuxing and Melgiri, N. D. and Cao, Yu and Jiang, Lihong and Huang, Rongzhong and Sun, Yang}, doi = {10.1073/pnas.2415933122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2415933122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The RNA-binding protein RBPMS inhibits smooth muscle cell–driven vascular remodeling in atherosclerosis and vascular injury}, volume = {122}, year = {2025}, }
• (2025). Radiation-induced cellular plasticity primes glioblastoma for forskolin-mediated differentiation. PNAS, 122(9), e2415557122. (www)

  @article{ , abstract = {Glioblastoma (GBM) is the deadliest brain cancer in adults, and all patients succumb to the tumor. While surgery followed by chemoradiotherapy delays disease progression, these treatments do not lead to tumor control, and targeted therapies or biologics have failed to further improve survival. Utilizing a transient radiation-induced state of multipotency, we used the adenylcyclase activator forskolin to alter the fate of irradiated glioma cells. The effects of the combined treatment on neuronal marker expression, cell cycle distribution, and proliferation were studied. Gene expression profiling was conducted using bulk RNA-seq. Changes in cell populations were investigated using single-cell RNA-seq. Effects on glioma stem cells (GSCs) were studied in extreme limiting dilution assays, and the effects on median survival were studied in both syngeneic and PDOX mouse models of GBM. The combined treatment induced the expression of neuronal markers in glioma cells, reduced proliferation, and led to a distinct gene expression profile. scRNA-seq revealed that the combined treatment forced glioma cells into a microglia- and neuron-like phenotype. In vivo, this treatment led to a loss of GSCs and prolonged median survival. Collectively, our data suggest that revisiting a differentiation therapy with forskolin in combination with radiation could lead to clinical benefit.}, archive = {J_PNAS}, author = {He, Ling and Azizad, Daria and Bhat, Kruttika and Ioannidis, Angeliki and Hoffmann, Carter J. and Arambula, Evelyn and Eghbali, Mansoureh and Bhaduri, Aparna and Kornblum, Harley I. and Pajonk, Frank}, doi = {10.1073/pnas.2415557122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2415557122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Radiation-induced cellular plasticity primes glioblastoma for forskolin-mediated differentiation}, volume = {122}, year = {2025}, }
• (2025). Structural variant and nucleosome occupancy dynamics postchemotherapy in a HER2+ breast cancer organoid model. PNAS, 122(9), e2415475122. (www)

  @article{ , abstract = {The most common chemotherapeutics induce DNA damage to eradicate cancer cells, yet defective DNA repair can propagate mutations, instigating therapy resistance and secondary malignancies. Structural variants (SVs), arising from copy-number-imbalanced and -balanced DNA rearrangements, are a major driver of tumor evolution, yet understudied posttherapy. Here, we adapted single-cell template-strand sequencing (Strand-seq) to a HER2+ breast cancer model to investigate the formation of doxorubicin-induced de novo SVs. We coupled this approach with nucleosome occupancy (NO) measurements obtained from the same single cell to enable simultaneous SV detection and cell-type classification. Using organoids from TetO-CMYC/TetO-Neu/MMTV-rtTA mice modeling HER2+ breast cancer, we generated 459 Strand-seq libraries spanning various tumorigenesis stages, identifying a 7.4-fold increase in large chromosomal alterations post-doxorubicin. Complex DNA rearrangements, deletions, and duplications were prevalent across basal, luminal progenitor (LP), and mature luminal (ML) cells, indicating uniform susceptibility of these cell types to SV formation. Doxorubicin further elevated sister chromatid exchanges (SCEs), indicative of genomic stress persisting posttreatment. Altered nucleosome occupancy levels on distinct cancer-related genes further underscore the broad genomic impact of doxorubicin. The organoid-based system for single-cell multiomics established in this study paves the way for unraveling the most important therapy-associated SV mutational signatures, enabling systematic studies of the effect of therapy on cancer evolution.}, archive = {J_PNAS}, author = {Starostecka, Maja and Jeong, Hyobin and Hasenfeld, Patrick and Benito-Garagorri, Eva and Christiansen, Tania and Stober Brasseur, Catherine and Gomes Queiroz, Maise and Garcia Montero, Marta and Jechlinger, Martin and Korbel, Jan O.}, doi = {10.1073/pnas.2415475122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2415475122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural variant and nucleosome occupancy dynamics postchemotherapy in a HER2+ breast cancer organoid model}, volume = {122}, year = {2025}, }
• (2025). Critical fragility in sociotechnical systems. PNAS, 122(9), e2415139122. (www)

  @article{ , abstract = {Sociotechnical systems, where technological and human elements interact in a goal-oriented manner, provide important functional support to our societies. Here, we draw attention to the underappreciated concept of timeliness—i.e., system elements being available at the right place at the right time—that has been ubiquitously and integrally adopted as a quality standard in the modus operandi of sociotechnical systems. We point out that a variety of incentives, often reinforced by competitive pressures, prompt system operators to myopically optimize for efficiencies, running the risk of inadvertently taking timeliness to the limit of its operational performance, correspondingly making the system critically fragile to perturbations by pushing the entire system toward the proverbial “edge of a cliff.” Invoking a stylized model for operational delays, we identify the limiting operational performance of timeliness, as a true critical point, where the smallest of perturbations can lead to a systemic collapse. Specifically for firm-to-firm production networks, we suggest that the proximity to critical fragility is an important ingredient for understanding the fundamental “excess volatility puzzle” in economics. Further, in generality for optimizing sociotechnical systems, we propose that critical fragility is a crucial aspect in managing the trade-off between efficiency and robustness.}, archive = {J_PNAS}, author = {Moran, José and Pijpers, Frank P. and Weitzel, Utz and Bouchaud, Jean-Philippe and Panja, Debabrata}, doi = {10.1073/pnas.2415139122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2415139122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Critical fragility in sociotechnical systems}, volume = {122}, year = {2025}, }
• (2025). Innovation in ant larval feeding facilitated queen–worker divergence and social complexity. PNAS, 122(9), e2413742122. (www)

  @article{ , abstract = {Building differences between genetically equivalent units is a fundamental challenge for all multicellular organisms and superorganisms. In ants, reproductive or worker fate is typically determined during the larval stage, through feeding regimes managed by adult caretakers. However, the feeding care provided to larvae varies significantly across ants, as does phenotypic divergence between queen and worker castes. Here, we employed comparative phylogenetic methods and causal inference to investigate the relationships between larval feeding care, caste size dimorphism, and social complexity across ant diversity. We digitized the life’s work of George and Jeanette Wheeler, cataloging the larval morphology of over 700 species, and we compiled data on species diets and larval feeding behaviors from the literature and our own observations. We measured queen–worker size dimorphism in 392 species and gathered data for colony size, worker polymorphism, and worker reproduction. Our analyses revealed that ancestral active-feeding larvae evolved passive morphologies when adults began feeding them individually, typically with processed material and often following a shift to nonpredatory diets. Greater queen–worker size dimorphism coevolved with larval passiveness, alongside traits indicative of increased social complexity, including larger colony sizes, worker subcastes, and a reduction in workers’ reproductive potential. Likelihood comparisons of causal phylogenetic models support that extended alloparental care facilitated stronger caste dimorphism, which, in turn and along with increased colony sizes, promoted higher social complexity. Our results suggest that enhanced adult control over larval development enabled greater phenotypic specialization within colonies, with profound implications for social evolution.}, archive = {J_PNAS}, author = {Matte, Arthur and LeBoeuf, Adria C.}, doi = {10.1073/pnas.2413742122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2413742122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Innovation in ant larval feeding facilitated queen–worker divergence and social complexity}, volume = {122}, year = {2025}, }
• (2025). Direct control of electron spin at an intrinsically chiral surface for highly efficient oxygen reduction reaction. PNAS, 122(9), e2413609122. (www)

  @article{ , abstract = {The oxygen reduction reaction (ORR) in acidic media suffers from sluggish kinetics, primarily due to the spin-dependent electron transfer involved. The direct generation of spin-polarized electrons at catalytic surfaces remains elusive, and the underlying mechanisms are still controversial due to the lack of intrinsically chiral catalysts. To address this challenge, we investigate topological homochiral PdGa (TH PdGa) crystals with intrinsically chiral catalytic surfaces for ORR. Through spin-resolved photoemission spectroscopy and theoretical simulations, we show that both structural chirality and spin–orbit coupling are critical for inducing spin polarization at the surface of TH PdGa. As a result, TH PdGa achieves a kinetic current density over 100 times higher than the achiral PdGa (AC PdGa) at 0.85 V versus the reversible hydrogen electrode. This work underscores the pivotal role of spin polarization in enhancing acidic ORR activity and lays the groundwork for the rational design of chiral catalysts for spin-dependent catalysis.}, archive = {J_PNAS}, author = {Wang, Xia and Peralta, Mayra and Li, Xiaodong and Möllers, Paul V. and Zhou, Dong and Merz, Patrick and Burkhardt, Ulrich and Borrmann, Horst and Robredo, Iñigo and Shekhar, Chandra and Zacharias, Helmut and Feng, Xinliang and Felser, Claudia}, doi = {10.1073/pnas.2413609122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2413609122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Direct control of electron spin at an intrinsically chiral surface for highly efficient oxygen reduction reaction}, volume = {122}, year = {2025}, }
• (2025). Limited and biased global conservation funding means most threatened species remain unsupported. PNAS, 122(9), e2412479122. (www)

  @article{ , abstract = {The conservation of biodiversity represents a global challenge as the world experiences its sixth mass extinction. Understanding how conservation efforts are allocated is paramount to effectively protect threatened species. We analyzed ~14,600 conservation projects over a 25-y period, revealing substantial taxonomic biases in funding. When matched with formal assessments of species’ threat status, several highly threatened groups such as amphibians receive little and ever-decreasing support. Within particular groups (e.g., Mammalia, Reptilia), funding is directed to a very narrow selection of taxa, leaving the majority of their threatened species with limited or no support. More attention is urgently needed to assess the extinction risks of neglected taxa, especially smaller species. Paradoxically, while approximately 6% of species identified as threatened were supported by conservation funds, 29% of the funding was allocated to species of “least concern”. A more holistic distribution of conservation funding is, therefore, urgently needed if we are to protect biodiversity efficiently. We suggest avenues and mechanisms for a more balanced coverage of threatened species within conservation programs and highlight some of the benefits that could be derived from such an approach.}, archive = {J_PNAS}, author = {Guénard, Benoit and Hughes, Alice C. and Lainé, Claudianne and Cannicci, Stefano and Russell, Bayden D. and Williams, Gray A.}, doi = {10.1073/pnas.2412479122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2412479122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Limited and biased global conservation funding means most threatened species remain unsupported}, volume = {122}, year = {2025}, }
• (2025). The modern pattern of insect herbivory predates the advent of angiosperms by 60 my. PNAS, 122(9), e2412036122. (www)

  @article{ , abstract = {Modern ecosystems display complex associations of plants–insects that underwent a long evolutionary process since the appearance of mid-Paleozoic vascular plants. Although several major hypotheses explain the evolution of these plant–insect associations, the initial pattern of modern insect herbivory is poorly understood. To understand the antiquity of modern patterns of terrestrial arthropod herbivory, functional feeding group–damage type (FFG-DT) data were used to analyze a 305 My interval from Late Pennsylvanian to present, in which 134 plant assemblages were used to assess turnover (replacement of some species by other species between sites) and nestedness (difference in composition when no species are replaced between sites) in pairwise comparisons of DTs. Results of beta diversity analyses indicate that the prototype pattern for modern insect herbivory was established on gymnosperm-dominated plant assemblages by late Middle Jurassic, antedating angiosperm dominance by 60 My. Turnover among plant groups and FFGs declined in earlier late Paleozoic, whereas during the later Cenozoic, nestedness generally increased. Insect feeding on gymnosperms showed one pattern of change with low turnover and high nestedness, whereas a bimodal pattern characterized angiosperms. Ferns and angiosperms exhibited less DT functional breadth (host-plant “specificity” by herbivores) than gymnosperms, reflecting major differences in links between insect herbivores and their host plants. This fundamental trophic shift is consistent with the Mid-Mesozoic Parasitoid Revolution, implying top–down control of herbivores by their consumers rather than bottom–up regulation of food sources that shaped the modern herbivory pattern. These findings provide a data-rich account of the ecological origins of modern herbivory.}, archive = {J_PNAS}, author = {Xiao, Lifang and Chen, Liang and Labandeira, Conrad C. and Azevedo-Schmidt, Lauren and Wang, Yongjie and Ren, Dong}, doi = {10.1073/pnas.2412036122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2412036122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The modern pattern of insect herbivory predates the advent of angiosperms by 60 my}, volume = {122}, year = {2025}, }
• (2025). The AaFoxA factor regulates female reproduction through chromatin remodeling in the mosquito vector aedes aegypti. PNAS, 122(9), e2411758122. (www)

  @article{ , abstract = {Female mosquitoes are vectors of many devastating human diseases because they require blood feeding to initiate reproduction. Thus, elucidation of molecular mechanisms managing female mosquito reproduction is essential. Although the regulation of gene expression during the mosquito gonadotrophic cycle has been studied in detail, how this process is controlled at the chromatin level remains unclear. Chromatin must be accessible for transcription factors (TFs) governing gene expression. A specialized class of TFs, called pioneer factors (PFs), binds and remodels closed chromatin, permitting other TFs to bind DNA and activate the gene expression. Here, we identified a homolog of the vertebrate PF FoxA in the mosquito Aedes aegypti and used the CRISPR-Cas9 system to generate mosquitoes deficient in AaFoxA . We found that ovary development was severely retarded in mutant females. Multiomics and molecular biology analyses have shown that AaFoxA increased histone acetylation and decreased methylation of H3K27 by controlling the chromatin accessibility of histone modification enzymes and chromatin remodelers. AaFoxA is bound to the loci of chromatin remodelers, changing their chromatin accessibility and modulating their temporal expression patterns. AaFoxA increased the accessibility of the ecdysone receptor (EcR) and E74 loci, indicating the important role of AaFoxA in the hormonal regulation of mosquito reproductive events. Further, the CUT&RUN and ATAC-seq analyses revealed that AaFoxA temporarily bound closed chromatin, making it differentially accessible during the mosquito gonadotrophic cycle. Hence, this study demonstrates that AaFoxA modulates chromatin dynamics throughout female mosquito reproduction.}, archive = {J_PNAS}, author = {Cheng, Yang and Wang, Xuesong and Ding, Yike and Zhang, Houhong and Jia, Zhenyu and Raikhel, Alexander S.}, doi = {10.1073/pnas.2411758122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2411758122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The AaFoxA factor regulates female reproduction through chromatin remodeling in the mosquito vector aedes aegypti}, volume = {122}, year = {2025}, }
• (2025). Protective role of parenthood on age-related brain function in mid- to late-life. PNAS, 122(9), e2411245122. (www)

  @article{ , abstract = {The experience of human parenthood is near ubiquitous and can profoundly alter one’s body, mind, and environment. However, we know very little about the long-term neural effects of parenthood for parents themselves, or the implications of pregnancy and caregiving experience on the aging adult brain. Here, we investigate the link between the number of children parented and age on brain function in 19,964 females and 17,607 males from the UK Biobank. In both females and males, parenthood was positively correlated with functional connectivity, such that higher number of children parented was associated with higher connectivity, particularly within the somato/motor network. Critically, the spatial topography of parenthood-linked effects was inversely correlated with the impact of age on functional connectivity across the brain for both females and males, such that the connections that were positively correlated with number of children were negatively correlated with age. This result suggests that a higher number of children is associated with patterns of brain function in the opposite direction to age-related alterations. Overall, these results indicate that the changes accompanying parenthood may confer benefits to brain health across the lifespan, altering aging trajectories, consistent with animal models of parenthood and preliminary findings of “younger-looking” brain structure in human parents. Observing this effect in both females and males implicates the caregiving environment, rather than pregnancy alone, and highlights the importance of future work to disentangle the underlying mechanisms related to the direct impact of caregiving, the indirect impact of the environment, and the result of covarying sociodemographic factors.}, archive = {J_PNAS}, author = {Orchard, Edwina R. and Chopra, Sidhant and Ooi, Leon Q. R. and Chen, Pansheng and An, Lijun and Jamadar, Sharna D. and Yeo, B. T. Thomas and Rutherford, Helena J. V. and Holmes, Avram J.}, doi = {10.1073/pnas.2411245122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2411245122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Protective role of parenthood on age-related brain function in mid- to late-life}, volume = {122}, year = {2025}, }
• (2025). GenAI synthetic data create ethical challenges for scientists. here’s how to address them.. PNAS, 122(9), e2409182122. (www)

  @article{ , archive = {J_PNAS}, author = {Resnik, David B. and Hosseini, Mohammad and Kim, Jeff J.H. and Epiphaniou, Gregory and Maple, Carsten}, doi = {10.1073/pnas.2409182122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2409182122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {GenAI synthetic data create ethical challenges for scientists. here’s how to address them.}, volume = {122}, year = {2025}, }
• (2025). Robust encoding of stimulus–response mapping by neurons in visual cortex. PNAS, 122(9), e2408079122. (www)

  @article{ , abstract = {Neural activity in sensory cortex is modulated by behavioral and cognitive factors, and this modulation is thought to contribute to the selection of specific sensory information needed to achieve behavioral goals. In contrast, more abstract behavioral variables that are independent of stimulus selection, such as stimulus–response mapping, are thought to be encoded by neurons outside of sensory cortex. We show that information about such mapping is robustly encoded in the responses of neurons in primate visual cortex. Monkeys were trained to alternate between two tasks that differed in the rule governing the mapping of a remembered visual cue onto an eye movement response. During the memory-delay period, neurons in area V4 reliably signaled the remembered cue location in both tasks. However, the encoding of cue location depended critically on the stimulus–response mapping rule. Thus, V4 delay activity encoded the mapping rule and signaled the preparation of the appropriate motor response rather than spatial working memory per se, contrary to previous assumptions. In addition, we probed the origins of motor-related delay activity and found that it was reduced during local inactivation of the frontal eye field (FEF). The results demonstrate that behavioral modulation of visual cortical activity is not solely related to the selection of sensory stimuli but instead reflects a distinct mechanism for sensory-guided motor output.}, archive = {J_PNAS}, author = {Jonikaitis, Donatas and Xia, Ruobing and Moore, Tirin}, doi = {10.1073/pnas.2408079122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2408079122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Robust encoding of stimulus–response mapping by neurons in visual cortex}, volume = {122}, year = {2025}, }
• (2025). Emergent quantum state unveiled by ultrafast collective dynamics in 1T-TaS2. PNAS, 122(9), e2406464122. (www)

  @article{ , abstract = {Charge density wave (CDW) material 1 T -TaS 2 was proposed as a quantum spin liquid candidate, on which a cluster Mott insulator comes into being below the transition temperature. We report an experimental ultrafast generation and detection of the coherent amplitude mode (AM) of its CDW state. A salient feature emerges: The coherent CDW mode AM exhibits an unusual T 3.56 temperature dependence below 65 K, in addition to the T 2 temperature dependence observed in the 65 to 200 K range. This behavior suggests the enhancement of in-gap electronic excitations below 65 K and the emergence of a new phase of matter. Consequently, the intriguing quantum state leads to a crossover. Our investigation provides insights into understanding the interplay among various degrees of freedom in quantum materials.}, archive = {J_PNAS}, author = {Hasaien, Jiazila and Wu, Yanling and Shi, Mengzhu and Zhai, Yanni and Wu, Qiong and Liu, Zheng and Zhou, Yi and Chen, Xianhui and Zhao, Jimin}, doi = {10.1073/pnas.2406464122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2406464122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Emergent quantum state unveiled by ultrafast collective dynamics in 1T-TaS2}, volume = {122}, year = {2025}, }
• (2025). Ectopic mouse TMC1 and TMC2 alone form mechanosensitive channels that are potently modulated by TMIE. PNAS, 122(9), e2403141122. (www)

  @article{ , abstract = {The mechanotransduction (MT) channel expressed in cochlear and vestibular hair cells converts the mechanical stimulation of sound and head movements into electrochemical signals. Recently, TMC1 and TMC2 (TMC1/2) have been recognized as the pore-forming subunit of the MT channel, but TMC1/2 functional expression in heterologous cells—which is critical for unequivocally identifying them as the bona fide pore-forming subunit of the MT channel—has not been achieved because ectopic TMC1/2 become trapped in the ER. Here, we report that adding a Fyn lipidation tag to mouse TMC1/2 (mTMC1/2) drove their cell-surface expression, and, importantly, full-length mTMC1/2 expressed alone functioned as mechanosensitive channels, underscoring the view that TMC1/2 constitute the sole pore-forming subunit of the MT channel. Moreover, mouse transmembrane inner ear (TMIE) (mTMIE) protein robustly stimulated TMC1/2 channel activity by modulating their gating. Intriguingly, the N-terminal 27 residues of mTMIE were dispensable for regulating TMC1/2 in our in vitro functional assay, whereas, in striking contrast, mutating mTMIE C76C77, the predicted palmitoylation sites, eliminated mTMIE stimulation of mTMC1/2, indicating a crucial role of the palmitoyl group in regulating TMC1/2 gating. mTMC1/2+mTMIE form 18 pS and 24 pS single channels, respectively. mTMC1/2+mTMIE single channels showed biophysical and pharmacological properties similar to those of the MT channel. Our findings provide insights into several fundamental and debated aspects of the function of TMC1/2 and TMIE, and our functional assay of TMC1/2 and TMIE in heterologous cells will facilitate further functional and structural characterization of these proteins and other MT-complex components.}, archive = {J_PNAS}, author = {Chen, Yixuan and Li, Yulin and Liu, Yonghong and Sun, Jiawen and Feng, Wanying and Chen, Yanfei and Tian, Ye and Lei, Tianlun and Huang, Pingbo}, doi = {10.1073/pnas.2403141122}, journal = {Proceedings of the National Academy of Sciences}, month = {3}, number = {9}, pages = {e2403141122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ectopic mouse TMC1 and TMC2 alone form mechanosensitive channels that are potently modulated by TMIE}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(8), eiti0825122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti0825122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {eiti0825122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). Greener skies? the quest for sustainable flying. PNAS, 122(8), e2502591122. (www)

  @article{ , archive = {J_PNAS}, author = {Battersby, Stephen}, doi = {10.1073/pnas.2502591122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2502591122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Greener skies? the quest for sustainable flying}, volume = {122}, year = {2025}, }
• (2025). Editorial expression of concern for duckworth et al., role of test motivation in intelligence testing. PNAS, 122(8), e2502439122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2502439122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2502439122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Editorial expression of concern for duckworth et al., role of test motivation in intelligence testing}, volume = {122}, year = {2025}, }
• (2025). Correction for talukder et al., olfaction with legs—Spiders use wall-pore sensilla for pheromone detection. PNAS, 122(8), e2501234122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2501234122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2501234122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for talukder et al., olfaction with legs—Spiders use wall-pore sensilla for pheromone detection}, volume = {122}, year = {2025}, }
• (2025). Correction for borniego et al., diverse plant RNAs coat arabidopsis leaves and are distinct from apoplastic RNAs. PNAS, 122(8), e2501042122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2501042122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2501042122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for borniego et al., diverse plant RNAs coat arabidopsis leaves and are distinct from apoplastic RNAs}, volume = {122}, year = {2025}, }
• (2025). Correction for luo et al., an acetyltransferase moonlights as a regulator of the RNA binding repertoire of the RNA chaperone hfq in escherichia coli. PNAS, 122(8), e2501041122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2501041122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2501041122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for luo et al., an acetyltransferase moonlights as a regulator of the RNA binding repertoire of the RNA chaperone hfq in escherichia coli}, volume = {122}, year = {2025}, }
• (2025). Correction for rachuri et al., mutational analysis of an antimalarial drug target, PfATP4. PNAS, 122(8), e2501024122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2501024122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2501024122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for rachuri et al., mutational analysis of an antimalarial drug target, PfATP4}, volume = {122}, year = {2025}, }
• (2025). Fungal effector disables cathepsin-driven toll immunity in insects. PNAS, 122(8), e2500911122. (www)

  @article{ , archive = {J_PNAS}, author = {Tay, Rebecca J. and Hsueh, Yen-Ping}, doi = {10.1073/pnas.2500911122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2500911122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fungal effector disables cathepsin-driven toll immunity in insects}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for chan and fried: Structural stability and thermodynamics of artistic composition. PNAS, 122(8), e2500746122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2500746122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2500746122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for chan and fried: Structural stability and thermodynamics of artistic composition}, volume = {122}, year = {2025}, }
• (2025). Options for student loan repayment matter. PNAS, 122(8), e2500540122. (www)

  @article{ , archive = {J_PNAS}, author = {Abraham, Katharine G.}, doi = {10.1073/pnas.2500540122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2500540122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Options for student loan repayment matter}, volume = {122}, year = {2025}, }
• (2025). Simple genetic mechanisms toward more intricate molecular complexes. PNAS, 122(8), e2500162122. (www)

  @article{ , archive = {J_PNAS}, author = {Cisneros, Angel F. and Landry, Christian R.}, doi = {10.1073/pnas.2500162122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2500162122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Simple genetic mechanisms toward more intricate molecular complexes}, volume = {122}, year = {2025}, }
• (2025). Reply to jones et al.: Opportunities and considerations for valuing seagrass ecosystem services. PNAS, 122(8), e2500092122. (www)

  @article{ , archive = {J_PNAS}, author = {Lamb, Joleah B. and Abu, Nur and Limbong, Steven R. and Jompa, Jamaluddin and Feeney, William E. and Harvell, C. Drew}, doi = {10.1073/pnas.2500092122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2500092122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to jones et al.: Opportunities and considerations for valuing seagrass ecosystem services}, volume = {122}, year = {2025}, }
• (2025). Correction for gao et al., cold-blooded vertebrate utilizes behavioral fever to alleviate t cell apoptosis and optimize antimicrobial immunity. PNAS, 122(8), e2427076122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2427076122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2427076122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for gao et al., cold-blooded vertebrate utilizes behavioral fever to alleviate t cell apoptosis and optimize antimicrobial immunity}, volume = {122}, year = {2025}, }
• (2025). A structural atlas of death domain fold proteins reveals their versatile roles in biology and function. PNAS, 122(8), e2426986122. (www)

  @article{ , abstract = {Death domain fold (DDF) superfamily proteins are critically important players in pathways of cell death and inflammation. DDFs are often essential scaffolding domains in receptors, adaptors, or effectors of these pathways by mediating homo- and hetero-oligomerization including helical filament assembly. At the downstream ends of these pathways, effector oligomerization by DDFs brings the enzyme domains into proximity for their dimerization and activation. Hundreds of structures of these domains have been solved. However, a comprehensive understanding of DDFs is lacking. In this article, we report the curation of a DDF structural atlas as a public website (deathdomain.org) and deduce the common and distinct principles of DDF-mediated oligomerization among the four families (death domain or DD, death effector domain or DED, caspase recruitment domain or CARD, and pyrin domain or PYD). We further annotate DDFs genome-wide based on AlphaFold-predicted models and protein sequences. These studies reveal mechanistic rules for this widely distributed domain superfamily.}, archive = {J_PNAS}, author = {Wu, Emily J. and Kandalkar, Ankita T. and Ehrmann, Julian F. and Tong, Alexander B. and Zhang, Jing and Cong, Qian and Wu, Hao}, doi = {10.1073/pnas.2426986122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2426986122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A structural atlas of death domain fold proteins reveals their versatile roles in biology and function}, volume = {122}, year = {2025}, }
• (2025). Risks of habitat loss from seaweed cultivation within seagrass. PNAS, 122(8), e2426971122. (www)

  @article{ , archive = {J_PNAS}, author = {Jones, Benjamin L. H. and Eklöf, Johan S. and Unsworth, Richard K. F. and Coals, Lucy and Christianen, Marjolijn J. A. and Clifton, Julian and Cullen-Unsworth, Leanne C. and de la Torre-Castro, Maricela and Esteban, Nicole and Huxham, Mark and Jiddawi, Narriman S. and McKenzie, Len J. and Nakaoka, Masahiro and Nordlund, Lina M. and Ooi, Jillian L. S. and Prathep, Anchana}, doi = {10.1073/pnas.2426971122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2426971122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Risks of habitat loss from seaweed cultivation within seagrass}, volume = {122}, year = {2025}, }
• (2025). Reply to krefeld-schwalb et al.: Measuring population heterogeneity requires upholding good scientific practice. PNAS, 122(8), e2426330122. (www)

  @article{ , archive = {J_PNAS}, author = {Holzmeister, Felix and Johannesson, Magnus and Böhm, Robert and Dreber, Anna and Huber, Jürgen and Kirchler, Michael}, doi = {10.1073/pnas.2426330122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2426330122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to krefeld-schwalb et al.: Measuring population heterogeneity requires upholding good scientific practice}, volume = {122}, year = {2025}, }
• (2025). Measuring population heterogeneity requires heterogeneous populations. PNAS, 122(8), e2425536122. (www)

  @article{ , archive = {J_PNAS}, author = {Krefeld-Schwalb, Antonia and Hua, Xuwen and Johnson, Eric J.}, doi = {10.1073/pnas.2425536122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2425536122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Measuring population heterogeneity requires heterogeneous populations}, volume = {122}, year = {2025}, }
• (2025). Stepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic. PNAS, 122(8), e2424906122. (www)

  @article{ , abstract = {Axon degeneration, driven by the NAD + hydrolyzing enzyme SARM1, is an early pathological hallmark of numerous neurodegenerative diseases. SARM1 exists in an inactive form and is activated following nerve injury. However, the precise molecular mechanism underlying SARM1 activation remains to be fully elucidated. In this study, we report the identification of a potent proactivator of SARM1, G10, which is converted into a direct activator (M1) by the enzyme nicotinamide phosphoribosyltransferase. Cryoelectron microscopy structures of SARM1 bound to M1, as well as to M1 and a nonhydrolyzable NAD + analog (1AD), captured two intermediate activation states and the fully active state, revealing a stepwise mechanism of SARM1 activation. Further, introducing a disulfide bond to prevent conformational transitions between the two intermediate states mediated by M1 stabilized SARM1 in its inactive form and blocked M1-induced cell death. Together, these findings propose a sequential, stepwise activation model for SARM1 and offer a framework for developing potential SARM1 inhibitors for the treatment of neurodegenerative diseases.}, archive = {J_PNAS}, author = {Huang, Yinpin and Zhang, Jun and Zhang, Wenbin and Chen, Jie and Chen, Sijia and Wu, Qincui and Zheng, Sanduo and Wang, Xiaodong}, doi = {10.1073/pnas.2424906122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2424906122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic}, volume = {122}, year = {2025}, }
• (2025). High spatial resolution charge sensing of quantum hall states. PNAS, 122(8), e2424781122. (www)

  @article{ , abstract = {Charge distribution offers a unique fingerprint of important properties of electronic systems, including dielectric response, charge ordering, and charge fractionalization. We develop an architecture for charge sensing in two-dimensional electronic systems in a strong magnetic field. We probe local change of the chemical potential in a proximitized detector layer using scanning tunneling microscopy, allowing us to infer the chemical potential and the charge profile in the sample. Our technique has both high energy (<0.3 meV) and spatial (<10 nm) resolution exceeding that of previous studies by an order of magnitude. We apply our technique to study the chemical potential of quantum Hall liquids in monolayer graphene under high magnetic fields and their responses to charge impurities. The chemical potential measurement provides a local probe of the thermodynamic gap of quantum Hall ferromagnets and fractional quantum Hall states. The screening charge profile reveals spatially oscillatory response of the quantum Hall liquids to charge impurities and is consistent with the composite Fermi liquid picture close to the half-filling. Our technique also paves the way to map moiré potentials, probe Wigner crystals, and investigate fractional charges in quantum Hall and Chern insulators.}, archive = {J_PNAS}, author = {Chiu, Cheng-Li and Wang, Taige and Fan, Ruihua and Watanabe, Kenji and Taniguchi, Takashi and Liu, Xiaomeng and Zaletel, Michael P. and Yazdani, Ali}, doi = {10.1073/pnas.2424781122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2424781122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High spatial resolution charge sensing of quantum hall states}, volume = {122}, year = {2025}, }
• (2025). A long-distance inhibitory system regulates haustoria numbers in parasitic plants. PNAS, 122(8), e2424557122. (www)

  @article{ , abstract = {The ability of parasitic plants to withdraw nutrients from their hosts depends on the formation of an infective structure known as the haustorium. How parasites regulate their haustoria numbers is poorly understood, and here, we uncovered that existing haustoria in the facultative parasitic plants Phtheirospermum japonicum and Parentucellia viscosa suppressed the formation of new haustoria located on distant roots. Using Phtheirospermum, we found that this effect depended on the formation of mature haustoria and could be induced through the application of external nutrients. To understand the molecular basis of this root plasticity, we analyzed hormone response and found that existing infections upregulated cytokinin-responsive genes first at the haustoria and then more distantly in Phtheirospermum shoots. We observed that infections increased endogenous cytokinin levels in Phtheirospermum roots and shoots, and this increase appeared relevant since local treatments with exogenous cytokinins blocked the formation of both locally and distantly formed haustoria. In addition, local overexpression of a cytokinin-degrading enzyme in Phtheirospermum prevented this systemic interhaustoria repression and increased haustoria numbers locally. We propose that a long-distance signal produced by haustoria negatively regulates future haustoria, and in Phtheirospermum , such a signaling system is mediated by a local increase in cytokinin to regulate haustoria numbers and balance nutrient acquisition.}, archive = {J_PNAS}, author = {Kokla, Anna and Leso, Martina and Šimura, Jan and Wärdig, Cecilia and Hayashi, Marina and Nishii, Naoshi and Tsuchiya, Yuichiro and Ljung, Karin and Melnyk, Charles W.}, doi = {10.1073/pnas.2424557122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2424557122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A long-distance inhibitory system regulates haustoria numbers in parasitic plants}, volume = {122}, year = {2025}, }
• (2025). Agouti and BMP signaling drive a naturally occurring fate conversion of melanophores to leucophores in zebrafish. PNAS, 122(8), e2424180122. (www)

  @article{ , abstract = {The often-distinctive pigment patterns of vertebrates are varied in form and function and depend on several types of pigment cells derived from embryonic neural crest or latent stem cells of neural crest origin. These cells and the patterns they produce have been useful for uncovering features of differentiation and morphogenesis that underlie adult phenotypes, and they offer opportunities to discover how patterns and the cell types themselves have diversified. In zebrafish, a body pattern of stripes arises by self-organizing interactions among three types of pigment cells. Yet these fish also exhibit white ornamentation on their fins that depends on the transdifferentiation of black melanophores to white cells, “melanoleucophores.” To identify mechanisms underlying this conversion we used ultrastructural, transcriptomic, mutational, and other approaches. We show that melanophore–melanoleucophore transition depends on regional BMP signals transduced through noncanonical receptors (Rgmb-Neo1a-Lrig2) as well as BMP-dependent signaling by Agouti genes, asip1 and asip2b . These signals lead to expression of transcription factor genes including foxd3 and runx3 that are necessary to induce loss of melanin, curtail new melanin production, and deploy a pathway for accumulating guanine crystals that, together, confer a white phenotype. These analyses uncover an important role for positional information in specifying ornamentation in zebrafish and show how tissue environmental cues and an altered gene regulatory program have allowed terminal addition of a distinct phenotype to a preexisting cell type.}, archive = {J_PNAS}, author = {Huang, Delai and Kapadia, Emaan H. and Liang, Yipeng and Shriver, Leah P. and Dai, Shengkun and Patti, Gary J. and Humbel, Bruno M. and Laudet, Vincent and Parichy, David M.}, doi = {10.1073/pnas.2424180122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2424180122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Agouti and BMP signaling drive a naturally occurring fate conversion of melanophores to leucophores in zebrafish}, volume = {122}, year = {2025}, }
• (2025). Cell-based glycoengineering for production of homogeneous and specific glycoform-enriched antibodies with improved effector functions. PNAS, 122(8), e2423853122. (www)

  @article{ , abstract = {Glycosylation of humanized antibody at Fc-Asn297 significantly affects the Fc-mediated killing of target cells through effector functions, especially antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent vaccinal effect (ADVE). Previous studies showed that therapeutic immunoglobulin G (IgG) antibodies with α2,6-sialyl complex type (SCT) glycan attached to Fc-Asn297 exhibited optimal binding to the Fc receptors on effector cells associated with ADCC, ADCP, and ADVE. However, the production of antibodies with homogeneous Fc-SCT glycan requires multiple in vitro enzymatic and purification steps. In this study, we report two cell-based methods to produce Fc-GlcNAc antibody and Fc-SCT-enriched antibodies with improved effector functions. First, we expressed endoglycosidase S2 in Expi293F GnT1- cells to trim all N-glycans to Fc-GlcNAc antibody for in vitro transglycosylation to generate homogeneous antibodies with well-defined Fc glycan. Second, we engineered the glycosylation pathway of HEK293T cells through knock-out of undesired glycosyltransferases and knock-in of desired glycosyltransferases to produce Fc-SCT-enriched antibodies and evaluated their binding to Fc receptors, and we found that the Fc-SCT-enriched antibody is like or better than the homogeneous Fc-SCT antibody in binding to the Fc receptors associated with ADCC, ADCP, and ADVE.}, archive = {J_PNAS}, author = {Huang, Han-Wen and Zeng, Yi-Fang and Shivatare, Vidya S. and Tseng, Tzu-Hao and Wong, Chi-Huey}, doi = {10.1073/pnas.2423853122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2423853122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cell-based glycoengineering for production of homogeneous and specific glycoform-enriched antibodies with improved effector functions}, volume = {122}, year = {2025}, }
• (2025). Nongenetic adaptation by collective migration. PNAS, 122(8), e2423774122. (www)

  @article{ , abstract = {Cell populations must adjust their phenotypic composition to adapt to changing environments. One adaptation strategy is to maintain distinct phenotypic subsets within the population and to modulate their relative abundances via gene regulation. Another strategy involves genetic mutations, which can be augmented by stress-response pathways. Here, we studied how a migrating bacterial population regulates its phenotypic distribution to traverse diverse environments. We generated isogenic Escherichia coli populations with varying distributions of swimming behaviors and observed their phenotype distributions during migration in liquid and porous environments. We found that the migrating populations became enriched with high-performing swimming phenotypes in each environment, allowing the populations to adapt without requiring mutations or gene regulation. This adaptation is dynamic and rapid, reversing in a few doubling times when migration ceases. By measuring the chemoreceptor abundance distributions during migration toward different attractants, we demonstrated that adaptation acts on multiple chemotaxis-related traits simultaneously. These measurements are consistent with a general mechanism in which adaptation results from a balance between cell growth generating diversity and collective migration eliminating underperforming phenotypes. Thus, collective migration enables cell populations with continuous, multidimensional phenotypes to flexibly and rapidly adapt their phenotypic composition to diverse environmental conditions.}, archive = {J_PNAS}, author = {Vo, Lam and Avgidis, Fotios and Mattingly, Henry H. and Edmonds, Karah and Burger, Isabel and Balasubramanian, Ravi and Shimizu, Thomas S. and Kazmierczak, Barbara I. and Emonet, Thierry}, doi = {10.1073/pnas.2423774122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2423774122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nongenetic adaptation by collective migration}, volume = {122}, year = {2025}, }
• (2025). Cryo-EM of native membranes reveals an intimate connection between the krebs cycle and aerobic respiration in mycobacteria. PNAS, 122(8), e2423761122. (www)

  @article{ , abstract = {To investigate the structure of the mycobacterial oxidative phosphorylation machinery, we prepared inverted membrane vesicles from Mycobacterium smegmatis , enriched for vesicles containing complexes of interest, and imaged the vesicles with electron cryomicroscopy. We show that this analysis allows determination of the structure of both mycobacterial ATP synthase and the supercomplex of respiratory complexes III and IV in their native membrane. The latter structure reveals that the enzyme malate:quinone oxidoreductase (Mqo) physically associates with the respiratory supercomplex, an interaction that is lost on extraction of the proteins from the lipid bilayer. Mqo catalyzes an essential reaction in the Krebs cycle, and in vivo survival of mycobacterial pathogens is compromised when its activity is absent. We show with high-speed spectroscopy that the Mqo:supercomplex interaction enables rapid electron transfer from malate to the supercomplex. Further, the respiratory supercomplex is necessary for malate-driven, but not NADH-driven, electron transport chain activity and oxygen consumption. Together, these findings indicate a connection between the Krebs cycle and aerobic respiration that directs electrons along a single branch of the mycobacterial electron transport chain.}, archive = {J_PNAS}, author = {Di Trani, Justin M. and Yu, Jiacheng and Courbon, Gautier M. and Lobez Rodriguez, Ana Paula and Cheung, Chen-Yi and Liang, Yingke and Coupland, Claire E. and Bueler, Stephanie A. and Cook, Gregory M. and Brzezinski, Peter and Rubinstein, John L.}, doi = {10.1073/pnas.2423761122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2423761122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryo-EM of native membranes reveals an intimate connection between the krebs cycle and aerobic respiration in mycobacteria}, volume = {122}, year = {2025}, }
• (2025). Manipulating hydrogenation pathways enables economically viable electrocatalytic aldehyde-to-alcohol valorization. PNAS, 122(8), e2423542122. (www)

  @article{ , abstract = {Electrocatalytic reduction (ECR) of furfural represents a sustainable route for biomass valorization. Unfortunately, traditional Cu-catalyzed ECR suffers from diversified product distribution and industrial-incompatible production rates, mainly caused by the intricate mechanism−performance relationship. Here, we manipulate hydrogenation pathways on Cu by introducing ceria as an auxiliary component, which enables the mechanism switching from proton-coupled electron transfer to electrochemical hydrogen-atom transfer (HAT) and thus high-speed furfural-to-furfuryl alcohol electroconversion. Theoretical and kinetic analyses show that oxygen-vacancy-rich ceria delivers an efficient formation−diffusion−hydrogenation chain of H* by diminishing H* adsorption. Spectroscopic characterizations indicate that Cu/ceria interfacial perimeter enriches the local furfural, synergistically lowering the barrier of the rate-determining HAT step across the perimeter. Our Cu/ceria catalyst realizes high-rate HAT-dominated ECR for electrosynthesis of single-product furfuryl alcohol, achieving a high production rate of 19.1 ± 0.4 mol h −1 m −2 and a Faradaic efficiency of 97 ± 1% at an economically viable partial current density of over 0.1 A cm −2 . Our results demonstrate a highly efficient route for biofeedstock valorization with enhanced techno-economic feasibility.}, archive = {J_PNAS}, author = {Yao, Ze-Cheng and Chai, Jing and Tang, Tang and Ding, Liang and Jiang, Zhe and Fu, Jiaju and Chang, Xiaoxia and Xu, Bingjun and Zhang, Liang and Hu, Jin-Song and Wan, Li-Jun}, doi = {10.1073/pnas.2423542122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2423542122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Manipulating hydrogenation pathways enables economically viable electrocatalytic aldehyde-to-alcohol valorization}, volume = {122}, year = {2025}, }
• (2025). Structures and functions of the limited natural polyclonal antibody response to parvovirus infection. PNAS, 122(8), e2423460122. (www)

  @article{ , abstract = {Host antibody responses are key components in the protection of animals against pathogens, yet the defining properties of viral antigens and induction of B cell responses that result in varied protection are still poorly understood. Parvoviruses are simple molecular structures that display 60 repeated motifs on their capsid surface, and rapidly induce strong antibody responses that protect animals from infection. We recently showed that following canine parvovirus infection of its natural host, the polyclonal response in the sera contained only two or three dominant antibodies that bound two epitopes on the capsid. Here, we characterize key antibodies present in that immune response, identifying their sequences, defining their binding properties on the capsid by cryoelectron microscopic (cryoEM) analysis, and testing their effects on viral infectivity. Two antibodies sharing the same heavy chain bound to the side of the capsid threefold spike (B-site), while another distinct antibody bound close to the threefold axis (A-site). The epitopes of these antibodies overlapped the binding site of the host receptor, the transferrin receptor type-1, but to varying degrees. The antibodies varied widely in their neutralization efficiencies as either immunoglobulins (IgGs) or monomeric antigen-binding fragments (Fabs), which was consistent with their ability to compete for the receptor. The monoclonal antibodies characterized here matched the structures from the cryoEM analysis of polyclonal sera, including those present in a different dog than the monoclonal source. This shows that after infection, a focused response to the viral antigen is produced that protects against infection.}, archive = {J_PNAS}, author = {Adu, Oluwafemi F. and Lee, Hyunwook and Früh, Simon P. and Schoenle, Marta V. and Weichert, Wendy S. and Flyak, Andrew I. and Hafenstein, Susan L. and Parrish, Colin R.}, doi = {10.1073/pnas.2423460122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2423460122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structures and functions of the limited natural polyclonal antibody response to parvovirus infection}, volume = {122}, year = {2025}, }
• (2025). Planar device–enabled speckle illumination for dark-field label-free imaging beyond the diffraction limit. PNAS, 122(8), e2423223122. (www)

  @article{ , abstract = {Dark-field microscopy is a technique used in optical microscopy to increase the contrast in unstained samples, making it possible to observe details that would otherwise be difficult to see under bright-field microscopy; thus, it has been widely employed in biological research, material science, and medical diagnostics. However, most dark-field microscopy methods cannot overcome the optical diffraction limit and require a bulky dark-field condenser and precise alignment of each optical element. In this study, we introduce a planar photonic device that can produce random speckles for dark-field illumination and improve the optical resolution. This planar device is made of random distribution fibers for injection of a laser beam, a scattering layer to produce random speckles, a one-dimensional photonic crystal (1DPC) to produce a hollow cone of light, and a metallic film to increase the energy efficiency. This planar device can work as a substrate for conventional microscopy. Taking advantage of the hollow cone of light with random speckles generated by the proposed planar device, we achieve a high-contrast, label-free image with a 1.55-fold improvement in spatial resolution. Furthermore, random evanescent speckles can be generated on the 1DPC just through tuning the incident wavelength, which demonstrates the ability for optical surface imaging beyond the diffraction limit. The advantage of this technique is that it does not require complex optical system or precise knowledge of the illumination pattern. This study will expand the potential applications of dark-field microscopy and provide insights into samples that might otherwise be invisible under traditional dark-field microscopy.}, archive = {J_PNAS}, author = {Fan, Zetao and You, Xinxiang and Zhang, Douguo}, doi = {10.1073/pnas.2423223122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2423223122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Planar device–enabled speckle illumination for dark-field label-free imaging beyond the diffraction limit}, volume = {122}, year = {2025}, }
• (2025). Profile of mark kirkpatrick. PNAS, 122(8), e2422883122. (www)

  @article{ , archive = {J_PNAS}, author = {Ravindran, Sandeep}, doi = {10.1073/pnas.2422883122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2422883122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profile of mark kirkpatrick}, volume = {122}, year = {2025}, }
• (2025). PH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies. PNAS, 122(8), e2422731122. (www)

  @article{ , abstract = {Anti-CTLA-4 Abs (ACAs) are a breakthrough for cancer therapy, but their potential is limited by immunotherapy-related adverse events (irAE). We previously reported that ACAs with acidic pH-sensitive binding to CTLA-4 exhibit higher antitumor activity with fewer irAE. We now test a panel of variants of Ipilimumab (Ipi), the first ACA cancer therapeutic, for tumoricidal efficacy and irAE. Surprisingly, not all pH-sensitive Ipi variants exhibited an enhanced therapeutic index. Ipi13, which retained binding to CTLA-4 at pH 6.0 but dissociated at lower pH, showed no enhancement. By contrast, Ipi25, which dissociates from CTLA-4 at pH 6.0, the pH of the early endosome (EE), showed greater tumor regression and less severe irAE. Confocal microscopy showed that Ipi13 maintained colocalization with CTLA-4 at the late endosomes (LE) and lysosomes resulting in lysosomal degradation of CTLA-4. Conversely, Ipi25 did not colocalize with CTLA-4 in LE or lysosomes after endocytosis but allowed both proteins to transfer to recycling endosomes. EE dissociation was also characteristic of variants of Tremelimumab (Treme), another clinical ACA, that showed better efficacy and fewer side effects. Thus, our data reveal the significance of early intracellular dissociation from CTLA-4 to improve ACAs for safer and more effective cancer immunotherapy.}, archive = {J_PNAS}, author = {Zhang, Meiyu and Li, Jinmei and Yan, Kepeng and Zhou, Haoyue and Mei, Song and Wang, Benyu and Li, Dongyang and Du, Xuexiang and Liu, Mingyue and Zhang, Peng and Fields, James K. and Ye, Lei and Zheng, Pan and Liu, Yang and Lenardo, Michael J. and Zhang, Yan}, doi = {10.1073/pnas.2422731122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2422731122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies}, volume = {122}, year = {2025}, }
• (2025). Do LLMs write like humans? variation in grammatical and rhetorical styles. PNAS, 122(8), e2422455122. (www)

  @article{ , abstract = {Large language models (LLMs) are capable of writing grammatical text that follows instructions, answers questions, and solves problems. As they have advanced, it has become difficult to distinguish their output from human-written text. While past research has found some differences in features such as word choice and punctuation and developed classifiers to detect LLM output, none has studied the rhetorical styles of LLMs. Using several variants of Llama 3 and GPT-4o, we construct two parallel corpora of human- and LLM-written texts from common prompts. Using Douglas Biber’s set of lexical, grammatical, and rhetorical features, we identify systematic differences between LLMs and humans and between different LLMs. These differences persist when moving from smaller models to larger ones and are larger for instruction-tuned models than base models. This observation of differences demonstrates that despite their advanced abilities, LLMs struggle to match human stylistic variation. Attention to more advanced linguistic features can hence detect patterns in their behavior not previously recognized.}, archive = {J_PNAS}, author = {Reinhart, Alex and Markey, Ben and Laudenbach, Michael and Pantusen, Kachatad and Yurko, Ronald and Weinberg, Gordon and Brown, David West}, doi = {10.1073/pnas.2422455122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2422455122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Do LLMs write like humans? variation in grammatical and rhetorical styles}, volume = {122}, year = {2025}, }
• (2025). A novel quinone biosynthetic pathway illuminates the evolution of aerobic metabolism. PNAS, 122(8), e2421994122. (www)

  @article{ , abstract = {The dominant organisms in modern oxic ecosystems rely on respiratory quinones with high redox potential (HPQs) for electron transport in aerobic respiration and photosynthesis. The diversification of quinones, from low redox potential (LPQ) in anaerobes to HPQs in aerobes, is assumed to have followed Earth’s surface oxygenation ~2.3 billion years ago. However, the evolutionary origins of HPQs remain unresolved. Here, we characterize the structure and biosynthetic pathway of an ancestral HPQ, methyl-plastoquinone (mPQ), that is unique to bacteria of the phylum Nitrospirota . mPQ is structurally related to the two previously known HPQs, plastoquinone from Cyanobacteriota /chloroplasts and ubiquinone from Pseudomonadota /mitochondria, respectively. We demonstrate a common origin of the three HPQ biosynthetic pathways that predates the emergence of Nitrospirota , Cyanobacteriota , and Pseudomonadota . An ancestral HPQ biosynthetic pathway evolved ≥ 3.4 billion years ago in an extinct lineage and was laterally transferred to these three phyla ~2.5 to 3.2 billion years ago. We show that Cyanobacteriota and Pseudomonadota were ancestrally aerobic and thus propose that aerobic metabolism using HPQs significantly predates Earth’s surface oxygenation. Two of the three HPQ pathways were later obtained by eukaryotes through endosymbiosis forming chloroplasts and mitochondria, enabling their rise to dominance in modern oxic ecosystems.}, archive = {J_PNAS}, author = {Elling, Felix J. and Pierrel, Fabien and Chobert, Sophie-Carole and Abby, Sophie S. and Evans, Thomas W. and Reveillard, Arthur and Pelosi, Ludovic and Schnoebelen, Juliette and Hemingway, Jordon D. and Boumendjel, Ahcène and Becker, Kevin W. and Blom, Pieter and Cordes, Julia and Nathan, Vinitra and Baymann, Frauke and Lücker, Sebastian and Spieck, Eva and Leadbetter, Jared R. and Hinrichs, Kai-Uwe and Summons, Roger E. and Pearson, Ann}, doi = {10.1073/pnas.2421994122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2421994122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A novel quinone biosynthetic pathway illuminates the evolution of aerobic metabolism}, volume = {122}, year = {2025}, }
• (2025). Antagonizing cis-regulatory elements of a conserved flowering gene mediate developmental robustness. PNAS, 122(8), e2421990122. (www)

  @article{ , abstract = {Developmental transitions require precise temporal and spatial control of gene expression. In plants, such regulation is critical for flower formation, which involves the progressive maturation of stem cell populations within shoot meristems to floral meristems, followed by rapid sequential differentiation into floral organs. Across plant taxa, these transitions are orchestrated by the F-box transcriptional cofactor gene UNUSUAL FLORAL ORGANS ( UFO ). The conserved and pleiotropic functions of UFO offer a useful framework for investigating how evolutionary processes have shaped the intricate cis- regulation of key developmental genes. By pinpointing a conserved promoter sequence in an accessible chromatin region of the tomato ortholog of UFO , we engineered in vivo a series of cis- regulatory alleles that caused both loss- and gain-of-function floral defects. These mutant phenotypes were linked to disruptions in predicted transcription factor binding sites for known transcriptional activators and repressors. Allelic combinations revealed dosage-dependent interactions between opposing alleles, influencing the penetrance and expressivity of gain-of-function phenotypes. These phenotypic differences support that robustness in tomato flower development requires precise temporal control of UFO expression dosage. Bridging our analysis to Arabidopsis , we found that although homologous sequences to the tomato regulatory region are dispersed within the UFO promoter, they maintain similar control over floral development. However, phenotypes from disrupting these sequences differ due to the differing expression patterns of UFO . Our study underscores the complex cis- regulatory control of dynamic developmental genes and demonstrates that critical short stretches of regulatory sequences that recruit both activating and repressing machinery are conserved to maintain developmental robustness.}, archive = {J_PNAS}, author = {Lanctot, Amy and Hendelman, Anat and Udilovich, Peter and Robitaille, Gina M. and Lippman, Zachary B.}, doi = {10.1073/pnas.2421990122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2421990122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Antagonizing cis-regulatory elements of a conserved flowering gene mediate developmental robustness}, volume = {122}, year = {2025}, }
• (2025). Listen for a change? a longitudinal field experiment on listening’s potential to enhance persuasion. PNAS, 122(8), e2421982122. (www)

  @article{ , abstract = {Scholars and practitioners widely posit that listening to other people enhances efforts to persuade them. Listening may enhance persuasion by promoting cognitive processing, reducing defensiveness, and improving perceptions of the persuader. However, empirical tests of this widely theorized hypothesis are surprisingly scarce. We review the case for and against this hypothesis, arguing previous research has not sufficiently attended to reasons why listening may not enhance persuasion. We test this hypothesis using a preregistered, well-powered field experiment in which trained professional canvassers, acting as confederates, had ∼10 min video conversations with U.S. participants ( N = 1,485) about unauthorized immigration, a salient topic of disagreement. We independently randomized whether confederates shared a persuasive narrative about an undocumented immigrant and whether they practiced high-quality nonjudgmental listening to participants’ opinions. We measured outcomes immediately after the conversation and again five weeks later. Sharing a persuasive narrative meaningfully and durably reduced prejudice and changed policy attitudes. The listening manipulation also successfully improved perceptions of the persuader and increased processing. Surprisingly, however, the listening manipulation did not enhance persuasion: Sharing a persuasive narrative was just as effective in the absence of high-quality listening. We discuss theoretical and practical implications.}, archive = {J_PNAS}, author = {Santoro, Erik and Broockman, David E. and Kalla, Joshua L. and Porat, Roni}, doi = {10.1073/pnas.2421982122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2421982122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Listen for a change? a longitudinal field experiment on listening’s potential to enhance persuasion}, volume = {122}, year = {2025}, }
• (2025). The endocannabinoid 2-arachidonoylglycerol is released and transported on demand via extracellular microvesicles. PNAS, 122(8), e2421717122. (www)

  @article{ , abstract = {While it is known that endocannabinoids (eCB) modulate multiple neuronal functions, the molecular mechanism governing their release and transport remains elusive. Here, we propose an “ on-demand release ” model, wherein the formation of microvesicles, a specific group of extracellular vesicles (EVs) containing the eCB, 2-arachidonoylglycerol (2-AG), is an important step. A coculture model system that combines a reporter cell line expressing the fluorescent eCB sensor, G protein-coupled receptor-based (GRAB) eCB2.0 , and neuronal cells revealed that neurons release EVs containing 2-AG, but not anandamide, in a stimulus-dependent process regulated by protein kinase C, Diacylglycerol lipase, Adenosinediphosphate (ADP) ribosylation factor 6 (Arf6), and which was sensitive to inhibitors of eCB facilitated diffusion. A vesicle contained approximately 2,000 2-AG molecules. Accordingly, hippocampal eCB-mediated synaptic plasticity was modulated by Arf6 and transport inhibitors. The “ on-demand release ” model, supported by mathematical analysis, offers a cohesive framework for understanding eCB trafficking at the molecular level and suggests that microvesicles carrying signaling lipids in their membrane regulate neuronal functions in parallel to canonical synaptic vesicles.}, archive = {J_PNAS}, author = {Straub, Verena M. and Barti, Benjamin and Tandar, Sebastian T. and Stevens, A. Floor and van Egmond, Noëlle and van der Wel, Tom and Zhu, Na and Rüegger, Joel and van der Horst, Cas and Heitman, Laura H. and Li, Yulong and Stella, Nephi and van Hasselt, J. G. Coen and Katona, István and van der Stelt, Mario}, doi = {10.1073/pnas.2421717122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2421717122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The endocannabinoid 2-arachidonoylglycerol is released and transported on demand via extracellular microvesicles}, volume = {122}, year = {2025}, }
• (2025). Druggable genome screens identify SPP as an antiviral host target for multiple flaviviruses. PNAS, 122(8), e2421573122. (www)

  @article{ , abstract = {Mosquito-borne flaviviruses, such as dengue virus (DENV), Zika virus (ZIKV), West Nile virus, and yellow fever virus, pose significant public health threats globally. Extensive efforts have led to the development of promising highly active compounds against DENV targeting viral non-structural protein 4B (NS4B) protein. However, due to the cocirculation of flaviviruses and to prepare for emerging flaviviruses, there is a need for more broadly acting antivirals. Host-directed therapy where one targets a host factor required for viral replication may be active against multiple viruses that use similar replication strategies. Here, we used a CRISPR-Cas9 library that we designed to target the druggable genome and identified signal peptide peptidase (SPP, encoded by Histocompatibility Minor 13, HM13), as a critical host factor in DENV infection. Genetic knockout or introducing mutations that disrupt the proteolytic activity of SPP markedly reduced the replication of multiple flaviviruses. Although their substrates differ, SPP has structural homology with γ-secretase, which has been pursued as a pharmacological target for Alzheimer’s disease. Notably, SPP-targeting compounds exhibited potent anti-DENV activity at low nanomolar concentrations across multiple primary and disease-relevant cell types, acting specifically through SPP inhibition rather than γ-secretase inhibition. Importantly, SPP inhibitors were active at low nanomolar concentrations against flaviviruses other than DENV including ZIKV while DENV NS4B inhibitors lost activity. This study emphasizes the strong potential of SPP as a pan-flaviviral target and provides a framework for identifying host druggable targets to screen for broad-spectrum antivirals.}, archive = {J_PNAS}, author = {Qiao, Wenjie and Xie, Xuping and Shi, Pei-Yong and Ooi, Yaw Shin and Carette, Jan E.}, doi = {10.1073/pnas.2421573122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2421573122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Druggable genome screens identify SPP as an antiviral host target for multiple flaviviruses}, volume = {122}, year = {2025}, }
• (2025). NPF binding to arp2 is allosterically linked to the release of ArpC5’s N-terminal tail and conformational changes in arp2/3 complex. PNAS, 122(8), e2421557122. (www)

  @article{ , abstract = {Arp2/3 complex generates branched actin networks essential for numerous motile functions of the cell. It comprises seven subunits: actin-related proteins (Arps) 2 and 3 and five scaffolding subunits (ArpC1-5). The complex adopts two major conformations: inactive, with the Arps interacting end-to-end, and active, with the Arps aligned side-by-side like subunits in the actin filament. Activation involves several cofactors, including ATP, WASP-family nucleation-promoting factors (NPFs), actin monomers, and the mother actin filament. NPFs bind to two sites, one on Arp2–ArpC1 and one on Arp3, delivering actin subunits at the barbed end of the Arps to initiate branch elongation. However, the mechanisms by which each NPF drives the equilibrium toward activation remain unclear. We present two cryo-electron microscopy (cryo-EM) structures of Arp2/3 complex at 2.9-Å resolution: one with NPFs bound to Arp3 and ArpC1 but not Arp2 and another with NPFs bound to Arp3 and Arp2–ArpC1. The structures reveal that NPF binding to Arp2 is allosterically linked to the release of ArpC5’s N-terminal tail from Arp2 and conformational changes in Arp2, including closure of its ATP-binding cleft and partial rotation and translation toward its position in the active complex at the branch. Previous work identified another allosteric switch linking NPF binding to Arp3 with the release of its inhibitory C-terminal tail, which we also observe. In summary, both NPF-binding sites induce allosteric changes in Arp2/3 complex, collectively shifting the equilibrium toward activation.}, archive = {J_PNAS}, author = {Saks, Andrew J. and Barrie, Kyle R. and Rebowski, Grzegorz and Dominguez, Roberto}, doi = {10.1073/pnas.2421557122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2421557122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {NPF binding to arp2 is allosterically linked to the release of ArpC5’s N-terminal tail and conformational changes in arp2/3 complex}, volume = {122}, year = {2025}, }
• (2025). PSKH1 kinase activity is differentially modulated via allosteric binding of ca2+ sensor proteins. PNAS, 122(8), e2420961122. (www)

  @article{ , abstract = {Protein Serine Kinase H1 (PSKH1) was recently identified as a crucial factor in kidney development and is overexpressed in prostate, lung, and kidney cancers. However, little is known about PSKH1 regulatory mechanisms, leading to its classification as a “dark” kinase. Here, we used biochemistry and mass spectrometry to define PSKH1’s consensus substrate motif, protein interactors, and how interactors, including Ca 2+ sensor proteins, promote or suppress activity. Intriguingly, despite the absence of a canonical Calmodulin binding motif, Ca 2+ -Calmodulin activated PSKH1 while, in contrast, the ER-resident Ca 2+ sensor of the Cab45, Reticulocalbin, Erc55, Calumenin (CREC) family, Reticulocalbin-3, suppressed PSKH1 catalytic activity. In addition to antagonistic regulation of the PSKH1 kinase domain by Ca 2+ sensing proteins, we identified UNC119B as a protein interactor that activates PSKH1 via direct engagement of the kinase domain. Our findings identify complementary allosteric mechanisms by which regulatory proteins tune PSKH1’s catalytic activity and raise the possibility that different Ca 2+ sensors may act more broadly to tune kinase activities by detecting and decoding extremes of intracellular Ca 2+ concentrations.}, archive = {J_PNAS}, author = {Horne, Christopher R. and Dite, Toby A. and Young, Samuel N. and Mather, Lucy J. and Dagley, Laura F. and Johnson, Jared L. and Yaron-Barir, Tomer M. and Huntsman, Emily M. and Daly, Leonard A. and Byrne, Dominic P. and Cadell, Antonia L. and Ng, Boaz H. and Yousef, Jumana and Multari, Dylan H. and Shen, Lianju and McAloon, Luke M. and Manning, Gerard and Febbraio, Mark A. and Means, Anthony R. and Cantley, Lewis C. and Tanzer, Maria C. and Croucher, David R. and Eyers, Claire E. and Eyers, Patrick A. and Scott, John W. and Murphy, James M.}, doi = {10.1073/pnas.2420961122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2420961122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PSKH1 kinase activity is differentially modulated via allosteric binding of ca2+ sensor proteins}, volume = {122}, year = {2025}, }
• (2025). Gene duplication captures morph-specific promoter usage in the evolution of aphid wing dimorphisms. PNAS, 122(8), e2420893122. (www)

  @article{ , abstract = {Understanding how morphology evolves requires identifying the types of mutations that contribute to changes in development. We integrated comparative genomics and transcriptomics to reconstruct the evolution and regulation of follistatin paralogs in relation to the evolution of aphid winged and wingless morphs. We find that different pea aphid follistatin duplicates play an essential molecular role in both the male and female wing dimorphisms, linking the genetic and environmental control of morph determination in each sex, respectively. We also find that an ancestral follistatin gene likely had multiple promoters and that the follistatin duplicates that evolved wingless-specific expression retained only the ancestral wingless-specific promoter. Our work provides a roadmap for how alternative promoter usage and subsequent gene duplication can enable the evolution of animal form.}, archive = {J_PNAS}, author = {Saleh Ziabari, Omid and Liu, Fangzhou and Deem, Kevin D. and Liu, Xiaomi and Kholwadwala, Akhil and Brisson, Jennifer A.}, doi = {10.1073/pnas.2420893122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2420893122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Gene duplication captures morph-specific promoter usage in the evolution of aphid wing dimorphisms}, volume = {122}, year = {2025}, }
• (2025). A circRNA–mRNA pairing mechanism regulates tumor growth and endocrine therapy resistance in ER-positive breast cancer. PNAS, 122(8), e2420383122. (www)

  @article{ , abstract = {The molecular mechanisms underlying estrogen receptor (ER)-positive breast carcinogenesis and drug resistance remain incompletely understood. Elevated expression of CCND1 is linked to enhanced invasiveness, poorer prognosis, and resistance to drug therapies in ER-positive breast cancer. In this study, we identify a highly expressed circular RNA (circRNA) derived from FOXK2 , called circFOXK2, which plays a key role in stabilizing CCND1 mRNA, thereby promoting cell cycle progression, cell growth, and endocrine therapy resistance in ER-positive breast cancer cells. Mechanistically, circFOXK2 binds directly to CCND1 mRNA via RNA–RNA pairing and recruits the RNA-binding protein ELAVL1/HuR, stabilizing the CCND1 mRNA and enhancing CCND1 protein levels. This results in activation of the CCND1–CDK4/6–p-RB–E2F signaling axis, driving the transcription of downstream E2F target genes and facilitating the G1/S transition during cell cycle progression. Notably, targeting circFOXK2 with antisense oligonucleotide (ASO-circFOXK2) suppresses ER-positive breast cancer cell growth both in vitro and in vivo. Moreover, combination therapy with ASO-circFOXK2 and tamoxifen exhibits synergistic effects and restores tamoxifen sensitivity in tamoxifen-resistant cells. Clinically, high circFOXK2 expression is positively correlated with CCND1 levels in both ER-positive breast cancer cell lines and patient tumor tissues. Overall, our findings reveal the critical role of circFOXK2 in stabilizing the oncogene CCND1 and promoting cancer progression, positioning circFOXK2 as a potential therapeutic target for ER-positive breast cancer in clinical settings.}, archive = {J_PNAS}, author = {Yi, Jia and Du, Jiao and Chen, Xue and Nie, Rui-chao and Hu, Guo-sheng and Wang, Lei and Zhang, Yue-ying and Chen, Shang and Wen, Xiao-sha and Luo, Di-xian and He, Hua and Liu, Wen}, doi = {10.1073/pnas.2420383122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2420383122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A circRNA–mRNA pairing mechanism regulates tumor growth and endocrine therapy resistance in ER-positive breast cancer}, volume = {122}, year = {2025}, }
• (2025). Illuminating an invisible state of the HIV-1 capsid protein CTD dimer using 19F NMR and weighted ensemble simulations. PNAS, 122(8), e2420371122. (www)

  @article{ , abstract = {The HIV-1 capsid protein (CA) assembles into a conical shell during viral maturation, encasing and protecting the viral RNA genome. The C-terminal domain (CTD) of the two-domain capsid protein dimerizes, and this dimer connects individual chains in the mature capsid lattice. Previous NMR studies have shown that different dimer arrangements can be formed by isolated capsid protein chains and in assembled capsid lattices; however, the dynamics and functional relevance of these alternate dimers are unknown. To explore the conformational landscape of the CA-CTD dimer, we carried out atomistic molecular dynamics simulations using the weighted ensemble path sampling strategy, generating an ensemble of conformations. Focusing on the two dimer forms previously observed via solution NMR, we refined the conformational ensemble to highlight two metastable states using a Markov state model. Experimentally, we measured the interconversion rates between the two alternate dimers using 19 F NMR, and these rates showed good agreement with the interconversion rates derived from the simulations. After identifying the key interactions that distinguish the dimer states, the alternate dimer was further experimentally verified through disulfide crosslinking. Our results demonstrate the advantages of pairing weighted ensemble path sampling with 19 F NMR to gain atomistic insights into the hidden dimer state of the HIV-1 capsid protein.}, archive = {J_PNAS}, author = {Yang, Darian T. and Chong, Lillian T. and Gronenborn, Angela M.}, doi = {10.1073/pnas.2420371122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2420371122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Illuminating an invisible state of the HIV-1 capsid protein CTD dimer using 19F NMR and weighted ensemble simulations}, volume = {122}, year = {2025}, }
• (2025). Experimental electronic structures of the FeIV=O bond in s=1 heme vs. nonheme sites: Effect of the porphyrin ligand. PNAS, 122(8), e2420205122. (www)

  @article{ , abstract = {High-valent Fe IV =O species are common intermediates in biological and artificial catalysts. Heme and nonheme S=1 Fe IV =O sites have been synthesized and studied for decades but little quantitative experimental comparison of their electronic structures has been available, due to the lack of direct methods focused on the iron. This study allows a rigorous determination of the electronic structure of a nonheme Fe IV =O center and its comparison to an Fe IV =O heme site using 1s2p resonant inelastic X-ray scattering (RIXS) and Fe L-edge X-ray absorption spectroscopy (XAS). Further, variable temperature magnetic circular dichroism (VT-MCD) of the ligand field transitions, combined with nuclear resonance vibrational spectroscopy of the two S=1 Fe IV =O systems show that the equatorial ligand field decreases from a nonheme to a heme Fe IV =O site. Alternatively, RIXS and Fe L-edge XAS combined with MCD show that the Fe d π orbitals are unperturbed in the Fe IV =O heme relative to the nonheme site because the strong axial Fe-O bond uncouples the Fe d π orbitals from the porphyrin π -system. As a consequence, the thermodynamics and kinetics of the H-atom abstraction reactions are actually very similar for heme compound II and nonheme Fe IV =O active sites.}, archive = {J_PNAS}, author = {Braun, Augustin and Gee, Leland B. and Waters, Max D. J. and Jose, Anex and Baker, Michael L. and Mara, Michael W. and Babicz, Jeffrey T. and Ehudin, Melanie A. and Quist, David A. and Zhou, Ang and Kroll, Thomas and Titus, Charles J. and Lee, Sang-Jun and Nordlund, Dennis and Sokaras, Dimosthenis and Yoda, Yoshitaka and Kobayashi, Yasuhiro and Tamasaku, Kenji and Hedman, Britt and Hodgson, Keith O. and Karlin, Kenneth D. and Que, Lawrence and Solomon, Edward I.}, doi = {10.1073/pnas.2420205122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2420205122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Experimental electronic structures of the FeIV=O bond in s=1 heme vs. nonheme sites: Effect of the porphyrin ligand}, volume = {122}, year = {2025}, }
• (2025). Subfunctionalization and epigenetic regulation of a biosynthetic gene cluster in solanaceae. PNAS, 122(8), e2420164122. (www)

  @article{ , abstract = {Biosynthetic gene clusters (BGCs) are sets of often heterologous genes that are genetically and functionally linked. Among eukaryotes, BGCs are most common in plants and fungi and ensure the coexpression of the different enzymes coordinating the biosynthesis of specialized metabolites. Here, we report the identification of a withanolide BGC in Physalis grisea (ground-cherry), a member of the nightshade family ( Solanaceae ). A combination of transcriptomic, epigenomic, and metabolic analyses revealed that, following a duplication event, this BGC evolved two tissue-specifically expressed subclusters, containing several pairs of paralogs that contribute to related but distinct biochemical processes; this subfunctionalization is tightly associated with epigenetic features and the local chromatin environment. The two subclusters appear strictly isolated from each other at the structural chromatin level, each forming a highly self-interacting chromatin domain with tissue-dependent levels of condensation. This correlates with gene expression in either above- or below-ground tissue, thus spatially separating the production of different withanolide compounds. By comparative phylogenomics, we show that the withanolide BGC most likely evolved before the diversification of the Solanaceae family and underwent lineage-specific diversifications and losses. The tissue-specific subfunctionalization is common to species of the Physalideae tribe but distinct from other, independent duplication events outside of this clade. In sum, our study reports on an instance of an epigenetically modulated subfunctionalization within a BGC and sheds light on the biosynthesis of withanolides, a highly diverse group of steroidal triterpenoids important in plant defense and amenable to pharmaceutical applications due to their anti-inflammatory, antibiotic, and anticancer properties.}, archive = {J_PNAS}, author = {Priego-Cubero, Santiago and Knoch, Eva and Wang, Zhidan and Alseekh, Saleh and Braun, Karl-Heinz and Chapman, Philipp and Fernie, Alisdair R. and Liu, Chang and Becker, Claude}, doi = {10.1073/pnas.2420164122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2420164122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Subfunctionalization and epigenetic regulation of a biosynthetic gene cluster in solanaceae}, volume = {122}, year = {2025}, }
• (2025). Quantum tunneling and its absence in deep wells and strong magnetic fields. PNAS, 122(8), e2420062122. (www)

  @article{ , abstract = {We present results on quantum tunneling between deep potential wells, in the presence of a strong constant magnetic field. We construct a family of double-well potentials containing examples for which the low-energy eigenvalue splitting vanishes, and hence quantum tunneling is eliminated. Further, by deforming within this family, the magnetic ground state can be made to transition from symmetric to antisymmetric. However, for typical double wells in a certain regime, tunneling is not suppressed, and we provide a lower bound for the eigenvalue splitting.}, archive = {J_PNAS}, author = {Fefferman, Charles L. and Shapiro, Jacob and Weinstein, Michael I.}, doi = {10.1073/pnas.2420062122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2420062122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantum tunneling and its absence in deep wells and strong magnetic fields}, volume = {122}, year = {2025}, }
• (2025). Adapting c4 photosynthesis to atmospheric change and increasing productivity by elevating rubisco content in sorghum and sugarcane. PNAS, 122(8), e2419943122. (www)

  @article{ , abstract = {Meta-analyses and theory show that with rising atmospheric [CO 2 ], Rubisco has become the greatest limitation to light-saturated leaf CO 2 assimilation rates ( A sat ) in C 4 crops. So would transgenically increasing Rubisco increase A sat and result in increased productivity in the field? Here, we successfully overexpressed the Rubisco small subunit ( RbcS ) with Rubisco accumulation factor 1 ( Raf1 ) in both sorghum and sugarcane, resulting in significant increases in Rubisco content of 13 to 25% and up to 90% respectively. A sat increased 12 to 15% and Rubisco enzyme activity ~40% in three independent transgenic events of both species. Sorghum plants also showed increased speeds of photosynthetic induction and decreased bundle sheath leakiness. These improvements translated into average increases of 15.5% in biomass in field-grown sorghum and a 37 to 81% increase in greenhouse-grown sugarcane. This suggests a potential opportunity to achieve substantial increases in productivity of this key economically important clade of C 4 crops, future proofing their value under global atmospheric change.}, archive = {J_PNAS}, author = {Salesse-Smith, Coralie E. and Adar, Noga and Kannan, Baskaran and Nguyen, Thaibinhduong and Wei, Wei and Guo, Ming and Ge, Zhengxiang and Altpeter, Fredy and Clemente, Tom E. and Long, Stephen P.}, doi = {10.1073/pnas.2419943122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2419943122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Adapting c4 photosynthesis to atmospheric change and increasing productivity by elevating rubisco content in sorghum and sugarcane}, volume = {122}, year = {2025}, }
• (2025). Tracking proteasome degradation: A cross-organ analysis via intact degradomics mass spectrometry. PNAS, 122(8), e2419607122. (www)

  @article{ , abstract = {The proteasome is a multisubunit degradation machinery that is essential for maintaining protein homeostasis by breaking down unnecessary or damaged proteins into peptides. While most of these peptides are further processed into amino acids, a subset evades complete degradation and plays key roles in biological processes such as antigen presentation, signaling, and apoptosis. However, the variability in peptide lengths and the diverse composition of proteasomes make their comprehensive identification and characterization particularly challenging. Here, we present a method that enables real-time identification of generated peptides, as well as uncleaved and partially cleaved protein substrates, revealing the processive nature of protein proteasomal degradation. Our intact degradomics workflow is based on intact mass spectrometry measurements and treats the enzymatically produced peptides as if they were generated within the mass spectrometer, akin to top–down products. We applied this approach to determine the kinetic profile of proteasome degradation and compare the real-time activity of proteasomes isolated from different mouse organs, uncovering distinct functionalities of the complex. Overall, this method offers a valuable tool for studying peptide degradation products across various proteasome configurations, while also enabling the investigation of how interacting proteins, inhibitors, and activators influence proteasome activity. Furthermore, its adaptability makes it applicable to a wide range of other proteolytic complexes, broadening its potential impact in the field.}, archive = {J_PNAS}, author = {Zittlau, Katharina I. and Zachor-Movshovitz, Daniel and Leushkin, Yegor and Schimmel Brener, Roy and Morgenstern, David and Ben-Nissan, Gili and Sharon, Michal}, doi = {10.1073/pnas.2419607122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2419607122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tracking proteasome degradation: A cross-organ analysis via intact degradomics mass spectrometry}, volume = {122}, year = {2025}, }
• (2025). Fungal-derived methyldeoxaphomins target plasmodium falciparum segregation through the inhibition of PfActin1. PNAS, 122(8), e2418871122. (www)

  @article{ , abstract = {Herein we report the finding and structure determination of a natural product based on the methyldeoxaphomin scaffold family from the fungus Trichocladium asperum that shows promising antiplasmodial activity and selectivity against host cells. In vitro evolution and whole genome analysis in Plasmodium falciparum with the most potent member, NPDG-F (EC 50 of 550 nM in Dd2; 290 nM in 3D7), shows that parasite resistance to methyldeoxaphomins is strongly associated with mutations in PfActin1 (PF3D7_1246200), a critically essential ATPase needed for all stages of parasite development. Molecular docking study with available PfActin1 crystal structure shows NPDG-F occupies the same allosteric binding pocket as the known actin inhibitor cytochalasin D. The direct PfActin1 target engagement in the allosteric site was supported by cross-resistance studies, isobologram analysis with other PfActin1 inhibitors, and the structure–activity relationships for the methyldeoxaphomin family. When added to in vitro culture, NPDG-F induced morphological abnormalities in merozoite cellularization during schizogony in both the Plasmodium blood and liver stages. Our data provide chemical validation that PfActin1 is an attractive, pan-lifecycle target and inform strategies for the design of more selective inhibitors.}, archive = {J_PNAS}, author = {Jiang, Tiantian and Lee, Jin Woo and Collins, Jennifer E. and Schaefer, Samuel and Chen, Daisy and Nardella, Flore and Wendt, Karen and Peramuna, Thilini G. and Paes, Raphaella and McLellan, James L. and Bhasin, Jasveen and Durst, Gregory L. and Hanson, Kirsten K. and Chakrabarti, Debopam and Cichewicz, Robert H. and Winzeler, Elizabeth A.}, doi = {10.1073/pnas.2418871122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2418871122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fungal-derived methyldeoxaphomins target plasmodium falciparum segregation through the inhibition of PfActin1}, volume = {122}, year = {2025}, }
• (2025). A hormone-to-neuropeptide pathway inhibits sexual receptivity in immature drosophila females. PNAS, 122(8), e2418481122. (www)

  @article{ , abstract = {Newborns, typically asexual, undergo a process of sexual transition to reach sexual maturity, but the regulatory mechanism underlying this transition is not clear. Here, we studied how female sexual behavior is modulated during sexual transition by hormones and neuromodulators in Drosophila . We found that neuropeptide Leucokinin (LK) inhibits female receptivity specifically during a sexual transition period in immature females, but not in younger or mature females. Moreover, the steroid hormone ecdysone, which is mainly synthesized in the female ovary during sexual maturation, acts on LK neurons via the ecdysone receptor to suppress sexual receptivity. We further found that LK suppresses female receptivity through its receptor LKR in central pC1 neurons, a decision center for female sexual behavior. These findings reveal a hormone-to-neuropeptide pathway that specifically inhibits sexual behavior during sexual maturation in female Drosophila , shedding light on how hormones and neuromodulators coordinate sexual development and behaviors.}, archive = {J_PNAS}, author = {Chen, Jie and Zhu, Peiwen and Jin, Sihui and Zhang, Zhaokun and Jiang, Simei and Li, Sheng and Liu, Suning and Peng, Qionglin and Pan, Yufeng}, doi = {10.1073/pnas.2418481122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2418481122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A hormone-to-neuropeptide pathway inhibits sexual receptivity in immature drosophila females}, volume = {122}, year = {2025}, }
• (2025). Biophysical modeling of membrane curvature generation and curvature sensing by the glycocalyx. PNAS, 122(8), e2418357122. (www)

  @article{ , abstract = {Generation of membrane curvature is fundamental to cellular function. Recent studies have established that the glycocalyx, a sugar-rich polymer layer at the cell surface, can generate membrane curvature. While there have been some theoretical efforts to understand the interplay between the glycocalyx and membrane bending, there remain open questions about how the properties of the glycocalyx affect membrane bending. For example, the relationship between membrane curvature and the density of glycosylated proteins on its surface remains unclear. In this work, we use polymer brush theory to develop a detailed biophysical model of the energetic interactions of the glycocalyx with the membrane. Using this model, we identify the conditions under which the glycocalyx can both generate and sense curvature. Our model predicts that the extent of membrane curvature generated depends on the grafting density of the glycocalyx and the backbone length of the polymers constituting the glycocalyx. Furthermore, when coupled with the intrinsic membrane properties such as spontaneous curvature and a line tension along the membrane, the curvature generation properties of the glycocalyx are enhanced. These predictions were tested experimentally by examining the propensity of glycosylated transmembrane proteins to drive the assembly of highly curved filopodial protrusions at the plasma membrane of adherent mammalian cells. Our model also predicts that the glycocalyx has curvature-sensing capabilities, in agreement with the results of our experiments. Thus, our study develops a quantitative framework for mapping the properties of the glycocalyx to the curvature generation capability of the membrane.}, archive = {J_PNAS}, author = {Xiao, Ke and Park, Sujeong and Stachowiak, Jeanne C. and Rangamani, Padmini}, doi = {10.1073/pnas.2418357122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2418357122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biophysical modeling of membrane curvature generation and curvature sensing by the glycocalyx}, volume = {122}, year = {2025}, }
• (2025). ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep. PNAS, 122(8), e2416578122. (www)

  @article{ , abstract = {Metabolism plays a key role in the maintenance of sleep/wake states. Brain lactate fluctuations are a biomarker of sleep/wake transitions, where increased interstitial fluid (ISF) lactate levels are associated with wakefulness and decreased ISF lactate is required for sleep. ATP-sensitive potassium (K ATP ) channels couple glucose-lactate metabolism with excitability. Using mice lacking K ATP channel activity (e.g., Kir6.2 −/− mice), we explored how changes in glucose utilization affect cortical electroencephalography (EEG) activity and sleep/wake homeostasis. In the brain, Kir6.2 −/− mice shunt glucose toward glycolysis, reducing neurotransmitter biosynthesis and dampening cortical EEG activity. Kir6.2 −/− mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-K ATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of sleep/wake states and providing the metabolic flexibility to transition between states.}, archive = {J_PNAS}, author = {Constantino, Nicholas J. and Carroll, Caitlin M. and Williams, Holden C. and Vekaria, Hemendra J. and Yuede, Carla M. and Saito, Kai and Sheehan, Patrick W. and Snipes, J. Andy and Raichle, Marcus E. and Musiek, Erik S. and Sullivan, Patrick G. and Morganti, Josh M. and Johnson, Lance A. and Macauley, Shannon L.}, doi = {10.1073/pnas.2416578122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2416578122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep}, volume = {122}, year = {2025}, }
• (2025). Identification of AK4 and RHOC as potential oncogenes addicted by adult t cell leukemia. PNAS, 122(8), e2416412122. (www)

  @article{ , abstract = {Adult T cell leukemia (ATL) is a highly aggressive T cell malignancy characterized by human T cell leukemia virus type 1 (HTLV-1) infection. ATL has a very poor prognosis and lacks satisfactory treatments; therefore, it is critical to identify potential targets in ATL cells in order to develop effective targeted therapeutics. Here, we report the identification of two oncogenes, AK4 and RHOC, as target genes of miR-455-3p, a tumor-suppressive microRNA in ATL patients. Importantly, AK4 and RHOC are highly expressed in ATL and exhibit oncogenic potentials in vitro and in vivo. Interestingly, transcriptome and metabolome analyses reveal a functional overlap of AK4 and RHOC, including activating oncogenic pathways such as Myc targets and deregulating lipid metabolism such as enhancing the production of sphingomyelin, a tumor-promoting lipid. In particular, compared to other types of T cell malignancy such as T cell acute lymphoblastic leukemia (T-ALL) and cutaneous T cell lymphoma (CTCL), ATL is sensitive to sphingomyelin inhibition and AK4 or RHOC depletion. Altogether, we report a distinct dependency of ATL on AK4 and RHOC oncogenes and an oncometabolite sphingomyelin, which together represent targetable vulnerabilities of ATL that could be exploited for developing effective therapeutics.}, archive = {J_PNAS}, author = {Liu, Benquan and Yasunaga, Jun-ichirou and Liang, Yi and Zhou, Ruoning and Yang, Sikai and Yuan, Xiaoyi and Liu, Jie and Zuo, Xiaorui and Miura, Michi and Higuchi, Yusuke and Matsumoto, Takashi and Toyoda, Kosuke and Matsuoka, Masao and Ma, Guangyong}, doi = {10.1073/pnas.2416412122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2416412122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identification of AK4 and RHOC as potential oncogenes addicted by adult t cell leukemia}, volume = {122}, year = {2025}, }
• (2025). OsNLP3 and OsPHR2 orchestrate direct and mycorrhizal pathways for nitrate uptake by regulating NAR2.1–NRT2s complexes in rice. PNAS, 122(8), e2416345122. (www)

  @article{ , abstract = {Nitrogen (N) is the most important essential nutrient required by plants. Most land plants have evolved two N uptake pathways, a direct root pathway and a symbiotic pathway, via association with arbuscular mycorrhizal (AM) fungi. However, the interaction between the two pathways is ambiguous. Here, we report that OsNAR2.1–OsNRT2s, the nitrate (NO 3 − ) transporter complexes with crucial roles in direct NO 3 − uptake, are also recruited for symbiotic NO 3 − uptake. OsNAR2.1 and OsNRT2.1/2.2 are coregulated by NIN-like protein 3 (OsNLP3), a key regulator in NO 3 − signaling, and OsPHR2, a major regulator of phosphate starvation responses. More importantly, AM symbiosis induces expression of OsNAR2.1 – OsNRT2s, OsNLP3, and OsSPX4 , encoding an intracellular Pi sensor, in arbuscular-containing cells, but weakens their expression in the epidermis. OsNAR2.1 and OsNLP3 can activate both mycorrhizal NO 3 − uptake and mycorrhization efficiency. Overall, we demonstrate that OsNLP3 and OsPHR2 orchestrate the direct and mycorrhizal NO 3 − uptake pathways by regulating the NAR2.1–NRT2s complexes in rice.}, archive = {J_PNAS}, author = {Wang, Shuangshuang and Ye, Hanghang and Yang, Congfan and Zhang, Yan and Pu, Jiawen and Ren, Yuhan and Xie, Kun and Wang, Lingxiao and Zeng, Dechao and He, Haoqiang and Ji, Haoyan and Herrera-Estrella, Luis Rafael and Xu, Guohua and Chen, Aiqun}, doi = {10.1073/pnas.2416345122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2416345122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {OsNLP3 and OsPHR2 orchestrate direct and mycorrhizal pathways for nitrate uptake by regulating NAR2.1–NRT2s complexes in rice}, volume = {122}, year = {2025}, }
• (2025). Explicitly unbiased large language models still form biased associations. PNAS, 122(8), e2416228122. (www)

  @article{ , abstract = {Large language models (LLMs) can pass explicit social bias tests but still harbor implicit biases, similar to humans who endorse egalitarian beliefs yet exhibit subtle biases. Measuring such implicit biases can be a challenge: As LLMs become increasingly proprietary, it may not be possible to access their embeddings and apply existing bias measures; furthermore, implicit biases are primarily a concern if they affect the actual decisions that these systems make. We address both challenges by introducing two measures: LLM Word Association Test, a prompt-based method for revealing implicit bias; and LLM Relative Decision Test, a strategy to detect subtle discrimination in contextual decisions. Both measures are based on psychological research: LLM Word Association Test adapts the Implicit Association Test, widely used to study the automatic associations between concepts held in human minds; and LLM Relative Decision Test operationalizes psychological results indicating that relative evaluations between two candidates, not absolute evaluations assessing each independently, are more diagnostic of implicit biases. Using these measures, we found pervasive stereotype biases mirroring those in society in 8 value-aligned models across 4 social categories (race, gender, religion, health) in 21 stereotypes (such as race and criminality, race and weapons, gender and science, age and negativity). These prompt-based measures draw from psychology’s long history of research into measuring stereotypes based on purely observable behavior; they expose nuanced biases in proprietary value-aligned LLMs that appear unbiased according to standard benchmarks.}, archive = {J_PNAS}, author = {Bai, Xuechunzi and Wang, Angelina and Sucholutsky, Ilia and Griffiths, Thomas L.}, doi = {10.1073/pnas.2416228122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2416228122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Explicitly unbiased large language models still form biased associations}, volume = {122}, year = {2025}, }
• (2025). A limitation lifted: A conditional knockdown system reveals essential roles for polo-like kinase and aurora kinase 1 in trypanosoma cruzi cell division. PNAS, 122(8), e2416009122. (www)

  @article{ , abstract = {While advances in genome editing technologies have simplified gene disruption in many organisms, the study of essential genes requires development of conditional disruption or knockdown systems that are not available in most organisms. Such is the case for Trypanosoma cruzi , a parasite that causes Chagas disease, a severely neglected tropical disease endemic to Latin America that is often fatal. Our knowledge of the identity of essential genes and their functions in T. cruzi has been severely constrained by historical challenges in very basic genetic manipulation and the absence of RNA interference machinery. Here, we describe the development and use of self-cleaving RNA sequences to conditionally regulate essential gene expression in T. cruzi . Using these tools, we identified essential roles for Polo-like and Aurora kinases in T. cruzi cell division, mirroring their functions in Trypanosoma brucei . Importantly, we demonstrate conditional knockdown of essential genes in intracellular amastigotes, the disease-causing stage of the parasite in its human host. This conditional knockdown system enables the efficient and scalable functional characterization of essential genes in T. cruzi and provides a framework for the development of conditional gene knockdown systems for other nonmodel organisms.}, archive = {J_PNAS}, author = {Wiedeman, Justin and Harrison, Ruby and Etheridge, Ronald Drew}, doi = {10.1073/pnas.2416009122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2416009122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A limitation lifted: A conditional knockdown system reveals essential roles for polo-like kinase and aurora kinase 1 in trypanosoma cruzi cell division}, volume = {122}, year = {2025}, }
• (2025). Mussel-inspired cross-linking mechanisms enhance gelation and adhesion of multifunctional mucin-derived hydrogels. PNAS, 122(8), e2415927122. (www)

  @article{ , abstract = {Mucus supports human health by hydrating, lubricating, and preventing infection of wet epithelial surfaces. The beneficial material properties and bioactivity of mucus stem from glycoproteins called mucins, motivating the development of mucin-derived hydrogels for wound dressings and antifouling coatings. However, these applications require robust gelation and adhesion to a wide range of substrates. Inspired by the chemical cross-linking and water-tolerant adhesion of marine mussel adhesive structures, we use catechol–thiol bonding to drive gelation of native mucin proteins and synthetic mucin-inspired polymers, forming soft, adhesive hydrogels that can be coated onto diverse surfaces. The gelation dynamics and adhesive properties can be systematically tuned by varying the hydrogel composition, polymer architecture, and thiol availability, with gelation timescales adjustable from seconds to hours, and values of elastic modulus, failure stress, and debonding work spanning orders of magnitude. We demonstrate the functionality of these gels in two applications: as tissue adhesives, using porcine skin as a proxy for human skin, and as bioactive surface coatings to prevent bacterial colonization. The results highlight the potential of catechol–thiol cross-linking as a versatile platform for engineering multifunctional glycoprotein hydrogels with applications in wound repair and antimicrobial surface engineering.}, archive = {J_PNAS}, author = {Degen, George D. and Stevens, Corey A. and Cárcamo-Oyarce, Gerardo and Song, Jake and Bej, Raju and Tang, Peng and Ribbeck, Katharina and Haag, Rainer and McKinley, Gareth H.}, doi = {10.1073/pnas.2415927122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2415927122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mussel-inspired cross-linking mechanisms enhance gelation and adhesion of multifunctional mucin-derived hydrogels}, volume = {122}, year = {2025}, }
• (2025). A size-dependent ideal solution model for liquid–solid phase equilibria prediction in aqueous organic solutions. PNAS, 122(8), e2415843122. (www)

  @article{ , abstract = {Predictive synthesis of aqueous organic solutions with desired liquid–solid phase equilibria could drive progress in industrial chemistry, cryopreservation, and beyond, but is limited by the predictive power of current solution thermodynamics models. In particular, few analytical models enable accurate liquidus and eutectic prediction based only on bulk thermodynamic properties of the pure components, requiring instead either direct measurement or costly simulation of solution properties. In this work, we demonstrate that a simple modification to the canonical ideal solution theory accounting for the entropic effects of dissimilar molecule sizes can transform its predictive power. Incorporating a Flory-style entropy of mixing term that includes both the mole and volume fractions of each component, we derive size-dependent equations for the ideal chemical potential and liquidus temperature, and use them to predict the binary phase diagrams of water and 10 organic solutes of varying sizes. We show that size-dependent prediction outperforms the ideal model in all cases, reducing average error in the predicted liquidus temperature by 59% (to 5.6 K), eutectic temperature by 45% (to 9.7 K), and eutectic composition by 43% (to 4.7 mol%), as compared to experimental data. Furthermore, by retaining the ideal assumption that the enthalpy of mixing is zero, we demonstrate that, for aqueous organic solutions, much of the deviation from ideality that is typically attributed to molecular interactions may in fact be explained by simple entropic size effects. These results suggest an underappreciated dominance of mixing entropy in these solutions, and provide a simple approach to predicting their phase equilibria.}, archive = {J_PNAS}, author = {Alliston, Spencer P. and Dames, Chris and Powell-Palm, Matthew J.}, doi = {10.1073/pnas.2415843122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2415843122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A size-dependent ideal solution model for liquid–solid phase equilibria prediction in aqueous organic solutions}, volume = {122}, year = {2025}, }
• (2025). Deep-water corals indicate the red sea survived the last glacial lowstand. PNAS, 122(8), e2415559122. (www)

  @article{ , abstract = {The Red Sea, a nascent ocean basin connected to the Indian Ocean via a shallow strait, is assumed to have experienced significant environmental changes during the last glacial period due to a sea-level drop likely exceeding 110 m. This study investigates the hypothesis that hydrodynamic restriction led to severe ecological impacts, including basin-wide extinction due to elevated salinity followed by a short time of oxygen depletion. Uranium–Thorium dating of deep-water corals (DWCs) from 26 northern Red Sea sites reveals coral growth during and after the Last Glacial sea-level lowstand, indicating tolerable seawater chemistry. Additional geochemical data show no significant difference in Red Sea chemistry or temperature between the Latest Pleistocene and Holocene. A meta-analysis of 27 deep-sea cores reveals that while planktonic foraminifera experienced local extinction, other microfossil groups seemingly persisted. These findings suggest that the Red Sea survived the last sea-level lowstand, challenging the paradigm of a complete ecological collapse and providing insights into the resilience of marine ecosystems.}, archive = {J_PNAS}, author = {Chakraborty, Morgan I. and Sharifi, Arash and Benzoni, Francesca and Tissot, François L. H. and Pourmand, Ali and Taviani, Marco and Howes, Bolton and Swart, Peter K. and Lu, Choajin and Rodrigue, Mattie and Purkis, Sam J.}, doi = {10.1073/pnas.2415559122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2415559122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deep-water corals indicate the red sea survived the last glacial lowstand}, volume = {122}, year = {2025}, }
• (2025). STING-induced noncanonical autophagy regulates endolysosomal homeostasis. PNAS, 122(8), e2415422122. (www)

  @article{ , abstract = {The cGAS–STING pathway mediates innate immune responses to cytosolic DNA. In addition to its well-established role in inducing inflammatory cytokines, activation of the cGAS–STING pathway also induces noncanonical autophagy, a process involving the conjugation of the ATG8 family of ubiquitin-like proteins to membranes of the endolysosomal system. The mechanisms and functions of STING-induced autophagy remain poorly understood. In this study, we demonstrated that STING activation induced formation of pH-elevated Golgi-derived vesicles that led to ATG16L1 and V-ATPase-dependent noncanonical autophagy. We showed that STING-induced noncanonical autophagy resulted in activation of the MiT/TFE family of transcription factors (TFEB, TFE3, and MITF), which regulate lysosome biogenesis. We found that lipidation of the ATG8 proteins, particularly GABARAPs, inhibited phosphorylation of MiT/TFE transcription factors by mTORC1. The lipidated GABARAPs bound to the Folliculin-interacting proteins (FNIPs), thereby sequestering the FNIP-folliculin protein complexes from activating mTORC1, resulting in dephosphorylation and nuclear translocation of MiT/TFE transcription factors. Furthermore, we found that STING-induced autophagy activated Leucine-rich repeat kinase 2 (LRRK2), a protein implicated in Parkinson’s disease, through GABARAPs lipidation. We further showed that STING-induced autophagy induced ALIX-mediated ESCRT machinery recruitment to mitigate endolysosomal perturbation. These results reveal the multifaceted functions of STING-induced noncanonical autophagy in regulating endolysosomal homeostasis.}, archive = {J_PNAS}, author = {Huang, Tuozhi and Sun, Chenglong and Du, Fenghe and Chen, Zhijian J.}, doi = {10.1073/pnas.2415422122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2415422122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {STING-induced noncanonical autophagy regulates endolysosomal homeostasis}, volume = {122}, year = {2025}, }
• (2025). Global diversity and energy of animals shaping the earth’s surface. PNAS, 122(8), e2415104122. (www)

  @article{ , abstract = {The collective influence of animals on the processes shaping the Earth’s surface remains largely unknown, with most studies limited to individual species and well-known exemplars. To establish the global geomorphic significance of animals, we systematically reviewed and synthesized evidence across freshwater and terrestrial ecosystems. Over 600 animal taxa had reported geomorphic effects. For the 495 wild animals and 5 livestock identified to species level, we estimated their global abundance, and collective biomass and energy. While our census is global in scope, a lack of research in the tropics and subtropics, and on less visible animals, leaves them underrepresented in analyses. Most reported species are globally widespread, but some are rare, endemic, and/or threatened, leading to risks that key geomorphic processes cease before we fully understand them. We estimate the collective biomass in wild animal geomorphic agents at ≈0.2 Mt Carbon, equating to a biological energy content of ≈7.6 million GJ. If a conservative minimum 1% of this energy contributes to geomorphic work annually, this yields an energy contribution from wild animal geomorphic agents of ≈76,000 GJ—equivalent to the energy of hundreds of thousands of extreme floods. Uncertainties in biomass estimates and energy partitioning mean this value could credibly be an order of magnitude higher, and countless species remain unreported or undiscovered. The livestock estimates exceed the wild animals estimates by three orders of magnitude. The geomorphic energy of animals is far more influential than previously recognized and future losses, dispersal and introductions of zoogeomorphic species may induce substantive landscape changes.}, archive = {J_PNAS}, author = {Harvey, Gemma L. and Khan, Zareena and Albertson, Lindsey K. and Coombes, Martin and Johnson, Matthew F. and Rice, Stephen P. and Viles, Heather A.}, doi = {10.1073/pnas.2415104122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2415104122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global diversity and energy of animals shaping the earth’s surface}, volume = {122}, year = {2025}, }
• (2025). Poly(ADP-ribose) binding sites on collagen i fibrils for nucleating intrafibrillar bone mineral. PNAS, 122(8), e2414849122. (www)

  @article{ , abstract = {Bone calcification is essential for vertebrate life. The mechanism by which mineral ions are transported into collagen fibrils to induce intrafibrillar mineral formation requires a calcium binding biopolymer that also has highly selective binding to the collagen fibril hole zones where intrafibrillar calcification begins, over other bone extracellular matrix components. Poly(ADP-ribose) (PAR) has been shown to be a candidate biopolymer for this process and we show here that PAR has high affinity, highly conserved binding sites in the collagen type I C-terminal telopeptides. The identification of these PAR–collagen binding sites gives insights into the chemical mechanisms underlying bone calcification and possible mechanisms behind pathologies where there is dysfunctional bone calcification.}, archive = {J_PNAS}, author = {Zecca, Marco A. and Greer, Heather F. and Müller, Karin H. and Duer, Melinda J.}, doi = {10.1073/pnas.2414849122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2414849122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Poly(ADP-ribose) binding sites on collagen i fibrils for nucleating intrafibrillar bone mineral}, volume = {122}, year = {2025}, }
• (2025). Structural requirements of KAI2 ligands for activation of signal transduction. PNAS, 122(8), e2414779122. (www)

  @article{ , abstract = {Karrikin Insensitive 2 (KAI2), identified as the receptor protein for karrikins (KARs), which are smoke-derived seed germination stimulants, belongs to the same α/β-hydrolase family as D14, the receptor for strigolactones (SLs). KAI2 is believed to recognize an endogenous butenolide (KAI2 ligand; KL), but the identity of this compound remains unknown. Recent studies have suggested that ligand hydrolysis by KAI2 is a prerequisite for receptor activation to induce interaction with the target proteins, similar to the situation with D14. However, direct experimental evidence has been lacking. Here, we designed KAI2 ligands (carba-dMGers) whose butenolide rings were modified so that they cannot be hydrolyzed or dissociated from the original ligand molecule by KAI2, by structurally modifying dMGer, a potent and selective KAI2 agonist. Using these dMGer analogs, we found that the strongly bioactive ligand, (+)-dMGer, was hydrolyzed by KAI2 at a lower enzymatic rate compared with the weakly bioactive ligand, (+)-1′-carba-dMGer, and the hydrolyzed butenolide ring of (+)-dMGer was transiently trapped in the catalytic pocket of KAI2. Additionally, structural analysis revealed that (+)-6′-carba-dMGer bound to the catalytic pocket of KAI2 in the unhydrolyzed state. However, this binding did not induce the interaction between KAI2 and SMAX1, indicating that ligand binding to the receptor alone was not sufficient for KAI2 signaling. This study showed experimental data from a ligand structure–activity study that ligand hydrolysis and subsequent covalent adduct formation with the catalytic triad plays a key role in KAI2 activation, providing insight into the chemical structure of the Arabidopsis KL.}, archive = {J_PNAS}, author = {Kushihara, Rito and Nakamura, Akihiko and Takegami, Katsuki and Seto, Yoshiya and Kato, Yusuke and Dohra, Hideo and Ohnishi, Toshiyuki and Todoroki, Yasushi and Takeuchi, Jun}, doi = {10.1073/pnas.2414779122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2414779122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural requirements of KAI2 ligands for activation of signal transduction}, volume = {122}, year = {2025}, }
• (2025). Early colonization of the deep-sea bottom—The protracted build-up of an ecosystem. PNAS, 122(8), e2414752122. (www)

  @article{ , abstract = {Our understanding of the patterns and processes behind the evolution of deep-marine ecosystems is limited because the body-fossil record of the deep sea is poor. However, that gap in knowledge may be filled as deposits are host to diverse and abundant trace fossils that record the activities of benthic deep-marine organisms. Here, we built a global dataset of trace-fossil occurrences from a comprehensive survey of 720 Ediacaran–Devonian units and show that the establishment of a modern-style deep-marine benthic ecosystem was protracted and coincident with global cooling and increase in oxygenation during the Ordovician. The formation of open burrows may have increased bioirrigation in the uppermost sediment zone, promoting ventilation and generating an ecosystem engineering feedback loop between bioturbation and pore-water oxygenation. Sharp changes in deep-marine bioturbation during the Devonian may have originated from oxygen variations resulting from climate-controlled oceanic circulation.}, archive = {J_PNAS}, author = {Buatois, Luis A. and Mángano, M. Gabriela and Paz, Maximiliano and Minter, Nicholas J. and Zhou, Kai}, doi = {10.1073/pnas.2414752122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2414752122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Early colonization of the deep-sea bottom—The protracted build-up of an ecosystem}, volume = {122}, year = {2025}, }
• (2025). Extensive location bias of the GPCR-dependent translatome via site-selective activation of mTOR. PNAS, 122(8), e2414738122. (www)

  @article{ , abstract = {G protein–coupled receptors (GPCRs) modulate various physiological functions by rewiring cellular gene expression in response to extracellular signals. Control of gene expression by GPCRs has been studied almost exclusively at the transcriptional level, neglecting an extensive amount of regulation that takes place translationally. Hence, little is known about the nature and mechanisms of gene-specific posttranscriptional regulation downstream of receptor activation. Here, we apply an unbiased multiomics approach to delineate an extensive translational regulatory program initiated by the prototypical beta2-adrenergic receptor (β2-AR) and provide mechanistic insights into how these processes are orchestrated. Using ribosome profiling (Ribo-seq), we identify nearly 120 gene targets of adrenergic receptor activity for which expression is exclusively regulated at the level of translation. We next show that all translational changes are induced selectively by endosomal β2-ARs and report that this proceeds through activation of the mammalian target of rapamycin (mTOR) pathway. Specifically, within the set of translational GPCR targets, we find significant enrichment of genes with 5’ terminal oligopyrimidine (TOP) motifs, a gene class classically known to be translationally regulated by mTOR. We then demonstrate that endosomal β2-ARs are required for mTOR activation and subsequent mTOR-dependent TOP mRNA translation. This site-selective crosstalk between the pathways is observed in multiple cell models with native β2-ARs, across a range of endogenous and synthetic adrenergic agonists, and for other GPCRs with intracellular activity. Together, this comprehensive analysis of drug-induced translational regulation establishes a critical role for location-biased GPCR signaling in fine-tuning the cellular protein landscape.}, archive = {J_PNAS}, author = {Klauer, Matthew J. and Hall, Katherine L. and Jagla, Caitlin A. D. and Tsvetanova, Nikoleta G.}, doi = {10.1073/pnas.2414738122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2414738122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Extensive location bias of the GPCR-dependent translatome via site-selective activation of mTOR}, volume = {122}, year = {2025}, }
• (2025). Enterobacter hormaechei replaces virulence with carbapenem resistance via porin loss. PNAS, 122(8), e2414315122. (www)

  @article{ , abstract = {Pathogenic Enterobacter species are of increasing clinical concern due to the multidrug-resistant nature of these bacteria, including resistance to carbapenem antibiotics. Our understanding of Enterobacter virulence is limited, hindering the development of new prophylactics and therapeutics targeting infections caused by Enterobacter species. In this study, we assessed the virulence of contemporary clinical Enterobacter hormaechei isolates in a mouse model of intraperitoneal infection and used comparative genomics to identify genes promoting virulence. Through mutagenesis and complementation studies, we found two porin-encoding genes, ompC and ompD , to be required for E. hormaechei virulence. These porins imported clinically relevant carbapenems into the bacteria, and thus loss of OmpC and OmpD desensitized E. hormaechei to the antibiotics. Our genomic analyses suggest porin-related genes are frequently mutated in E. hormaechei , perhaps due to the selective pressure of antibiotic therapy during infection. Despite the importance of OmpC and OmpD during infection of immunocompetent hosts, we found the two porins to be dispensable for virulence in a neutropenic mouse model. Moreover, porin loss provided a fitness advantage during carbapenem treatment in an ex vivo human whole blood model of bacteremia. Our data provide experimental evidence of pathogenic Enterobacter species gaining antibiotic resistance via loss of porins and argue antibiotic therapy during infection of immunocompromised patients is a conducive environment for the selection of porin mutations enhancing the multidrug-resistant profile of these pathogens.}, archive = {J_PNAS}, author = {Perault, Andrew I. and John, Amelia St. and DuMont, Ashley L. and Shopsin, Bo and Pironti, Alejandro and Torres, Victor J.}, doi = {10.1073/pnas.2414315122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2414315122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Enterobacter hormaechei replaces virulence with carbapenem resistance via porin loss}, volume = {122}, year = {2025}, }
• (2025). Fluoride-based hydrogen bond chemistry in a layered double hydroxide cathode toward high-performance aqueous NH4+ storage. PNAS, 122(8), e2414112122. (www)

  @article{ , abstract = {In aqueous ammonium-ion storage, hydrogen bonds play a pivotal role in the reversible insertion/extraction of NH 4 + within transition metal oxides/hydroxides. Although fluorine (F) is known for its strong electronegativity and potential to form robust hydrogen bonds with NH 4 + , its specific influence on NH 4 + storage remains unexplored. Herein, we systematically investigate the effects of F-based hydrogen bond chemistry within a layered double hydroxide matrix, where F species are introduced and subsequently partially removed via an electrochemical method. Our findings demonstrate that while increasing F doping content accelerates NH 4 + diffusion due to F’s strong electronegativity, it also triggers crystal shrinkage and depresses storage capacity. To this end, controlled partial removal of F, employing a lye-assistant electrochemical strategy, induces expanded interlayer spacing and distinct edge lattice tearing, thereby facilitating improved NH 4 + accommodation. The retained F sites couple with emerging exposed O sites maintain a high hydrogen bonding capability, which is further enhanced by the formation of highly active, curved hydroxyl groups centered around F sites. These manipulations significantly boost the NH 4 + storage performance of the electrode, providing insights into leveraging the strongest F-based hydrogen bond chemistry in developing high-performance ammonium-ion energy storage devices.}, archive = {J_PNAS}, author = {Sun, Fang-Fang and Guan, Xinwei and Huang, Zi-Hang and Han, Xu and Li, Hui and Ma, Tianyi}, doi = {10.1073/pnas.2414112122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2414112122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fluoride-based hydrogen bond chemistry in a layered double hydroxide cathode toward high-performance aqueous NH4+ storage}, volume = {122}, year = {2025}, }
• (2025). Resilience of the electric grid through trustable IoT-coordinated assets. PNAS, 122(8), e2413967121. (www)

  @article{ , abstract = {The electricity grid has evolved from a physical system to a cyberphysical system with digital devices that perform measurement, control, communication, computation, and actuation. The increased penetration of distributed energy resources (DERs) including renewable generation, flexible loads, and storage provides extraordinary opportunities for improvements in efficiency and sustainability. However, they can introduce new vulnerabilities in the form of cyberattacks, which can cause significant challenges in ensuring grid resilience. We propose a framework in this paper for achieving grid resilience through suitably coordinated assets including a network of Internet of Things devices. A local electricity market is proposed to identify trustable assets and carry out this coordination. Situational Awareness (SA) of locally available DERs with the ability to inject power or reduce consumption is enabled by the market, together with a monitoring procedure for their trustability and commitment. With this SA, we show that a variety of cyberattacks can be mitigated using local trustable resources without stressing the bulk grid. Multiple demonstrations are carried out using a high-fidelity cosimulation platform, real-time hardware-in-the-loop validation, and a utility-friendly simulator.}, archive = {J_PNAS}, author = {Nair, Vineet J. and Srivastava, Priyank and Venkataramanan, Venkatesh and Sarker, Partha S. and Srivastava, Anurag and Marinovici, Laurentiu D. and Zha, Jun and Irwin, Christopher and Mittal, Prateek and Williams, John and Kumar, Jayant and Poor, H. Vincent and Annaswamy, Anuradha M.}, doi = {10.1073/pnas.2413967121}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2413967121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Resilience of the electric grid through trustable IoT-coordinated assets}, volume = {122}, year = {2025}, }
• (2025). Integrative analysis of KCNQ1 variants reveals molecular mechanisms of type 1 long QT syndrome pathogenesis. PNAS, 122(8), e2412971122. (www)

  @article{ , abstract = {Loss-of-function (LOF) pathogenic variants in KCNQ1 encoding a cardiac potassium channel predispose to sudden cardiac death in type 1 congenital long QT syndrome (LQT1). To determine the spectrum of molecular mechanisms responsible for this life-threatening condition, we used an integrative approach to determine the biophysical, functional, and trafficking properties of 61 KCNQ1 variants distributed throughout all domains of the channel. Impaired trafficking to the plasma membrane was the most common cause of LOF across all channel domains, often but not always coinciding with protein instability. However, many LOF variants, particularly in transmembrane domains, trafficked normally, but when coexpressed with KCNE1 exhibited impaired conductance, altered voltage dependence, or abnormal gating kinetics, highlighting diverse pathogenic mechanisms. This indicates a need for personalized treatment approaches for LQT1. Use of our data to benchmark variant pathogenicity prediction methods demonstrated that prediction accuracy depends on the exact mechanism of pathogenicity associated with a given variant.}, archive = {J_PNAS}, author = {Brewer, Kathryn R. and Vanoye, Carlos G. and Huang, Hui and Clowes Moster, Katherine R. and Desai, Reshma R. and Hayes, James B. and Burnette, Dylan T. and George, Alfred L. and Sanders, Charles R.}, doi = {10.1073/pnas.2412971122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2412971122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Integrative analysis of KCNQ1 variants reveals molecular mechanisms of type 1 long QT syndrome pathogenesis}, volume = {122}, year = {2025}, }
• (2025). Weak individual preferences stabilize culture. PNAS, 122(8), e2412380122. (www)

  @article{ , abstract = {Outcomes in the cultural arena are due to many factors but are there general rules that can suggest what makes some cultural traits successful and others not? Research in cultural evolution theory distinguishes factors related to social influence (such as copying from the majority, or from certain individuals) from factors related to individual, nonsocially influenced, propensities such as evolved cognitive predispositions, or physical, biological, and environmental constraints. Here, we show, using analytical and individual-based models, that individual preferences, even when weak, determine the equilibrium point of cultural dynamics when acting together with nondirectional social influence in three out of four cases we study. The results have implications regarding the importance of keeping into account individual-level, nonsocial, factors, when studying cultural evolution, as well as regarding the interpretation of cross-cultural regularities, that must be expected, but can be product of weak directional forces, intensified by social influence.}, archive = {J_PNAS}, author = {Acerbi, Alberto and de Courson, Benoît}, doi = {10.1073/pnas.2412380122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2412380122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Weak individual preferences stabilize culture}, volume = {122}, year = {2025}, }
• (2025). Urban groundwater supplies facing dual pressures of depletion and contamination in china. PNAS, 122(8), e2412338122. (www)

  @article{ , abstract = {Groundwater is essential to urban water supplies throughout the world, but we do not understand how quantity and quality issues may jeopardize the ability of cities to meet their water needs. Here, we present a national analysis of both quantity and quality challenges facing China’s urban groundwater supply security, using high-resolution groundwater depletion modeling and a recently compiled dataset detailing quality violations in drinking groundwater sources. We estimate that 180 cities (about half of the prefecture-level-and-above cities), accounting for 311 million urban residents, face at least one groundwater pressure between 2016 and 2021. Cities that face dual quantity and quality pressures pinpoints hotspots of intense groundwater threats— Specifically, 40 cities, mainly situated in Northeast China and the middle to lower reaches of the Yellow River, are exposed to dual groundwater pressures. The results highlight the interconnected and possibly mutually reinforcing nature of groundwater depletion and quality issues. The logistic regression models indicate that groundwater depletion and quality violations are associated with natural water endowment and anthropogenic factors. Particularly, drinking groundwater quality issues are clustered in relation to socioeconomic gaps, with larger, wealthier cities being less prone to such problems. We argue that securing drinking water sources in small and poor cities through integrated groundwater management and economic assistance should be an important national priority for achieving groundwater supply sustainability.}, archive = {J_PNAS}, author = {Sun, Siao and Liu, Hui and Konar, Megan and Fu, Guangtao and Fang, Chuanglin and Huang, Zhongwei and Li, Guagndong and Qi, Wei and Tang, Qiuhong}, doi = {10.1073/pnas.2412338122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2412338122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Urban groundwater supplies facing dual pressures of depletion and contamination in china}, volume = {122}, year = {2025}, }
• (2025). PCSK9 potentiates innate immune response to RNA viruses by preventing AIP4-mediated polyubiquitination and degradation of VISA/MAVS. PNAS, 122(8), e2412206122. (www)

  @article{ , abstract = {Upon viral infection, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) detect viral RNA to initiate antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA virus-induced signaling adaptor; also known as mitochondiral antiviral-signaling protein (MAVS). The stability and activity of VISA are tightly regulated by various posttranslational modifications, among which polyubiquitination plays important roles. Various E3 ubiquitin ligases, including atrophin interacting protein 4 (AIP4), mediate polyubiquitination of VISA and result in its degradation. However, how polyubiquitination of VISA is regulated remains unclear. Here, we uncovered a dual function for proprotein convertase subtilisin/kexin type 9 (PCSK9), a key enzyme in cholesterol homeostasis and a well-known therapeutic target in cardiovascular diseases, modulating host responses to RNA viruses both extracellularly and intracellularly. Secreted PCSK9 inhibited sendai virus (SeV) and vesicular stomatitis virus (VSV) infection, while the intracellular PCSK9 potentiated RLRs-mediated interferons (IFNs) induction by stabilizing VISA on mitochondria. Viral infection induced the translocation of PCSK9 to mitochondria where it competed with AIP4 for VISA, thereby inhibiting its polyubiquitination and degradation. Consequently, overexpression of PCSK9 enhanced VISA-mediated innate immune response against RNA viral infection, whereas its deficiency had the opposite effects and resulted in more robust replication of the virus. Pcsk9 −/− mice produced lower levels of type I IFNs and proinflammatory cytokines, rendering the increased sensitivity to VSV and influenza A virus infection. Altogether, our findings uncovered an important and unexpected role of PCSK9 in virus–host interaction and contribute to the understanding of the sophisticated mechanism governing the proper and efficient immune response to viral infection.}, archive = {J_PNAS}, author = {Fang, Han and Shi, Mengling and Wang, Cong and Zhang, Saiting and Kong, Na and Ji, Mengyao and Wang, Yan and Zhou, Yidan and Zhu, Qiyun and Zhang, Yu and Du, Shishen and Xu, Shuai and Lei, Caoqi}, doi = {10.1073/pnas.2412206122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2412206122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PCSK9 potentiates innate immune response to RNA viruses by preventing AIP4-mediated polyubiquitination and degradation of VISA/MAVS}, volume = {122}, year = {2025}, }
• (2025). Learning-based inference of longitudinal image changes: Applications in embryo development, wound healing, and aging brain. PNAS, 122(8), e2411492122. (www)

  @article{ , abstract = {Longitudinal imaging data are routinely acquired for health studies and patient monitoring. A central goal in longitudinal studies is tracking relevant change over time. Traditional methods remove nuisance variation with custom pipelines to focus on significant changes. In this work, we present a machine learning–based method that automatically ignores irrelevant changes and extracts the time-varying signal of interest. Our method, called Learning-based Inference of Longitudinal imAge Changes (LILAC), performs a pairwise comparison of longitudinal images in order to make a temporal difference prediction. LILAC employs a convolutional Siamese architecture to extract feature pairs, followed by subtraction and a bias-free fully connected layer to learn meaningful temporal image differences. We first showcase LILAC’s ability to capture key longitudinal changes by simply training it to predict the temporal ordering of images. In our experiments, temporal ordering accuracy exceeded 0.98, and predicted time differences were strongly correlated with actual changes in relevant variables (Pearson Correlation Coefficient r = 0.911 with embryo phase change, and r = 0.875 with time interval in wound healing). Next, we trained LILAC to explicitly predict specific targets, such as the change in clinical scores in patients with mild cognitive impairment. LILAC models achieved over a 40% reduction in root mean square error compared to baseline methods. Our empirical results demonstrate that LILAC effectively localizes and quantifies relevant individual-level changes in longitudinal imaging data, offering valuable insights for studying temporal mechanisms or guiding clinical decisions.}, archive = {J_PNAS}, author = {Kim, Heejong and Karaman, Batuhan K. and Zhao, Qingyu and Wang, Alan Q. and Sabuncu, Mert R. and null, null and Weiner, Michael and Aisen, Paul and Petersen, Ronald and Jack, Clifford R. and Jagust, William and Landau, Susan and Rivera-Mindt, Monica and Okonkwo, Ozioma and Shaw, Leslie M. and Lee, Edward B. and Toga, Arthur W. and Beckett, Laurel and Harvey, Danielle and Green, Robert C. and Saykin, Andrew J. and Nho, Kwangsik and Perrin, Richard J. and Tosun, Duygu and Sachdev, Pallavi and Drake, Erin and Montine, Tom and Conti, Cat and Weiner, Michael W. and Nosheny, Rachel and Truran Sacrey, Diana and Fockler, Juliet and Miller, Melanie J. and Kwang, Winnie and Jin, Chengshi and Diaz, Adam and Ashford, Miriam and Flenniken, Derek and Kormos, Adrienne and Rafii, Michael and Raman, Rema and Jimenez, Gustavo and Donohue, Michael and Salazar, Jennifer and Fidell, Andrea and Boatwright, Virginia and Robison, Justin and Zimmerman, Caileigh and Cabrera, Yuliana and Walter, Sarah and Clanton, Taylor and Shaffer, Elizabeth and Webb, Caitlin and Hergesheimer, Lindsey and Smith, Stephanie and Ogwang, Sheila and Adegoke, Olusegun and Mahboubi, Payam and Pizzola, Jeremy and Jenkins, Cecily and Saito, Naomi and Hussen, Kedir Adem and Amaza, Hannatu and Thao, Mai Seng and Parkins, Shaniya and Ayo, Omobolanle and Glittenberg, Matt and Hoang, Isabella and Germano, Kaori Kubo and Strong, Joe and Weisensel, Trinity and Magana, Fabiola and Thomas, Lisa and Guzman, Vanessa and Ajayi, Adeyinka and Di Benedetto, Joseph and Talavera, Sandra and Felmlee, Joel and Fox, Nick C. and Thompson, Paul and DeCarli, Charles and Forghanian-Arani, Arvin and Borowski, Bret and Reyes, Calvin and Hedberg, Caitie and Ward, Chad and Schwarz, Christopher and Reyes, Denise and Gunter, Jeff and Moore-Weiss, John and Kantarci, Kejal and Matoush, Leonard and Senjem, Matthew and Vemuri, Prashanthi and Reid, Robert and Malone, Ian and Thomopoulos, Sophia I. and Nir, Talia M. and Jahanshad, Neda and Knaack, Alexander and Fletcher, Evan and Tosun-Turgut, Duygu and Rossi Chen, Stephanie and Choe, Mark and Crawford, Karen and Yushkevich, Paul A. and Das, Sandhitsu and Koeppe, Robert A. and Rabinovici, Gil and Villemagne, Victor and LoPresti, Brian and Morris, John and Franklin, Erin and Bernhardt, Haley and Cairns, Nigel J. and Taylor-Reinwald, Lisa and Shaw, Leslie and Lee, Virginia M.Y. and Korecka, Magdalena and Brylska, Magdalena and Wan, Yang and Trojanowki, J.Q. and Neu, Scott and Foroud, Tatiana M. and Jo, Taeho and Risacher, Shannon L. and Craft, Hannah and Apostolova, Liana G. and Nudelman, Kelly and Faber, Kelley and Potter, Zoë and Lacy, Kaci and Kaddurah-Daouk, Rima and Shen, Li and Karlawish, Jason and Erickson, Claire and Grill, Joshua and Largent, Emily and Harkins, Kristin and Thal, Leon and Kachaturian, Zaven and Frank, Richard and Snyder, Peter J. and Buckholtz, Neil and Hsiao, John K. and Ryan, Laurie and Molchan, Susan and Khachaturian, Zaven and Carrillo, Maria and Potter, William and Barnes, Lisa and Bernard, Marie and González, Hector and Ho, Carole and Jackson, Jonathan and Masliah, Eliezer and Masterman, Donna and Perrin, Richard and Silverberg, Nina and Silbert, Lisa and Kaye, Jeffrey and White, Sylvia and Pierce, Aimee and Thomas, Amy and Clay, Tera and Schwartz, Daniel and Devereux, Gillian and Taylor, Janet and Ryan, Jennifer and Nguyen, Mike and DeCapo, Madison and Shang, Yanan and Schneider, Lon and Munoz, Cynthia and Ferman, Diana and Conant, Carlota and Martin, Katherin and Oleary, Kristin and Pawluczyk, Sonia and Trejo, Elizabeth and Dagerman, Karen and Teodoro, Liberty and Becerra, Mauricio and Fairooz, Madiha and Garrison, Sonia and Boudreau, Julia and Avila, Yair and Brewer, James and Jacobson, Aaron and Gama, Antonio and Kim, Chi and Little, Emily and Frascino, Jennifer and Ferng, Nichol and Trujillo, Socorro and Heidebrink, Judith and Koeppe, Robert and MacDonald, Steven and Malyarenko, Dariya and Ziolkowski, Jaimie and O’Connor, James and Robert, Nicole and Lowe, Suzan and Rogers, Virginia and Clinic, Mayo and Hackenmiller, Barbara and Boeve, Bradley and Albers, Colleen and Kreuger, Connie and Jones, David and Knopman, David and Botha, Hugo and Magnuson, Jessica and Graff-Radford, Jonathan and Crawley, Kerry and Schumacher, Michael and McKinzie, Sanna and Smith, Steven and Helland, Tascha and Lowe, Val and Ramanan, Vijay and Pavlik, Valory and Faircloth, Jacob and Bishop, Jeffrey and Nath, Jessica and Chaudhary, Maria and Kataki, Maria and Yu, Melissa and Pacini, Nathiel and Barker, Randall and Brooks, Regan and Aggarwal, Ruchi and Honig, Lawrence and Stern, Yaakov and Mintz, Akiva and Cordona, Jonathan and Hernandez, Michelle and Long, Justin and Arnold, Abbey and Groves, Alex and Middleton, Anna and Vogler, Blake and McCurry, Cierra and Mayo, Connie and Raji, Cyrus and Amtashar, Fatima S. and Klemp, Heather and Ruszkiewicz, James and Kusuran, Jasmina and Stewart, Jasmine and Horenkamp, Jennifer and Greeson, Julia and Wever, Kara and Vo, Katie and Larkin, Kelly and Rao, Lesley and Schoolcraft, Lisa and Gallagher, Lora and Paczynski, Madeline and McMillan, Maureen and Holt, Michael and Gagliano, Nicole and Henson, Rachel and LaBarge, Renee and Swarm, Robert and Munie, Sarah and Cepeda, Serena and Winterton, Stacey and Hegedus, Stephen and Wilson, TaNisha and Harte, Tanya and Bonacorsi, Zach and Geldmacher, David and Watkins, Amber and Barger, Brandi and Smelser, Bryan and Bates, Charna and Stover, Cynthia and McKinley, Emily and Ikner, Gregory and Hendrix, Haley and Cooper, Harold Matthew and Mahaffey, Jennifer and Booth Robbins, Lindsey and Brown Ashley, Loren and Natelson-Love, Marissa and Carter, Princess and Solomon, Veronika and Grossman, Hillel and Groome, Alexandra and Ardolino, Allison and Kaplan, Anthony and Sheppard, Faye and Burgos-Rivera, Genesis and Garcia-Camilo, Gina and Lim, Joanne and Neugroschl, Judith and Jackson, Kimberly and Evans, Kirsten and Soleimani, Laili and Sano, Mary and Ghesani, Nasrin and Binder, Sarah and Apuango, Xiomara Mendoza and Sood, Ajay and Troutman, Amelia and Blanchard, Kimberly and Richards, Arlene and Nelson, Grace and Hendrickson, Kirsten and Yurko, Erin and Plenge, Jamie and Rufo, Victoria and Shah, Raj and Duara, Ranjan and Lynch, Brendan and Chirinos, Cesar and Dittrich, Christine and Campbell, Debbie and Mejia, Diego and Perez, Gilberto and Colvee, Helena and Gonzalez, Joanna and Gondrez, Josalen and Knaack, Joshua and Acevedo, Mara and Cereijo, Maria and Greig-Custo, Maria and Villar, Michelle and Wishnia, Morris and Detling, Sheryl and Barker, Warren and Albert, Marilyn and Moghekar, Abhay and Rodzon, Barbara and Demsky, Corey and Pontone, Gregory and Pekar, Jim and Farrington, Leonie and Pomper, Martin and Johnson, Nicole and Alo, Tolulope and Sadowski, Martin and Ulysse, Anaztasia and Masurkar, Arjun and Marti, Brittany and Mossa, David and Geesey, Emilie and Petrocca, Emily and Schulze, Evan and Wong, Jennifer and Boonsiri, Joseph and Kenowsky, Sunnie and Martinez, Tatianne and Briglall, Veronica and Doraiswamy, P. Murali and Nwosu, Adaora and Adhikari, Alisa and Hellegers, Cammie and Petrella, Jeffrey and James, Olga and Wong, Terence and Hawk, Thomas and Vaishnavi, Sanjeev and McCoubrey, Hannah and Nasrallah, Ilya and Rovere, Rachel and Maneval, Jeffrey and Robinson, Elizabeth and Rivera, Francisco and Uffelman, Jade and Combs, Martha and O’Donnell, Patricia and Manning, Sara and King, Richard and Nieto, Alayne and Glueck, Amanda and Mandal, Anjana and Swain, Audrie and Gamble, Bethanie and Meacham, Beverly and Forenback, Denece and Ross, Dorothy and Cheatham, Elizabeth and Hartman, Ellen and Cornell, Gary and Harp, Jordan and Ashe, Laura and Goins, Laura and Watts, Linda and Yazell, Morgan and Mandal, Prabin and Buckler, Regan and Vincent, Sylvia and Rudd, Triana and Lopez, Oscar and Malia, Ann Arlene and Chiado, Caitlin and Zik, Cary and Savage, Kathleen and Fenice, Linda and Oakley, MaryAnn and Tacey, Paige C and Berman, Sarah and Bowser, Sarah and Saganis, Xanthia and Porsteinsson, Anton and Mathewson, Abigail and Widman, Asa and Holvey, Bridget and Clark, Emily and Morales, Esmeralda and Young, Iris and Hopkins, Kevin and Martin, Kimberly and Kowalski, Nancy and Hunt, Rebecca and Calzavara, Roberta and Kurvach, Russell and D’Ambrosio, Stephen and Thai, Gaby and Vides, Beatriz and Lieb, Brigit and McAdams-Ortiz, Catherine and Toso, Cyndy and Mares, Ivan and Moorlach, Kathryn and Liu, Luter and Corona, Maria and Nguyen, Mary and Tallakson, Melanie and McDonnell, Michelle and Rangel, Milagros and Basheer, Neetha and Place, Patricia and Romero, Romina and Tam, Steven and Nguyen, Trung and Thomas, Abey and Frolov, Alexander and Khera, Alka and Browning, Amy and Kelley, Brendan and Dawson, Courtney and Mathews, Dana and Most, Elaine and Phillips, Elizeva and Nguyen, Lynn and Nunez, Maribel and Miller, Matalin and Jones, Matthew R. and Martinez, Natalie and Logan, Rebecca and McColl, Roderick and Pham, Sari and Fox, Tiffani and Moore, Tracey and Levey, Allan and Brown, Abby and Kippels, Andrea and Ellison, Ashton and Lyons, Casie and Hales, Chadwick and Parry, Cindy and Williams, Courtney and McCorkle, Elizabeth and Harris, Guy and Rose, Heather and Jooma, Inara and Al-Amin, Jahmila and Lah, James and Webster, James and Swiniarski, Jessica and Chapman, Latasha and Donnelly, Laura and Mariotti, Lauren and Locke, Mary and Vaughn, Phyllis and Penn, Rachael and Carpentier, Sallie and Yeboah, Samira and Basadre, Sarah and Malakauskas, Sarah and Lyron, Stefka and Villinger, Tara and Burney, Terra and Burns, Jeffrey and Abusalim, Ala and Dahlgren, Alexandra and Montero, Alexandria and Arthur, Anne and Dooly, Heather and Kreszyn, Katelynn and Berner, Katherine and Gillen, Lindsey and Scanlan, Maria and Madison, Mercedes and Mathis, Nicole and Switzer, Phyllis and Townley, Ryan and Fikru, Samantha and Sullivan, Samantha and Wright, Ella and Beigi, Maryam and Daley, Anthony and Ko, Ashley and Luong, Brittney and Nyborg, Glen and Morales, Jessica and Durbin, Kelly and Garcia, Lauren and Parand, Leila and Macias, Lorena and Monserratt, Lorena and Farchi, Maya and Wu, Pauline and Hernandez, Robert and Rodriguez, Thao and Graff-Radford, Neill and Marolt, A’llana and Thomas, Anton and Aloszka, Deborah and Moncayo, Ercilia and Westerhold, Erin and Day, Gregory and Chrestensen, Kandise and Imhansiemhonehi, Mary and Stephens, Sochenda and Grant, Sylvia and Brosch, Jared and Perkins, Amy and Saunders, Aubree and Kovac, Debra Silberberg and Polson, Heather and Mwaura, Isabell and Mejia, Kassandra and Britt, Katherine and King, Kathy and Nichols, Kayla and Lawrence, Kayley and Rankin, Lisa and Farlow, Martin and Wiesenauer, Patricia and Bryant, Robert and Herring, Scott and Lynch, Sheryl and Wilson, Skylar and Day, Traci and Korst, William and van Dyck, Christopher and Mecca, Adam and Miller, Alyssa and Brennan, Amanda and Khan, Amber and Ruan, Audrey and Gunnoud, Carol and Mendonca, Chelsea and Raynes-Goldfinger, Danielle and Salardini, Elaheh and Hidalgo, Elisa and Cooper, Emma and Singh, Erawadi and Murphy, Erin and May, Jeanine and Stanhope, Jesse and Lam, Jessica and Waszak, Julia and Nelsen, Kimberly and Sacaza, Kimberly and Hasbani, Mayer Joshua and Donahue, Meghan and Chen, Ming-Kai and Barcelos, Nicole and Eigenberger, Paul and Bonomi, Robin and O’Dell, Ryan and Jefferson, Sarah and Khasnavis, Siddharth and Smilowitz, Stephen and DeStefano, Susan and Good, Susan and Camarro, Terry and Clayton, Vanessa and Cavrel, Yanis and Lu, YuQuan and Chertkow, Howard and Bergman, Howard and Hosein, Chris and Black, Sandra and Kapadia, Anish and Bhan, Aparna and Lam, Benjamin and Scott, Christopher and Gabriel, Gillian and Bray, Jennifer and Zotovic, Ljubica and Gutierrez, Maria Samira and Masellis, Mario and Farshadi, Marjan and Gui, Maurylette and Mitchell, Meghan and Taylor, Rebecca and Endre, Ruby and Taghi-Zada, Zhala and Hsiung, Robin and English, Carolyn and Kim, Ellen and Yau, Eugene and Tong, Haley and Barlow, Laura and Jennings, Lauren and Assaly, Michele and Nunes, Paula and Marian, Tahlee and Kertesz, Andrew and Rogers, John and Trost, Dick and Wint, Dylan and Bernick, Charles and Munic, Donna and Grant, Ian and Korkoyah, Aaliyah and Raja, Ali and Lapins, Allison and Ryan, Caila and Pejic, Jelena and Basham, Kailey and Lukose, Leena and Haddad, Loreece and Quinlan, Lucas and Houghtaling, Nathaniel and Sadowsky, Carl and Martinez, Walter and Villena, Teresa and Reynolds, Brigid and Forero, Angelica and Ward, Carolyn and Brennan, Emma and Figueroa, Esteban and Esposito, Giuseppe and Mallory, Jessica and Johnson, Kathleen and Turner, Kathryn and Seidenberg, Katie and McCann, Kelly and Bassett, Margaret and Chadwick, Melanie and Turner, Raymond Scott and Bean, Robin and Sharma, Saurabh and Marshall, Gad and Haviari, Aferdita and Pietras, Alison and Wallace, Bradley and Munro, Catherine and Rivera-Delpin, Gladiliz and Hustead, Hadley and Levesque, Isabella and Ramirez, Jennifer and Nolan, Karen and Glennon, Kirsten and Palou, Mariana and Erkkinen, Michael and DaSilva, Nicole and Friedman, Pamela and Silver, Regina M. and Salazar, Ricardo and Polleys, Roxxanne and McGinnis, Scott and Gale, Seth and Hall, Tia and Luu, Tuan and Chao, Steven and Lin, Emmeline and Coleman, Jaila and Epperson, Kevin and Vasanawala, Minal and Atri, Alireza and Rangel, Amy and Evans, Brittani and Monarrez, Candy and Cline, Carol and Liebsack, Carolyn and Bandy, Daniel and Goldfarb, Danielle and Intorcia, Debbie and Olgin, Jennifer and Clark, Kelly and King, Kelsey and York, Kylee and Reade, Marina and Callan, Michael and Glass, Michael and Johnson, Michaela and Gutierrez, Michele and Goddard, Molly and Trncic, Nadira and Choudhury, Parichita and Reyes, Priscilla and Lowery, Serena and Hall, Shaundra and Olgin, Sonia and de Santiago, Stephanie and Alosco, Michael and Ton, Alyssa and Jimenez, Amanda and Ellison, Andrew and Tran, Anh and Anderson, Brandon and Carter, Della and Veronelli, Donna and Lenio, Steven and Steinberg, Eric and Mez, Jesse and Weller, Jason and Johns, Jennifer and Harkins, Jessica and Puleio, Alexa and Hoti, Ina and Mwicigi, Jane and Schultz, Olivia and Lauture, Mona and Denis, Ridiane and Killiany, Ronald and Singh, Sarab and Qiu, Wendy and Devis, Ycar and Obisesan, Thomas and Stone, Andrew and Ordor, Debra and Udodong, Ifreke and Okonkwo, Immaculata and Khan, Javed and Turner, Jillian and Hughes, Kyliah and Kadiri, Oshoze and Duffy, Charles and Moss, Ariana and Stapleton, Katherine and Toth, Maria and Sanders, Marianne and Ayres, Martin and Hamski, Melissa and Fatica, Parianne and Ogrocki, Paula and Ash, Sarah and Pot, Stacy and Chen, Doris and Soto, Andres and Tanase, Costin and Bissig, David and Vanya, Hafsanoor and Russell, Heather and Patel, Hitesh and Zhang, Hongzheng and Wallace, Kelly and Ayers, Kristi and Gallegos, Maria and Forloines, Martha and Sinn, Meghan and Kahulugan, Queennie Majorie S and Isip, Richard and Calderon, Sandra and Hamm, Talia and Borrie, Michael and Lee, T-Y and Bartha, Rob and Johnson, Sterling and Asthana, Sanjay and Carlsson, Cynthia M. and Perrin, Allison and Tariot, Pierre and Fleisher, Adam and Reeder, Stephanie and Capote, Horacio and Emborsky, Allison and Mattle, Anna and Ajtai, Bela and Wagner, Benjamin and Myers, Bennett and Slazyk, Daryn and Fragale, Delaney and Fransen, Erin and Macnamara, Heather and Falletta, Jonathan and Hirtreiter, Joseph and Mechtler, Laszlo and King, Megan and Asbach, Michael and Rainka, Michelle and Zawislak, Richard and Wisniewski, Scott and O’Malley, Stephanie and Jimenez-Knight, Tatiana and Peehler, Todd and Aladeen, Traci and Bates, Vernice and Wenner, Violet and Elmalik, Wisam and Scharre, Douglas W. and Ramamurthy, Arun and Bouchachi, Soumya and Tarawneh, Rawan and Celmins, Dzintra and Leader, Alicia and Figueroa, Chris and Bauerle, Heather and Patterson, Katlynn and Reposa, Michael and Presto, Steven and Ahmed, Tuba and Stewart, Wendy and Hosp, Hartford and Pearlson, Godfrey D. and Blank, Karen and Anderson, Karen and Santulli, Robert B. and Schwartz, Eben S. and Williamson, Jeff and Jessup, Alicia and Williams, Andrea and Duncan, Crystal and O’Connell, Abigail and Gagnon, Karen and Zamora, Ezequiel and Bateman, James and Crawford, Freda and Thompson, Deb and Walker, Eboni and Rowell, Jennifer and White, Mikell and Ledford, Phillip and Bohlman, Sarah and Henkle, Susan and Bottoms, Joseph and Moretz, Lena and Hoover, Bevan and Shannon, Michael and Rogers, Samantha and Baker, Wendy and Harrison, William and Wu, Chuang-Kuo and DeMarco, Alexis and Stipanovich, Ava and Arcuri, Daniel and Clark, Jan and Davis, Jennifer and Doyon, Kerstin and Amoyaw, Marie and Acosta, Mauro Veras and Bailey, Ronald and Warren, Scott and Fogerty, Terry and Sanborn, Victoria and Riddle, Meghan and Salloway, Stephen and Malloy, Paul and Correia, Stephen and Windon, Charles and Blackburn, Morgan and Rosen, Howard J. and Miller, Bruce L. and Smith, Amanda and Mba, Ijeoma and Echevarria, Jenny and Janavs, Juris and Roglaski, Emily and Yong, Meagan and Devine, Rebecca and Okhravi, Hamid and Rivera, Edgardo and Kalowsky, Teresa and Smith, Caroline and Rosario, Christina and Masdeu, Joseph and Le, Richard and Gurung, Maushami and Sabbagh, Marwan and Garcia, Angelica and Ellis Slaughter, Micah and Elayan, Nadeen and Acothley, Skieff and Pomara, Nunzio and Hernando, Raymundo and Pomara, Vita and Reichert, Chelsea and Brawman-Mintzer, Olga and Acree, Allison and Williams, Arthur and Long, Campbell and Long, Rebecca and Newhouse, Paul and Hill, Sydni Jenee and Boegel, Amy and Seshadri, Sudha and Saklad, Amy and Jones, Floyd and Hu, William and Sotelo, V. and Gonazalez Rojas, Yaneicy and Mintzer, Jacobo and Flynn Longmire, Crystal and Spicer, Kenneth}, doi = {10.1073/pnas.2411492122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2411492122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Learning-based inference of longitudinal image changes: Applications in embryo development, wound healing, and aging brain}, volume = {122}, year = {2025}, }
• (2025). Temporal autocorrelation is predictive of age—An extensive MEG time-series analysis. PNAS, 122(8), e2411098122. (www)

  @article{ , abstract = {Understanding the evolving dynamics of the brain throughout life is pivotal for anticipating and evaluating individual health. While previous research has described age effects on spectral properties of neural signals, it remains unclear which ones are most indicative of age-related processes. This study addresses this gap by analyzing resting-state data obtained from magnetoencephalography (MEG) in 350 adults (18 to 88 y). We employed advanced time-series analysis at the brain region level and machine learning to predict age. While traditional spectral features achieved low to moderate accuracy, over a hundred time-series features proved superior. Notably, temporal autocorrelation (AC) emerged as the most robust predictor of age. Distinct patterns of AC within the visual and temporal cortex were most informative, offering a versatile measure of age-related signal changes for comprehensive health assessments based on brain activity.}, archive = {J_PNAS}, author = {Stier, Christina and Balestrieri, Elio and Fehring, Jana and Focke, Niels K. and Wollbrink, Andreas and Dannlowski, Udo and Gross, Joachim}, doi = {10.1073/pnas.2411098122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2411098122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Temporal autocorrelation is predictive of age—An extensive MEG time-series analysis}, volume = {122}, year = {2025}, }
• (2025). Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of the influenza a virus. PNAS, 122(8), e2410813122. (www)

  @article{ , abstract = {Viral proteins frequently mutate to evade host innate immune responses, yet the impact of these mutations on the molecular energy landscape remains unclear. Epistasis, the intramolecular communications between mutations, often renders the combined mutational effects unpredictable. Nonstructural protein 1 (NS1) is a major virulence factor of the influenza A virus (IAV) that activates host PI3K by binding to its p85β subunit. Here, we present a deep analysis of the impact of evolutionary mutations in NS1 that emerged between the 1918 pandemic IAV strain and its descendant PR8 strain. Our analysis reveals how the mutations rewired interresidue communications, which underlie long-range allosteric and epistatic networks in NS1. Our findings show that PR8 NS1 binds to p85β with approximately 10-fold greater affinity than 1918 NS1 due to allosteric mutational effects, which are further tuned by epistasis. NMR chemical shift perturbation and methyl-axis order parameter analyses revealed that the mutations induced long-range structural and dynamic changes in PR8 NS1, relative to 1918 NS1, enhancing its affinity to p85β. Complementary molecular dynamics simulations and graph theory-based network analysis for conformational dynamics on the submicrosecond timescales uncover how these mutations rewire the dynamic network, which underlies the allosteric epistasis. Significantly, we find that conformational dynamics of residues with high betweenness centrality play a crucial role in communications between network communities and are highly conserved across influenza A virus evolution. These findings advance our mechanistic understanding of the allosteric and epistatic communications between distant residues and provide insight into their role in the molecular evolution of NS1.}, archive = {J_PNAS}, author = {Gonzales, James E. and Kim, Iktae and Bastiray, Abhishek and Hwang, Wonmuk and Cho, Jae-Hyun}, doi = {10.1073/pnas.2410813122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2410813122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of the influenza a virus}, volume = {122}, year = {2025}, }
• (2025). GABAergic synapses between auditory efferent neurons and type II spiral ganglion afferent neurons in the mouse cochlea. PNAS, 122(8), e2409921122. (www)

  @article{ , abstract = {Cochlear outer hair cells (OHCs) are electromotile and implicated in amplification of responses to sound that enhance sound sensitivity and frequency tuning. They send afferent information through glutamatergic synapses onto type II spiral ganglion neurons (SGNs). These synapses are weaker than those from cochlear inner hair cells onto type I SGN, suggesting that type II SGNs respond only to intense sound levels. OHCs also receive efferent innervation from medial olivocochlear (MOC) neurons. MOC neurons are cholinergic yet inhibit OHCs due to the functional coupling of alpha9/alpha10 nicotinic acetylcholine receptors (nAChRs) to calcium-activated SK potassium channels. The resulting hyperpolarization reduces OHC activity-evoked electromotility and is implicated in cochlear gain control, protection against acoustic trauma, and attention. MOC neurons also label for markers of GABA and GABA synthesis. GABA B autoreceptor (GABA B R) activation on MOC terminals has been demonstrated to reduce ACh release, confirming important negative feedback roles. However, the full complement of GABAergic activity in the cochlea is not currently understood, including mechanisms of GABA release from MOC axons, whether GABA diffuses from MOC axons to other postsynaptic cells, and the location and function of GABA A receptors (GABA A Rs). We used optical neurotransmitter detection, immunohistochemistry, and patch-clamp electrophysiology to demonstrate that in addition to presynaptic GABA B autoreceptor activation, MOC efferent terminals release GABA onto type II SGN afferent dendrites with postsynaptic activity mediated by GABA A Rs. This synapse may have roles including developmental regulation of cochlear innervation, fine-tuning of OHC activity, or providing feedback to the brain about MOC and OHC activity.}, archive = {J_PNAS}, author = {Bachman, Julia L. and Kitcher, Siân R. and Vattino, Lucas G. and Beaulac, Holly J. and Chaves, M. Grace and Hernandez Rivera, Israel and Katz, Eleonora and Wedemeyer, Carolina and Weisz, Catherine J. C.}, doi = {10.1073/pnas.2409921122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2409921122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {GABAergic synapses between auditory efferent neurons and type II spiral ganglion afferent neurons in the mouse cochlea}, volume = {122}, year = {2025}, }
• (2025). Independent effects of the human circadian system and sleep/eating cycles on caloric intake in adolescents vary by weight status. PNAS, 122(8), e2407907122. (www)

  @article{ , abstract = {Late-day eating is linked to increased obesity risk; however, whether the endogenous circadian system independently influences caloric intake and if this control differs among individuals based on weight status is unknown. Here, we investigated in adolescents the independent roles of the endogenous circadian system and of the behavioral sleep/wake cycle (sleep/wake, fasting/eating, rest/activity, dark/dim light, social interaction, posture, etc.) on self-selected caloric intake using a Forced Desynchrony protocol. Fifty-one male and female adolescents across three weight status categories (24 with healthy weight, 13 with overweight, and 14 with obesity) completed the protocol where participants lived on seven 28-h sleep/wake cycles in dim light during wake and complete darkness during sleep. Results suggest that the circadian system and the behavioral cycle each affected caloric intake, with a decrease across the wake episode and an increase from circadian morning to circadian evening in caloric intake. The endogenous circadian rhythm in caloric intake showed a circadian peak-to-trough difference of 196 [CI 95% 164, 226] kcal per meal with peak timing of 296° [288°, 304°; equivalent to ~17:30 in these participants]. In those with overweight/obesity, more calories were consumed later in the waking episode and later in the circadian cycle, and with blunted amplitudes compared to those with healthy weight. Results implicate both the endogenous circadian system and the behavioral cycle in shaping the daily rhythm of food intake. Furthermore, these results help explain the increased drive for caloric intake toward the evening, especially in those at risk for obesity.}, archive = {J_PNAS}, author = {Barker, David H. and Carskadon, Mary A. and Gredvig-Ardito, Caroline and Hart, Chantelle N. and Raynor, Hollie A. and Scheer, Frank A. J. L.}, doi = {10.1073/pnas.2407907122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2407907122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Independent effects of the human circadian system and sleep/eating cycles on caloric intake in adolescents vary by weight status}, volume = {122}, year = {2025}, }
• (2025). A bacterial effector manipulates host lysosomal protease activity–dependent plasticity in cell death modalities to facilitate infection. PNAS, 122(8), e2406715122. (www)

  @article{ , abstract = {Crosstalk between cell death programs confers appropriate host anti-infection immune responses, but how pathogens co-opt host molecular switches of cell death pathways to reprogram cell death modalities for facilitating infection remains largely unexplored. Here, we identify mammalian cell entry 3C (Mce3C) as a pathogenic cell death regulator secreted by Mycobacterium tuberculosis (Mtb), which causes tuberculosis featured with lung inflammation and necrosis. Mce3C binds host cathepsin B (CTSB), a noncaspase protease acting as a lysosome-derived molecular determinant of cell death modalities, to inhibit its protease activity toward BH3-interacting domain death agonist (BID) and receptor-interacting protein kinase 1 (RIPK1), thereby preventing the production of proapoptotic truncated BID (tBID) while maintaining the abundance of pronecroptotic RIPK1. Disrupting the Mce3C–CTSB interaction promotes host apoptosis while suppressing necroptosis with attenuated Mtb survival and mitigated lung immunopathology in mice. Thus, pathogens manipulate host lysosomal protease activity–dependent plasticity in cell death modalities to promote infection and pathogenicity.}, archive = {J_PNAS}, author = {Lu, Zhe and Zhang, Yong and Zhong, Yanzhao and Qiang, Lihua and Ge, Pupu and Lei, Zehui and Zhao, Mengyuan and Fang, Yingxu and Li, Bingxi and Wang, Jing and Chai, Qiyao and Liu, Cui Hua}, doi = {10.1073/pnas.2406715122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2406715122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A bacterial effector manipulates host lysosomal protease activity–dependent plasticity in cell death modalities to facilitate infection}, volume = {122}, year = {2025}, }
• (2025). Volumetric imaging of the 3D orientation of cellular structures with a polarized fluorescence light-sheet microscope. PNAS, 122(8), e2406679122. (www)

  @article{ , abstract = {Polarized fluorescence microscopy is a valuable tool for measuring molecular orientations in biological samples, but techniques for recovering three-dimensional orientations and positions of fluorescent ensembles are limited. We report a polarized dual-view light-sheet system for determining the diffraction-limited three-dimensional distribution of the orientations and positions of ensembles of fluorescent dipoles that label biological structures. We share a set of visualization, histogram, and profiling tools for interpreting these positions and orientations. We model the distributions based on the polarization-dependent efficiency of excitation and detection of emitted fluorescence, using coarse-grained representations we call orientation distribution functions (ODFs). We apply ODFs to create physics-informed models of image formation with spatio-angular point-spread and transfer functions. We use theory and experiment to conclude that light-sheet tilting is a necessary part of our design for recovering all three-dimensional orientations. We use our system to extend known two-dimensional results to three dimensions in FM1-43-labeled giant unilamellar vesicles, fast-scarlet-labeled cellulose in xylem cells, and phalloidin-labeled actin in U2OS cells. Additionally, we observe phalloidin-labeled actin in mouse fibroblasts grown on grids of labeled nanowires and identify correlations between local actin alignment and global cell-scale orientation, indicating cellular coordination across length scales.}, archive = {J_PNAS}, author = {Chandler, Talon and Guo, Min and Su, Yijun and Chen, Jiji and Wu, Yicong and Liu, Junyu and Agashe, Atharva and Fischer, Robert S. and Mehta, Shalin B. and Kumar, Abhishek and Baskin, Tobias I. and Jaumouillé, Valentin and Liu, Huafeng and Swaminathan, Vinay and Nain, Amrinder S. and Oldenbourg, Rudolf and La Riviere, Patrick J. and Shroff, Hari}, doi = {10.1073/pnas.2406679122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2406679122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Volumetric imaging of the 3D orientation of cellular structures with a polarized fluorescence light-sheet microscope}, volume = {122}, year = {2025}, }
• (2025). A binary trait model reveals the fitness effects of HIV-1 escape from t cell responses. PNAS, 122(8), e2405379122. (www)

  @article{ , abstract = {Natural selection often acts on multiple traits simultaneously. For example, the virus HIV-1 faces pressure to evade host immunity while also preserving replicative fitness. While past work has studied selection during HIV-1 evolution, as in other examples where selection acts on multiple traits, it is challenging to quantitatively separate different contributions to fitness. This task is made more difficult because a single mutation can affect both immune escape and replication. Here, we develop an evolutionary model that disentangles the effects of escaping CD8 + T cell–mediated immunity, which we model as a binary trait, from other contributions to fitness. After validation in simulations, we applied this model to study within-host HIV-1 evolution in a clinical dataset. We observed strong selection for immune escape, sometimes greatly exceeding past estimates, especially early in infection. Conservative estimates suggest that roughly half of HIV-1 fitness gains during the first months to years of infection can be attributed to T cell escape. Our approach is not limited to HIV-1 or viruses and could be adapted to study the evolution of quantitative traits in other contexts.}, archive = {J_PNAS}, author = {Gao, Yirui and Barton, John P.}, doi = {10.1073/pnas.2405379122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2405379122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A binary trait model reveals the fitness effects of HIV-1 escape from t cell responses}, volume = {122}, year = {2025}, }
• (2025). Toward equitable major histocompatibility complex binding predictions. PNAS, 122(8), e2405106122. (www)

  @article{ , abstract = {Deep learning tools that predict peptide binding by major histocompatibility complex (MHC) proteins play an essential role in developing personalized cancer immunotherapies and vaccines. In order to ensure equitable health outcomes from their application, MHC binding prediction methods must work well across the vast landscape of MHC alleles observed across human populations. Here, we show that there are alarming disparities across individuals in different racial and ethnic groups in how much binding data are associated with their MHC alleles. We introduce a machine learning framework to assess the impact of this data imbalance for predicting binding for any given MHC allele, and apply it to develop a state-of-the-art MHC binding prediction model that additionally provides per-allele performance estimates. We demonstrate that our MHC binding model successfully mitigates much of the data disparities observed across racial groups. To address remaining inequities, we devise an algorithmic strategy for targeted data collection. Our work lays the foundation for further development of equitable MHC binding models for use in personalized immunotherapies.}, archive = {J_PNAS}, author = {Glynn, Eric and Ghersi, Dario and Singh, Mona}, doi = {10.1073/pnas.2405106122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2405106122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Toward equitable major histocompatibility complex binding predictions}, volume = {122}, year = {2025}, }
• (2025). Hypothalamic opsin 3 suppresses MC4R signaling and potentiates kir7.1 to promote food consumption. PNAS, 122(8), e2403891122. (www)

  @article{ , abstract = {Mammalian opsin 3 (OPN3) is a member of the opsin family of G-protein-coupled receptors with ambiguous light sensitivity. OPN3 was first identified in the brain (and named encephalopsin) and subsequently found to be expressed in other tissues. In adipocytes, OPN3 is necessary for light responses that modulate lipolysis and glucose uptake, while OPN3 in human skin melanocytes regulates pigmentation in a light-independent manner. Despite its initial discovery in the brain, OPN3 functional mechanisms in the brain remain elusive. Here, we investigated the molecular mechanism of OPN3 function in the paraventricular nucleus (PVN) of the hypothalamus. We show that Opn3 is coexpressed with the melanocortin 4 receptor ( Mc4r ) in a population of PVN neurons, where it negatively regulates MC4R-mediated cAMP signaling in a specific and Gα i/o -dependent manner. Under baseline conditions, OPN3 via Gα i/o potentiates the activity of the inward rectifying Kir7.1 channel, previously shown to be closed in response to agonist-mediated activation of MC4R in a Gα s -independent manner. In mice, we found that Opn3 in Mc4r -expressing neurons regulates food consumption. Our results reveal the first mechanistic insight into OPN3 function in the hypothalamus, uncovering a unique mechanism by which OPN3 functions to potentiate Kir7.1 activity and negatively regulate MC4R-mediated cAMP signaling, thereby promoting food intake.}, archive = {J_PNAS}, author = {Haddad, Hala K. and Mercado-Reyes, Jonathan I. and Mustafá, E. Román and D’Souza, Shane P. and Chung, C. Sean and Nestor, Ramses R. M. and Olinski, Lauren E. and Martinez Damonte, Valentina and Saskin, Joshua and Vemaraju, Shruti and Raingo, Jesica and Kauer, Julie A. and Lang, Richard A. and Oancea, Elena}, doi = {10.1073/pnas.2403891122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2403891122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hypothalamic opsin 3 suppresses MC4R signaling and potentiates kir7.1 to promote food consumption}, volume = {122}, year = {2025}, }
• (2025). Control of flow behavior in complex fluids using automatic differentiation. PNAS, 122(8), e2403644122. (www)

  @article{ , abstract = {Inverse design of complex flows is notoriously challenging because of the high cost of high dimensional optimization. Usually, optimization problems are either restricted to few control parameters, or adjoint-based approaches are used to convert the optimization problem into a boundary value problem. Here, we show that the recent advances in automatic differentiation (AD) provide a generic platform for solving inverse problems in complex fluids. To demonstrate the versatility of the approach, we solve an array of optimization problems related to active matter motion in Newtonian fluids, dispersion in structured porous media, and mixing in journal bearing. Each of these problems highlights the advantages of AD in ease of implementation and computational efficiency to solve high-dimensional optimization problems involving particle-laden flows.}, archive = {J_PNAS}, author = {Alhashim, Mohammed G. and Hausknecht, Kaylie and Brenner, Michael P.}, doi = {10.1073/pnas.2403644122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2403644122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Control of flow behavior in complex fluids using automatic differentiation}, volume = {122}, year = {2025}, }
• (2025). Entanglement transition in random rod packings. PNAS, 122(8), e2401868122. (www)

  @article{ , abstract = {Random packings of stiff rods are self-supporting mechanical structures stabilized by long-range interactions induced by contacts. To understand the geometrical and topological complexity of the packings, we first deploy X-ray computerized tomography to unveil the structure of the packing. This allows us to directly visualize the spatial variations in density, orientational order, and the entanglement, a mesoscopic field that we define in terms of a local average crossing number, a measure of the topological complexity of the packing. We find that increasing the aspect ratio of the constituent rods in a packing leads to a proliferation of regions of strong entanglement that eventually percolate through the system and correlated with a sharp transition in the mechanical stability of the packing. To corroborate our experimental findings, we use numerical simulations of contacting elastic rods and characterize their stability to static and dynamic loadings. Our experiments and computations lead us to an entanglement phase diagram which we also populate using published experimental data from pneumatically tangled filaments, worm blobs, and bird nests along with additional numerical simulations using these datasets. Together, these show the regimes associated with mechanically stable entanglement as a function of the statistics of the packings and loading, with lessons for a range of systems from reconfigurable architectures and textiles to active morphable filamentous assemblies.}, archive = {J_PNAS}, author = {Jung, Yeonsu and Plumb-Reyes, Thomas and Lin, Hao-Yu Greg and Mahadevan, L.}, doi = {10.1073/pnas.2401868122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2401868122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Entanglement transition in random rod packings}, volume = {122}, year = {2025}, }
• (2025). Viral circular RNA–encoded protein, ceVP28, divulges an antiviral response in invertebrates. PNAS, 122(8), e2321707122. (www)

  @article{ , abstract = {Invertebrates mostly use innate immunity to counteract pathogenic infections. In this study, shrimp was used as a model organism to explore the functions of circular RNAs (circRNAs) derived from white spot syndrome virus (WSSV). We identified four viral circRNAs, termed circWSSV147, circWSSV326, circWSSV458, and circVP28, from transcriptomic data of WSSV-infected shrimp. CircVP28, which contains an internal ribosome entry site, was further characterized to determine its potential as a template for protein translation. We observed the presence of a truncated, circRNA-encoded VP28 (ceVP28) in infected shrimp. Both ceVP28 and its parental counterpart, VP28, share the same host cell binding partner Rab7, which is a host receptor for WSSV. Coadministration of recombinant ceVP28 protein and WSSV to penaeid shrimps reduced both viral copy numbers and mortality upon WSSV challenges. These findings uncovered a host defense mechanism by which a protein encoded by a viral circRNA modulates virus–receptor interactions, resulting in blocking of viral entry.}, archive = {J_PNAS}, author = {Limkul, Sirawich and Phiwthong, Tannatorn and Wanvimonsuk, Supitcha and Seabkongseng, Tuangrak and Aunkam, Phirom and Jaree, Phattarunda and Luangtrakul, Waruntorn and Mahanil, Kanjana and Teamtisong, Kamonluck and Tittabutr, Panlada and Teaumroong, Neung and Sarnow, Peter and Wang, Han-Ching and Somboonwiwat, Kunlaya and Boonchuen, Pakpoom}, doi = {10.1073/pnas.2321707122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2321707122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Viral circular RNA–encoded protein, ceVP28, divulges an antiviral response in invertebrates}, volume = {122}, year = {2025}, }
• (2025). Short-term exposure to filter-bubble recommendation systems has limited polarization effects: Naturalistic experiments on YouTube. PNAS, 122(8), e2318127122. (www)

  @article{ , abstract = {An enormous body of literature argues that recommendation algorithms drive political polarization by creating “filter bubbles” and “rabbit holes.” Using four experiments with nearly 9,000 participants, we show that manipulating algorithmic recommendations to create these conditions has limited effects on opinions. Our experiments employ a custom-built video platform with a naturalistic, YouTube-like interface presenting real YouTube videos and recommendations. We experimentally manipulate YouTube’s actual recommendation algorithm to simulate filter bubbles and rabbit holes by presenting ideologically balanced and slanted choices. Our design allows us to intervene in a feedback loop that has confounded the study of algorithmic polarization—the complex interplay between supply of recommendations and user demand for content—to examine downstream effects on policy attitudes. We use over 130,000 experimentally manipulated recommendations and 31,000 platform interactions to estimate how recommendation algorithms alter users’ media consumption decisions and, indirectly, their political attitudes. Our results cast doubt on widely circulating theories of algorithmic polarization by showing that even heavy-handed (although short-term) perturbations of real-world recommendations have limited causal effects on policy attitudes. Given our inability to detect consistent evidence for algorithmic effects, we argue the burden of proof for claims about algorithm-induced polarization has shifted. Our methodology, which captures and modifies the output of real-world recommendation algorithms, offers a path forward for future investigations of black-box artificial intelligence systems. Our findings reveal practical limits to effect sizes that are feasibly detectable in academic experiments.}, archive = {J_PNAS}, author = {Liu, Naijia and Hu, Xinlan Emily and Savas, Yasemin and Baum, Matthew A. and Berinsky, Adam J. and Chaney, Allison J. B. and Lucas, Christopher and Mariman, Rei and de Benedictis-Kessner, Justin and Guess, Andrew M. and Knox, Dean and Stewart, Brandon M.}, doi = {10.1073/pnas.2318127122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2318127122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Short-term exposure to filter-bubble recommendation systems has limited polarization effects: Naturalistic experiments on YouTube}, volume = {122}, year = {2025}, }
• (2025). Modeling energy requirements for oxygen production on the moon. PNAS, 122(8), e2306146122. (www)

  @article{ , abstract = {Spacecraft using combustion engines require substantial amounts of oxygen for their propellant. The Moon could be a source of oxygen for rocket propellant, since the material composing the lunar surface can be processed to extract oxygen. However, little is known about overall energy requirements of the processes described in the literature for oxygen extraction from lunar regolith. This knowledge gap constrains the planning of lunar missions, since the scale of energy infrastructure required for oxygen production facilities is not well characterized. This study presents an energy consumption model for oxygen production via hydrogen reduction of the mineral ilmenite (FeTiO 3 ). We consider an end-to-end production chain starting from dry regolith as the feedstock. The production includes the following process steps: excavation, transportation, beneficiation, hydrogen reduction, water electrolysis, liquefaction, and zero boil-off storage. The model predicts the energy demand per kilogram oxygen produced based on adjustable parameters for each process step. As expected, the model indicates a strong dependence on feedstock composition. For regolith composed of 10 wt% ilmenite, the model predicts that a total of 24.3 (± 5.8) kWh is needed per kg of liquid oxygen produced. This study confirms that the hydrogen reduction and electrolysis steps have the highest energy requirements in the production chain. Sensitivity analysis reveals that the enrichment factor of the beneficiation process is the most critical parameter for optimizing energy utilization. Overall, this study provides a parameterized end-to-end model of energy consumption that can serve as a foundation for various production systems on the Moon.}, archive = {J_PNAS}, author = {Leger, Dorian and Ghaffari-Tabrizi, Fardin and Shaw, Matthew and Rasera, Joshua and Dickson, David and Valentin, Baptiste and Morlock, Anton and Thoresen, Freja and Cowley, Aidan}, doi = {10.1073/pnas.2306146122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {8}, pages = {e2306146122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Modeling energy requirements for oxygen production on the moon}, volume = {122}, year = {2025}, }
• (2025). Correction for li et al., recurrent DNA nicks drive massive expansions of (GAA)n repeats. PNAS, 122(7), e2500424122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2500424122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {7}, pages = {e2500424122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for li et al., recurrent DNA nicks drive massive expansions of (GAA)n repeats}, volume = {122}, year = {2025}, }
• (2025). Correction for joshy et al., accelerated cell-type-specific regulatory evolution of the human brain. PNAS, 122(7), e2500334122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2500334122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {7}, pages = {e2500334122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for joshy et al., accelerated cell-type-specific regulatory evolution of the human brain}, volume = {122}, year = {2025}, }
• (2025). Correction for zhu et al., bioinspired nanogels as cell-free DNA trapping and scavenging organelles for rheumatoid arthritis treatment. PNAS, 122(7), e2500091122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2500091122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {7}, pages = {e2500091122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for zhu et al., bioinspired nanogels as cell-free DNA trapping and scavenging organelles for rheumatoid arthritis treatment}, volume = {122}, year = {2025}, }
• (2025). Correction for hasson et al., automated determination of transport and depositional environments in sand and sandstones. PNAS, 122(7), e2427297122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2427297122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {7}, pages = {e2427297122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for hasson et al., automated determination of transport and depositional environments in sand and sandstones}, volume = {122}, year = {2025}, }
• (2025). Profile of christopher b. barrett. PNAS, 122(7), e2427150122. (www)

  @article{ , archive = {J_PNAS}, author = {Viegas, Jennifer}, doi = {10.1073/pnas.2427150122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {7}, pages = {e2427150122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profile of christopher b. barrett}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for guo et al., structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27–Retromer complex. PNAS, 122(7), e2426756122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426756122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {7}, pages = {e2426756122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for guo et al., structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27–Retromer complex}, volume = {122}, year = {2025}, }
• (2025). Correction for sun et al., JFK, a kelch domain-containing F-box protein, links the SCF complex to p53 regulation. PNAS, 122(7), e2426753122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426753122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {7}, pages = {e2426753122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for sun et al., JFK, a kelch domain-containing F-box protein, links the SCF complex to p53 regulation}, volume = {122}, year = {2025}, }
• (2025). The canonical RPA complex interacts with est3 to regulate yeast telomerase activity. PNAS, 122(7), e2419309122. (www)

  @article{ , abstract = {In most eukaryotic organisms, cells that rely on continuous cell division employ the enzyme telomerase which replenishes chromosome termini through the addition of telomeric repeats. In budding yeast, the telomerase holoenzyme is composed of a catalytic core associated with two regulatory subunits, Est1 and Est3. The Est1 protein binds a telomere-specific RPA-like complex to recruit telomerase to chromosome ends. However, the regulatory function of the Est3 subunit has remained elusive. We report here that an interaction between Est3 and the canonical RPA complex is required for in vivo telomerase function, as revealed by mutations in RPA2 that confer an Est (Ever shorter telomeres) phenotype, characteristic of a defect in the telomerase pathway. Binding between RPA and telomerase, which is supported by compensatory charge-swap mutations in EST3 and RPA2 , utilizes a surface on Est3 that is structurally analogous to an interface on the human TPP1 protein that is required for telomerase processivity. Mutations in a subset of conserved DNA contact residues in RPA also result in short telomeres and senescence, which we show is due to a requirement for DNA binding after RPA interacts with telomerase. We propose that once RPA forms a complex with telomerase, RPA utilizes a subset of DNA-binding domains to stabilize the interaction between the telomerase active site and telomeric substrates, thereby facilitating enzyme processivity. These results, combined with prior observations, show that yeast telomerase interacts with two different high-affinity ssDNA-binding complexes, indicating that management of single-stranded DNA is integral to effective telomerase function.}, archive = {J_PNAS}, author = {Moeller-McCoy, Corinne A. and Wieser, Thomas A. and Lubin, Johnathan W. and Gillespie, Abigail E. and Ramirez, Jocelyn A. and Paschini, Margherita and Wuttke, Deborah S. and Lundblad, Victoria}, doi = {10.1073/pnas.2419309122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {7}, pages = {e2419309122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The canonical RPA complex interacts with est3 to regulate yeast telomerase activity}, volume = {122}, year = {2025}, }
• (2025). Profile of bik-kwoon tye. PNAS, 122(6), e2500916122. (www)

  @article{ , archive = {J_PNAS}, author = {Viegas, Jennifer}, doi = {10.1073/pnas.2500916122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2500916122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profile of bik-kwoon tye}, volume = {122}, year = {2025}, }
• (2025). QnAs with jeremy j. michalek and corey d. harper. PNAS, 122(6), e2500725122. (www)

  @article{ , archive = {J_PNAS}, author = {Hardcastle, Matthew}, doi = {10.1073/pnas.2500725122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2500725122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {QnAs with jeremy j. michalek and corey d. harper}, volume = {122}, year = {2025}, }
• (2025). Correction to doruska et al., modeling how and why aquatic vegetation removal can free rural households from poverty-disease traps. PNAS, 122(6), e2426934122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426934122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2426934122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to doruska et al., modeling how and why aquatic vegetation removal can free rural households from poverty-disease traps}, volume = {122}, year = {2025}, }
• (2025). Correction for foley et al., single-nuclei sequencing of uterine serous carcinoma reveals racial differences in immune signaling. PNAS, 122(6), e2426918122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426918122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2426918122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for foley et al., single-nuclei sequencing of uterine serous carcinoma reveals racial differences in immune signaling}, volume = {122}, year = {2025}, }
• (2025). Correction for knight and zhang, residential mobility and persistently depressed voting among disadvantaged adults in a large housing experiment. PNAS, 122(6), e2426750122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426750122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2426750122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for knight and zhang, residential mobility and persistently depressed voting among disadvantaged adults in a large housing experiment}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for takaki and thirumalai, sequence complexity and monomer rigidity control the morphologies and aging dynamics of protein aggregates. PNAS, 122(6), e2426631122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426631122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2426631122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for takaki and thirumalai, sequence complexity and monomer rigidity control the morphologies and aging dynamics of protein aggregates}, volume = {122}, year = {2025}, }
• (2025). Correction for baekgaard et al., long-term employment and health effects of active labor market programs. PNAS, 122(6), e2426629122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426629122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2426629122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for baekgaard et al., long-term employment and health effects of active labor market programs}, volume = {122}, year = {2025}, }
• (2025). An ear for an ear, but only if you are a deomyinid. PNAS, 122(6), e2426545122. (www)

  @article{ , archive = {J_PNAS}, author = {Maden, Malcolm}, doi = {10.1073/pnas.2426545122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2426545122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An ear for an ear, but only if you are a deomyinid}, volume = {122}, year = {2025}, }
• (2025). Correction for gilboa et al., measurement of α-synuclein as protein cargo in plasma extracellular vesicles. PNAS, 122(6), e2426543122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426543122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2426543122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for gilboa et al., measurement of α-synuclein as protein cargo in plasma extracellular vesicles}, volume = {122}, year = {2025}, }
• (2025). Yet another twist to the regulation of the TGF-β family ligands. PNAS, 122(6), e2426535122. (www)

  @article{ , archive = {J_PNAS}, author = {Hyvönen, Marko}, doi = {10.1073/pnas.2426535122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2426535122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Yet another twist to the regulation of the TGF-β family ligands}, volume = {122}, year = {2025}, }
• (2025). Simulating atmospheric freezing of single aqueous droplets to ice in a cryogenically cooled ultrasonic levitator. PNAS, 122(6), e2425543122. (www)

  @article{ , abstract = {Atmospheric freezing of water droplets suspended in air followed by cloud formation and precipitation represent fundamental steps of the terrestrial water cycle. These aqueous droplets exhibit distinct freezing mechanisms and thermodynamic requirements compared to bulk water often forming metastable supercooled water at subzero temperatures on the Celsius scale (<273 K) prior to crystallization. Here, we report on a real-time spectroscopic investigation combined with simultaneous visualizations of single aqueous droplet freezing events inside a cryogenically cooled ultrasonic levitation chamber with the ultimate goal of probing the molecular structure evolution and stages of ice formation. The observed droplet freezing follows a pseudoheterogeneous ice nucleation mechanism mimicking the process that occurs for atmospherically supercooled water droplets at the air–water interface. This proof-of-concept experimental setup allows future crystallization studies of homo- and heterogeneously doped aqueous droplets under simulated atmospheric environments—also in the presence of reactive trace gases, thus untangling dynamic molecular interactions and chemical reactions, which are of fundamental interest to low-temperature atmospheric chemistry delineating with ice nucleation mechanisms.}, archive = {J_PNAS}, author = {Biswas, Souvick and Paul, Dababrata and Mondal, Koushik and Kaiser, Ralf I.}, doi = {10.1073/pnas.2425543122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2425543122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Simulating atmospheric freezing of single aqueous droplets to ice in a cryogenically cooled ultrasonic levitator}, volume = {122}, year = {2025}, }
• (2025). Light’s hidden power: Vacuum fluctuations reshape superconductivity from within. PNAS, 122(6), e2424675122. (www)

  @article{ , archive = {J_PNAS}, author = {Nova, T. F. and Caviglia, A. D.}, doi = {10.1073/pnas.2424675122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2424675122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Light’s hidden power: Vacuum fluctuations reshape superconductivity from within}, volume = {122}, year = {2025}, }
• (2025). Aqueous power source integrated on a microfluidic chip. PNAS, 122(6), e2423610122. (www)

  @article{ , abstract = {The growing demand for portable sensors for point-of-care (POC) and onsite health monitoring has led to significant interest in developing suitable power sources. In this study, we developed a microfluidic chip-integrated reverse electrodialysis (μRED) system for ecofriendly power generation with monolithic operation. Leveraging its fully ionic characteristic, μRED was successfully applied to an ionic diode, thereby demonstrating its capability for seamless integration. The feasibility of operating a bipolar electrode sensor without an external power supply was demonstrated, highlighting its broad applicability in electrochemical portable sensors. μRED has great potential for future applications, including electrochemical sensors for POC diagnostics and wearable devices.}, archive = {J_PNAS}, author = {Yeon, Song Yi and Kim, Yunju and Kang, Chung Mu and Park, Sanguk and Chung, Taek Dong}, doi = {10.1073/pnas.2423610122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2423610122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Aqueous power source integrated on a microfluidic chip}, volume = {122}, year = {2025}, }
• (2025). Translation elongation defects activate the caenorhabditis elegans ZIP-2 bZIP transcription factor–mediated toxin defense. PNAS, 122(6), e2423578122. (www)

  @article{ , abstract = {The Caenorhabditis elegans bZIP transcription factor ZIP-2 is activated by toxins or mutations that inhibit translational elongation. The zip-2 DNA-binding protein is encoded in a downstream main open reading frame (mORF), but under normal translation elongation conditions only an upstream overlapping oORF -1 frameshifted from mORF is translated. Mutations or toxins that slow translational elongation, but not inhibitors of translational initiation or termination, activate ZIP-2. An mORF initiation codon mutation does not disrupt the normal zip-2 response to translational elongation defects, suggesting that zip-2 activation does not depend on this ATG. An mORF early termination mutant can be activated by strong translation elongation inhibition, suggesting that translation initiated upstream on oORF +1 frameshifts when elongation is inhibited to the mORF reading frame downstream of the stop codon to activate a fused oORF/mORF ZIP-2 transcription factor. The protein and DNA sequences of zip-2 oORF and mORF are conserved across the Caenorhabditis , suggesting selection for particular codons sensitive to translational elongation defects. Mutations that disrupt the oORF initiation codon constitutively activate zip-2 , but not if the mORF initiation codon is also mutant, showing that zip-2 oORF competes with mORF for translational initiation. oORF initiation codon mutation-activated zip-2 slows C. elegans growth, and this slow growth is suppressed by a zip-2 null mutation. A zip-2 null mutant also strongly suppresses the growth arrest caused by translational elongation inhibitors. Thus, ZIP-2 is both a sensor of translational elongation attack, and a defense regulatory output via its activation of response genes.}, archive = {J_PNAS}, author = {Kniazeva, Marina and Ruvkun, Gary}, doi = {10.1073/pnas.2423578122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2423578122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Translation elongation defects activate the caenorhabditis elegans ZIP-2 bZIP transcription factor–mediated toxin defense}, volume = {122}, year = {2025}, }
• (2025). Creation, stabilization, and investigation at ambient pressure of pressure-induced superconductivity in Bi0.5Sb1.5Te3. PNAS, 122(6), e2423102122. (www)

  @article{ , abstract = {In light of breakthroughs in superconductivity under high pressure, and considering that record critical temperatures (T c s) across various systems have been achieved under high pressure, the primary challenge for higher T c should no longer solely be to increase T c under extreme conditions but also to reduce, or ideally eliminate, the need for applied pressure in retaining pressure-induced or -enhanced superconductivity. The topological semiconductor Bi 0.5 Sb 1.5 Te 3 (BST) was chosen to demonstrate our approach to addressing this challenge and exploring its intriguing physics. Under pressures up to ~50 GPa, three superconducting phases (BST-I, -II, and -III) were observed. A superconducting phase in BST-I appears at ~4 GPa, without a structural transition, suggesting the possible topological nature of this phase. Using the pressure-quench protocol (PQP) recently developed by us, we successfully retained this pressure-induced phase at ambient pressure and revealed the bulk nature of the state. Significantly, this demonstrates recovery of a pressure-quenched sample from a diamond anvil cell at room temperature with the pressure-induced phase retained at ambient pressure. Other superconducting phases were retained in BST-II and -III at ambient pressure and subjected to thermal and temporal stability testing. Superconductivity was also found in BST with T c up to 10.2 K, the record for this compound series. While PQP maintains superconducting phases in BST at ambient pressure, both depressurization and PQP enhance its T c , possibly due to microstructures formed during these processes, offering an added avenue to raise T c . These findings are supported by our density-functional theory calculations.}, archive = {J_PNAS}, author = {Deng, Liangzi and Wang, Busheng and Halbert, Clayton and Schulze, Daniel J. and Gooch, Melissa and Bontke, Trevor and Kuo, Ting-Wei and Shi, Xin and Song, Shaowei and Salke, Nilesh and Yang, Hung-Duen and Ren, Zhifeng and Hemley, Russell J. and Zurek, Eva and Prasankumar, Rohit P. and Chu, Ching-Wu}, doi = {10.1073/pnas.2423102122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2423102122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Creation, stabilization, and investigation at ambient pressure of pressure-induced superconductivity in Bi0.5Sb1.5Te3}, volume = {122}, year = {2025}, }
• (2025). Mec1-mediated atg9 phosphorylation regulates the PAS recruitment of atg9 vesicles upon energy stress. PNAS, 122(6), e2422582122. (www)

  @article{ , abstract = {Mec1 plays an essential role in both the DNA damage response and glucose starvation–induced autophagy. We recently reported that Mec1 regulates glucose starvation–induced autophagy through its direct binding to Atg13. However, the role of Mec1’s kinase activity in autophagy remains unclear. In this study, we demonstrate that the kinase activity of Mec1 is required for glucose starvation–induced autophagy by regulating the phagophore assembly site (PAS) recruitment of Atg9 vesicles. Mechanistic and functional analyses identified Atg9 as a direct phosphorylation substrate of Mec1, with phosphorylation occurring at the S35, T203, and T243 sites. Mutations at these sites reduce the association of Atg9 with Atg17, Atg23, and Atg27, thereby impairing the PAS recruitment of Atg9 vesicles. Notably, we found that the Mec1–Atg13 binding is a prerequisite for the phosphorylation of Atg9 by Mec1. Furthermore, Mec1-mediated phosphorylation of Atg9 is also crucial for the PAS recruitment of Atg9 vesicles in response to DNA damage. We thus propose that Mec1’s kinase activity regulates the PAS recruitment of Atg9 vesicles by phosphorylating Atg9 in response to energy stress and DNA damage.}, archive = {J_PNAS}, author = {Fan, Siyu and Dong, Shuling and Yao, Weijing and Zhang, Yi and Fan, Mingzhu and Feng, Shan and Wu, Choufei and Zhang, Liqin and Yi, Cong}, doi = {10.1073/pnas.2422582122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2422582122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mec1-mediated atg9 phosphorylation regulates the PAS recruitment of atg9 vesicles upon energy stress}, volume = {122}, year = {2025}, }
• (2025). The genomic and epigenomic landscapes of hemizygous genes across crops with contrasting reproductive systems. PNAS, 122(6), e2422487122. (www)

  @article{ , abstract = {Hemizygous genes, which are present on only one of the two homologous chromosomes of diploid organisms, have been mainly studied in the context of sex chromosomes and sex-linked genes. However, these genes can also occur on the autosomes of diploid plants due to structural variants (SVs), such as a deletion/insertion of one allele, and this phenomenon largely unexplored in plants. Here, we investigated the genomic and epigenomic landscapes of hemizygous genes across 22 genomes with varying propagation histories: eleven clonal lineages, seven outcrossed samples, and four inbred and putatively homozygous genomes. We identified SVs leading to genic hemizygosity. As expected, very few genes (0.01 to 1.2%) were hemizygous in the homozygous genomes, representing negative controls. Hemizygosity was appreciable among outcrossed lineages, averaging 8.7% of genes, but consistently elevated for the clonal samples at 13.8% genes, likely reflecting heterozygous SV accumulation during clonal propagation. Compared to diploid genes, hemizygous genes were more often situated in centromeric than telomeric regions and experienced weaker purifying selection. They also had reduced levels of expression, averaging ~20% of the expression levels of diploid genes, violating the evolutionary model of dosage compensation. We also detected higher DNA methylation levels in hemizygous genes and transposable elements, which may contribute to their reduced expression. Finally, expression profiles showed that hemizygous genes were more specifically expressed in contexts related to fruit development, organ differentiation, and stress responses. Overall, hemizygous genes accumulate in clonally propagated lineages and display distinct genetic and epigenetic features compared to diploid genes, shedding unique insights into genetic studies and breeding programs of clonal crops.}, archive = {J_PNAS}, author = {Peng, Yanling and Wang, Yiwen and Liu, Yuting and Fang, Xinyue and Cheng, Lin and Long, Qiming and Su, Dalu and Zhang, Tianhao and Shi, Xiaoya and Xu, Xiaodong and Xu, Qi and Wang, Nan and Zhang, Fan and Liu, Zhongjie and Xiao, Hua and Yao, Jin and Tian, Ling and Hu, Wei and Chen, Songbi and Wang, Haibo and Huang, Sanwen and Gaut, Brandon S. and Zhou, Yongfeng}, doi = {10.1073/pnas.2422487122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2422487122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The genomic and epigenomic landscapes of hemizygous genes across crops with contrasting reproductive systems}, volume = {122}, year = {2025}, }
• (2025). Microtubule inner proteins of plasmodium are essential for transmission of malaria parasites. PNAS, 122(6), e2421737122. (www)

  @article{ , abstract = {Microtubule inner proteins (MIPs) are microtubule-associated proteins that bind to tubulin from the luminal side. MIPs can be found in axonemes to stabilize flagellar beat or within cytoplasmic microtubules. Plasmodium spp. are the causative agents of malaria that feature different parasite forms across a complex life cycle with both unique and divergent microtubule-based arrays. Here, we investigate four MIPs in a rodent malaria parasite for their role in transmission to and from the mosquito. We show by single and double gene deletions that SPM1 and TrxL1, MIPs associated with subpellicular microtubules, are dispensable for transmission from the vertebrate host to the mosquito and back. In contrast, FAP20 and FAP52, MIPs associated with the axonemes of gametes, are essential for transmission to mosquitoes but only if both genes are deleted. In the absence of both FAP20 and FAP52, the B-tubule of the axoneme partly detaches from the A-tubule, resulting in the deficiency of axonemal beating and hence gamete formation and egress. Our data suggest that a high level of redundancy ensures microtubule stability in the transmissive stages of Plasmodium , which is important for parasite transmission.}, archive = {J_PNAS}, author = {Hentzschel, Franziska and Binder, Annika M. and Dorner, Lilian P. and Herzel, Lea and Nuglisch, Fenja and Sema, Meslo and Röver, Katharina and He, Buyuan and Aguirre-Botero, Manuela C. and Cyrklaff, Marek and Funaya, Charlotta and Frischknecht, Friedrich}, doi = {10.1073/pnas.2421737122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2421737122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Microtubule inner proteins of plasmodium are essential for transmission of malaria parasites}, volume = {122}, year = {2025}, }
• (2025). Quantifying the impact of air pollution from coal-fired electricity generation on crop productivity in india. PNAS, 122(6), e2421679122. (www)

  @article{ , abstract = {Air pollution from coal electricity generation is a major driver of poor air quality in India and its effects on human health have been extensively studied. Despite considerable evidence that the same pollution also reduces crop productivity, we lack similar quantitative assessments of coal electricity’s crop damages. Here, we estimate rice and wheat crop losses from coal generation’s nitrogen dioxide (NO 2 ) emissions using a regression model that combines station-level electricity generation and wind direction, satellite-measured NO 2 , and its association with crop productivity. Coal emissions impact yields up to 100 km away from power stations. In parts of West Bengal, Madhya Pradesh, and Uttar Pradesh heavily exposed to coal-linked NO 2 , annual yield losses exceed 10%, equivalent to approximately 6 y worth of average annual yield growth in both rice and wheat in India between 2011 and 2020. While station-specific crop damages (value of lost output) are almost always lower than mortality damages (monetized value of annual premature PM 2.5 -related deaths), crop damage intensity (crop damage per GWh of electricity generated) is frequently higher than mortality damage intensity (mortality damage/GWh). Rice damage intensity exceeds mortality damage intensity at 58, and wheat damage intensity at 35 of the 144 power stations studied. The stations associated with the largest crop losses differ from those associated with the highest mortality. Co-optimizing for crop gains and mortality reduction slightly increases and meaningfully changes the distribution of social benefits from reducing emissions, highlighting the importance of considering crop losses alongside health impacts when regulating coal electricity emissions in India.}, archive = {J_PNAS}, author = {Singh, Kirat and Lobell, David B. and Azevedo, Inês M. L.}, doi = {10.1073/pnas.2421679122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2421679122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantifying the impact of air pollution from coal-fired electricity generation on crop productivity in india}, volume = {122}, year = {2025}, }
• (2025). Top-performing girls are more impactful peer role models than boys, teachers say. PNAS, 122(6), e2421436122. (www)

  @article{ , abstract = {We examine teachers’ perceptions toward top-performing students and their role model influence on others in an online survey-based experiment. We randomly expose teachers to profiles of top-performing students and inquire whether they consider the profiled top performers to be influential role models. These profiles varied by gender and field of study (STEM or Non-STEM). Our findings show that teachers perceive top-performing girls as more influential peer role models compared to top-performing boys ( β ̂ = 0.289 ; P < 0.001 ). We also investigate the qualities teachers perceive top performers who are successful role models to have. We show that teachers associate a greater sense of learning autonomy and sense of being an example with top-performing girls compared to top-performing boys. Estimated effects are more pronounced among teachers with children and teachers in urban areas. Administrative data from a representative sample show limited observed differences between top-performing boys’ and girls’ educational outcomes that could justify the differences in teachers’ gender perceptions. These findings carry significant implications for education, as teachers play a crucial role in the cultivation of positive externalities between students.}, archive = {J_PNAS}, author = {Goulas, Sofoklis and Megalokonomou, Rigissa and Sotirakopoulos, Panagiotis}, doi = {10.1073/pnas.2421436122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2421436122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Top-performing girls are more impactful peer role models than boys, teachers say}, volume = {122}, year = {2025}, }
• (2025). The revised elastic field of an edge dislocation. PNAS, 122(6), e2420808122. (www)

  @article{ , abstract = {We modify the traditional linear-elastic field of an edge dislocation. The modifications stem from symmetry and energy requirements imposed in terms of embedded (deformed) coordinates. These requirements are satisfied if a line force is added to the dislocation field. The modification to the stress field is expressed by coefficients that are a function only of Poisson’s ratio. Qualitatively, the field of the dislocation is increased in the glide direction and decreased in the climb direction. There are small changes to the field of a screw dislocation that do not entail the addition of a line force. Effects of nonlinearity, anisotropic elasticity, and image forces are briefly considered.}, archive = {J_PNAS}, author = {Hirth, J. P. and Anderson, P. M.}, doi = {10.1073/pnas.2420808122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2420808122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The revised elastic field of an edge dislocation}, volume = {122}, year = {2025}, }
• (2025). Contextual neural dynamics during time perception in the primate ventral premotor cortex. PNAS, 122(6), e2420356122. (www)

  @article{ , abstract = {Understanding how time perception adapts to cognitive demands remains a significant challenge. In some contexts, the brain encodes time categorically (as “long” or “short”), while in others, it encodes precise time intervals on a continuous scale. Although the ventral premotor cortex (VPC) is known for its role in complex temporal processes, such as speech, its specific involvement in time estimation remains underexplored. In this study, we investigated how the VPC processes temporal information during a time interval comparison task (TICT) and a time interval categorization task (TCT) in primates. We found a notable heterogeneity in neuronal responses associated with time perception across both tasks. While most neurons responded during time interval presentation, a smaller subset retained this information during the working memory periods. Population-level analysis revealed distinct dynamics between tasks: In the TICT, population activity exhibited a linear and parametric relationship with interval duration, whereas in the TCT, neuronal activity diverged into two distinct dynamics corresponding to the interval categories. During delay periods, these categorical or parametric representations remained consistent within each task context. This contextual shift underscores the VPC’s adaptive role in interval estimation and highlights how temporal representations are modulated by cognitive demands.}, archive = {J_PNAS}, author = {Díaz, Héctor and Bayones, Lucas and Alvarez, Manuel and Andrade-Ortega, Bernardo and Valero, Sebastián and Zainos, Antonio and Romo, Ranulfo and Rossi-Pool, Román}, doi = {10.1073/pnas.2420356122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2420356122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Contextual neural dynamics during time perception in the primate ventral premotor cortex}, volume = {122}, year = {2025}, }
• (2025). Uncovering the hidden RNA virus diversity in lake nam co: Evolutionary insights from an extreme high-altitude environment. PNAS, 122(6), e2420162122. (www)

  @article{ , abstract = {Alpine lakes, characterized by isolation, low temperatures, oligotrophic conditions, and intense ultraviolet radiation, remain a poorly explored ecosystem for RNA viruses. Here, we present the first comprehensive metatranscriptomic study of RNA viruses in Lake Nam Co, a high-altitude alkaline saline lake on the Tibetan Plateau. Using a combination of sequence- and structure-based homology searches, we identified 742 RNA virus species, including 383 novel genus-level groups and 84 novel family-level groups exclusively found in Lake Nam Co. These findings significantly expand the known diversity of the Orthornavirae , uncovering evolutionary adaptations such as permutated RNA-dependent RNA polymerase motifs and distinct RNA secondary structures. Notably, 14 additional RNA virus families potentially infecting prokaryotes were predicted, broadening the known host range of RNA viruses and questioning the traditional assumption that RNA viruses predominantly target eukaryotes. The presence of auxiliary metabolic genes in viral genomes suggested that RNA viruses (families f . 0102 and Nam-Co_family_51) exploit host energy production mechanisms in energy-limited alpine lakes. Low nucleotide diversity, single nucleotide polymorphism frequencies, and pN/pS ratios indicate strong purifying selection in Nam Co viral populations. Our findings offer insights into RNA virus evolution and ecology, highlighting the importance of extreme environments in uncovering hidden viral diversity and further shed light into their potential ecological implications, particularly in the context of climate change.}, archive = {J_PNAS}, author = {Wu, Lilin and Liu, Yongqin and Shi, Wenqing and Chang, Tianyi and Liu, Pengfei and Liu, Keshao and He, Yong and Li, Zhaorong and Shi, Mang and Jiao, Nianzhi and Lang, Andrew S. and Dong, Xiyang and Zheng, Qiang}, doi = {10.1073/pnas.2420162122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2420162122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Uncovering the hidden RNA virus diversity in lake nam co: Evolutionary insights from an extreme high-altitude environment}, volume = {122}, year = {2025}, }
• (2025). The structure of full-length AFPK supports the ACP linker in a role that regulates iterative polyketide and fatty acid assembly. PNAS, 122(6), e2419884122. (www)

  @article{ , abstract = {The polyketide synthases (PKSs) in microbes and the cytoplasmic fatty acid synthases in humans (FASs) are related enzymes that have been well studied. As a result, there is a paradigm explaining in general terms how FASs repeatedly use a set of enzymatic domains to produce simple fats, while PKSs use the domains in a much more complex manner to produce pharmaceuticals and other elaborate molecules. However, most animals also have PKSs that do not conform to the rules described in microbes, including a large family of enzymes that bridge fatty acid and polyketide metabolism, the animal FAS-like PKSs (AFPKs). Here, we present the cryoelectron microscopy structures of two AFPKs from sea slugs. While the AFPK resemble mammalian FASs, their chemical products mimic those of PKSs in complexity. How then does the architecture of AFPKs facilitate this structural complexity? Unexpectedly, chemical complexity is controlled not solely by the enzymatic domains but is aided by the dynamics of the acyl carrier protein (ACP), a shuttle that moves intermediates between these domains. We observed interactions between enzyme domains and the linker-ACP domain, which, when manipulated, altered the kinetic properties of the enzyme to change the resulting chemical products. This unveils elaborate mechanisms and enzyme motions underlying lipid and polyketide biochemistry across the domains of life.}, archive = {J_PNAS}, author = {Schubert, Heidi L. and Li, Feng and Hill, Christopher P. and Schmidt, Eric W.}, doi = {10.1073/pnas.2419884122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2419884122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The structure of full-length AFPK supports the ACP linker in a role that regulates iterative polyketide and fatty acid assembly}, volume = {122}, year = {2025}, }
• (2025). HflX-mediated drug resistance through ribosome splitting and rRNA disordering in mycobacteria. PNAS, 122(6), e2419826122. (www)

  @article{ , abstract = {HflX is a highly conserved ribosome-associated GTPase implicated in rescuing stalled ribosomes and mediating antibiotic resistance in several bacteria, including macrolide-lincosamide antibiotic resistance in mycobacteria. Mycobacterial HflXs carry a distinct N-terminal extension (NTE) and a small insertion, as compared to their eubacterial homologs. Here, we present several high-resolution cryo-EM structures of mycobacterial HflX in complex with the 70S ribosome and its 50S subunit, with and without antibiotics. These structures reveal a distinct mechanism for HflX-mediated ribosome splitting and antibiotic resistance in mycobacteria. Our findings indicate that the NTE of mycobacterial HflX induces persistent disordering of multiple 23S rRNA helices, facilitating the dissociation of the 70S ribosome and generating an inactive pool of 50S subunits. During this process, HflX undergoes a large conformational change that stabilizes its NTE. Mycobacterial HflX also acts as an anti-association factor by binding to predissociated 50S subunits. Our structures show that a mycobacteria-specific insertion in HflX reaches far into the peptidyl transferase center (PTC), such that it would overlap with the ribosome-bound macrolide antibiotics. However, in the presence of antibiotics, this insertion retracts, adjusts around, and interacts with the antibiotic molecules. These results suggest that mycobacterial HflX is agnostic to antibiotic presence in the PTC. It mediates antibiotic resistance by splitting antibiotic-stalled 70S ribosomes and inactivating the resulting 50S subunits.}, archive = {J_PNAS}, author = {Majumdar, Soneya and Kashyap, Amuliya and Koripella, Ravi K. and Sharma, Manjuli R. and Hurst-Hess, Kelley and Manjari, Swati R. and Banavali, Nilesh K. and Ghosh, Pallavi and Agrawal, Rajendra K.}, doi = {10.1073/pnas.2419826122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2419826122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {HflX-mediated drug resistance through ribosome splitting and rRNA disordering in mycobacteria}, volume = {122}, year = {2025}, }
• (2025). Deep learning–driven bacterial cytological profiling to determine antimicrobial mechanisms in mycobacterium tuberculosis. PNAS, 122(6), e2419813122. (www)

  @article{ , abstract = {Tuberculosis (TB), caused by Mycobacterium tuberculosis , remains a significant global health threat, affecting an estimated 10.6 million people in 2022. The emergence of multidrug resistant and extensively drug resistant strains necessitates the development of novel and effective drugs. Accelerating the determination of mechanisms of action (MOAs) for these drugs is crucial for advancing TB treatment. This study introduces MycoBCP, a unique adaptation of bacterial cytological profiling (BCP) tailored to M. tuberculosis , utilizing the application of convolutional neural networks (CNNs) within BCP to overcome challenges posed by traditional image analysis techniques. Using MycoBCP, we analyzed the morphological effects of various antimicrobial compounds on M. tuberculosis , capturing broad patterns rather than relying on precise cell segmentation. This approach circumvented issues such as cell clumping and uneven staining, which are prevalent in M. tuberculosis . In a blind test, MycoBCP accurately identified the MOA for 96% of the compounds, with a single misclassification of rifabutin, which was incorrectly categorized as affecting translation rather than transcription. The similar morphologies resulting from transcription and translation inhibition indicate a need for further refinement to distinguish them more effectively. Application of MycoBCP to a series of antitubercular agents successfully identified known MOAs and revealed unique effects, demonstrating its utility in early drug discovery and development. Our findings underscore the potential of CNN-based BCP to enhance the accuracy and efficiency of MOA determination, particularly for challenging pathogens like M. tuberculosis . MycoBCP represents a significant advancement in TB drug development, offering a robust and adaptable method for high-throughput screening of antimicrobial compounds.}, archive = {J_PNAS}, author = {Quach, Diana and Sharp, Marc and Ahmed, Sara and Ames, Lauren and Bhagwat, Amala and Deshpande, Aditi and Parish, Tanya and Pogliano, Joe and Sugie, Joseph}, doi = {10.1073/pnas.2419813122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2419813122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deep learning–driven bacterial cytological profiling to determine antimicrobial mechanisms in mycobacterium tuberculosis}, volume = {122}, year = {2025}, }
• (2025). Spatiotemporal distribution of the north american indigenous population prior to european contact. PNAS, 122(6), e2419454122. (www)

  @article{ , abstract = {We examine spatiotemporal trends in the pre-European-contact Indigenous population of North America using radiocarbon ( 14 C) dates of the past 2000 y. At a continental scale, the Indigenous population of the past ~14,000 y peaked at ~1150 CE and then declined until a brief recovery shortly before 1500 CE, after which 14 C probability declines precipitously. After testing, we reject the hypothesis that the 1150 CE peak and decline is a result of 14 C sampling issues. We then examine the 14 C record of the past 2000 y in each of 18 watersheds where we find peaks ranging from ~800 to 770 CE to after European contact, with the majority, in the interior of the continent, declining ~1080 to 1300 CE. Although all Indigenous populations declined after European contact, that of a large portion of the country (the Great Lakes, New England, the Mid-Atlantic, the Central Plains, the Northwest, and California) did not decline until after contact.}, archive = {J_PNAS}, author = {Kelly, Robert L. and Mackie, Madeline E. and Pelton, Spencer R. and Robinson, Erick}, doi = {10.1073/pnas.2419454122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2419454122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatiotemporal distribution of the north american indigenous population prior to european contact}, volume = {122}, year = {2025}, }
• (2025). Synergistic anion–π interactions in peptidomimetic polyethers. PNAS, 122(6), e2419404122. (www)

  @article{ , abstract = {Anion–π interactions are crucial in various biological processes, such as enzyme catalysis and ion transport. Despite their significance, the exploitation of anion–π interactions in synthetic polymer systems remains underexplored. This study investigates anion–π interactions using chemically well-defined peptidomimetics guided by the composition of mussel foot proteins. Specifically, polyether-based polymers were designed utilizing two functional epoxide monomers—catechol acetonide glycidyl ether and 4,4-dimethyl-2-oxazoline glycidyl ether—to mimic the key amino acids 3,4-dihydroxyphenylalanine and aspartic acid, respectively. A surface forces apparatus was employed to study the anion–π interaction between the polymers, considering the effects of relative monomer composition and pH conditions. The maximum cohesion energy of 15.0 mJ/m 2 was observed at an equimolar monomer composition at pH 7. Incorporating a phenyl group instead of the catechol group and introducing competing anions confirmed the dominant role of anion–π interactions. This study highlights the significance of anion–π interactions, posing a high potential in the design and synthesis of functional materials.}, archive = {J_PNAS}, author = {Lee, Seunghyun and Shin, Aram and Park, Jinwoo and Yun, Sowon and Kim, Minseong and Lee, Dong Woog and Kim, Byeong-Su}, doi = {10.1073/pnas.2419404122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2419404122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synergistic anion–π interactions in peptidomimetic polyethers}, volume = {122}, year = {2025}, }
• (2025). Thermal-solutal-induced bistability of evaporating multicomponent liquid thin films. PNAS, 122(6), e2418487122. (www)

  @article{ , abstract = {Volatile multicomponent liquid films show rich dynamics, due to the complex interplay of gradients in temperature and in solute concentrations. Here, we study the evaporation dynamics of a tricomponent liquid film, consisting of water, ethanol, and trans-anethole oil (known as “ouzo”). With the preferential evaporation of ethanol, cellular convective structures are observed both in the thermal patterns and in the nucleated oil droplet patterns. However, the feature sizes of these two patterns can differ, indicating dual instability mechanisms dominated by either temperature or solute concentration. Using numerical simulations, we quantitatively compare the contributions of temperature and solute concentration on the surface tension. Our results reveal that the thermal Marangoni effect predominates at the initial evaporation stage, resulting in cellular patterns in thermal images, while the solutal Marangoni effect gradually becomes dominant. By regulating the transition time of this thermal-solutal-induced bistability and the nucleation time of oil microdroplets in the ternary mixture, the oil droplet patterns can be well controlled. This capability not only enhances our understanding of the evaporation dynamics but also paves the way for precise manipulation of nucleation and deposition processes at larger scales.}, archive = {J_PNAS}, author = {Wakata, Yuki and Wang, Feng and Sun, Chao and Lohse, Detlef}, doi = {10.1073/pnas.2418487122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2418487122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Thermal-solutal-induced bistability of evaporating multicomponent liquid thin films}, volume = {122}, year = {2025}, }
• (2025). Touching the classical scaling in penetrative convection. PNAS, 122(6), e2418468122. (www)

  @article{ , abstract = {The Cassini missions have identified the tiger stripes on Enceladus as the source of both thermal emission and plume jets. The hot spots in the tiger stripes are highly localized, and the plumes suggest active hydrothermal processes within the subglacial ocean of Enceladus. However, understanding the mechanism responsible for the heat anomalies in the tiger stripes remains a challenge. About 60 y ago, geoscientist George Veronis proposed a model for cold water oceans, along with the classical notion of a 1/3 scaling relationship between vertical heat transfer and the Rayleigh number ( Ra ), a dimensionless number representing the strength of buoyancy driving the convection within the fluid body. In this study, by delving into the steady coherent rolls arising in Veronis’ model, we first confirm the existence of the classical scaling as proposed. We identify two distinct pathways, characterized by different flow patterns, that converge to the unified classical scaling. In scenarios where stratification resulting from the density’s nonlinear temperature dependence is insignificant, convection rolls with fixed (width-to-height) aspect ratios achieve the classical scaling as Ra approaches infinity. Conversely, under high stratification levels, convection rolls with a heat-transport-maximizing aspect ratio achieve the classical scaling. This investigation also reveals a notable correspondence between optimal coherent rolls and turbulent flow patterns. Based on these coherent rolls, we offer insights into the formation of heat anomalies in the tiger stripes. The predicted heat flux through the ocean and the lateral flow length, are consistent with the measurements obtained by the Cassini spacecraft.}, archive = {J_PNAS}, author = {Ouyang, Zhen and Wang, Qi and Li, Kai and Wen, Baole and Ding, Zijing}, doi = {10.1073/pnas.2418468122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2418468122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Touching the classical scaling in penetrative convection}, volume = {122}, year = {2025}, }
• (2025). The c2 domain augments ras GTPase-activating protein catalytic activity. PNAS, 122(6), e2418433122. (www)

  @article{ , abstract = {Regulation of Ras GTPases by GTPase-activating proteins (GAPs) is essential for their normal signaling. Nine of the ten GAPs for Ras contain a C2 domain immediately proximal to their canonical GAP domain, and in RasGAP (p120GAP, p120RasGAP; RASA1 ) mutation of this domain is associated with vascular malformations in humans. Here, we show that the C2 domain of RasGAP is required for full catalytic activity toward Ras. Analyses of the RasGAP C2-GAP crystal structure, AlphaFold models, and sequence conservation reveal direct C2 domain interaction with the Ras allosteric lobe. This is achieved by an evolutionarily conserved surface centered around RasGAP residue R707, point mutation of which impairs the catalytic advantage conferred by the C2 domain in vitro. In mice, R707C mutation phenocopies the vascular and signaling defects resulting from constitutive disruption of the RASA1 gene. In SynGAP, mutation of the equivalent conserved C2 domain surface impairs catalytic activity. Our results indicate that the C2 domain is required to achieve full catalytic activity of GAPs for Ras.}, archive = {J_PNAS}, author = {Paul, Maxum E. and Chen, Di and Vish, Kimberly J. and Lartey, Nathaniel L. and Hughes, Elizabeth and Freeman, Zachary T. and Saunders, Thomas L. and Stiegler, Amy L. and King, Philip D. and Boggon, Titus J.}, doi = {10.1073/pnas.2418433122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2418433122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The c2 domain augments ras GTPase-activating protein catalytic activity}, volume = {122}, year = {2025}, }
• (2025). Human beauty illustrates the economic impact of heritable physical traits. PNAS, 122(6), e2418424122. (www)

  @article{ , abstract = {Intergenerational transmission of inequality is a central question in the social sciences. We use one trait, beauty, to infer how much parents’ physical characteristics transmit inequality across generations. Analyses of a large-scale longitudinal dataset in the United States, and a much smaller dataset of Chinese parents and children, show that increases in parents’ looks are associated with increases in their child’s looks. A large dataset of U.S. siblings shows a positive correlation of their beauty. The appropriate weighted average from the three samples shows that a one SD increase in ratings of both parents’ looks is associated with a 0.25 SD increase in their child’s. Coupling these estimates with those from large literatures measuring the impact of beauty on earnings and the intergenerational elasticity of income suggests that a one SD difference in parents’ looks is correlated with a 0.074 SD difference in their adult child’s earnings, about U.S. $2,170 annually.}, archive = {J_PNAS}, author = {Hamermesh, Daniel S. and Zhang, Anwen}, doi = {10.1073/pnas.2418424122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2418424122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Human beauty illustrates the economic impact of heritable physical traits}, volume = {122}, year = {2025}, }
• (2025). Estimating the legibility of international borders. PNAS, 122(6), e2417812122. (www)

  @article{ , abstract = {Researchers in the social sciences are interested in the consequences of institutions, increasingly on a global scale. Institutions that may be negotiated between states can have consequences at a microlevel, as local populations adjust their expectations and ultimately even their behavior to take institutional rules into account. However, large-scale fine-grained analyses that test for the complex evidence of such institutions locally are rare. This article focuses on a key institution: International borders. Using computer vision techniques, we show that it is possible to produce a geographically specific, validated, and replicable way to characterize border legibility , by which we mean the ability to visually detect the presence of an international border in physical space. We develop and compare computer vision techniques to automatically estimate legibility scores for 627,656 imagery tiles from virtually every border in the world. We evaluate statistical and data-driven computer vision methods, finding that fine-tuning pretrained visual recognition models on a small set of human judgments allows us to produce local legibility scores globally that align well with human notions of legibility. Finally, we interpret these scores as useful approximations of states’ border orientations, a concept that prior literature has used to capture the visible investments states make in border areas to maintain jurisdictional authority territorially. We validate our measurement strategy using both human judgments and five nomological validation indicators.}, archive = {J_PNAS}, author = {Kenwick, Michael and Lim, Junghyun and Crane, Skyler and Wehrwein, Scott and Simmons, Beth A.}, doi = {10.1073/pnas.2417812122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2417812122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Estimating the legibility of international borders}, volume = {122}, year = {2025}, }
• (2025). Ethylene-independent modulation of root development by ACC via downregulation of WOX5 and group i CLE peptide expression. PNAS, 122(6), e2417735122. (www)

  @article{ , abstract = {In seed plants, the canonical role of 1-aminocyclopropane-1-carboxylic acid (ACC) is to serve as the precursor in the biosynthesis of the phytohormone ethylene, and indeed, ACC treatment is often used as a proxy for ethylene treatment. Increasing evidence suggests that ACC can also act independently of ethylene to regulate various aspects of plant growth and development. Here, we explore the effects of ACC on Arabidopsis thaliana root growth and the mechanisms by which it acts. ACC inhibits growth of the primary root in Arabidopsis seedlings when ethylene signaling is blocked, which becomes evident after 36 h of treatment with ACC. This reduced root growth is in part the result of suppressed cell proliferation in the root meristem resulting from altered expression of a key regulator of stem cell niche activity, WOX5. ACC also promotes lateral root (LR) development, in contrast to ethylene, which inhibits LR formation. Transcriptomic analysis of roots revealed no significant changes in gene expression after 45 min or 4 h of ACC treatment, but longer treatment times revealed a large number of differentially expressed genes, including the downregulation of the expression of a small group of phylogenetically related CLE peptides. Reduced expression of these group 1 CLEs in response to ACC leads to the activation of a transcription factor, LBD18, which promotes LR development. These results suggest that ACC acts to modulate multiple aspects of Arabidopsis root growth independently of ethylene via distinct transcriptional effects in the root meristem and LR precursor cells.}, archive = {J_PNAS}, author = {Mou, Wangshu and Khare, Ria and Polko, Joanna K. and Taylor, Isaiah and Xu, Juan and Xue, Dawei and Benfey, Philip and Van de Poel, Bram and Chang, Caren and Kieber, Joseph J.}, doi = {10.1073/pnas.2417735122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2417735122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Ethylene-independent modulation of root development by ACC via downregulation of WOX5 and group i CLE peptide expression}, volume = {122}, year = {2025}, }
• (2025). CO2 potentiates echinocandin efficacy during invasive candidiasis therapy via dephosphorylation of hsp90 by ptc2 in condensates. PNAS, 122(6), e2417721122. (www)

  @article{ , abstract = {Carbon dioxide is a signaling cue critical for fungal pathogenesis. Ptc2, a type 2C protein phosphatase (PP2C), serves as a conserved CO 2 sensor in fungi. By combining phosphoproteomic and biochemical assays, we identified Hsp90 as a direct target of Ptc2 at host CO 2 concentrations and Ssb1 as a Ptc2 target protein regardless of CO 2 levels in Candida albicans , the most prevalent human fungal pathogen. Ptc2 forms reversible condensates at elevated CO 2 , which enables the recruitment of Hsp90, but not Ssb1, to condensates, allowing efficient dephosphorylation. This process confers an enhanced susceptibility to caspofungin in vitro and during in vivo infection therapy. Importantly, we demonstrate this phenomenon in non-albicans Candida species. Sequential passages of C. albicans in mice with caspofungin treatment readily induce in vivo drug tolerance, causing therapeutic failure. These evolved strains display increased resistance to caspofungin under host concentrations of CO 2 but remain susceptible in air. Collectively, our study reveals a profound impact of host concentrations of CO 2 on antifungal drug susceptibility and connects this phenotype to therapeutic outcomes and highlights condensate formation as an efficient means that enables selective recruitment of substrates for certain signaling events.}, archive = {J_PNAS}, author = {Zhang, Mao and Zhao, Youzhi and Cui, Hao and Huang, Wenqiang and Xiong, Kang and Yang, Shan and Duan, Yuanyuan and He, Yong and Yang, Lianjuan and Su, Chang and Lu, Yang}, doi = {10.1073/pnas.2417721122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2417721122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CO2 potentiates echinocandin efficacy during invasive candidiasis therapy via dephosphorylation of hsp90 by ptc2 in condensates}, volume = {122}, year = {2025}, }
• (2025). TRNA selectivity during ribosome-associated quality control regulates the critical sterility-inducing temperature in two-line hybrid rice. PNAS, 122(6), e2417526122. (www)

  @article{ , abstract = {The two-line hybrid rice system, a cutting-edge hybrid rice breeding technology, has greatly boosted global food security. In thermo-sensitive genic male sterile (TGMS) lines, the critical sterility-inducing temperature (CSIT; the temperature at which TGMS lines change from male fertile to complete male sterile) acts as a key threshold. We recently uncovered that thermo-sensitive genic male sterility 5 ( tms5 ), a sterile locus presenting in over 95% of TGMS lines, leads to the overaccumulation of 2′,3′-cyclic phosphate (cP)-ΔCCA-tRNAs and a deficiency of mature tRNAs, which underlies the molecular mechanism of tms5 -mediated TGMS. However, there are a few reports on the regulatory mechanism controlling CSIT. Here, we identified a suppressor of tms5 , an amino acid substitution (T552I) in the rice Rqc2 (ribosome-associated quality control 2), increases the CSIT in tms5 lines through its C-terminal alanine and threonine modification (CATylation) activity. This substitution alters tRNA selectivity, leading to the recruitment of different tRNAs to the A-site of ribosome and CATylation rate by OsRqc2 during ribosome-associated quality control (RQC), a process that rescues stalled ribosomes and degrades abnormal nascent chains during translational elongation. Further, the mutation restores the levels of mature tRNA-Ser/Ile to increase the CSIT of tms5 lines. Our findings reveal the origin of overaccumulated cP-ΔCCA-tRNAs in tms5 lines, further deepening our understanding of the regulatory network in governing CSIT of TGMS lines containing tms5.}, archive = {J_PNAS}, author = {Zhou, Can and Liu, Chunyan and Yan, Bin and Sun, Jing and Li, Shengdong and Li, Ji and Wang, Jia and Huang, Xiahe and Yan, Wei and Yang, Shuying and Fu, Chenjian and Qin, Peng and Fu, Xingxue and Zhao, Xinghui and Wu, Yaxian and Song, Xianwei and Wang, Yingchun and Qian, Wenfeng and Yang, Yuanzhu and Cao, Xiaofeng}, doi = {10.1073/pnas.2417526122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2417526122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TRNA selectivity during ribosome-associated quality control regulates the critical sterility-inducing temperature in two-line hybrid rice}, volume = {122}, year = {2025}, }
• (2025). Co-zorbs: Motile, multispecies biofilms aid transport of diverse bacterial species. PNAS, 122(6), e2417327122. (www)

  @article{ , abstract = {Biofilms are three-dimensional structures containing one or more bacterial species embedded in extracellular polymeric substances. Although most biofilms are stationary, Flavobacterium johnsoniae forms a motile spherical biofilm called a zorb, which is propelled by its base cells and contains a polysaccharide core. Here, we report the formation of spatially organized, motile, multispecies biofilms, designated “co-zorbs,” that are distinguished by a core–shell structure. F. johnsoniae forms zorbs whose cells collect other bacterial species and transport them to the zorb core, forming a co-zorb. Live imaging revealed that co-zorbs also form in zebrafish, thereby demonstrating a different type of bacterial movement in vivo. This finding opens different avenues for understanding community behaviors, the role of biofilms in bulk bacterial transport, and collective strategies for microbial success in various environments.}, archive = {J_PNAS}, author = {Magesh, Shruthi and Schrope, Jonathan H. and Soto, Nayanna Mercado and Li, Chao and Hurley, Amanda I. and Huttenlocher, Anna and Beebe, David J. and Handelsman, Jo}, doi = {10.1073/pnas.2417327122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2417327122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Co-zorbs: Motile, multispecies biofilms aid transport of diverse bacterial species}, volume = {122}, year = {2025}, }
• (2025). Out-of-distribution generalization via composition: A lens through induction heads in transformers. PNAS, 122(6), e2417182122. (www)

  @article{ , abstract = {Large language models (LLMs) such as GPT-4 sometimes appear to be creative, solving novel tasks often with a few demonstrations in the prompt. These tasks require the models to generalize on distributions different from those from training data—which is known as out-of-distribution (OOD) generalization. Despite the tremendous success of LLMs, how they approach OOD generalization remains an open and underexplored question. We examine OOD generalization in settings where instances are generated according to hidden rules, including in-context learning with symbolic reasoning. Models are required to infer the hidden rules behind input prompts without any fine-tuning. We empirically examined the training dynamics of Transformers on a synthetic example and conducted extensive experiments on a variety of pretrained LLMs, focusing on a type of component known as induction heads. We found that OOD generalization and composition are tied together—models can learn rules by composing two self-attention layers, thereby achieving OOD generalization. Furthermore, a shared latent subspace in the embedding (or feature) space acts as a bridge for composition by aligning early layers and later layers, which we refer to as the common bridge representation hypothesis.}, archive = {J_PNAS}, author = {Song, Jiajun and Xu, Zhuoyan and Zhong, Yiqiao}, doi = {10.1073/pnas.2417182122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2417182122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Out-of-distribution generalization via composition: A lens through induction heads in transformers}, volume = {122}, year = {2025}, }
• (2025). Spatial propagation of temperate phages within and among biofilms. PNAS, 122(6), e2417058122. (www)

  @article{ , abstract = {Bacteria form groups composed of cells and a secreted polymeric matrix that controls their spatial organization. These groups—termed biofilms—can act as refuges from environmental disturbances and from biotic threats, including phages. Despite the ubiquity of temperate phages and bacterial biofilms, live propagation of temperate phages within biofilms has not been characterized on cellular spatial scales. Here, we leverage several approaches to track temperate phages and distinguish between lytic and lysogenic host infections. We determine that lysogeny within Escherichia coli biofilms initially occurs within a predictable region of cell group packing architecture on the biofilm periphery. Because lysogens are generally found on the periphery of large cell groups, where lytic viral infections also reduce local biofilm structural integrity, lysogens are predisposed to disperse into the passing liquid and are overrepresented in downstream biofilms formed from the dispersal pool of the original biofilm-phage system. Comparing our results with those for virulent phages reveals that temperate phages have unique advantages in propagating over long spatial and time scales within and among bacterial biofilms.}, archive = {J_PNAS}, author = {Winans, James B. and Zeng, Lanying and Nadell, Carey D.}, doi = {10.1073/pnas.2417058122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2417058122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatial propagation of temperate phages within and among biofilms}, volume = {122}, year = {2025}, }
• (2025). The ER–PM interaction is essential for cytokinesis and recruits the actin cytoskeleton through the SCAR/WAVE complex. PNAS, 122(6), e2416927122. (www)

  @article{ , abstract = {Plant cytokinesis requires coordination between the actin cytoskeleton, microtubules, and membranes to guide division plane formation and cell plate expansion; how these regulatory factors are coordinated remains unknown. The actin cytoskeleton assembly is controlled by several actin nucleation factors, such as the SCAR/WAVE complex, which regulates actin nucleation and branching through the activation of the ARP2/3 complex. The activity of these actin regulatory proteins is likely influenced by interactions with specific membranes; however, the molecular basis and the biological relevance of SCAR–membrane interactions are also unclear. In this study, we demonstrate that the ER–PM tethering protein VAP27-1 directly interacts with SCAR2 at the ER membrane and that they colocalize to guide cell plate orientation during cell division. In the root meristem, both VAP27-1 and SCAR2 exhibit polarized localization at the cell plates, where the interaction between ER and PM is abundant. VAP27-1 recruits SCAR2 to the cell division plane, where there is a high concentration of actin filaments. In the vap27-1346 mutant, the densities of cortical ER, SCAR2, and consequently actin filaments are significantly reduced at the cell division plane, affecting cell plate orientation, cell division, and root development. A similar phenomenon is also observed in the scar1234 mutant, suggesting that VAP27 and SCAR proteins regulate cell division through a similar pathway. In conclusion, our data reveal a plant-specific function of VAP27-regulated ER–PM interaction and advance our understanding of plant ER–PM contact site and its role in cell division.}, archive = {J_PNAS}, author = {Xu, Zhijing and Zang, Jingze and Zhang, Xintong and Zheng, Qiwei and Li, Yifan and Field, Nadine and Fiserova, Jindriska and Hua, Bing and Qu, Xiaolu and Kriechbaumer, Verena and Deeks, Michael J. and Hussey, Patrick J. and Wang, Pengwei}, doi = {10.1073/pnas.2416927122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2416927122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The ER–PM interaction is essential for cytokinesis and recruits the actin cytoskeleton through the SCAR/WAVE complex}, volume = {122}, year = {2025}, }
• (2025). Robust inattentive discrete choice. PNAS, 122(6), e2416643122. (www)

  @article{ , abstract = {Rational inattention models characterize optimal decision-making in data-rich environments. In such environments, it can be costly to look carefully at all of the information. Some information is much more salient for the decision at hand and merits closer scrutiny. The inattention decision model formalizes this choice and deduces how best to navigate through the potentially vast array of data when making decisions. In the rational formulation, the decision-maker commits fully to a subjective prior distribution over the possible states of the world that could be realized. We relax this assumption and look for a robustly optimal solution to the inattention problem by allowing the decision-maker to be ambiguity averse with respect to this prior. We feature a setup that is deliberately simple by a) assuming a discrete set of choices, b) using Shannon’s mutual information to quantify attention costs, and c) imposing relative entropy with respect to a baseline probability distribution to quantify prior divergence. We provide necessary and sufficient conditions for the robust solution and develop numerical methods to solve it. In comparison to the rational solution with no prior uncertainty, our decision-maker slants priors in more cautious or pessimistic directions when deducing how to allocate attention over the range of available information. This approach implements a form of robustness to prior misspecification, or equivalently, a form of ambiguity aversion. We explore some examples that show how the robust solution differs from the rational solution with a commitment to a subjective prior distribution and how it differs from imposing risk aversion.}, archive = {J_PNAS}, author = {Hansen, Lars Peter and Miao, Jianjun and Xing, Hao}, doi = {10.1073/pnas.2416643122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2416643122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Robust inattentive discrete choice}, volume = {122}, year = {2025}, }
• (2025). Fixational eye movements as active sensation for high visual acuity. PNAS, 122(6), e2416266122. (www)

  @article{ , abstract = {Perception and action are inherently entangled: our world view is shaped by how we explore our environment through complex and variable self-motion. Even when fixating stable stimuli, our eyes undergo small, involuntary movements. Fixational eye movements (FEM) render a stable world jittery on our retinae, which can be expected to harm neural coding. Yet, empirical evidence suggests that FEM help rather than harm human perception of fine detail. Here, we elucidate this paradox by uncovering under which conditions FEM improve or impair retinal coding and human acuity. We combine theory and experiment: model accuracy is directly compared to that of healthy human subjects in a visual acuity task. Acuity is modeled by applying an ideal Bayesian classifier to simulations of retinal spiking activity in the presence of FEM. In addition, empirical FEM are monitored using high-resolution eye-tracking by an adaptive optics scanning laser ophthalmoscope. FEM introduce variability in retinal ganglion cell activity, but they also effectively preprocess inputs to facilitate retinal information encoding. Based on an interplay of these mechanisms, our model predicts a relation between visual acuity, FEM amplitude, and single-trial stimulus size that quantitatively accounts for experimental observations and captures the beneficial effect of FEM. Moreover, we observe that while human subjects’ FEM statistics vary with stimulus size, our model suggests that subjects’ FEM amplitude remains within a near-optimal range, where acuity is enhanced compared to much larger or smaller amplitudes. Overall, our findings indicate that perception benefits from action even at the fine spatiotemporal scale of FEM.}, archive = {J_PNAS}, author = {Nghiem, Trang-Anh E. and Witten, Jenny L. and Dufour, Oscar and Harmening, Wolf M. and Azeredo da Silveira, Rava}, doi = {10.1073/pnas.2416266122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2416266122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fixational eye movements as active sensation for high visual acuity}, volume = {122}, year = {2025}, }
• (2025). Anomalous suppression of large-scale density fluctuations in classical and quantum spin liquids. PNAS, 122(6), e2416111122. (www)

  @article{ , abstract = {Classical spin liquids (CSLs) are intriguing states of matter that do not exhibit long-range magnetic order and are characterized by an extensive ground-state degeneracy. Adding quantum fluctuations, which induce dynamics between these different classical ground states, can give rise to quantum spin liquids (QSLs). QSLs are highly entangled quantum phases of matter characterized by fascinating emergent properties, such as fractionalized excitations and topological order. One such exotic quantum liquid is the Z 2 QSL, which can be regarded as a resonating valence bond (RVB) state formed from superpositions of dimer coverings of an underlying lattice. In this work, we unveil a hidden large-scale structural property of archetypal CSLs and QSLs known as hyperuniformity, i.e., normalized infinite-wavelength density fluctuations are completely suppressed in these systems. In particular, we first demonstrate that classical ensembles of close-packed dimers and their corresponding quantum RVB states are perfectly hyperuniform in general. Subsequently, we focus on a ruby-lattice spin liquid that was recently realized in a Rydberg-atom quantum simulator, and show that the QSL remains effectively hyperuniform even in the presence of a finite density of spinon and vison excitations, as long as the dimer constraint is still largely preserved. Moreover, we demonstrate that metrics based on the framework of hyperuniformity can be used to distinguish the QSL from other proximate quantum phases. These metrics can help identify potential QSL candidates, which can then be further analyzed using more advanced, computationally intensive quantum numerics to confirm their status as true QSLs.}, archive = {J_PNAS}, author = {Chen, Duyu and Samajdar, Rhine and Jiao, Yang and Torquato, Salvatore}, doi = {10.1073/pnas.2416111122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2416111122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Anomalous suppression of large-scale density fluctuations in classical and quantum spin liquids}, volume = {122}, year = {2025}, }
• (2025). Impact of APOE, klotho, and sex on cognitive decline with aging. PNAS, 122(6), e2416042122. (www)

  @article{ , abstract = {The effects of apolipoprotein E ( APOE ) and Klotho genes, both implicated in aging, on human cognition as a function of sex and age are yet to be definitively established. Here, we showed in the largest cohort studied to date ( N = 320,861) that APOE homozygous ε4 carriers had a greater decline in cognition with aging compared to ε3 carriers (ε3/ε4 and ε3/ε3) as well as smaller hippocampi and amygdala ( N = 29,510). Critically, sex and age differentially affected the decline in cognition. Younger (40 to 50 y) female homozygous ε4 carriers showed a cognitive advantage over female ε3 carriers, but this advantage was not present in males. By contrast, Klotho-VS heterozygosity did not affect cognition or brain volume, regardless of APOE genotype, sex, or age. These cognitive trajectories with aging demonstrate clear sex-dependent antagonistic pleiotropy effects of APOE ε4, but no effects of Klotho genotype on cognition and brain volume.}, archive = {J_PNAS}, author = {Shibata, Kengo and Chen, Cheng and Tai, Xin You and Manohar, Sanjay G. and Husain, Masud}, doi = {10.1073/pnas.2416042122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2416042122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Impact of APOE, klotho, and sex on cognitive decline with aging}, volume = {122}, year = {2025}, }
• (2025). Variable transduction of thyroid hormone signaling in structures of the mouse brain. PNAS, 122(6), e2415970122. (www)

  @article{ , abstract = {L-thyroxine (L-T4) monotherapy is the standard treatment for hypothyroidism, administered daily to normalize TSH levels. Once absorbed, T4 is converted to T3 to alleviate most symptoms. However, this treatment abnormally elevates plasma T4 levels in over 50% of patients. Using L-T4-treated Thyroid Hormone (TH) Action Indicator mice, which express a T3-regulated luciferase (Luc) reporter, we examined whether these T4 elevations disrupt TH signaling. Hypothyroid mice exhibited reduced Luc expression across brain regions, and L-T4 treatment failed to restore T3 signaling uniformly. There was also variability in the activity of type 2 deiodinase (D2), the enzyme that generates most brain T3. Intracerebroventricular T4 administration achieved higher elevation of Luc expression in the mediobasal hypothalamus compared to the cortex, and studies on cultured cortical astrocytes and hypothalamic tanycytes revealed cell-type-specific responses to T4. In tanycytes, exposure to T4 sustained D2 activity, leading to progressive T3 signaling, whereas in astrocytes, T4 exposure triggered a drop in D2 activity, limiting T3 production through a ubiquitin-dependent, self-limiting mechanism. The sustained D2 activity in tanycytes was linked to rapid deubiquitination by USP33, as confirmed using a ubiquitin-specific protease (USP) pan-inhibitor and USP33 knockout mice. In conclusion, the brain’s response to L-T4 treatment is heterogeneous, influenced by cell-specific regulation of D2-mediated T3 production. While cortical astrocytes exhibit limited T3 signaling due to D2 ubiquitination, tanycytes coexpressing USP33 amplify T3 signaling by rescuing ubiquitinated D2 from proteasomal degradation. These findings provide mechanistic insights into the limitations of L-T4 therapy and highlight the need for tailored approaches to managing hypothyroidism.}, archive = {J_PNAS}, author = {Sinkó, Richárd and Salas-Lucia, Federico and Mohácsik, Petra and Halmos, Emese and Wittmann, Gábor and Egri, Péter and Bocco, Barbara M. L. C. and Batistuzzo, Alice and Fonseca, Tatiana L. and Fekete, Csaba and Bianco, Antonio C. and Gereben, Balázs}, doi = {10.1073/pnas.2415970122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2415970122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Variable transduction of thyroid hormone signaling in structures of the mouse brain}, volume = {122}, year = {2025}, }
• (2025). Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer. PNAS, 122(6), e2415308122. (www)

  @article{ , abstract = {Inhibiting the androgen receptor (AR) is effective for treatment of advanced prostate cancers because of their AR-dependent luminal epithelial cell identity. Tumors progress during therapy to castration-resistant prostate cancer (CRPC) by restoring AR signaling and maintaining luminal identity or by converting through lineage plasticity to a neuroendocrine (NE) identity or double-negative CRPC (DNPC) lacking luminal or NE identities. Here, we show that DNPC cells express genes defining basal, club, and hillock epithelial cells from benign prostate. We identified KLF5 as a regulator of genes defining this mixed basal, club, and hillock cell identity in DNPC models. KLF5-mediated upregulation of RARG uncovered a DNPC sensitivity to growth inhibition by retinoic acid receptor agonists, which down-regulated KLF5 and up-regulated AR. These findings offer CRPC classifications based on prostate epithelial cell identities and nominate KLF5 and RARG as therapeutic targets for CRPC displaying a mixed basal, club, and hillock identity.}, archive = {J_PNAS}, author = {Pitzen, Samuel P. and Rudenick, Amber N. and Qiu, Yinjie and Zhang, Weijie and Munro, Sarah A. and McCluskey, Braedan M. and Forster, Colleen and Bergom, Hannah E. and Ali, Atef and Boytim, Ella and Lafin, John T. and Linder, Simon and Ismail, Mazlina and Devlies, Wout and Sessions, Conner J. and Claessens, Frank and Joniau, Steven and Attard, Gerhardt and Zwart, Wilbert and Nelson, Peter S. and Corey, Eva and Wang, Yuzhuo and Lang, Joshua M. and Beltran, Himisha and Strand, Douglas and Antonarakis, Emmanuel S. and Hwang, Justin and Murugan, Paari and Huang, R. Stephanie and Dehm, Scott M.}, doi = {10.1073/pnas.2415308122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2415308122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer}, volume = {122}, year = {2025}, }
• (2025). The unique reactivity of EKODE lipid peroxidation products allows in vivo detection of inflammation. PNAS, 122(6), e2415039122. (www)

  @article{ , abstract = {Lipid peroxidation is a complex biochemical process associated with oxidative stress, and its products play crucial roles in cellular signaling and the pathophysiology of many diseases. Among the diverse array of lipid peroxidation (LPO) products, epoxyketooctadecenoic acids (EKODEs) have emerged as intriguing molecules with potential impacts on inflammatory diseases. EKODEs arise from linoleic acid reacting with reactive oxygen and nitrogen species present during inflammation. A hallmark of many LPO products is an electrophilic chemical functionality that can react with different biological nucleophiles to form adducts that impact a broad swath of physiologic processes. Here, we present the identification of reactivity patterns exhibited by the EKODE class of LPO products that arise due to the unique chemistry of the EKODE electrophiles, namely α, β-unsaturated epoxyketones of variable regiochemistry. Our initial investigations with models of the EKODE reactive core showed that surrogates of lysine did not react, and histidine nucleophiles formed reversible Michael adducts. However, when models of cysteine nucleophiles were tested, a unique reactivity profile emerged where rapid Michael addition was followed by slow rearrangement and epoxide opening at an unpredicted electrophilic site, affording what we postulated to be an advanced lipoxidation end product (ALE). After confirming the EKODE reactivity in model systems, we produced polyclonal antibodies of a stable epitope of the EKODE-based ALE and used these antibodies to investigate an approach for in vivo monitoring of inflammatory disease progression.}, archive = {J_PNAS}, author = {Shi, Chuan and Eskandari, Roozbeh and Zhang, Jianye and Zhang, Guofang and Li, Li and Hawkins, Deandrea and Zhu, Xiongwei and Tochtrop, Gregory P.}, doi = {10.1073/pnas.2415039122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2415039122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The unique reactivity of EKODE lipid peroxidation products allows in vivo detection of inflammation}, volume = {122}, year = {2025}, }
• (2025). The estimated cost of preventing extinction and progressing recovery for australia’s priority threatened species. PNAS, 122(6), e2414985122. (www)

  @article{ , abstract = {The global extinction crisis is intensifying rapidly, driven by habitat loss, overexploitation, climate change, invasive species, and disease. This unprecedented loss of species not only threatens ecological integrity but also undermines ecosystem services vital for human survival. In response, many countries have set ambitious conservation targets such as halting species extinctions, yet the necessary financial commitments to achieve this are rarely prescribed. Estimating costs can be achieved using an ensemble of spatially variable species-specific cost models for threat abatement activities. We employ this method to provide a cost assessment to halt extinctions for Australia’s priority terrestrial and freshwater species. We show that it will cost ~AUD15.6 billion/year for 30 y to halt extinctions for these 99 priority species (comparable to 1% of Australia’s GDP). The more ambitious objectives to move priority species down one threat category (~AUD103.7 billion/year) or remove from the threatened species list entirely (~AUD157.7 billion/year) would require considerably more investment. Regardless of what is spent, we found that 16 (16%) priority species could not be removed from the threatened species list due to extensive historical declines and pervasive, ongoing, unmanageable threats, such as climate change. But implementing these efforts could ensure conservation benefits for over 43% of all nationally listed nonmarine threatened species. Adequate funding is crucial for meeting government commitments and requires both government leadership and private sector investment.}, archive = {J_PNAS}, author = {Ward, Michelle and Possingham, Hugh P. and Wintle, Brendan A. and Woinarski, John C. Z. and Marsh, Jessica R. and Chapple, David G. and Lintermans, Mark and Scheele, Ben C. and Whiterod, Nick S. and Hoskin, Conrad J. and Aska, Bora and Yong, Chuanji and Tulloch, Ayesha and Stewart, Romola and Watson, James E. M.}, doi = {10.1073/pnas.2414985122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2414985122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The estimated cost of preventing extinction and progressing recovery for australia’s priority threatened species}, volume = {122}, year = {2025}, }
• (2025). A 5,000-fold increase in the HAT reactivity of a nonheme FeIV=O complex simply by replacing two pyridines of the pentadentate N4Py ligand with pyrazoles. PNAS, 122(6), e2414962122. (www)

  @article{ , abstract = {A pentadentate [N5] ligand (N2Py2Pz) based on the classic N4Py ( N,N -bis(2-pyridylmethyl)- N -bis(2-pyridyl)methylamine) framework has been synthesized by replacing the two pyridylmethyl arms with corresponding ( N -methyl)pyrazolylmethyl units to form [ N- bis(1-methyl-2-pyrazolyl)methyl- N -( bis -2-pyridylmethyl)amine] (L1). The oxidation of the iron(II) precursor (N2Py2Pz)Fe II (OTf) 2 ( 1 ) with ( t BuSO 2 )C 6 H 4 IO at 298 K leads to the formation of the [Fe IV (O)(N2Py2Pz)] 2+ intermediate ( 2 ) with a near-IR band at 750 nm (ε M = 250 M −1 cm −1 ) and a t 1/2 ~ 2 min at 298 K. The introduction of the less basic pyrazolylmethyl ligands in place of two pyridylmethyl units generates Fe IV =O intermediate 2 that exhibits a cyclohexane oxidation rate of 0.29 s −1 at 298 K, which is 5,000-fold faster than that observed for the classic Fe IV (O)N4Py parent complex and 40,000-fold more reactive than the least reactive Fe IV (O)N2Py2Q′ complex in this series (Py = pyridine, Q′ = isoquinoline) recently reported by Nordlander.}, archive = {J_PNAS}, author = {Pal, Nabhendu and Xiong, Jin and Jahja, Mehmet and Mahri, Sami and Young, Victor G. and Guo, Yisong and Swart, Marcel and Que, Lawrence}, doi = {10.1073/pnas.2414962122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2414962122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A 5,000-fold increase in the HAT reactivity of a nonheme FeIV=O complex simply by replacing two pyridines of the pentadentate N4Py ligand with pyrazoles}, volume = {122}, year = {2025}, }
• (2025). Bilateral cellular flows display asymmetry prior to left–right organizer formation in amniote gastrulation. PNAS, 122(6), e2414860122. (www)

  @article{ , abstract = {A bilateral body plan is predominant throughout the animal kingdom. Bilaterality of amniote embryos becomes recognizable as midline morphogenesis begins at gastrulation, bisecting an embryonic field into the left and right sides, and left–right (LR) asymmetry patterning follows. While a series of laterality genes expressed after the LR compartmentalization has been extensively studied, the laterality patterning prior to and at the initiation of midline morphogenesis has remained unclear. Here, through a biophysical quantification in a high spatial and temporal resolution, applied to a chick model system, we show that a large-scale bilateral counterrotating cellular flow, termed “polonaise movements”, display LR asymmetries in early gastrulation. This cell movement starts prior to the formation of the primitive streak (PS) (the earliest midline structure) and the subsequent appearance of Hensen’s node (the LR organizer). The cellular flow speed and vorticity unravel the location and timing of the LR asymmetries. The bilateral flows displayed a Right dominance after 6 h since the start of cell movements. Mitotic arrest that diminishes PS formation resulted in changes in the bilateral flow pattern, but the Right dominance persisted. Our data indicate that the LR asymmetry in amniote gastrula becomes detectable earlier than suggested by current models, which assume that the asymmetric regulation of the laterality signals at the node leads to the LR patterning. More broadly, our results suggest that physical processes can play an unexpected but significant role in influencing LR laterality during embryonic development.}, archive = {J_PNAS}, author = {Asai, Rieko and Sinha, Shubham and Prakash, Vivek N. and Mikawa, Takashi}, doi = {10.1073/pnas.2414860122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2414860122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bilateral cellular flows display asymmetry prior to left–right organizer formation in amniote gastrulation}, volume = {122}, year = {2025}, }
• (2025). Prey depletion, interspecific competition, and the energetics of hunting in endangered african wild dogs, lycaon pictus. PNAS, 122(6), e2414772122. (www)

  @article{ , abstract = {Large herbivores are in decline in much of the world, including sub-Saharan Africa, and true apex carnivores like the lion ( Panthera leo ) decline in parallel with their prey. As a consequence, competitively subordinate carnivores like the African wild dog ( Lycaon pictus ) are simultaneously experiencing a costly reduction in resources and a beneficial reduction in dominant competitors. The net effect is not intuitively obvious, but wild dogs’ density, survival, and reproduction are all low in areas that are strongly affected by prey depletion. To assess whether these correlations are causal, we tested the hypothesized mechanism, using data from 13 wild dog packs in two ecosystems to relate the energetic costs and benefits of hunting to variation in prey density, while controlling for the effects of local lion density, pack size, the number of dependent pups, and the level of protection. All of these variables affected the energetic costs and benefits of hunting. In areas with low prey density, the magnitude of movements and vectorial dynamic body acceleration (a measure of energy expenditure) both increased, the mass of killed prey decreased, and the number of kills per day did not change detectably. Programs to reduce or reverse the decline of large herbivore populations should be an effective means of improving the status of endangered subordinate competitors like the wild dog, and should be a high priority. Our results demonstrate the utility of research that integrates data from biomonitoring with direct, long-term observation of endangered species, their competitors, and their resources.}, archive = {J_PNAS}, author = {Creel, Scott and Redcliffe, James and Goodheart, Ben and Reyes de Merkle, Johnathan and Mwape, Henry and Matsushima, Stephanie and Dart, Chase and Banda, Kachama and Mayani, Bridget and Njobvu, Johane and Kabungo, Reuben and Mungolo, Michelo and Kabwe, Ruth and Kaseketi, Emmanuel and Donald, Will and Kaluka, Adrian and Chifunte, Clive and Maimbo, Howard and Plankenhorn, Luzy and Christianson, David and Becker, Matthew S. and Wilson, Rory P.}, doi = {10.1073/pnas.2414772122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2414772122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Prey depletion, interspecific competition, and the energetics of hunting in endangered african wild dogs, lycaon pictus}, volume = {122}, year = {2025}, }
• (2025). Human MAIT cell response profiles biased toward IL-17 or IL-10 are distinct effector states directed by the cytokine milieu. PNAS, 122(6), e2414230122. (www)

  @article{ , abstract = {Mucosal-associated invariant T (MAIT) cells are unconventional T cells that mediate rapid antimicrobial immune responses to antigens derived from microbial riboflavin pathway metabolites presented by the evolutionarily conserved MR1 molecules. MAIT cells represent a large pre-expanded T cell subset in humans and are involved in both protective immunity and inflammatory immunopathology. However, what controls the functional heterogeneity of human MAIT cell responses is still largely unclear. Here, combining functional and transcriptomic analyses, we investigate how MAIT cell response programs are influenced by the cytokine milieu at the time of antigen recognition. Activation by MR1-presented antigen together with IL-12 induces intermediate levels of IFNγ and TNF, as well as a regulatory profile with substantial IL-10 production and elevated expression of TIM-3, LAG-3, and PD-1. Activation by the combination of antigen and IL-12 induces a c-MAF-dependent program required for IL-10 production. The MAIT cell-derived IL-10 mediates both autocrine and paracrine immune regulation. In contrast, coactivation of MAIT cells with IL-18 induces IL-17, GM-CSF, IFNγ, and TNF, without IL-10. Notably, IL-18 dominantly counteracts IL-10 expression. The activation states biased toward IL-10 or IL-17 production are reversible and do not represent stable subsets. Finally, MR1-restricted TCR-mediated activation without cytokine coactivation drives primarily granzyme B cytolytic arming. Altogether, these findings demonstrate that human MAIT cells adapt their functional effector response during antigen recognition to cytokine cues in the microenvironment, and identify programs biased toward either regulatory c-MAF-dependent IL-10 expression, or an inflammatory IL-17 and GM-CSF profile.}, archive = {J_PNAS}, author = {Boulouis, Caroline and Mouchtaridi, Elli and Müller, Thomas R. and Mak, Jeffrey Y. W. and Fairlie, David P. and Bergman, Peter and Michaëlsson, Jakob and Halfvarson, Jonas and Mjösberg, Jenny and Buggert, Marcus and Sandberg, Johan K.}, doi = {10.1073/pnas.2414230122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2414230122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Human MAIT cell response profiles biased toward IL-17 or IL-10 are distinct effector states directed by the cytokine milieu}, volume = {122}, year = {2025}, }
• (2025). Engineering drive–selection balance for localized population suppression with neutral dynamics. PNAS, 122(6), e2414207122. (www)

  @article{ , abstract = {While the release of sterile males has been highly successful in suppressing some pest populations, it is impractical for many species due to the males disappearing after a single generation, necessitating large, repeated releases to maintain sufficient impact. Synthetic gene drives promise more efficient approaches since they can increase in frequency from rare, yet this also allows them to spread across a landscape, which may not always be desired. Between these two extremes are selectively neutral genetic constructs which persist at the frequency they are released, offering the potential for efficient suppression that remains localized. One way to achieve this would be to have perfect balance, at all construct frequencies, between gene drive increasing frequency and selection decreasing it. Here, we describe a way to closely approximate this balance using a toxin–antidote genetic construct that causes recessive lethality or sterility, encodes a genomic editor that makes dominant lethal or sterile edits in the genome, and provides protection against the action or consequences of the editing. Computer modeling shows that this design can be 100-fold more efficient than sterile males, increasing to 1,000-fold when released alongside a genetic booster. We describe designs for CRISPR-based molecular construction, including options that avoid using recoded genes as antidotes.}, archive = {J_PNAS}, author = {Willis, Katie and Burt, Austin}, doi = {10.1073/pnas.2414207122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2414207122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Engineering drive–selection balance for localized population suppression with neutral dynamics}, volume = {122}, year = {2025}, }
• (2025). Turbulence enhances wave attenuation of seagrass in combined wave–current flows. PNAS, 122(6), e2414150122. (www)

  @article{ , abstract = {The wave attenuation properties of seagrasses are key to accurately predict how effective these plants are at protecting coasts from erosion and floods. While recent studies have significantly advanced the understanding of seagrass wave attenuation in pure-wave conditions, the presence of a current introduces several complications that have yet to be fully explored. In the present study, we quantify the wave attenuation of seagrass canopies in the presence of a current parallel to the direction of wave propagation via experiments conducted with dynamically scaled mimics of seagrass installed in a laboratory flume facility. The dataset we present is the largest of its kind and spans a broad range of wave properties, current velocities, water depths, and plant densities for a total of over 300 experiments. Using our experimental results, we show that the commonly employed approach of modeling wave attenuation as a result of vegetation drag works well for a range of conditions but underpredicts systematically when turbulence generated by the interaction between the seagrass canopy and the current is sufficiently strong. We then employ phenomenological arguments and experimental data to identify a nondimensional parameter that effectively quantifies the relative importance of turbulence and drag in dictating the overall observed wave attenuation. Moreover, we propose a simple but physically based modeling approach that is consistent with the proposed phenomenology and can be used for applications in coastal waters.}, archive = {J_PNAS}, author = {Vettori, Davide and Giordana, Francesco and Manes, Costantino}, doi = {10.1073/pnas.2414150122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2414150122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Turbulence enhances wave attenuation of seagrass in combined wave–current flows}, volume = {122}, year = {2025}, }
• (2025). G-quadruplexes catalyze protein folding by reshaping the energetic landscape. PNAS, 122(6), e2414045122. (www)

  @article{ , abstract = {Many proteins have slow folding times in vitro that are physiologically untenable. To combat this challenge, ATP-dependent chaperonins are thought to possess the unique ability to catalyze protein folding. Performing quantitative model selection using protein folding and unfolding data, we here show that short nucleic acids containing G-quadruplex (G4) structure can also catalyze protein folding. Performing the experiments as a function of temperature demonstrates that the G4 reshapes the underlying driving forces of protein folding. As short nucleic acids can catalyze protein folding without the input of ATP, the ability of the cell to fold proteins is far higher than previously anticipated.}, archive = {J_PNAS}, author = {Huang, Zijue and Ghosh, Kingshuk and Stull, Frederick and Horowitz, Scott}, doi = {10.1073/pnas.2414045122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2414045122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {G-quadruplexes catalyze protein folding by reshaping the energetic landscape}, volume = {122}, year = {2025}, }
• (2025). Activation-induced thrombospondin-4 works with thrombospondin-1 to build cytotoxic supramolecular attack particles. PNAS, 122(6), e2413866122. (www)

  @article{ , abstract = {Cytotoxic attack particles released by CTLs and NK cells include diverse phospholipid membrane and glycoprotein encapsulated entities that contribute to target cell killing. Supramolecular attack particles (SMAPs) are one type of particle characterized by a cytotoxic core enriched in granzymes and perforin surrounded by a proteinaceous shell including thrombospondin (TSP)-1. TSP-4 was also detected in bulk analysis of SMAPs released by CTLs; however, it has not been investigated whether TSP-4 contributes to distinct SMAP types or the same SMAP type as TSP-1 and, if in the same type of SMAP, whether TSP-4 and TSP-1 cooperate or compete. Here, we observed that TSP-4 expression increased upon CD8 + T cell activation while, surprisingly, TSP-1 was down-regulated. Correlative Light and Electron Microscopy and Stimulated Emission Depletion microscopy localized TSP-4 and TSP-1 in SMAP-containing multicore granules. Superresolution dSTORM revealed that TSP-4 and TSP-1 are usually enriched in the same SMAPs while particles with single-positive shells are rare. Retention Using Selective Hooks assays showed that TSP-4 localizes to the lytic granules faster than TSP-1 and promotes its accumulation therein. TSP-4 contributed to direct CTL-mediated killing, as previously shown for TSP-1. TSP-4 and TSP-1 were both required for latent SMAP-mediated cell killing, in which released SMAPs kill targets after removal of the CTLs. Of note, we found that chronic lymphocytic leukemia (CLL) cell culture supernatants suppressed expression of TSP-4 in CTL and latent SMAP-mediated killing. These results identify TSP-4 as a functionally important component of SMAPs and suggest that SMAPs may be targeted for immune suppression by CLL.}, archive = {J_PNAS}, author = {Cassioli, Chiara and Capitani, Nagaja and Staton, Claire C. and Schirra, Claudia and Finetti, Francesca and Onnis, Anna and Alawar, Nadia and Tu, Szu-Min and Lopresti, Ludovica and Tatangelo, Vanessa and Tangredi, Carmela and Valvo, Salvatore and Chang, Hsin-Fang and Miccoli, Annachiara and Compeer, Ewoud B. and Nicholls, Jemma and Blazar, Bruce R. and Marotta, Giuseppe and Wood, Matthew J. A. and Trentin, Livio and Patrussi, Laura and Dustin, Michael L. and Becherer, Ute and Baldari, Cosima T.}, doi = {10.1073/pnas.2413866122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2413866122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Activation-induced thrombospondin-4 works with thrombospondin-1 to build cytotoxic supramolecular attack particles}, volume = {122}, year = {2025}, }
• (2025). Evidence for domain-general arousal from semantic and neuroimaging meta-analyses reconciles opposing views on arousal. PNAS, 122(6), e2413808122. (www)

  @article{ , abstract = {Arousal refers to changes in brain-body state underpinning motivated behavior but lacks a proper definition and taxonomy. Neuroscience and psychology textbooks offer surprisingly different views on what arousal is, from a global brain-wide modulation of neuronal activity to a multidimensional construct, with specific brain-body patterns tuned to a given situation. The huge number of scientific articles mentioning arousal (~50,000) highlights the importance of the concept but also explains why such a vast literature has never been systematically reviewed so far. Here, we leverage the tools of natural language processing to probe the nature of arousal in a data-driven, comprehensive manner. We show that arousal comes in seven varieties: cognitive, emotional, physiological, sexual, related to stress disorders, to sleep, or to sleep disorders. We then ask whether domain-general arousal exists at the cortical level, and run meta-analyses of the brain imaging literature to reveal that all varieties of arousal, except arousal in sleep disorders for lack of data, converge onto a cortical network composed of the presupplementary motor area and the left and right dorsal anterior insula. More precisely, we find that activity in dysgranular insular area 7 (Jülich atlas), the region with the highest convergence across varieties of arousal, is also specifically associated with arousal. The domain-general arousal network might trigger the reorganization of large-scale brain networks—a global mechanism—resulting in a context-specific configuration—in line with the multidimensional view. Future taxonomies of arousal refining the alignment between concepts and data should include domain-general arousal as a central component.}, archive = {J_PNAS}, author = {Sabat, Magdalena and de Dampierre, Charles and Tallon-Baudry, Catherine}, doi = {10.1073/pnas.2413808122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2413808122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evidence for domain-general arousal from semantic and neuroimaging meta-analyses reconciles opposing views on arousal}, volume = {122}, year = {2025}, }
• (2025). Temperature-dependent polar lignification of a seed coat suberin layer promoting dormancy in arabidopsis thaliana. PNAS, 122(6), e2413627122. (www)

  @article{ , abstract = {The seed is a landmark plant adaptation where the embryo is sheltered by a protective seed coat to facilitate dispersion. In Arabidopsis , the seed coat, derived from ovular integuments, plays a critical role in maintaining dormancy, ensuring germination occurs during a favorable season. Dormancy is enhanced by cold temperatures during seed development by affecting seed coat permeability through changes in apoplastic barriers. However, their localization and composition are poorly understood. This study identifies and investigates a polar barrier in the seed coat’s outer integument (oi1) cells. We present histological, biochemical, and genetic evidence showing that cold promotes polar seed coat lignification of the outer integument 1 (oi1) cells and suberization throughout the entire oi1 cell boundary. The polar oi1 barrier is regulated by the transcription factors MYB107 and MYB9. MYB107, in particular, is crucial for the lignified polar oi1 barrier formation under cold temperatures. The absence of the oi1 barrier in mutant seeds correlates with increased permeability and reduced dormancy. Our findings elucidate how temperature-induced modifications in seed coat composition regulate dormancy, highlighting the roles of suberin and lignin in this process.}, archive = {J_PNAS}, author = {Hyvärinen, Lena and Fuchs, Christelle and Utz-Pugin, Anne and Gully, Kay and Megies, Christian and Holbein, Julia and Iwasaki, Mayumi and Demonsais, Lara and Capitão, Maria Beatriz and Barberon, Marie and Franke, Rochus B. and Nawrath, Christiane and Loubéry, Sylvain and Lopez-Molina, Luis}, doi = {10.1073/pnas.2413627122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2413627122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Temperature-dependent polar lignification of a seed coat suberin layer promoting dormancy in arabidopsis thaliana}, volume = {122}, year = {2025}, }
• (2025). Free-electron resonance transition radiation via brewster randomness. PNAS, 122(6), e2413336122. (www)

  @article{ , abstract = {Free-electron radiation, such as Cherenkov radiation and transition radiation, can generate light at arbitrary frequencies and is fundamental to diverse applications, ranging from electron microscopy, spectroscopy, lasers, to particle detectors. Generally, the features of free-electron radiation are stochastic when electrons interact with random media. Counterintuitively, here, we reveal a type of free-electron radiation that has both its intensity and directionality invariant to specific sorts of long-range structural randomness. Essentially, this invariance is enabled by the Brewster effect and the judiciously engineered phase coherence condition of emitted light, namely that the light induced by electron’s penetration through a layered aperiodic nanostructure is engineered to interfere constructively at the Brewster angle. As such, when each constituent layer with a random thickness fulfills this phase coherence condition, there is always the emergence of free-electron resonance transition radiation at the Brewster angle. At this resonant Brewster angle, we further find that the radiation intensity and directionality could be enhanced by orders of magnitude by readily increasing the interface number. The revealed resonance transition radiation via long-range Brewster randomness may offer a feasible route to explore more enticing photonic applications driven by free electrons, such as light sources at previously unreachable spectral regimes, optical frequency combs, particle detectors, and random lasers.}, archive = {J_PNAS}, author = {Gong, Zheng and Chen, Ruoxi and Wang, Zun and Xi, Xiangfeng and Yang, Yi and Zhang, Baile and Chen, Hongsheng and Kaminer, Ido and Lin, Xiao}, doi = {10.1073/pnas.2413336122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2413336122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Free-electron resonance transition radiation via brewster randomness}, volume = {122}, year = {2025}, }
• (2025). Extrinsic induction of apoptosis and tumor suppression via the p53–Reprimo–Hippo–YAP/TAZ–p73 pathway. PNAS, 122(6), e2413126122. (www)

  @article{ , abstract = {Tumor progression is suppressed by inherent cellular mechanisms such as apoptosis. The p53 tumor suppressor gene is the most commonly mutated gene in human cancer and plays a pivotal role in tumor suppression. RPRM is a target gene of p53 known to be involved in tumor suppression, but its molecular function has remained elusive. Here, we report that Reprimo (the protein product of RPRM ) is secreted and extrinsically induces apoptosis in recipient cells. We identified FAT1, FAT4, CELSR1, CELSR2, and CELSR3, members of the protocadherin family, as receptors for Reprimo. Subsequent analyses revealed that Reprimo acts upstream of the Hippo–YAP/TAZ–p73 axis and induces apoptosis by transactivating various proapoptotic genes. In vivo analyses further support the tumor-suppressive effects of secreted Reprimo. These findings identify the p53–Reprimo–Hippo–YAP/TAZ–p73 axis as an extrinsic apoptosis pathway that plays a crucial role in tumor suppression. Our finding of the innate tumor eliminator Reprimo and the downstream pathway offers a promising avenue for the pharmacological treatment of cancer.}, archive = {J_PNAS}, author = {Takikawa, Masahiro and Nakano, Airi and Krishnaraj, Jayaraman and Tabata, Yuko and Watanabe, Yuzo and Okabe, Atsushi and Sakaguchi, Yukiko and Fujiki, Ryoji and Mochizuki, Ami and Tajima, Tomoko and Sada, Akane and Matsushita, Shu and Wakabayashi, Yuichi and Araki, Kimi and Kaneda, Atsushi and Ishikawa, Fuyuki and Sadaie, Mahito and Ohki, Rieko}, doi = {10.1073/pnas.2413126122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2413126122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Extrinsic induction of apoptosis and tumor suppression via the p53–Reprimo–Hippo–YAP/TAZ–p73 pathway}, volume = {122}, year = {2025}, }
• (2025). Active vision in freely moving marmosets using head-mounted eye tracking. PNAS, 122(6), e2412954122. (www)

  @article{ , abstract = {Our understanding of how vision functions as primates actively navigate the real-world is remarkably sparse. As most data have been limited to chaired and typically head-restrained animals, the synergistic interactions of different motor actions/plans inherent to active sensing—e.g., eyes, head, posture, movement, etc.—on visual perception are largely unknown. To address this considerable gap in knowledge, we developed an innovative wireless head-mounted eye-tracking system that performs Chair-free Eye-Recording using Backpack mounted micROcontrollers (CEREBRO) for small mammals, such as marmoset monkeys. Because eye illumination and environment lighting change continuously in natural contexts, we developed a segmentation artificial neural network to perform robust pupil tracking in these conditions. Leveraging this innovative system to investigate active vision, we demonstrate that although freely moving marmosets exhibit frequent compensatory eye movements equivalent to other primates, including humans, the predictability of the visual behavior (gaze) is higher when animals are freely moving relative to when they are head-fixed. Moreover, despite increases in eye/head-motion during locomotion, gaze stabilization remains steady because of an increase in vestibularocular reflex gain during locomotion. These results demonstrate the efficient, dynamic visuo-motor mechanisms and related behaviors that enable stable, high-resolution foveal vision in primates as they explore the natural world.}, archive = {J_PNAS}, author = {Singh, Vikram Pal and Li, Jingwen and Dawson, Kana and Mitchell, Jude F. and Miller, Cory T.}, doi = {10.1073/pnas.2412954122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2412954122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Active vision in freely moving marmosets using head-mounted eye tracking}, volume = {122}, year = {2025}, }
• (2025). Broad-spectrum tolerance to disinfectant-mediated bacterial killing due to mutation of the PheS aminoacyl tRNA synthetase. PNAS, 122(6), e2412871122. (www)

  @article{ , abstract = {Disinfectants are essential tools for controlling infectious diseases and maintaining sterile conditions in many medical and food-industry settings. Recent work revealed that a deficiency in the carbohydrate phosphotransferase system (PTS) confers pan-tolerance to killing by diverse disinfectant types through its interaction with the cAMP-CRP regulatory network. The present work characterized a pan-tolerance mutant obtained by enrichment using phenol as a lethal probe and an Escherichia coli PTS null mutant as a parental strain. The resulting super-pan-tolerant mutant, which harbored an F158C substitution in PheS, inhibited bacterial killing by multiple disinfectant classes with surprisingly little effect on antimicrobial lethality. The PheS substitution, which was expected to lower substrate recognition efficiency and result in deacylated tRNA phe occupying the ribosomal A site, activated relA expression and synthesis of ppGpp, even in the absence of disinfectant exposure. ppGpp, along with DksA, increased RpoS function by activating promoters of dsrA and iraP , two genes whose products increase the expression and stability of RpoS. Subsequently, RpoS upregulated the expression of genes encoding a universal stress protein (UspB) and an oxidative stress peroxidase (KatE), which preconditioned bacteria to better survive a variety of disinfectants. Disinfectant-mediated accumulation of reactive oxygen species (ROS) and bacterial killing were abolished/reduced by exogenous dimethyl sulfoxide and by a PheS F158C substitution up-regulating genes encoding ROS-detoxifying enzymes ( katE, sodA, oxyR, ahpC ). These data identify a pheS mutation-triggered, ppGpp-stimulated transcriptional regulatory cascade that negates biocide-mediated lethality, thereby tying the stringent response to protection from ROS-mediated biocide lethality.}, archive = {J_PNAS}, author = {Chen, Miaomiao and Cui, Runbo and Hong, Shouqiang and Zhu, Weiwei and Yang, Qiong and Li, Jiahao and Nie, Zihan and Zhang, Xue and Ye, Yanghui and Xue, Yunxin and Wang, Dai and Hong, Yuzhi and Drlica, Karl and Niu, Jianjun and Zhao, Xilin}, doi = {10.1073/pnas.2412871122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2412871122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Broad-spectrum tolerance to disinfectant-mediated bacterial killing due to mutation of the PheS aminoacyl tRNA synthetase}, volume = {122}, year = {2025}, }
• (2025). Energyscapes pinpoint marine megafauna feeding hotspots in the mediterranean. PNAS, 122(6), e2412845122. (www)

  @article{ , abstract = {Ocean giants shape the structure and functioning of marine food webs via trophic top–down controls, landscapes of fear, vertical and horizontal redistribution of nutrients, energy, and matter. Yet, they face threats from overfishing, pollution, habitat degradation, and climate change, and one-third of marine megafauna species are at risk of extinction, ultimately endangering the resilience of entire ecosystems. In such a context, knowing when and where megafauna find resources to balance their substantial energy requirements is critical for their management. Through an energyscape approach integrating abundance censuses, diet, and energy requirements, we investigated the prey consumption patterns of Mediterranean marine megafauna during the summer. We thereby shed light on a diverse guild of species composed of fishes, mammals, reptiles, and birds and estimated that 4.1 million individuals consume 1.6 million tons of prey each summer, pelagic cephalopods being the primary food resource and cetaceans and tunas being key players in the community. Spatial patterns in prey consumption reflected the diverse distribution and needs of the megafauna species and underlined the critical importance of the western Mediterranean for the megafauna community. Conservation strategies should prioritize spatial and biological diversity to safeguard megafauna and ecosystem functions across the Mediterranean basin.}, archive = {J_PNAS}, author = {Lambert, Charlotte and Broderick, Annette C. and Beton, Damla and Cañadas, Ana and Dars, Cécile and Di Matteo, Andrew and Gilbert, Lola and Giménez, Joan and Keramidas, Ioannis and Navarro, Joan and Palmer, Josie L. and Snape, Robin T. E. and Sparks, Laura and Spitz, Jérôme and Tsikliras, Athanassios C. and Virgili, Auriane and Grémillet, David}, doi = {10.1073/pnas.2412845122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2412845122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Energyscapes pinpoint marine megafauna feeding hotspots in the mediterranean}, volume = {122}, year = {2025}, }
• (2025). Bonobos point more for ignorant than knowledgeable social partners. PNAS, 122(6), e2412450122. (www)

  @article{ , abstract = {Numerous uniquely human phenomena, from teaching to our most complex forms of cooperation, depend on our ability to tailor our communication to the knowledge and ignorance states of our social partners. Despite four decades of research into the “theory of mind” capacities of nonhuman primates, there remains no evidence that primates can communicate on the basis of their mental state attributions, to enable feats of coordination. Moreover, recent reevaluation of the experimental literature has questioned whether primates can represent others’ ignorance at all. The present preregistered study investigated whether bonobos are capable of attributing knowledge or ignorance about the location of a hidden food reward to a cooperative human partner, and utilizing this attribution to modify their communicative behavior in the service of coordination. Bonobos could receive a reward that they had watched being hidden under one of several cups, if their human partner could locate the reward. If bonobos can represent a partner’s ignorance and are motivated to communicate based on this mental state attribution, they should point more frequently, and more quickly, to the hidden food’s location when their partner is ignorant about that location than when he is knowledgeable. Bonobos indeed flexibly adapted the frequency and speed of their communication to their partner’s mental state. These findings suggest that apes can represent (and act on) others’ ignorance in some form, strategically and appropriately communicating to effectively coordinate with an ignorant partner and change his behavior.}, archive = {J_PNAS}, author = {Townrow, Luke A. and Krupenye, Christopher}, doi = {10.1073/pnas.2412450122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2412450122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bonobos point more for ignorant than knowledgeable social partners}, volume = {122}, year = {2025}, }
• (2025). Spatial patterning analysis of cellular ensembles (SPACE) finds complex spatial organization at the cell and tissue levels. PNAS, 122(6), e2412146122. (www)

  @article{ , abstract = {Spatial patterns of cells and other biological elements drive physiologic and pathologic processes within tissues. While many imaging and transcriptomic methods document tissue organization, discerning these patterns is challenging, especially when they involve multiple elements in complex arrangements. To address this challenge, we present Spatial Patterning Analysis of Cellular Ensembles (SPACE), an R package for analysis of high-plex spatial data. SPACE is compatible with any data collection modality that records values (i.e., categorical cell/structure types or quantitative expression levels) at fixed spatial coordinates (i.e., 2d pixels or 3d voxels). SPACE detects not only broad patterns of co-occurrence but also context-dependent associations, quantitative gradients and orientations, and other organizational complexities. Via a robust information theoretic framework, SPACE explores all possible ensembles of tissue elements—single elements, pairs, triplets, and so on—and ranks the most strongly patterned ensembles. For single images, rankings reflect differences from random assortment. For sets of images, rankings reflect differences across sample groups (e.g., genotypes, treatments, timepoints, etc.). Further tools then characterize the nature of each pattern for intuitive interpretation. We validate SPACE and demonstrate its advantages using murine lymph node images for which ground truth has been defined. We then detect new patterns across varied datasets, including tumors and tuberculosis granulomas.}, archive = {J_PNAS}, author = {Schrom, Edward C. and McCaffrey, Erin F. and Sreejithkumar, Vivek and Radtke, Andrea J. and Ichise, Hiroshi and Arroyo-Mejias, Armando and Speranza, Emily and Arakkal, Leanne and Thakur, Nishant and Grant, Spencer and Germain, Ronald N.}, doi = {10.1073/pnas.2412146122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2412146122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Spatial patterning analysis of cellular ensembles (SPACE) finds complex spatial organization at the cell and tissue levels}, volume = {122}, year = {2025}, }
• (2025). Circadian clock control of interactions between eIF2α kinase CPC-3 and GCN1 with ribosomes regulates rhythmic translation initiation. PNAS, 122(6), e2411916122. (www)

  @article{ , abstract = {Misregulation of the activity of GCN2, the kinase that phosphorylates and inactivates translation initiation factor eIF2α, has been implicated in several health disorders, underscoring the need to determine the mechanisms controlling GCN2 activation. During nutrient starvation, increased uncharged tRNA levels trigger GCN1 and GCN20 proteins to mediate the binding of uncharged tRNA to GCN2 to activate the kinase to phosphorylate eIF2α. Under constant conditions, activation of the Neurospora crassa homolog of GCN2, CPC-3, is controlled by the circadian clock. However, how the circadian clock controls the rhythmic activity of CPC-3 was not known. We found that the clock regulates CPC-3 and GCN1 interaction with ribosomes and show that these interactions are necessary for clock regulation of CPC-3 activity. CPC-3 activity rhythms, and the rhythmic interaction of CPC-3 and GCN1 with ribosomes, are abolished in a temperature-sensitive valyl-tRNA synthetase mutant ( un-3 ts ) that has high levels of uncharged tRNA Val at all times of the day. Disrupting the interaction between GCN1 and uncharged tRNA in the absence of GCN20 altered rhythmic CPC-3 activity, indicating that the clock controls the interaction between uncharged tRNA and GCN1. Together, these data support that circadian rhythms in mRNA translation through CPC-3 activity require rhythms in uncharged tRNA levels that drive the rhythmic interaction between CPC-3 and GCN1 with ribosomes. This regulation uncovers a fundamental mechanism to ensure temporal coordination between peak cellular energy levels and the energetically demanding process of mRNA translation.}, archive = {J_PNAS}, author = {Preh, Ebimobowei O. and Ramirez, Manuel A. and Mohan, Sidharth and Guy, Chanté R. and Bell-Pedersen, Deborah}, doi = {10.1073/pnas.2411916122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2411916122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Circadian clock control of interactions between eIF2α kinase CPC-3 and GCN1 with ribosomes regulates rhythmic translation initiation}, volume = {122}, year = {2025}, }
• (2025). Observed declines in upper ocean phosphate-to-nitrate availability. PNAS, 122(6), e2411835122. (www)

  @article{ , abstract = {Climate warming is increasing ocean stratification, which in turn should decrease the nutrient flux to the upper ocean. This may slow marine primary productivity, causing cascading effects throughout food webs. However, observing changes in upper ocean nutrients is challenging because surface concentrations are often below detection limits. We show that the nutricline depth, where nutrient concentrations reach well-detected levels, is tied to productivity and upper ocean nutrient availability. Next, we quantify nutricline depths from a global database of observed vertical nitrate and phosphate profiles to assess contemporary trends in global nutrient availability (1972–2022). We find strong evidence that the P-nutricline (phosphacline) is mostly deepening, especially throughout the southern hemisphere, but the N-nutricline (nitracline) remains mostly stable. Earth System Model (ESM) simulations support the hypothesis that reduced iron stress and increased nitrogen fixation buffer the nitracline, but not phosphacline, against increasing stratification. These contemporary trends are expected to continue in the coming decades, leading to increasing phosphorus but not nitrogen stress for marine phytoplankton, with important ramifications for ocean biogeochemistry and food web dynamics.}, archive = {J_PNAS}, author = {Gerace, Skylar D. and Yu, Jun and Moore, J. Keith and Martiny, Adam C.}, doi = {10.1073/pnas.2411835122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2411835122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Observed declines in upper ocean phosphate-to-nitrate availability}, volume = {122}, year = {2025}, }
• (2025). Global natural history infrastructure requires international solidarity, support, and investment in local capacity. PNAS, 122(6), e2411232122. (www)

  @article{ , abstract = {Amid global challenges like climate change, extinctions, and disease epidemics, science and society require nuanced, international solutions that are grounded in robust, interdisciplinary perspectives and datasets that span deep time. Natural history collections, from modern biological specimens to the archaeological and fossil records, are crucial tools for understanding cultural and biological processes that shape our modern world. At the same time, natural history collections in low and middle-income countries are at-risk and underresourced, imperiling efforts to build the infrastructure and scientific capacity necessary to tackle critical challenges. The case of Mongolia exemplifies the unique challenges of preserving natural history collections in a country with limited financial resources under the thumb of scientific colonialism. Specifically, the lack of biorepository infrastructure throughout Mongolia stymies efforts to study or respond to large-scale environmental changes of the modern era. Investment in museum capacity and training to develop locally-accessible collections that characterize natural communities over time and space must be a key priority for a future where understanding climate scenarios, predicting, and responding to zoonotic disease, making informed conservation choices, or adapting to agricultural challenges, will be all but impossible without relevant and accessible collections.}, archive = {J_PNAS}, author = {Boldgiv, Bazartseren and Lkhagva, Ariuntsetseg and Edwards, Scott and Stenseth, Nils C. and Bayarsaikhan, Jamsranjav and Altangerel, Dondog and Usukhjargal, Dorj and Dovchin, Badamgarav and Gombobaatar, Sundev and Batsaikhan, Nyamsuren and Warinner, Christina and Hart, Isaac and Galbreath, Kurt and Greiman, Stephen E. and Malaney, Jason and Murdoch, James D. and McLean, Bryan and DeWitte, Sharon N. and Manzitto-Tripp, Erin and Chin, Karen and Karim, Talia S. and Simpson, Carl and Stevens, Nancy J. and Dunnum, Jonathan L. and Cook, Joseph A. and Taylor, William Timothy Treal}, doi = {10.1073/pnas.2411232122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2411232122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Global natural history infrastructure requires international solidarity, support, and investment in local capacity}, volume = {122}, year = {2025}, }
• (2025). Cataract-prone variants of γD-crystallin populate a conformation with a partially unfolded N-terminal domain under native conditions. PNAS, 122(6), e2410860122. (www)

  @article{ , abstract = {Human γD-crystallin, a monomeric protein abundant in the eye lens nucleus, must remain stably folded for an individual’s entire lifetime to avoid aggregation and protein deposition-associated cataract formation. γD-crystallin contains two homologous domains, an N-terminal domain (NTD) and a C-terminal domain (CTD), which interact via a hydrophobic interface. Several familial mutations in the gamma crystallin gene are linked to congenital early-onset cataract, most of which affect the NTD. Some of these, including V75D and W42R, are known to populate intermediates under partially denaturing conditions possessing a natively folded CTD and a completely unfolded NTD. We employed hydrogen–deuterium exchange mass spectrometry to probe the structural and energetic features of variants of γD-crystallin under both native and partially denaturing conditions. For V75D and W42R, we identify a species under native conditions that retains partial structure in the NTD and is structurally and energetically distinct from the intermediate populated under partially denaturing conditions. Residues at the NTD–CTD interface play crucial roles in stabilizing this intermediate, and disruption of interface contacts either by amino acid substitution or partial denaturation permits direct observation of two intermediates simultaneously. These data suggest that the intermediate identified under native conditions is accessed from the native state and not on the folding pathway. The intermediate we have identified here exposes hydrophobic amino acids that are buried in both the folded full-length protein and in the protein’s stable isolated domains. Such nonnative exposure of a hydrophobic patch may play an important role in cataract formation.}, archive = {J_PNAS}, author = {Volz, Sara and Malone, Jadyn R. and Guseman, Alex J. and Gronenborn, Angela M. and Marqusee, Susan}, doi = {10.1073/pnas.2410860122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2410860122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cataract-prone variants of γD-crystallin populate a conformation with a partially unfolded N-terminal domain under native conditions}, volume = {122}, year = {2025}, }
• (2025). Highly deformable flapping membrane wings suppress the leading edge vortex in hover to perform better. PNAS, 122(6), e2410833121. (www)

  @article{ , abstract = {Airborne insects generate a leading edge vortex when they flap their wings. This coherent vortex is a low-pressure region that enhances the lift of flapping wings compared to fixed wings. Insect wings are thin membranes strengthened by a system of veins that does not allow large wing deformations. Bat wings are thin compliant skin membranes stretched between their limbs, hand, and body that show larger deformations during flapping wing flight. This study examines the role of the leading edge vortex on highly deformable membrane wings that passively change shape under fluid dynamic loading maintaining a positive camber throughout the hover cycle. Our experiments reveal that unsteady wing deformations suppress the formation of a coherent leading edge vortex as flexibility increases. At lift and energy optimal aeroelastic conditions, there is no more leading edge vortex. Instead, vorticity accumulates in a bound shear layer covering the wing’s upper surface from the leading to the trailing edge. Despite the absence of a leading edge vortex, the optimal deformable membrane wings demonstrate enhanced lift and energy efficiency compared to their rigid counterparts. It is possible that small bats rely on this mechanism for efficient hovering. We relate the force production on the wings with their deformation through scaling analyses. Additionally, we identify the geometric angles at the leading and trailing edges as observable indicators of the flow state and use them to map out the transitions of the flow topology and their aerodynamic performance for a wide range of aeroelastic conditions.}, archive = {J_PNAS}, author = {Gehrke, Alexander and Mulleners, Karen}, doi = {10.1073/pnas.2410833121}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2410833121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Highly deformable flapping membrane wings suppress the leading edge vortex in hover to perform better}, volume = {122}, year = {2025}, }
• (2025). Microlevel structural poverty estimates for southern and eastern africa. PNAS, 122(6), e2410350122. (www)

  @article{ , abstract = {For many countries in the Global South traditional poverty estimates are available only infrequently and at coarse spatial resolutions, if at all. This limits decision-makers’ and analysts’ ability to target humanitarian and development interventions and makes it difficult to study relationships between poverty and other natural and human phenomena at finer spatial scales. Advances in Earth observation and machine learning-based methods have proven capable of generating more granular estimates of relative asset wealth indices. They have been less successful in predicting the consumption-based poverty measures most commonly used by decision-makers, those tied to national and international poverty lines. For a study area including four countries in southern and eastern Africa, we pilot a two-step approach that combines Earth observation, accessible machine learning methods, and asset-based structural poverty measurement to address this gap. This structural poverty approach to machine learning-based poverty estimation preserves the interpretability and policy-relevance of consumption-based poverty measures, while allowing us to explain 72 to 78% of cluster-level variation in a pooled model and 40 to 54% even when predicting out-of-country.}, archive = {J_PNAS}, author = {Tennant, Elizabeth and Ru, Yating and Sheng, Peizan and Matteson, David S. and Barrett, Christopher B.}, doi = {10.1073/pnas.2410350122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2410350122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Microlevel structural poverty estimates for southern and eastern africa}, volume = {122}, year = {2025}, }
• (2025). Black and latinx workers reap lower rewards than white workers from years spent working in big cities. PNAS, 122(6), e2409935122. (www)

  @article{ , abstract = {The large labor markets of big cities offer greater possibilities for workers to gain skills and experience through successively better employment opportunities. This “experience effect” contributes to the higher average wages that are found in big cities compared to the economy as a whole. Racial wage inequality is also higher in bigger cities than in the economy on average. We offer an explanation for this pattern, demonstrating that there is substantial racial inequality in the economic returns to work experience acquired in big cities. Using data from the National Longitudinal Survey of Youth, 1979 we find that each year of work experience in a big city increases Black and Latinx workers’ wages by about one quarter to half as much as White workers’ wages. A substantial amount of this inequality can be explained by further racial disparities in the benefits of high-skill work experience. This research identifies a heretofore unknown source of inequality that is distinctly urban in nature, and expands our knowledge of the challenges to reaching interracial wage equality.}, archive = {J_PNAS}, author = {Buchholz, Maximilian and Storper, Michael}, doi = {10.1073/pnas.2409935122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2409935122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Black and latinx workers reap lower rewards than white workers from years spent working in big cities}, volume = {122}, year = {2025}, }
• (2025). Intracranial substrates of meditation-induced neuromodulation in the amygdala and hippocampus. PNAS, 122(6), e2409423122. (www)

  @article{ , abstract = {Meditation is an accessible mental practice associated with emotional regulation and well-being. Loving-kindness meditation (LKM), a specific subtype of meditative practice, involves focusing one’s attention on thoughts of well-being for oneself and others. Meditation has been proven to be beneficial in a variety of settings, including therapeutic applications, but the neural activity underlying meditative practices and their positive effects are not well understood. It has been difficult to understand the contribution of deep limbic structures given the difficulty of studying neural activity directly in the human brain. Here, we leverage a unique patient population, epilepsy patients chronically implanted with responsive neurostimulation devices that allow chronic, invasive electrophysiology recording to investigate the physiological correlates of LKM in the amygdala and hippocampus of novice meditators. We find that LKM-associated changes in physiological activity were specific to periodic, but not aperiodic, features of neural activity. LKM was associated with an increase in γ (30 to 55 Hz) power and an alternation in the duration of β (13 to 30 Hz) and γ oscillatory bursts in both the amygdala and hippocampus, two regions associated with mood disorders. These findings reveal the nature of LKM-induced modulation of limbic activity in first-time meditators.}, archive = {J_PNAS}, author = {Maher, Christina and Tortolero, Lea and Jun, Soyeon and Cummins, Daniel D. and Saad, Adam and Young, James and Nunez Martinez, Lizbeth and Schulman, Zachary and Marcuse, Lara and Waters, Allison and Mayberg, Helen S. and Davidson, Richard J. and Panov, Fedor and Saez, Ignacio}, doi = {10.1073/pnas.2409423122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2409423122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Intracranial substrates of meditation-induced neuromodulation in the amygdala and hippocampus}, volume = {122}, year = {2025}, }
• (2025). Identifying new classes of financial price jumps with wavelets. PNAS, 122(6), e2409156121. (www)

  @article{ , abstract = {We introduce an unsupervised classification framework that leverages a multiscale wavelet representation of time-series and apply it to stock price jumps. In line with previous work, we recover the fact that time-asymmetry of volatility is the major feature that separates exogenous, news-induced jumps from endogenously generated jumps. Local mean-reversion and trend are found to be two additional key features, allowing us to identify new classes of jumps. Using our wavelet-based representation, we investigate the endogenous or exogenous nature of cojumps, which occur when multiple stocks experience price jumps within the same minute. Perhaps surprisingly, our analysis suggests that a significant fraction of cojumps result from an endogenous contagion mechanism.}, archive = {J_PNAS}, author = {Aubrun, Cecilia and Morel, Rudy and Benzaquen, Michael and Bouchaud, Jean-Philippe}, doi = {10.1073/pnas.2409156121}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2409156121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identifying new classes of financial price jumps with wavelets}, volume = {122}, year = {2025}, }
• (2025). Identification of a central regulator of ginkgolide biosynthesis in ginkgo biloba that integrates jasmonate and light signaling. PNAS, 122(6), e2408891122. (www)

  @article{ , abstract = {Ginkgolides are secondary metabolites unique to Ginkgo biloba with the potential to prevent and treat cardiovascular and cerebrovascular diseases. Although the biosynthetic pathways of ginkgolides have been partly uncovered, the mechanism regulating their biosynthesis is still largely unknown. Here, using multiomic and genetic analyses, we report the identification of a transcription factor, named ETHYLENE RESPONSE FACTOR ASSOCIATED WITH GINKGOLIDE BIOSYNTHESIS (GbEAG), as a critical regulator of ginkgolide biosynthesis. GbEAG is highly expressed in the roots of G. biloba, and its expression is significantly induced by methyl jasmonate (MeJA). Ginkgolide content was significantly increased in roots by overexpressing GbEAG using a “cut-dip-regeneration” system. GbEAG positively regulates ginkgolide biosynthesis by directly binding to the GCC-boxes in the promoter regions of genes involved in the biosynthesis of ginkgolides, such as ISOPENTENYL DIPHOSPHATE ISOMERASE ( GbIDI ) and CYTOCHROME P450 7005C3 ( GbCYP7005C3 ). GbEAG mediates the jasmonic acid (JA)-activated ginkgolide synthesis through its direct interaction with the JASMONATE ZINC-FINGER INFLORESCENCE MERISTEM DOMAIN 3 (GbJAZ3) repressor. Importantly, we also found that the central light-response regulator ELONGATED HYPOCOTYL 5 (GbHY5) mediates light induction of ginkgolide biosynthesis by binding to the G-box in the GbEAG promoter. Our findings provide mechanistic insights into the coordinated regulation of ginkgolide biosynthesis via JA and light signals, with GbEAG as a central regulator in G. biloba, and shed light on the potential to develop ginkgolide-rich varieties through molecular breeding and gene editing.}, archive = {J_PNAS}, author = {Du, Jinfa and Zhao, Zhen and Jin, Lingqi and Huang, Lijin and Jin, Dian and Zheng, Xiaoyan and Wang, Qiaolei and Xu, Wenbo and Guo, Huijun and Xing, Xinyue and Alolga, Raphael N. and Tran, Lam-Son Phan and Herrera-Estrella, Luis Rafael and Li, Ping and Yin, Xiaojian and Lu, Xu}, doi = {10.1073/pnas.2408891122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2408891122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Identification of a central regulator of ginkgolide biosynthesis in ginkgo biloba that integrates jasmonate and light signaling}, volume = {122}, year = {2025}, }
• (2025). Rapid restoration of potent neutralization activity against the latest omicron variant JN.1 via AI rational design and antibody engineering. PNAS, 122(6), e2406659122. (www)

  @article{ , abstract = {The rapid evolution of the viral genome has led to the continual generation of new variants of SARS-CoV-2. Developing antibody drugs with broad-spectrum and high efficiency is a long-term task. It is promising but challenging to develop therapeutic neutralizing antibodies (nAbs) through in vitro evolution based on antigen–antibody binding interactions. From an early B cell antibody repertoire, we isolated antibody 8G3 that retains its nonregressive neutralizing activity against Omicron BA.1 and various other strains in vitro. 8G3 protected ACE2 transgenic mice from BA.1 and WA1/2020 virus infection without adverse clinical manifestations and completely cleared viral load in the lungs. Similar to most IGHV3–53 antibodies, the binding sites of 8G3 and ACE2 largely overlap, enabling competition with ACE2 for binding to RBD. By comprehensively considering the binding free energy changes of the antigen–antibody complexes, the biological environment of their interactions, and the evolutionary direction of the antibodies, we were able to select 50 mutants. Among them, 11 were validated by experiments showing better neutralizing activities. Further, a combination of four mutations were identified in 8G3 that increased its neutralization potency against JN.1, the latest Omicron mutant, by approximately 1,500-fold, and one of the mutations led to an improvement in activity against multiple variants to a certain extent. Together, we established a procedure of rapid selection of neutralizing antibodies with potent SARS-CoV-2 neutralization activity. Our results provide a reference for engineering neutralizing antibodies against future SARS-CoV-2 variants and even other pandemic viruses.}, archive = {J_PNAS}, author = {Liao, Yunji and Ma, Hang and Wang, Zhenyu and Wang, Shusheng and He, Yang and Chang, Yunsong and Zong, Huifang and Tang, Haoneng and Wang, Lei and Ke, Yong and Cai, Huiyu and Li, Ping and Tang, Jian and Chen, Hua and Drelich, Aleksandra and Peng, Bi-Hung and Hsu, Jason and Tat, Vivian and Tseng, Chien-Te K. and Song, Jingjing and Yuan, Yunsheng and Wu, Mingyuan and Liu, Junjun and Yue, Yali and Zhang, Xiaoju and Wang, Ziqi and Yang, Li and Li, Jing and Ni, Xiaodan and Li, Hongshi and Xiang, Yuning and Bian, Yanlin and Zhang, Baohong and Yin, Haiyang and Dimitrov, Dimiter S. and Gilly, John and Han, Lei and Jiang, Hua and Xie, Yueqing and Zhu, Jianwei}, doi = {10.1073/pnas.2406659122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2406659122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rapid restoration of potent neutralization activity against the latest omicron variant JN.1 via AI rational design and antibody engineering}, volume = {122}, year = {2025}, }
• (2025). Abscisic acid signaling gates salt-induced responses of plant roots. PNAS, 122(6), e2406373122. (www)

  @article{ , abstract = {Soil salinity presents a dual challenge for plants, involving both osmotic and ionic stress. In response, plants deploy distinct yet interconnected mechanisms to cope with these facets of salinity stress. In this investigation, we observed a substantial overlap in the salt (NaCl)-induced transcriptional responses of Arabidopsis roots with those triggered by osmotic stress or the plant stress hormone abscisic acid (ABA), as anticipated. Notably, a specific cluster of genes responded uniquely to sodium (Na + ) ions and are not regulated by the known monovalent cation sensing mechanism MOCA1 . Surprisingly, expression of sodium-induced genes exhibited a negative correlation with the ABA response and preceded the activation of genes induced by the osmotic stress component of salt. Elevated exogenous ABA levels resulted in the complete abolition of sodium-induced responses. Consistently, the ABA insensitive snrk2.2/2.3 double mutant displayed prolonged sodium-induced gene expression, coupled with increased root cell damage and root swelling under high salinity conditions. Moreover, ABA biosynthesis and signaling mutants were unable to redirect root growth to avoid high sodium concentrations and had increased sodium accumulation in the shoot. In summary, our findings unveil an unexpected and pivotal role for ABA signaling in mitigating cellular damage induced by salinity stress and modulating sodium-induced responses in plant roots.}, archive = {J_PNAS}, author = {Lamers, Jasper and Zhang, Yanxia and van Zelm, Eva and Leong, Cheuk Ka and Meyer, A. Jessica and de Zeeuw, Thijs and Verstappen, Francel and Veen, Mark and Deolu-Ajayi, Ayodeji O. and Gommers, Charlotte M. M. and Testerink, Christa}, doi = {10.1073/pnas.2406373122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2406373122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Abscisic acid signaling gates salt-induced responses of plant roots}, volume = {122}, year = {2025}, }
• (2025). Biochemical and structural bases for talin ABSs–F-actin interactions. PNAS, 122(6), e2405922122. (www)

  @article{ , abstract = {Focal adhesions (FAs) are large intracellular macromolecular assemblies that play a critical role in cell polarization and migration. Talin serves as a direct connection between integrin receptor and actomyosin cytoskeleton within FAs. Talin contains three actin-binding sites (ABS1-3) that engage discreetly during the development of FAs, thus acting as a critical player in FA initiation and maturation. However, the molecular basis of the ABS–F-actin interactions remains unknown. Here, we explore interactions of ABSs with F-actin to understand the multivalent behavior of talin. Particularly, the cryo-EM structure of the F-actin–ABS3 complex at 2.9 Å shows ABS3 spanning through two actin monomers along the filament axis, each occupied by the R13 rod subdomain and the DD domain. The dimerization of ABS3 occurs through the DD domain where both protomers interact on the actin surface, and the dimerization of talin to the actin surface is necessary for the engagement to F-actin. The R13 helical bundle is distorted upon binding to F-actin and releases the H1 helix from the rest of the bundle. This phenomenon has also been observed with other tension-sensing proteins like vinculin and α-catenin, highlighting that unfolding is relevant for its force sensing activity. On the contrary, ABS2 (R4R8 subdomains), which is thought to be critical for the maintenance of mature FAs, had multiple F-actin-binding regions within ABS2 and the binding likely occurred by these subdomains running through the surface of F-actin, thus strengthening the interactions upon the maturation of FAs.}, archive = {J_PNAS}, author = {Biertümpfel, Christian and Yamada, Yurika and Vasquez-Montes, Victor and Truong, Thien Van and Cada, A. King and Mizuno, Naoko}, doi = {10.1073/pnas.2405922122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2405922122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Biochemical and structural bases for talin ABSs–F-actin interactions}, volume = {122}, year = {2025}, }
• (2025). The regulatory-associated protein of target of rapamycin 1B (RAPTOR 1B) interconnects with the photoperiod pathway to promote flowering in arabidopsis. PNAS, 122(6), e2405536122. (www)

  @article{ , abstract = {The transition from vegetative to reproductive growth, or floral transition, is a tightly regulated, energy-demanding process. In Arabidopsis , the interplay of light perception and circadian rhythms detects changes in photoperiod length, accelerating flowering under long days (LD). CONSTANS (CO), a transcription factor, upregulates FLOWERING LOCUS T (FT) in leaves during dusk. The FT protein then moves to the shoot apical meristem, triggering the floral transition. While light and circadian signals control CO protein levels, less is known about how the nutrients/energy sensing regulates the photoperiod pathway for flowering modulation in this process. In our study, we identify the contribution of the Regulatory-associated protein of target of rapamycin 1B (RAPTOR1B), a component of the nutrient-sensing TOR complex (TORC), in the induction of specific flowering genes under CO control. While transcription of CO remains unaffected in raptor1b mutants, a reduction in its protein levels at dusk is observed compared to the wild type. Remarkably, the mutant also exhibits compromised GIGANTEA (GI) protein levels, crucial for CO stabilization during dusk. Our results indicate that the interaction and colocalization of RAPTOR1B with GI in the nucleus might influence GI levels through an unknown posttranscriptional mechanism. Genetic crosses position RAPTOR1B upstream of CO and GI. This is supported by phenotypic and molecular analyses. Our findings demonstrate that RAPTOR1B, likely as part of TORC, contributes to the photoperiod pathway of the flowering network, ensuring the timely initiation of floral transition under LD conditions.}, archive = {J_PNAS}, author = {Urrea-Castellanos, Reynel and Calderan-Rodrigues, Maria J. and Artins, Anthony and Musialak-Lange, Magdalena and Macharanda-Ganesh, Appanna and Fernie, Alisdair R. and Wahl, Vanessa and Caldana, Camila}, doi = {10.1073/pnas.2405536122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2405536122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The regulatory-associated protein of target of rapamycin 1B (RAPTOR 1B) interconnects with the photoperiod pathway to promote flowering in arabidopsis}, volume = {122}, year = {2025}, }
• (2025). Adoption of improved crop varieties limited biodiversity losses, terrestrial carbon emissions, and cropland expansion in the tropics. PNAS, 122(6), e2404839122. (www)

  @article{ , abstract = {Research investments in crop improvements, including by national and international agricultural research centers, have made significant contributions to raising yields of staple food crops in developing countries. Although mostly intended to improve food security and rural incomes, innovations in crop production also have major implications for the environment. Building on the latest productivity estimates from historical crop improvements in developing countries and using a gridded (0.25 degrees) equilibrium model of global agriculture, we assess the impacts of improved crop varieties on cropland use, threatened biodiversity, and terrestrial carbon stocks over 1961–2015. We replicate a historical baseline and produce a counterfactual scenario which shows the impact of omitting productivity improvements from these technologies. The results show that higher crop productivity generally lowered commodity prices, which reduced incentives to expand cropland except in those areas where productivity gains outweighed price declines. The net global effect of technology adoption was to limit conversion of natural habitat to agricultural use, although it did cause cropland to expand in some areas. We estimate that adoption of improved crop varieties in developing countries saved on net 16.03 [95% CI, 12.33 to 20.89] million hectares worldwide. With more natural habitat preserved, around 1,043 [95% CI, 616 to 1,503] threatened animal and plant species extinctions were avoided over this period. In addition, net land use savings from the improved crop varieties resulted in avoided terrestrial greenhouse gas (GHG) emissions of around 5.35 [95% CI, 3.75 to 7.22] billion metric tons CO 2 equivalent retained in terrestrial carbon stocks.}, archive = {J_PNAS}, author = {Baldos, Uris Lantz C. and Cisneros-Pineda, Alfredo and Fuglie, Keith O. and Hertel, Thomas W.}, doi = {10.1073/pnas.2404839122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2404839122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Adoption of improved crop varieties limited biodiversity losses, terrestrial carbon emissions, and cropland expansion in the tropics}, volume = {122}, year = {2025}, }
• (2025). High-throughput discovery of inhibitory protein fragments with AlphaFold. PNAS, 122(6), e2322412122. (www)

  @article{ , abstract = {Peptides can bind to specific sites on larger proteins and thereby function as inhibitors and regulatory elements. Peptide fragments of larger proteins are particularly attractive for achieving these functions due to their inherent potential to form native-like binding interactions. Recently developed experimental approaches allow for high-throughput measurement of protein fragment inhibitory activity in living cells. However, it has thus far not been possible to predict de novo which of the many possible protein fragments bind to protein targets, let alone act as inhibitors. We have developed a computational method, FragFold, that employs AlphaFold to predict protein fragment binding to full-length proteins in a high-throughput manner. Applying FragFold to thousands of fragments tiling across diverse proteins revealed peaks of predicted binding along each protein sequence. Comparisons with experimental measurements establish that our approach is a sensitive predictor of fragment function: Evaluating inhibitory fragments from known protein–protein interaction interfaces, we find 87% are predicted by FragFold to bind in a native-like mode. Across full protein sequences, 68% of FragFold-predicted binding peaks match experimentally measured inhibitory peaks. Deep mutational scanning experiments support the predicted binding modes and uncover superior inhibitory peptides in high throughput. Further, FragFold is able to predict previously unknown protein binding modes, explaining prior genetic and biochemical data. The success rate of FragFold demonstrates that this computational approach should be broadly applicable for discovering inhibitory protein fragments across proteomes.}, archive = {J_PNAS}, author = {Savinov, Andrew and Swanson, Sebastian and Keating, Amy E. and Li, Gene-Wei}, doi = {10.1073/pnas.2322412122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {6}, pages = {e2322412122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {High-throughput discovery of inhibitory protein fragments with AlphaFold}, volume = {122}, year = {2025}, }
• (2025). In this issue. PNAS, 122(5), eiti0525122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/iti0525122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {eiti0525122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In this issue}, volume = {122}, year = {2025}, }
• (2025). How towns can adapt to fire as bigger burns loom. PNAS, 122(5), e2500926122. (www)

  @article{ , archive = {J_PNAS}, author = {McDermott, Amy}, doi = {10.1073/pnas.2500926122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2500926122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How towns can adapt to fire as bigger burns loom}, volume = {122}, year = {2025}, }
• (2025). Correction for luo et al., bioluminescence imaging of smad signaling in living mice shows correlation with excitotoxic neurodegeneration. PNAS, 122(5), e2426314122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426314122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2426314122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for luo et al., bioluminescence imaging of smad signaling in living mice shows correlation with excitotoxic neurodegeneration}, volume = {122}, year = {2025}, }
• (2025). Correction for he et al., structural insights into the assembly and energy transfer of haptophyte photosystem i–light-harvesting supercomplex. PNAS, 122(5), e2426147122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426147122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2426147122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for he et al., structural insights into the assembly and energy transfer of haptophyte photosystem i–light-harvesting supercomplex}, volume = {122}, year = {2025}, }
• (2025). Correction for humbert et al., functional SARS-CoV-2 cross-reactive CD4+ t cells established in early childhood decline with age. PNAS, 122(5), e2426095122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426095122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2426095122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for humbert et al., functional SARS-CoV-2 cross-reactive CD4+ t cells established in early childhood decline with age}, volume = {122}, year = {2025}, }
• (2025). Managing protected areas takes a village. PNAS, 122(5), e2425972122. (www)

  @article{ , archive = {J_PNAS}, author = {Buřivalová, Zuzana and Rakotonarivo, O. Sarobidy}, doi = {10.1073/pnas.2425972122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2425972122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Managing protected areas takes a village}, volume = {122}, year = {2025}, }
• (2025). Poverty–disease–environment traps: Locally tailored solutions and collective action. PNAS, 122(5), e2425786122. (www)

  @article{ , archive = {J_PNAS}, author = {Barbier, Edward B.}, doi = {10.1073/pnas.2425786122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2425786122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Poverty–disease–environment traps: Locally tailored solutions and collective action}, volume = {122}, year = {2025}, }
• (2025). Reply to machida et al.: Although embryology cannot establish the “Protura-sister”, phylogenomics can. PNAS, 122(5), e2425775122. (www)

  @article{ , archive = {J_PNAS}, author = {Du, Shiyu and Tihelka, Erik and Yu, Daoyuan and Chen, Wan-Jun and Bu, Yun and Cai, Chenyang and Engel, Michael S. and Luan, Yun-Xia and Zhang, Feng}, doi = {10.1073/pnas.2425775122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2425775122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to machida et al.: Although embryology cannot establish the “Protura-sister”, phylogenomics can}, volume = {122}, year = {2025}, }
• (2025). Correction for cao et al., circadian clock cryptochrome proteins regulate autoimmunity. PNAS, 122(5), e2425633121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2425633121}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2425633121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for cao et al., circadian clock cryptochrome proteins regulate autoimmunity}, volume = {122}, year = {2025}, }
• (2025). Correction for nestor et al., future scientific innovation requires the transformative power of philanthropy. PNAS, 122(5), e2425629121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2425629121}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2425629121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for nestor et al., future scientific innovation requires the transformative power of philanthropy}, volume = {122}, year = {2025}, }
• (2025). Correction for wu et al., NR2B subunit of the NMDA glutamate receptor regulates appetite in the parabrachial nucleus. PNAS, 122(5), e2425524121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2425524121}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2425524121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for wu et al., NR2B subunit of the NMDA glutamate receptor regulates appetite in the parabrachial nucleus}, volume = {122}, year = {2025}, }
• (2025). Efficient, scalable, and near-nucleotide-resolution profiling of protein occupancy in the genome with deaminases. PNAS, 122(5), e2425203122. (www)

  @article{ , archive = {J_PNAS}, author = {Chang, Lei and Ren, Bing}, doi = {10.1073/pnas.2425203122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2425203122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Efficient, scalable, and near-nucleotide-resolution profiling of protein occupancy in the genome with deaminases}, volume = {122}, year = {2025}, }
• (2025). A pentatomomorpha-specific salivary protein activates plant immunity and is critical for insect feeding. PNAS, 122(5), e2425190122. (www)

  @article{ , abstract = {The stinkbug Riptortus pedestris , notorious for inducing soybean staygreen-like syndrome, employs a range of salivary proteins to manipulate the host plant for its benefit. Here, we show that RpSP1, a salivary protein specific to Pentatomomorpha, triggers plant defense responses in multiple plant species. RpSP1 interacts with and stabilizes a HSP40 family protein GmSPIP1 and is dependent on GmSPIP1 to induce cell death. We show that a critical 22-amino acid peptide within RpSP1 acts as an intracellular insect-derived elicitor. Furthermore, RpSP1 enhances insect-feeding efficiency. The dual functionality of RpSP1 is highlighted by the significant reduction of soybean staygreen-like syndrome following its overexpression in soybean plants or knockdown in insects. Our findings elucidate the complex molecular interactions between plants and herbivores, positioning RpSP1 as a crucial target for developing advanced pest management strategies with broad implications for agricultural biology.}, archive = {J_PNAS}, author = {Hu, Biao and Feng, Xiuli and Xu, Manru and Huang, Yue and Guo, Chunyun and Yuan, Ruikun and Li, Yiyuan and Wei, Zhongyan and Chen, Jianping and Sun, Zongtao}, doi = {10.1073/pnas.2425190122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2425190122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A pentatomomorpha-specific salivary protein activates plant immunity and is critical for insect feeding}, volume = {122}, year = {2025}, }
• (2025). Maria iandolo new (1928–2024): Pioneering pediatric endocrinologist. PNAS, 122(5), e2424275122. (www)

  @article{ , archive = {J_PNAS}, author = {White, Perrin C. and Miller, Walter L.}, doi = {10.1073/pnas.2424275122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2424275122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Maria iandolo new (1928–2024): Pioneering pediatric endocrinologist}, volume = {122}, year = {2025}, }
• (2025). Embryology cannot establish the “Protura-sister”. PNAS, 122(5), e2423813122. (www)

  @article{ , archive = {J_PNAS}, author = {Machida, Ryuichiro and Fukui, Makiko and Tomizuka, Shigekazu and Ikeda, Yatsukaho and Sekiya, Kaoru and Masumoto, Mika}, doi = {10.1073/pnas.2423813122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2423813122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Embryology cannot establish the “Protura-sister”}, volume = {122}, year = {2025}, }
• (2025). Cyanobacteria and chloroflexota cooperate to structure light-responsive biofilms. PNAS, 122(5), e2423574122. (www)

  @article{ , abstract = {Microbial mats are stratified communities often dominated by unicellular and filamentous phototrophs within an exopolymer matrix. It is challenging to quantify the dynamic responses of community members in situ as they experience steep gradients and rapid fluctuations of light. To address this, we developed a binary consortium using two representative isolates from hot spring mats: the unicellular oxygenic phototrophic cyanobacterium Synechococcus OS-B′ (Syn OS-B′) and the filamentous anoxygenic phototroph Chloroflexus MS-CIW-1 (Chfl MS-1). We quantified the motility of individual cells and entire colonies and demonstrated that Chfl MS-1 formed bundles of filaments that moved in all directions with no directional bias to light. Syn OS-B′ was slightly less motile but exhibited positive phototaxis. This binary consortium displayed cooperative behavior by moving further than either species alone and formed ordered arrays where both species aligned with the light source. No cooperative motility was observed when a nonmotile pilB mutant of Syn OS-B′ was used instead of Syn OS-B′. The binary consortium also produced more adherent biofilm than individual species, consistent with the close interspecies association revealed by electron microscopy. We propose that cyanobacteria and Chloroflexota cooperate in forming natural microbial mats by colonizing new niches and building robust biofilms.}, archive = {J_PNAS}, author = {Bunbury, Freddy and Rivas, Carlos and Calatrava, Victoria and Malkovskiy, Andrey V. and Joubert, Lydia-Marie and Parvate, Amar D. and Evans, James E. and Grossman, Arthur R. and Bhaya, Devaki}, doi = {10.1073/pnas.2423574122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2423574122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cyanobacteria and chloroflexota cooperate to structure light-responsive biofilms}, volume = {122}, year = {2025}, }
• (2025). Growth decline in european beech associated with temperature-driven increase in reproductive allocation. PNAS, 122(5), e2423181122. (www)

  @article{ , abstract = {Climate change is impacting forests in complex ways, with indirect effects arising from interactions between tree growth and reproduction often overlooked. Our 43-y study of European beech ( Fagus sylvatica ) showed that rising summer temperatures since 2005 have led to more frequent seed production events. This shift increases reproductive effort but depletes the trees’ stored resources due to insufficient recovery periods between seed crops. Consequently, annual tree ring increments have declined by 28%, dropping from a stable average of 1.60 mm y −1 between 1980 and 2005 to 1.16 mm y −1 thereafter. Importantly, this growth decline occurred without an accompanying trend in summer drought, indicating that altered reproductive patterns—not moisture stress—are driving the reduction. This creates a “perfect storm”: Increased reproductive effort drains resources, viable seed output falls due to the loss of mast-seeding benefits via pollination and lower seed predation, and the ongoing growth decline reduces current carbon uptake and future reproductive potential. These compounding factors threaten the sustainability of Europe’s most widespread forest tree. Our findings unveil a critical yet underrecognized indirect mechanism by which climate change endangers forest ecosystems, emphasizing the need to consider interactions between demographic processes when assessing species vulnerability to climate change.}, archive = {J_PNAS}, author = {Hacket-Pain, Andrew and Szymkowiak, Jakub and Journé, Valentin and Barczyk, Maciej K. and Thomas, Peter A. and Lageard, Jonathan G. A. and Kelly, Dave and Bogdziewicz, Michał}, doi = {10.1073/pnas.2423181122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2423181122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Growth decline in european beech associated with temperature-driven increase in reproductive allocation}, volume = {122}, year = {2025}, }
• (2025). Uterine organoids reveal insights into epithelial specification and plasticity in development and disease. PNAS, 122(5), e2422694122. (www)

  @article{ , abstract = {Understanding how epithelial cells in the female reproductive tract (FRT) differentiate is crucial for reproductive health, yet the underlying mechanisms remain poorly defined. At birth, FRT epithelium is highly malleable, allowing differentiation into various epithelial types, but the regulatory pathways guiding these early cell fate decisions are unclear. Here, we use neonatal mouse endometrial organoids and assembloid coculture models to investigate how innate cellular plasticity and external mesenchymal signals influence epithelial differentiation. Our findings demonstrate that uterine epithelium undergoes marked age-dependent changes, transitioning from a highly plastic state capable of forming both monolayered and multilayered structures to a more restricted fate as development progresses. Interestingly, parallels emerge between the developmental plasticity of neonatal uterine epithelium and pathological conditions such as endometrial cancer, where similar regulatory mechanisms may reactivate, driving abnormal epithelial differentiation and tumorigenesis. These results not only deepen our understanding of early uterine development but also offer a valuable model for studying the progression of reproductive diseases and cancers.}, archive = {J_PNAS}, author = {Rizo, Jason A. and Ahmad, Vakil and Pru, Jacob M. and Winuthayanon, Sarayut and Challa, Sridevi and Kim, Tae Hoon and Jeong, Jae-Wook and Spencer, Thomas E. and Kelleher, Andrew M.}, doi = {10.1073/pnas.2422694122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2422694122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Uterine organoids reveal insights into epithelial specification and plasticity in development and disease}, volume = {122}, year = {2025}, }
• (2025). Hsp90, DnaK, and ClpB collaborate in protein reactivation. PNAS, 122(5), e2422640122. (www)

  @article{ , abstract = {Hsp70, Hsp90, and ClpB/Hsp100 are molecular chaperones that help regulate proteostasis. Bacterial and yeast Hsp70s and their cochaperones function synergistically with Hsp90s to reactivate inactive and aggregated proteins by a mechanism that requires a direct interaction between Hsp90 and Hsp70 both in vitro and in vivo. Escherichia coli and yeast Hsp70s also collaborate in bichaperone systems with ClpB and Hsp104, respectively, to disaggregate and reactivate aggregated proteins and amyloids such as prions. These collaborations are dependent on direct interactions between ClpB/Hsp104 and Hsp70. We explored the possibility that E. coli homologs of Hsp70, Hsp90, and ClpB, referred to as DnaK, Hsp90 Ec , and ClpB, respectively, in combination with two DnaK cochaperones, DnaJ and GrpE, could promote protein disaggregation and reactivation under conditions where bichaperone systems are ineffective. Our results show that Hsp90 Ec is able to overcome the inhibition of protein disaggregation and reactivation observed when the concentration of DnaK is approaching physiological concentrations. We found that ATP hydrolysis and substrate binding by all three chaperones are essential for the collaborative function. The work further shows that ClpB acts early in protein reactivation with DnaK and its cochaperones; E. coli Hsp90 acts at a later stage after ClpB. The results highlight the collaboration among chaperones to regulate and maintain proteostasis.}, archive = {J_PNAS}, author = {Hoskins, Joel R. and Wickramaratne, Anushka C. and Jewell, Connor P. and Jenkins, Lisa M. and Wickner, Sue}, doi = {10.1073/pnas.2422640122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2422640122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hsp90, DnaK, and ClpB collaborate in protein reactivation}, volume = {122}, year = {2025}, }
• (2025). Subunit-specific conductance of single homomeric and heteromeric HCN pacemaker channels at femtosiemens resolution. PNAS, 122(5), e2422533122. (www)

  @article{ , abstract = {In mammals, the four subunit isoforms HCN1–4 assemble to form functional homotetrameric and heterotetrameric hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channels. Despite the outstanding relevance of HCN channels for organisms, including generating electrical rhythmicity in cardiac pacemaker cells and diverse types of brain neurons, key channel properties are still elusive. In particular, the unitary conductance, γ, of HCN channels is highly controversial. We analyzed the unitary conductance at femtosiemens resolution of all four homotetrameric channels of the mouse, mHCN1–4. All conductance values are in the range of 1 pS which is exceptionally small compared to most other ion channels. Surprisingly, the conductance among the isoforms differs up to threefold (γ mHCN2 = 1.54 pS > γ mHCN1 = 0.84 pS > γ mHCN3 = 0.54 pS ≈ γ mHCN4 = 0.51 pS) though the residues in the two narrow parts of the pore, the selectivity filter and the inner gate, are conserved. Mutagenesis and all-atom molecular dynamics simulations demonstrate that the differences in the conductance are generated by different amounts of negative charges in the outer channel vestibule, which control ion accumulation. In line with these results, heterotetrameric channels exhibit intermediate unitary conductance values with respect to the homotetrameric channels. Our approach demonstrates how HCN channels can be functionally differentiated at the single-channel level, paving the way to target specific channels with selective drugs.}, archive = {J_PNAS}, author = {Benndorf, Klaus and Enke, Uta and Tewari, Debanjan and Kusch, Jana and Liu, Haoran and Sun, Han and Schmauder, Ralf and Sattler, Christian}, doi = {10.1073/pnas.2422533122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2422533122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Subunit-specific conductance of single homomeric and heteromeric HCN pacemaker channels at femtosiemens resolution}, volume = {122}, year = {2025}, }
• (2025). Serine phosphorylation facilitates protein degradation by the human mitochondrial ClpXP protease. PNAS, 122(5), e2422447122. (www)

  @article{ , abstract = {ClpXP is a two-component mitochondrial matrix protease. The caseinolytic mitochondrial matrix peptidase chaperone subunit X (ClpX) recognizes and translocates protein substrates into the degradation chamber of the caseinolytic protease P (ClpP) for proteolysis. ClpXP degrades damaged respiratory chain proteins and is necessary for cancer cell survival. Despite the critical role of ClpXP in mitochondrial protein quality control, the specific degrons, or modifications that tag substrate proteins for degradation by human ClpXP, are still unknown. We demonstrated that phosphorylated serine (pSer) targets substrates to ClpX and facilitates their degradation by ClpXP in biochemical assays. In contrast, ClpP hyperactivated by the small-molecule drug ONC201 lost the preference for phosphorylated substrates. Hydrogen deuterium exchange mass spectrometry combined with biochemical assays showed that pSer binds the RKL loop of ClpX. ClpX variants with substitutions in the RKL loop failed to recognize phosphorylated substrates. In intact cells, ClpXP also preferentially degraded substrates with pSer. Moreover, ClpX substrates with the pSer were selectively found in aggregated mitochondrial proteins. Our work uncovers a mechanism for substrate recognition by ClpXP, with implications for targeting acute myeloid leukemia and other disorders involving ClpXP dysfunction.}, archive = {J_PNAS}, author = {Feng, Yue and Goncalves, Monica M. and Jitkova, Yulia and Keszei, Alexander F. A. and Yan, Yongran and Sarathy, Chaitra and St-Germain, Jonathan and Kenney, Tristan M. G. and Tcheng, Matthew and Trudel, Vincent and Mancini, Ross S. and Upadhyay, Rahul and Hurren, Rose and Gronda, Marcela and Schultz, Matthew and Soriano, Kaylen and Lees, Kaitlin and Pomroy, Neil C. and Currie, S. Quinn W. and Privé, Gilbert G. and Reed, Mark A. and Yudin, Andrei K. and Penn, Linda Z. and Arrowsmith, Cheryl H. and Raught, Brian and Mazhab-Jafari, Mohammad T. and Vahidi, Siavash and Schimmer, Aaron D.}, doi = {10.1073/pnas.2422447122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2422447122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Serine phosphorylation facilitates protein degradation by the human mitochondrial ClpXP protease}, volume = {122}, year = {2025}, }
• (2025). Unconventional magnetic oscillations in a kagome mott insulator. PNAS, 122(5), e2421390122. (www)

  @article{ , abstract = {In metals, electrons in a magnetic field undergo cyclotron motion, leading to oscillations in physical properties called quantum oscillations. This phenomenon has never been seen in a robust insulator because there are no mobile electrons. We report an exception to this rule. We study a Mott insulator on a kagome lattice which does not order magnetically down to milli-Kelvin temperatures despite antiferromagnetic interactions. We observe a plateau at magnetization equal to 1 9 Bohr magneton per magnetic ion, accompanied by oscillations in the magnetic torque, reminiscent of quantum oscillations in metals. The temperature dependence obeys Fermi distribution. These phenomena are consistent with a quantum spin liquid state whose excitations are fermionic spinons with a Dirac-like spectrum coupled to an emergent gauge field.}, archive = {J_PNAS}, author = {Zheng, Guoxin and Zhu, Yuan and Chen, Kuan-Wen and Kang, Byungmin and Zhang, Dechen and Jenkins, Kaila and Chan, Aaron and Zeng, Zhenyuan and Xu, Aini and Valenzuela, Oscar A. and Blawat, Joanna and Singleton, John and Li, Shiliang and Lee, Patrick A. and Li, Lu}, doi = {10.1073/pnas.2421390122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2421390122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unconventional magnetic oscillations in a kagome mott insulator}, volume = {122}, year = {2025}, }
• (2025). Fatty acid metabolism and the oxidative stress response support bacterial predation. PNAS, 122(5), e2420875122. (www)

  @article{ , abstract = {Despite growing awareness of their importance in soil ecology, the genetic and physiological traits of bacterial predators are still relatively poorly understood. In the course of a Myxococcus xanthus predator evolution experiment, we identified a class of genotypes leading to enhanced predation against diverse species. RNA-seq analysis demonstrated that this phenotype is linked to the constitutive activation of a predation-specific program. Functional analysis of the mutations accumulated across the evolutionary time in a two-component system and Acyl-CoA-manipulating enzymes revealed the critical roles of fatty acid metabolism and antioxidant gene induction. The former likely adapts the predator to metabolites derived from the prey while the latter protects predatory cells from reactive oxygen species generated by prey cells under stress and released upon lysis during predation. These findings reveal interesting parallels between bacterial predator–prey dynamics and pathogen–host cell interactions.}, archive = {J_PNAS}, author = {Jain, Rikesh and Le, Nguyen-Hung and Bertaux, Lionel and Baudry, Jean and Bibette, Jérôme and Denis, Yann and Habermann, Bianca H. and Mignot, Tâm}, doi = {10.1073/pnas.2420875122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2420875122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fatty acid metabolism and the oxidative stress response support bacterial predation}, volume = {122}, year = {2025}, }
• (2025). Electric transportation and electroreception in hummingbird flower mites. PNAS, 122(5), e2419214122. (www)

  @article{ , abstract = {Electric fields in terrestrial environments are used by caterpillars to detect their predators, as foraging cues by pollinators, and facilitate ballooning by spiders. This study shows that electric fields facilitate transportation and detection of hummingbirds in a guild of tropical phoretic mites. Hummingbird flower mites feed on nectar and pollen and complete their life cycle inside flowers. Mites colonize new flowers by hitching rides on hummingbird beaks. Flower mites emerge from hummingbird nostrils and disembark when the beak touches a flower. We tested whether flower mites are attracted to unmodulated electrostatic, or to modulated electric fields with amplitudes and frequencies in the range of those previously reported for hummingbirds. In a laboratory setup, mites were only attracted to modulated electric fields. In a choice experiment between positive or negative polarities, mites almost instantaneously chose positive charges, but only when the field was modulated. Mites display questing behavior, moving their front legs toward an electrostatic source. In experiments where we removed one or both front leg tarsi, we show that modulated fields are detected by sensory structures present in the front legs. We also show that flower mites use electrostatic attraction to bridge the gap to the beaks of hummingbirds, for a few milliseconds becoming one of the fastest terrestrial organisms. Our results confirm that hummingbird flower mites evolved an additional sensory modality — electroreception — to quickly detect hummingbirds and use electrostatics to facilitate transportation onto their hosts.}, archive = {J_PNAS}, author = {García-Robledo, Carlos and Dierick, Diego and Manser, Konstantine}, doi = {10.1073/pnas.2419214122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2419214122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electric transportation and electroreception in hummingbird flower mites}, volume = {122}, year = {2025}, }
• (2025). New evidence for early indian ocean trade routes into the south african interior. PNAS, 122(5), e2419077122. (www)

  @article{ , abstract = {The rise and spread of ancient Indian Ocean Rim (IOR) trade networks profoundly impacted southern Africa. Control over this trade played a critical role in the rise and maintenance of complex societies of the second millennium CE such as Mapungubwe and Great Zimbabwe. While the African origins of this trade lie in the first millennium CE, understanding its earliest phases and subsequent development in the far south has been hampered by a general paucity of research. The recovery of Persian Gulf ceramic sherds and Asian glass beads from the Letaba region of northeastern South Africa demonstrates that communities up to 400 km inland were already part of IOR trade by the 10th century. Although glass beads have been found at several late first millennium CE sites throughout the region, glazed wares are much rarer by comparison. In southern Africa, archaeological sites with Persian Gulf ceramics largely date to between the 9th and 10th centuries with a distribution limited to the Limpopo River’s main tributaries. This distribution poses new questions about early IOR trade routes into the southern African interior and suggests Xai-Xai in southern Mozambique as a possible entry point for early IOR trade.}, archive = {J_PNAS}, author = {Antonites, Alexander and Antonites, Annie R. and Peterson, Christian E. and Hopf, Tyron and Ndlovu, Ndukuyakhe}, doi = {10.1073/pnas.2419077122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2419077122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {New evidence for early indian ocean trade routes into the south african interior}, volume = {122}, year = {2025}, }
• (2025). PgpP is a broadly conserved phosphatase required for phosphatidylglycerol lipid synthesis. PNAS, 122(5), e2418775122. (www)

  @article{ , abstract = {The cytoplasmic membrane of bacteria is composed of a phospholipid bilayer made up of a diverse set of lipids. Phosphatidylglycerol (PG) is one of the principal constituents and its production is essential for growth in many bacteria. All the enzymes required for PG biogenesis in Escherichia coli have been identified and characterized decades ago. However, it has remained poorly understood how gram-positive bacteria perform the terminal step in the pathway that produces this essential lipid. In E. coli, this reaction is mediated by three functionally redundant phosphatases that convert phosphatidylglycerophosphate (PGP) into PG. Here, we show that homologs of these enzymes in Bacillus subtilis are not required for PG synthesis. Instead, we identified a previously uncharacterized B. subtilis protein, YqeG (renamed PgpP), as an essential enzyme required for the conversion of PGP into PG. Expression of B. subtilis or Staphylococcus aureus PgpP in E. coli lacking all three Pgp enzymes supported the growth of the strain. Furthermore, depletion of PgpP in B. subtilis led to growth arrest, reduced membrane lipid staining, and accumulation of PGP. PgpP is broadly conserved among Firmicutes and Cyanobacteria. Homologs are also present in yeast mitochondria and plant chloroplasts, suggesting that this widely distributed enzyme has an ancient origin. Finally, evidence suggests that PgpP homologs are essential in many gram-positive pathogens and thus the enzyme represents an attractive target for antibiotic development.}, archive = {J_PNAS}, author = {Gründling, Angelika and Brogan, Anna P. and James, Michael J. and Ramirez-Guadiana, Fernando H. and Roney, Ian J. and Bernhardt, Thomas G. and Rudner, David Z.}, doi = {10.1073/pnas.2418775122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2418775122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PgpP is a broadly conserved phosphatase required for phosphatidylglycerol lipid synthesis}, volume = {122}, year = {2025}, }
• (2025). Activation of the conserved hippo kinases by inflammasome-triggered proteolytic cleavage controls programmed cell death in macrophages. PNAS, 122(5), e2418613122. (www)

  @article{ , abstract = {The mammalian Hippo kinases, MST1 and MST2, regulate organ development and suppress tumor formation by balancing cell proliferation and death. In macrophages, inflammasomes detect molecular patterns from invading pathogens or damaged host cells and trigger programmed cell death. In addition to lytic pyroptosis, the signatures associated with apoptosis are induced by inflammasome activation, but how the inflammasomes coordinate different cell death processes remains unclear. Here, we identify the crucial role of MST1/2 in inflammasome-triggered cell death. Macrophages proteolytically convert full-length MST1/2 into the MST1/2 N-terminal fragments (MST1/2-NT) when the NLRC4 inflammasome detects flagellin from the pathogenic bacterium, Legionella pneumophila . Activation of the NLRP3 inflammasome by the damage-associated molecular pattern, extracellular ATP, also produces MST1/2-NT. Caspase-1, the protease activated by these inflammasomes, directly cleaves MST1/2, and blockage of caspase-1 inhibits MST1/2-NT production in macrophages challenged with L. pneumophila . Importantly, MST1/2-NT production is critical for macrophages to trigger a set of death processes associated with apoptosis upon inflammasome activation and knocking out Mst1/2 causes dysregulated gasdermin protein cleavage for pyroptotic death. Furthermore, macrophages lacking MST1/2 have increased susceptibility to virulent L. pneumophila, revealing that the Hippo kinases are important restriction factors against the pathogen. These findings demonstrate that proteolytic cleavage of MST1/2 induced by inflammatory stimuli is an immune pathway to regulate programmed cell death in macrophages and uncover a unique link between the tumor-suppressive Hippo kinases and the inflammasomes in innate immunity.}, archive = {J_PNAS}, author = {Su, Yu-Ting and Quagliato, Sydney M. and St. Louis, Brendyn M. and Abdelaziz, Mohamed H. and He, Yuan and Bondage, Devanand and Lehman, Stephanie S. and Lee, Pei-Chung}, doi = {10.1073/pnas.2418613122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2418613122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Activation of the conserved hippo kinases by inflammasome-triggered proteolytic cleavage controls programmed cell death in macrophages}, volume = {122}, year = {2025}, }
• (2025). Neomorphic leukemia-derived mutations in the TET2 enzyme induce genome instability via a substrate shift from 5-methylcytosine to thymine. PNAS, 122(5), e2418318122. (www)

  @article{ , abstract = {Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (mC) in DNA, contributing to the regulation of gene transcription. Diverse mutations of TET2 are frequently found in various blood cancers, yet the full scope of their functional consequences has been unexplored. Here, we report that a subset of TET2 mutations identified in leukemia patients alter the substrate specificity of TET2 from acting on mC to thymine. This neomorphic activity results from substitutions at key residues involved in the interactions with the mC base, including Asn1387 and His1904. Recombinant human TET2 proteins harboring the mutation of these residues can catalyze the oxidation of thymine to 5-hydroxymethyluracil (hmU) and 5-formyluracil (fU). Exogenous expression of the mutant TET2 Asn1387Thr (N1387T) in HEK293T cells leads to hmU accumulation, with levels further increased in cells lacking the glycosylase SMUG1. Endogenous knock-in of N1300T, the murine equivalent of N1387T, in mouse embryonic stem cells induces hmU production, causing DNA lesions and transcriptional activation of DNA damage response genes. N1300T cells accumulate more additional mutations with extended culture and exhibit heightened sensitivity to ATR inhibition compared to Tet2 knockout cells. Our study reveals that certain patient-derived TET2 mutations can acquire unexpected gain-of-function activities beyond impairing mC oxidation, offering a fresh perspective on the diverse molecular etiology of mutant TET2-related leukemogenesis.}, archive = {J_PNAS}, author = {Jin, Guang-Bo and Rong, Shao-Qin and Yin, Dong-Rui and Deng, Zhou-Hao and Ding, Xiao and Sheng, Meng-Yao and Gao, Hai and Kohli, Rahul M. and Xu, Guo-Liang and Zhou, Dan}, doi = {10.1073/pnas.2418318122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2418318122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Neomorphic leukemia-derived mutations in the TET2 enzyme induce genome instability via a substrate shift from 5-methylcytosine to thymine}, volume = {122}, year = {2025}, }
• (2025). CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex. PNAS, 122(5), e2417529122. (www)

  @article{ , abstract = {Chromobox 2 (CBX2), a crucial component of the polycomb repressive complex (PRC), has been implicated in the development of various human cancers. However, its role in the regulation of tumor immunogenicity and immune evasion remains inadequately understood. In this study, we found that ablation of CBX2 led to tumor growth inhibition, activation of the tumor immune microenvironment, and enhanced therapeutic efficacy of anti-PD1 or adoptive T cell therapies by using murine syngeneic tumor models. By analysis of the CBX2-regulated transcriptional program coupled with mass spectrometry screening of CBX2-interacting proteins, we found that CBX2 suppresses interferon signaling independent of its function in the canonical PRC. Mechanistically, CBX2 directly interacts with RACK1 and facilitates the recruitment of HDAC1, which attenuates the H3K27ac modification on the promoter regions of interferon-stimulated genes, thereby suppressing interferon signaling. Consequently, CBX2 reduces tumor immunogenicity and enables immune evasion. Moreover, a high expression level of CBX2 is associated with immune suppressive tumor microenvironment and reduced efficacy of immunotherapy across various human cancer types. Our study identifies a noncanonical CBX2–RACK1–HDAC1 corepressor complex in suppression of tumor immunogenicity, thereby presenting a potential target and biomarker for tumor immunotherapy.}, archive = {J_PNAS}, author = {Lin, Yanxun and Jin, Huan and She, Yong and Zhang, Yiqun and Cui, Lei and Xie, Chunyuan and Liu, Yongxiang and Zhang, Huanling and Guo, Hui and Wu, Jiaxin and Li, Lin and Guo, Zixuan and Wang, Xiaojuan and Jiang, Wu and Chen, Xu and He, Shuai and Zhou, Penghui and Tan, Jing and Bei, Jin-Xin and Liu, Jinyun and Chen, Yan-Xing and Zhao, Qi and Xia, Xiaojun and Wang, Zining}, doi = {10.1073/pnas.2417529122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2417529122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex}, volume = {122}, year = {2025}, }
• (2025). Suppressing APOE4-induced neural pathologies by targeting the VHL–HIF axis. PNAS, 122(5), e2417515122. (www)

  @article{ , abstract = {The ε4 variant of human apolipoprotein E ( APOE4 ) is a key genetic risk factor for neurodegeneration in Alzheimer’s disease and elevated all-cause mortality in humans. Understanding the factors and mechanisms that can mitigate the harmful effects of APOE4 has significant implications. In this study, we find that inactivating the VHL-1 (Von Hippel–Lindau) protein can suppress mortality, neural and behavioral pathologies caused by transgenic human APOE4 in Caenorhabditis elegans . The protective effects of VHL-1 deletion are recapitulated by stabilized HIF-1 (hypoxia-inducible factor), a transcription factor degraded by VHL-1. HIF-1 activates a genetic program that safeguards against mitochondrial dysfunction, oxidative stress, proteostasis imbalance, and endolysosomal rupture—critical cellular events linked to neural pathologies and mortality. Furthermore, genetic inhibition of Vhl reduces cerebral vascular injury and synaptic lesions in APOE4 mice, suggesting an evolutionarily conserved mechanism. Thus, we identify the VHL–HIF axis as a potent modulator of APOE4 -induced neural pathologies and propose that targeting this pathway in nonproliferative tissues may curb cellular damage, protect against neurodegeneration, and reduce tissue injuries and mortality.}, archive = {J_PNAS}, author = {Jiang, Wei I. and Cao, Yiming and Xue, Yue and Ji, Yichun and Winer, Benjamin Y. and Chandra, Rashmi and Zhang, Xingyuan Fischer and Zhang, Mengqi and Singhal, Neel S. and Pierce, Jonathan T. and Chen, Song and Ma, Dengke K.}, doi = {10.1073/pnas.2417515122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2417515122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Suppressing APOE4-induced neural pathologies by targeting the VHL–HIF axis}, volume = {122}, year = {2025}, }
• (2025). Natural variations in TT8 and its neighboring STK confer yellow seed with elevated oil content in brassica juncea. PNAS, 122(5), e2417264122. (www)

  @article{ , abstract = {Seed color is a critical quality trait in numerous plant species. In oilseed Brassica crops, including rapeseed and mustard, yellow seeds are distinguished by their significantly higher oil content and faster germination rates compared to black or brown counterparts. Despite the agronomic significance of the yellow seeds being a prime breeding target, the mechanisms underlying elevated oil content remain obscure. In this study, we assembled the first telomere-to-telomere (T2T) genome of B. juncea and further investigated the genetic regulation, molecular mechanism, and the evolutionary history of yellow seeds in B. juncea. Through an analysis of allelic variation in the TRANSPARENT TESTA 8 ( TT8 ) genes across 1,002 worldwide B . juncea accessions, we traced the single origin of yellow seeds to approximately 2,300 y ago in Southwestern China. Furthermore, we discovered the MADS-box gene SEEDSTICK ( STK ) coevolved with TT8 , and they coordinately regulated seed size, oil accumulation, and seed coat proportion in B. juncea . These findings open broad avenues for targeted breeding of yellow-seeded Brassica crops with elevated oil content.}, archive = {J_PNAS}, author = {Qian, Lunwen and Yang, Liu and Liu, Xianjun and Wang, Tianyi and Kang, Lei and Chen, Hao and Lu, Yin and Zhang, Yukun and Yang, Shujie and You, Liang and Yao, Min and Xiang, Xingru and Cui, Kan and Guo, Ying and Yang, Bin and Yan, Mingli and Xia, Shitou and Meng, Jinling and Lin, Tao and Mason, Annaliese S. and Snowdon, Rod J. and Liu, Zhongsong}, doi = {10.1073/pnas.2417264122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2417264122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Natural variations in TT8 and its neighboring STK confer yellow seed with elevated oil content in brassica juncea}, volume = {122}, year = {2025}, }
• (2025). Bubble coalescence principle in saline water. PNAS, 122(5), e2417043122. (www)

  @article{ , abstract = {Bubbles present in saline water typically exhibit a prolonged lifetime, making them attractive for various engineering processes. Herein, we unveil a transition from delayed bubble coalescence to rapid bursting within about one millisecond in salty solutions. The key aspect in understanding this transition lies in the combined influences of surface deformation and ion surface excess instead of characterizing the ions alone. Only with a sufficiently deformed region trapped between the colliding bubble and fluid surfaces can the coalescence inhibition effect be maintained to cause the bouncing behavior. Thus, we quantify a consistent upper limit of ion transfer content required for instant coalescence under different salty conditions. Furthermore, we present numerical ranges associated with different bubble behaviors in terms of E o , R e , and W e and determine the critical values to predict bubble dynamics. Our findings shed light on the bubble coalescence principle in saline water and allow access to the regulation of coalescence time based on the requirement of technological applications.}, archive = {J_PNAS}, author = {Li, Danlong and Manica, Rogerio and Chen, Zhixiang and Wang, Shuo and Liu, Qingxia and Zhang, Haijun}, doi = {10.1073/pnas.2417043122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2417043122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bubble coalescence principle in saline water}, volume = {122}, year = {2025}, }
• (2025). No gender differences in attraction to young partners: A study of 4500 blind dates. PNAS, 122(5), e2416984122. (www)

  @article{ , abstract = {In mixed-gender couples, men are older than women on average. Scholars and laypeople presume that this arrangement reflects mirrored preferences such that men desire younger partners and women desire older partners. Nevertheless, relevant published data on in-person romantic evaluations—that is, studies where adults interact in person and report their initial attraction to each other—are nearly nonexistent. We examined the association of a partner’s age with romantic desire ( N = 9,084 dyadic reports) among N = 6,262 blind daters who used a matchmaking service in hopes of finding a long-term partner. Preregistered tests revealed that people were (slightly) attracted to younger partners on average—and this association did not differ by gender. Conclusions were identical if we examined a) age difference from one’s own age, and b) a dataset limited to women 40-and-under and mixed-gender dates. Furthermore, participant’s self-reported “upper-age limits” played no meaningful role: Participants had a modest preference for youth overall, but it did not matter whether the partner’s age fell below or above this personal maximum. We discuss the implications of the nonexistent initial-attraction gender difference for the age difference in mixed-gender couples.}, archive = {J_PNAS}, author = {Eastwick, Paul W. and Finkel, Eli J. and Meza, Eva M. and Ammerman, Kellie}, doi = {10.1073/pnas.2416984122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2416984122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {No gender differences in attraction to young partners: A study of 4500 blind dates}, volume = {122}, year = {2025}, }
• (2025). Toxoplasma chitinase-like protein orchestrates cyst wall glycosylation to facilitate effector export and cyst turnover. PNAS, 122(5), e2416870122. (www)

  @article{ , abstract = {Toxoplasma bradyzoites reside in tissue cysts that undergo cycles of expansion, rupture, and release to foster chronic infection. The glycosylated cyst wall acts as a protective barrier, although the processes responsible for formation, remodeling, and turnover are not understood. Herein, we identify a noncanonical chitinase-like enzyme TgCLP1 that localizes to micronemes and is targeted to the cyst wall after secretion. Genetic deletion of TgCLP1 resulted in a thickened cyst wall that decreased cyst turnover, blocked the export of virulence effectors into host cells, and resulted in failure to persist during chronic infection. Genetic complementation with a series of mutants revealed that the GH19 glycosidase domain was crucial for regulating glycosylation of several glycoproteins in the cyst wall. Overall, our findings reveal that TgCLP1 is a multifunctional survival factor that modifies glycoproteins within the cyst wall to modulate export of virulence effectors and regulate turnover of tissue cysts.}, archive = {J_PNAS}, author = {Fu, Yong and Tomita, Tadakimi and Weiss, Louis M. and West, Christopher M. and Sibley, L. David}, doi = {10.1073/pnas.2416870122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2416870122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Toxoplasma chitinase-like protein orchestrates cyst wall glycosylation to facilitate effector export and cyst turnover}, volume = {122}, year = {2025}, }
• (2025). Errors are robustly tamed in cumulative knowledge processes. PNAS, 122(5), e2416866122. (www)

  @article{ , abstract = {As knowledge accumulates in science and society in a distributed fashion, erroneous derivations can be introduced into the corpus of knowledge. Such derivations can compromise the validity of any units of knowledge that rely on them in the future. Can societal knowledge maintain some level of integrity given simple distributed error-checking mechanisms? In this paper, we investigate the following formulation of the question: assuming that a constant fraction of the new derivations is wrong, is it possible for simple error-checking mechanisms that apply when a new unit of knowledge is derived to maintain the integrity of the corpus of knowledge? This question was introduced by Ben-Eliezer et al. [“Is this correct? Let’s check!” in 14th Innovations in Theoretical Computer Science Conference (ITCS, 2023)], who gave a robust affirmative answer in a specific probabilistic model for knowledge accumulation. Namely, this model required that new units depend on just one existing unit and join the process according to a preferential attachment rule. In this work, we consider much more general families of processes of knowledge accumulation, where new units may depend on multiple existing units and join according to varied attachment mechanisms. We also consider models with a (random) fraction of insertions of adversarial nodes. We give a robust affirmative answer to the above question by showing that for all of these models, as long as many of the units follow simple local heuristics for checking a bounded number of units they depend on, all errors will be eventually eliminated.}, archive = {J_PNAS}, author = {Brandenberger, Anna and Marcussen, Cassandra and Mossel, Elchanan and Sudan, Madhu}, doi = {10.1073/pnas.2416866122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2416866122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Errors are robustly tamed in cumulative knowledge processes}, volume = {122}, year = {2025}, }
• (2025). Triethylamine-mediated protonation–deprotonation unlocks dual-drug self assembly to suppress breast cancer progression and metastasis. PNAS, 122(5), e2416796122. (www)

  @article{ , abstract = {Carrier-free nanomedicines exhibited significant potential in elevating drug efficacy and safety for tumor management, yet their self assembly typically relied on chemical modifications of drugs or the incorporation of surfactants, thereby compromising the drug’s inherent pharmacological activity. To address this challenge, we proposed a triethylamine (TEA)-mediated protonation–deprotonation strategy that enabled the adjustable-proportion self assembly of dual drugs without chemical modification, achieving nearly 100% drug loading capacity. Molecular dynamic simulations, supported by experiment evidence, elucidated the underlying self-assembly mechanism. Specifically, TEA facilitated the deprotonation of Doxorubicin (Dox) and α-Tocopherol succinate (α-tos), causing Dox to transition from a hydrophilic to a hydrophobic state, while simultaneously increasing the hydrophilicity of α-tos. This allowed for a fine-tuned balance between the hydrophilic and hydrophobic properties of the two compounds, enabling their precise self assembly into a carrier-free nanomedicine (DT) with a tailored drug ratio. The engineered DT demonstrated the ability to accumulate at the tumor sites and release its therapeutic drugs in a controlled manner. The combination of Dox and α-tos synergistically generated reactive oxygen species and modulated the expression of tumor matrix metalloproteinase-9, leading to superior antitumor efficacy without significant metastasis, while maintaining excellent safety profiles. Our findings provided unique perspectives on the design of carrier-free nanomedicine for cancer therapy, thereby laying a solid foundation for its potential clinical translation.}, archive = {J_PNAS}, author = {Lei, Lei and Song, Yujun and Yang, Lianyi and Wang, Yazhen and Xia, Xue and Zhang, Yiwei and Zhang, Xiaoxian and Zhang, Xuequan and Duggal, Ishaan and He, Bin and Peppas, Nicholas A. and Cao, Jun and Gao, Huile}, doi = {10.1073/pnas.2416796122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2416796122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Triethylamine-mediated protonation–deprotonation unlocks dual-drug self assembly to suppress breast cancer progression and metastasis}, volume = {122}, year = {2025}, }
• (2025). Optimal strategies for correcting merotelic chromosome attachments in anaphase. PNAS, 122(5), e2416459122. (www)

  @article{ , abstract = {Accurate chromosome segregation in mitosis depends on proper connections of sister chromatids, through microtubules, to the opposite poles of the early mitotic spindle. Transiently, many inaccurate connections are formed and rapidly corrected throughout the mitotic stages, but a small number of merotelic connections, in which a chromatid is connected to both spindle poles, remain lagging at the spindle’s equator in anaphase. Most of the lagging chromatids are eventually moved to one or the other pole, likely by a combination of microtubules’ turnover and the brute force of pulling by the microtubules’ majority from the one pole against the microtubules’ minority from the other pole. We use computer simulations from two stochastic models (1D and full 3D CellDynaMo model) combining force balances and microtubules’ dynamics for the lagging chromatids to investigate what maximizes the percentage of segregated laggards. We find that a) brute force tug-of-war with slow (< 0.0001 s −1 ) microtubules’ detachment rate can move asymmetric laggards to the poles in limited time, b) rapid (> 0.01 s −1 ) microtubules’ detachment rate leads to a significant loss of the laggards, and c) intermediate (~ 0.001 s −1 ) microtubules’ detachment rate ensures higher than 90% accuracy of segregation. The simulations also shed light on the waiting time required to correct the merotelic errors in anaphase and on the roles of chromatid-attached microtubule number and Aurora B–mediated, spatially graded regulation of microtubule kinetics in anaphase.}, archive = {J_PNAS}, author = {Kliuchnikov, Evgenii and Marx, Kenneth A. and Barsegov, Valeri and Mogilner, Alex}, doi = {10.1073/pnas.2416459122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2416459122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Optimal strategies for correcting merotelic chromosome attachments in anaphase}, volume = {122}, year = {2025}, }
• (2025). Impaired spatial coding of the hippocampus in a dentate gyrus hypoplasia mouse model. PNAS, 122(5), e2416214122. (www)

  @article{ , abstract = {The hippocampal dentate gyrus (DG) is thought to orthogonalize inputs from the entorhinal cortex (pattern separation) and relay this information to the CA3 region. In turn, attractor dynamics in CA3 perform a pattern completion or error correction operation before sending its output to CA1. In a mouse model of congenital hypoplasia of the DG, a deficiency in the Wntless (Wls) gene, specifically in cells expressing Gfap-Cre , which targets neuronal progenitors, led to an almost total absence of dentate granule cells and modestly impaired performance in spatial tasks. Here, we investigated the physiological consequences of granule cell loss in these mice by conducting in vivo calcium imaging from CA1 principal cells during behavior. The spatial selectivity of these cells was preserved without the DG. On a linear track, place fields in mutant mice were more likely to be near track terminals and to encode the distance from the start point in each running direction. In an open box, CA1 cells in mutant mice exhibited reductions in the percentage of place cells, in spatial information, and in place field stability. The reduction in place field stability across repeated exposures to the same environment resulted in a reduction in the differential representations of two different contexts in mutant mice compared to wild-type mice. These results suggest that DG helps to stabilize CA1 spatial representations, especially in 2-D environments, and that the lack of stability across similar environments may play a key role in the deficits of animals with DG dysfunction in discriminating different environments.}, archive = {J_PNAS}, author = {Chen, Xiaojing and Cheng, Ning and Wang, Cheng and Knierim, James J.}, doi = {10.1073/pnas.2416214122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2416214122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Impaired spatial coding of the hippocampus in a dentate gyrus hypoplasia mouse model}, volume = {122}, year = {2025}, }
• (2025). Retinoic acid antagonizes estrogen signaling to maintain adult uterine cell fate. PNAS, 122(5), e2416089122. (www)

  @article{ , abstract = {Classical tissue recombination experiments demonstrate that cell-fate determination along the anterior–posterior axis of the Müllerian duct occurs prior to postnatal day 7 in mice. However, little is known about how these cell types are maintained in adults. In this study, we provide genetic evidence that a balance between antagonistic retinoic acid (RA) and estrogen signaling activity is required to maintain simple columnar cell fate in adult uterine epithelium. Transdifferentiation of simple columnar uterine epithelium into stratified cervicovaginal-like epithelium was observed in three related mouse genetic models, in which RA signaling was perturbed in the postnatal uterus. Single-cell RNA sequencing analysis identified the transformed epithelial cell populations and revealed extensive immune cell infiltration resulting from loss of RA signaling. Surprisingly, disruption of RA signaling led to dysregulated expression of a substantial number of estrogen target genes, suggesting that these two pathways may functionally oppose each other in determining and maintaining uterine epithelial cell fate. Consistent with this model, neonatal exposure to the strong synthetic estrogen, diethylstilbestrol, downregulated expression of a group of RA target genes and led to epithelial stratification and immune cell infiltration in wild-type uterus. Treating RA receptor triple conditional knockout pups with fulvestrant, an estrogen antagonist, reestablished the balance between the two signaling pathways, and effectively prevented the transformation of mutant simple columnar epithelia to metaplastic stratified epithelia. These findings implicate an essential role for RA signaling in maintaining uterine cytodifferentiation by antagonizing estrogen signaling in the postnatal uterus.}, archive = {J_PNAS}, author = {Yin, Yan and Haller, Meade and Goldinger, Lauren and Bharadwaj, Shivani and So, Emily and Robles-Pinos, Vivian and Chen, David and Ma, Liang}, doi = {10.1073/pnas.2416089122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2416089122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Retinoic acid antagonizes estrogen signaling to maintain adult uterine cell fate}, volume = {122}, year = {2025}, }
• (2025). Chronic stress–induced cholesterol metabolism abnormalities promote ESCC tumorigenesis and predict neoadjuvant therapy response. PNAS, 122(5), e2415042122. (www)

  @article{ , abstract = {Recent studies have demonstrated that chronic stress can enhance the development of multiple human diseases, including cancer. However, the role of chronic stress in esophageal carcinogenesis and its underlying molecular mechanisms remain unclear. This study uncovered that dysregulated cholesterol metabolism significantly promotes esophageal carcinogenesis under chronic stress conditions. Our findings indicate that the persistent elevation of glucocorticoids induced by chronic stress stimulates cholesterol uptake, contributing to esophageal carcinogenesis. The activated glucocorticoid receptor (GCR) enrichment at the promoter region of High Mobility Group Box 2 (HMGB2) facilitates its transcription. As a transcription coactivator, HMGB2 enhances Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1) transcription and regulates cholesterol metabolism through LDL particle uptake into cells via Low Density Lipoprotein Receptor (LDLR). These results emphasize the significant impact of chronic stress on esophageal carcinogenesis and establish cholesterol metabolism disorder as a crucial link between chronic stress and the development of ESCC. The implications suggest that effectively managing chronic stress may serve as a viable strategy for preventing and treating ESCC.}, archive = {J_PNAS}, author = {Wang, Ting and Wang, Xiangyu and Wang, Keke and Yu, Mengyuan and Bai, Ruihua and Zhang, Yiru and Zhang, Zihan and Liu, Feifei and Wang, Rui and Shi, Xiaodan and Jia, Ludan and Liu, Kangdong and Li, Xiang and Jin, Guoguo and Zhao, Simin and Dong, Zigang}, doi = {10.1073/pnas.2415042122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2415042122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chronic stress–induced cholesterol metabolism abnormalities promote ESCC tumorigenesis and predict neoadjuvant therapy response}, volume = {122}, year = {2025}, }
• (2025). AMH protects the ovary from doxorubicin by regulating cell fate and the response to DNA damage. PNAS, 122(5), e2414734122. (www)

  @article{ , abstract = {Anti-Müllerian hormone (AMH) protects the ovarian reserve from chemotherapy, and this effect is most pronounced with Doxorubicin (DOX). However, DOX toxicity and AMH rescue mechanisms in the ovary have remained unclear. Herein, we characterize the consequences of these treatments in ovarian cell types using scRNAseq. DOX-induced DNA damage activates Tp53 class mediators across ovarian cell types. In the mesenchyme, cotreatment with AMH halts theca progenitor differentiation and reduces apoptotic gene expression. In preantral granulosa cells, DOX upregulates the cell cycle inhibitor Cdkn1a and dysregulates Wnt signaling, which are ameliorated by AMH cotreatment. Finally, AMH induces Id3 , a gene involved in DNA repair, which is necessary to prevent the accumulation of DNA lesions marked by γ-H2AX. Altogether these mechanisms of AMH protection contribute to sustained fertility in mice, offering promising broad avenues for fertility preservation in cancer patients undergoing chemotherapy.}, archive = {J_PNAS}, author = {Nguyen, Ngoc Minh Phuong and Chang, Eun Mi and Chauvin, Maeva and Sicher, Natalie and Kashiwagi, Aki and Nagykery, Nicholas and Chow, Christina and May, Phoebe and Mermin-Bunnell, Alana and Cleverdon, Josephine and Duong, Thy and Kano, Motohiro and Godin, Philippe and Meinsohn, Marie-Charlotte and Gao, Dadi and Donahoe, Patricia K. and Pepin, David}, doi = {10.1073/pnas.2414734122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2414734122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {AMH protects the ovary from doxorubicin by regulating cell fate and the response to DNA damage}, volume = {122}, year = {2025}, }
• (2025). Enzymes in a human cytoplasm model organize into submetabolon complexes. PNAS, 122(5), e2414206122. (www)

  @article{ , abstract = {Enzyme–enzyme interactions are fundamental to the function of cells. Their atomistic mechanisms remain elusive mainly due to limitations of in-cell measurements. We address this challenge by atomistically modeling, for a total of ≈80 μs, a slice of the human cell cytoplasm that includes three successive enzymes along the glycolytic pathway: glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), and phosphoglycerate mutase (PGM). We tested the model for nonspecific protein stickiness, an artifact of current atomistic force fields in crowded environments. The simulations reveal that the human enzymes co-organize in-cell into transient submetabolon complexes, consistent with previous experimental results. Our data both reiterate known specificity between GAPDH and PGK and reveal extensive direct interactions between GAPDH and PGM. Our simulations further reveal, through force field benchmarking, the critical role of protein solvation in facilitating these enzyme–enzyme interactions. Transient interenzyme interactions with μs lifetime occur repeatedly in our simulations via specific sticky protein surface patches, with interactions often mediated by charged patch residues. Some of the residues that interact frequently with one another lie in or near the active site of the enzymes. We show that some of these patches correspond to a general mode to interact with several partners for promiscuous enzymes like GAPDH. We further show that the non-native yeast PGK is stickier than human PGK in our human cytoplasm model, supporting the idea of evolutionary pressure to reduce sticking. Our cytoplasm modeling paves the way toward capturing the atomistic dynamics of an entire enzymatic pathway in-cell.}, archive = {J_PNAS}, author = {Samuel Russell, Premila P. and Rickard, Meredith M. and Pogorelov, Taras V. and Gruebele, Martin}, doi = {10.1073/pnas.2414206122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2414206122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Enzymes in a human cytoplasm model organize into submetabolon complexes}, volume = {122}, year = {2025}, }
• (2025). Emergence and evolution of heterocyte glycolipid biosynthesis enabled specialized nitrogen fixation in cyanobacteria. PNAS, 122(5), e2413972122. (www)

  @article{ , abstract = {Heterocytes, specialized cells for nitrogen fixation in cyanobacteria, are surrounded by heterocyte glycolipids (HGs), which contribute to protection of the nitrogenase enzyme from oxygen. Diverse HGs preserve in the sediment and have been widely used as evidence of past nitrogen fixation, and structural variation has been suggested to preserve taxonomic information and reflect paleoenvironmental conditions. Here, by comprehensive HG identification and screening of HG biosynthetic gene clusters throughout cyanobacteria, we reconstruct the convergent evolutionary history of HG structure, in which different clades produce the same HGs. We find that rudimentary HG biosynthetic machinery was already present in cyanobacteria before the emergence of heterocytes for functions unrelated to nitrogen fixation and identify HG analogs produced by specific and distantly related nonheterocytous cyanobacteria. These structurally less complex molecules represent precursors of HGs, suggesting that HGs arose after a genomic reorganization and expansion of ancestral biosynthetic machinery, enabling the rise of cyanobacterial heterocytes in an increasingly oxygenated atmosphere. Our results open a chapter in the potential use of diagenetic products of HGs and HG analogs as fossils for reconstructing the evolution of multicellularity and division of labor in cyanobacteria.}, archive = {J_PNAS}, author = {Pérez Gallego, Ruth and von Meijenfeldt, F. A. Bastiaan and Bale, Nicole J. and Sinninghe Damsté, Jaap S. and Villanueva, Laura}, doi = {10.1073/pnas.2413972122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2413972122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Emergence and evolution of heterocyte glycolipid biosynthesis enabled specialized nitrogen fixation in cyanobacteria}, volume = {122}, year = {2025}, }
• (2025). Establishment and application of a zebrafish model of werner syndrome identifies sapanisertib as a potential antiaging drug. PNAS, 122(5), e2413719122. (www)

  @article{ , abstract = {Aging is a complex process that affects multiple organs, and the discovery of a pharmacological approach to ameliorate aging is considered the Holy Grail of medicine. Here, we performed an N-ethyl-N-nitrosourea forward genetic screening in zebrafish and identified an accelerated aging mutant named meteor ( met ), harboring a mutation in the Werner syndrome RecQ - like helicase ( wrn ) gene. Loss of wrn leads to a short lifespan and age-related characteristics in the intestine of zebrafish embryos, such as cellular senescence, genomic instability, and epigenetic alteration. Therefore, we conducted a screening of antiaging drugs using the met mutant and revealed that sapanisertib effectively ameliorated most of the aging phenotypes of the mutant. Mechanistically, the geroprotective effects of sapanisertib may be attributed to inhibition of mTORC1/2. Furthermore, sapanisertib also attenuated chronological aging in wild-type aged zebrafish and replicative-senescence in human foreskin fibroblasts. Taken together, our study introduces a unique and efficient model for large-scale antiaging drug screening in vertebrates and suggests sapanisertib as a potential therapeutic option for treating premature aging and promoting healthy aging.}, archive = {J_PNAS}, author = {Ma, Jianlong and Chen, Yang and Song, Jingmei and Ruan, Qingfeng and Li, Lianghui and Luo, Lingfei}, doi = {10.1073/pnas.2413719122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2413719122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Establishment and application of a zebrafish model of werner syndrome identifies sapanisertib as a potential antiaging drug}, volume = {122}, year = {2025}, }
• (2025). 14-3-3 promotes sarcolemmal expression of cardiac CaV1.2 and nucleates isoproterenol-triggered channel superclustering. PNAS, 122(5), e2413308122. (www)

  @article{ , abstract = {The L-type Ca 2+ channel (Ca V 1.2) is essential for cardiac excitation–contraction coupling. To contribute to the inward Ca 2+ flux that drives Ca 2+ -induced-Ca 2+ -release, Ca V 1.2 channels must be expressed on the sarcolemma; thus the regulatory mechanisms that tune Ca V 1.2 expression to meet contractile demand are an emerging area of research. A ubiquitously expressed protein called 14-3-3 has been proposed to affect Ca 2+ channel trafficking in nonmyocytes; however, whether 14-3-3 has similar effects on Ca V 1.2 in cardiomyocytes is unknown. 14-3-3 preferentially binds phospho-serine/threonine residues to affect many cellular processes and is known to regulate cardiac ion channels including Na V 1.5 and the human ether-à-go-go–related gene (hERG) potassium channel. Altered 14-3-3 expression and function have been implicated in cardiac pathologies including hypertrophy. Accordingly, we tested the hypothesis that 14-3-3 interacts with Ca V 1.2 in a phosphorylation-dependent manner and regulates cardiac Ca V 1.2 trafficking and recycling. Confocal imaging, proximity ligation assays, superresolution imaging, and coimmunoprecipitation revealed a population of 14-3-3 colocalized and closely associated with Ca V 1.2. The degree of 14-3-3/Ca V 1.2 colocalization increased upon stimulation of β -adrenergic receptors with isoproterenol. Notably, only the 14-3-3-associated Ca V 1.2 population displayed increased cluster size with isoproterenol, revealing a role for 14-3-3 as a nucleation factor that directs Ca V 1.2 superclustering. Isoproterenol-stimulated augmentation of sarcolemmal Ca V 1.2 expression, Ca 2+ currents, and Ca 2+ transients in ventricular myocytes were strengthened by 14-3-3 overexpression and attenuated by 14-3-3 inhibition. These data support a model where 14-3-3 interacts with Ca V 1.2 in a phosphorylation-dependent manner to promote enhanced trafficking/recycling, clustering, and activity during β -adrenergic stimulation.}, archive = {J_PNAS}, author = {Spooner, Heather C. and Costa, Alexandre D. and Westhoff, Maartje and Hernández-González, Adriana and Ibrahimkhail, Husna and Yarov-Yarovoy, Vladimir and Horne, Mary C. and Dickson, Eamonn J. and Dixon, Rose E.}, doi = {10.1073/pnas.2413308122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2413308122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {14-3-3 promotes sarcolemmal expression of cardiac CaV1.2 and nucleates isoproterenol-triggered channel superclustering}, volume = {122}, year = {2025}, }
• (2025). A planar-sheet nongraphitic zero-bandgap sp2 carbon phase made by the low-temperature reaction of γ-graphyne. PNAS, 122(5), e2413194122. (www)

  @article{ , abstract = {The highest sheet symmetry form of graphyne, with one triple bond between each neighboring hexagon in graphene, irreversibly transforms exothermically at ambient pressure and low temperatures into a nongraphitic, planar-sheet, zero-bandgap phase consisting of intrasheet-bonded sp 2 carbons. The synthesis of this sp 2 carbon phase is demonstrated, and other carbon phases are described for possible future synthesis from graphyne without breaking graphyne bonds. While measurements and theory indicate that the reacting graphyne becomes nonplanar because of sheet wrinkling produced by dimensional mismatch between reacted and nonreacted sheet regions, sheet planarity is regained when the reaction is complete. Although the observed elimination of triple bonds to make parallel planar sp 2 carbon sheets likely requires ordered transformation within each sheet, diffraction data for reacted multisheet stacks indicate that the relative lateral positions of neighboring sheets are disordered, as predicted, since no crystalline diffraction peak (other than for the intersheet spacing) is observed.}, archive = {J_PNAS}, author = {Aliev, Ali E. and Guo, Yongzhe and Fonseca, Alexandre F. and Razal, Joselito M. and Wang, Zhong and Galvão, Douglas S. and Bolding, Claire M. and Chapman-Wilson, Nathaniel E. and Desyatkin, Victor G. and Leisen, Johannes E. and Ribeiro Junior, Luiz A. and Kanegae, Guilherme B. and Lynch, Peter and Zhang, Jizhen and Judicpa, Mia A. and Parra, Aaron M. and Zhang, Mengmeng and Gao, Enlai and Hu, Lifang and Rodionov, Valentin O. and Baughman, Ray H.}, doi = {10.1073/pnas.2413194122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2413194122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A planar-sheet nongraphitic zero-bandgap sp2 carbon phase made by the low-temperature reaction of γ-graphyne}, volume = {122}, year = {2025}, }
• (2025). Transferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron-dependent manner. PNAS, 122(5), e2412473122. (www)

  @article{ , abstract = {Tumor cells reshape iron and lipid metabolism for their rapid proliferation. However, how tumor cells coordinate the interplay between tumor cell–specific iron homeostasis and lipid metabolism reprogramming to counteract energy shortages remains unclear. Here, we demonstrated that glucose deprivation in hepatocellular carcinoma (HCC) cells induced AMPK-dependent Transferrin S685 phosphorylation, which exposed Transferrin nuclear localization signal (NLS) for binding to importin α7 and subsequent nuclear translocation. Nucleus-translocated Transferrin interacts with PPARα and enhance its protein stability to increase fatty acid oxidation (FAO) upon glucose deprivation. Mechanistically, PPARα-associated Transferrin upregulates iron-dependent PHD2-mediated PPARα P87 hydroxylation and subsequently disrupts the binding of MDM2 to PPARα, therefore inhibiting MDM2-mediated PPARα ubiquitination and degradation. Reconstitution of Transferrin S685A and NLS mutation or knock-in expression of PPARα P87A inhibited PPARα-mediated FAO upon energy stress, enhanced HCC cell apoptosis, and impeded liver tumor growth in mice. Importantly, combined treatment with Transferrin pS685 blocking peptide suppressing AMPK-Transferrin-PPARα axis could synergize with a well-established AMPK activator Metformin to inhibit tumor growth. Additionally, Transferrin pS685-mediated PPARα P87 hydroxylation is positively correlated with PPARα expression levels in human HCC specimens and poor patient prognosis. These findings revealed a mechanism by which Transferrin can sense energy stress to promote the hydroxylation and protein stability of PPARα through iron-dependent activation of PHD2 and underscore the moonlighting function of Transferrin in lipid catabolism and liver tumor development.}, archive = {J_PNAS}, author = {Qian, Xu and Zhou, Qimin and Ouyang, Yuan and Wu, Xiaohong and Sun, Xue and Wang, Shuo and Duan, Yuran and Hu, Zhiqiang and Hou, Yueru and Wang, Zheng and Chen, Xiaohan and Wang, Katherine L. and Shen, Yuli and Dong, Bofei and Lin, Yanni and Wen, Ting and Tian, Qi and Guo, Zhanpeng and Li, Min and Xiao, Liwei and Wu, Qingang and Meng, Ying and Liu, Guijun and Ying, Hangjie and Zhou, Yahui and Zhang, Wuchang and Duan, Shengzhong and Bai, Xueli and Liu, Tong and Zhan, Peng and Lu, Zhimin and Xu, Daqian}, doi = {10.1073/pnas.2412473122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2412473122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Transferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron-dependent manner}, volume = {122}, year = {2025}, }
• (2025). Art promotes exploration of negative content. PNAS, 122(5), e2412406122. (www)

  @article{ , abstract = {Experiencing negative content through art has a unique power to transform our perceptions and foster engagement. While this idea has been widely discussed, empirical evidence is scarce, since experimental testing of art experiences poses significant challenges. Here, we aimed to fill this gap by quantifying and comparing individuals’ preference for engaging with art and nonart depicting matched negative content via two behavioral measures: the choice to engage vs. avoid and the duration of engagement. Across five studies (total N = 1,063), results revealed a preference for engaging with negative content through art as compared to nonart. Specifically, people more frequently chose to view negative art images, and looked at them for longer, as compared to photographs of similar content. To understand what underlies this preference for art, we examined the psychological impact of engaging with negative content through art and nonart depictions. Results showed that art experiences evoked higher aesthetic appreciation, while nonart gave the viewer a more realistic perspective and was emotionally more costly to engage with. Further, our analysis of engagement motives revealed that individuals were driven by expectations of aesthetic appreciation, thought-provocativeness, and an original perspective, both in art and nonart, while they were discouraged by emotional costs, even more strongly when engaging with nonart. These findings align with the idea of aesthetic distance, where art, as an abstraction of reality, facilitates exploration of negative content with less emotional costs and the prospect of aesthetic rewards.}, archive = {J_PNAS}, author = {Ozbay, Yagmur and Stamkou, Eftychia and Oosterwijk, Suzanne}, doi = {10.1073/pnas.2412406122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2412406122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Art promotes exploration of negative content}, volume = {122}, year = {2025}, }
• (2025). Extremal structures with embedded prefailure indicators. PNAS, 122(5), e2412285122. (www)

  @article{ , abstract = {Preemptive identification of potential failure under loading of engineering structures is a critical challenge. Our study presents an innovative approach to design built-in prefailure indicators within multiscale structural designs with optimized load carrying capabilities utilizing the design freedom of topology optimization. The indicators are engineered to visibly signal load conditions approaching the global critical buckling load at predefined locations. By showing noncritical local buckling when activated, the indicators provide early warning without compromising the overall structural integrity of the design. This proactive safety feature enhances structural reliability. The method is particularly beneficial for offshore wind turbines, where many sensors are located below sea level and are inaccessible for maintenance. By allowing the placement of indicators in accessible predetermined locations, our method can reduce the number of required sensors and improve structural health monitoring. Additionally, the potential use of memory overload indicators exploiting plasticity offers a reliable means of detecting overloads during offline periods. Experimental testing of 3D-printed designs confirms a strong correlation between measurements and numerical simulations, demonstrating the feasibility of creating structures that can signal the need for load reduction or maintenance at predetermined locations. This research contributes to the design of safer structures by introducing built-in early-warning failure systems.}, archive = {J_PNAS}, author = {Christensen, Christoffer Fyllgraf and Engqvist, Jonas and Wang, Fengwen and Sigmund, Ole and Wallin, Mathias}, doi = {10.1073/pnas.2412285122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2412285122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Extremal structures with embedded prefailure indicators}, volume = {122}, year = {2025}, }
• (2025). Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain. PNAS, 122(5), e2412029122. (www)

  @article{ , abstract = {Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson’s disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation. In addition, we observe that a pool of the Rab-specific, protein phosphatase family member 1H phosphatase, is transcriptionally up-regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signaling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioral studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived-neurotrophic factor transcription. This is not exacerbated in double-mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism toward PD. Our data suggest that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients, whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.}, archive = {J_PNAS}, author = {Bagnoli, Enrico and Lin, Yu-En and Burel, Sophie and Jaimon, Ebsy and Antico, Odetta and Themistokleous, Christos and Nikoloff, Jonas M. and Squires, Samuel and Morella, Ilaria and Watzlawik, Jens O. and Fiesel, Fabienne C. and Springer, Wolfdieter and Tonelli, Francesca and Lis, Pawel and Brooks, Simon P. and Dunnett, Stephen B. and Brambilla, Riccardo and Alessi, Dario R. and Pfeffer, Suzanne R. and Muqit, Miratul M. K.}, doi = {10.1073/pnas.2412029122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2412029122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain}, volume = {122}, year = {2025}, }
• (2025). The actin filament pointed-end depolymerase Srv2/CAP depolymerizes barbed ends, displaces capping protein, and promotes formin processivity. PNAS, 122(5), e2411318122. (www)

  @article{ , abstract = {Cellular actin networks exhibit distinct assembly and disassembly dynamics, primarily driven by multicomponent reactions occurring at the two ends of actin filaments. While barbed ends are recognized as the hotspot for polymerization, depolymerization is predominantly associated with pointed ends. Consequently, mechanisms promoting barbed-end depolymerization have received relatively little attention. Here, using microfluidics-assisted three-color single-molecule imaging, we reveal that cyclase-associated protein (CAP), long known for its roles in nucleotide exchange and pointed-end depolymerization, also acts as a processive depolymerase at filament barbed ends. CAP molecules track barbed ends for several minutes, inducing depolymerization rates of up to 60 subunits per second. Importantly, CAP modulates barbed-end dynamics even under cytosol-mimicking assembly promoting conditions. We further show that CAP can colocalize with both formin and capping protein (CP) at barbed ends. CAP enhances formin processivity by 10-fold, allowing CAP–formin complexes to track fast-elongating barbed ends. In contrast, CAP destabilizes CP-bound barbed ends and accelerates dissociation of CP by fourfold. Our findings, combined with CAP’s previously reported activities, firmly establish CAP as a key regulator of cellular actin dynamics.}, archive = {J_PNAS}, author = {Towsif, Ekram M. and Shekhar, Shashank}, doi = {10.1073/pnas.2411318122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2411318122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The actin filament pointed-end depolymerase Srv2/CAP depolymerizes barbed ends, displaces capping protein, and promotes formin processivity}, volume = {122}, year = {2025}, }
• (2025). Design of a light and ca2+ switchable organic–peptide hybrid. PNAS, 122(5), e2411316122. (www)

  @article{ , abstract = {The design of organic–peptide hybrids has the potential to combine our vast knowledge of protein design with small molecule engineering to create hybrid structures with complex functions. Here, we describe the computational design of a photoswitchable Ca 2+ -binding organic–peptide hybrid. The designed molecule, designated Ca 2+ -binding switch (CaBS), combines an EF-hand motif from classical Ca 2+ -binding proteins such as calmodulin with a photoswitchable group that can be reversibly isomerized between a spiropyran (SP) and merocyanine (MC) state in response to different wavelengths of light. The MC/SP group acts both as a photoswitch as well as an optical sensor of Ca 2+ binding. Photoconversion of the SP to the corresponding MC unmasks an acidic phenol, which CaBS uses as an integral part of both its Ca 2+ -binding site as well as its tertiary and quaternary structure. By design, the SP state of CaBS is monomeric, while the Ca 2+ -bound form of the MC state is an obligate dimer, with two Ca 2+ -binding sites formed at the interface of a domain-swapped dimer. Thus, light and Ca 2+ were expected to serve as an “AND gate” that powers a change in backbone structure/dynamics, oligomerization state, and fluorescence properties of the designed molecule. CaBS was designed using Rosetta and molecular dynamics simulations, and experimentally characterized by nuclear magnetic resonance, isothermal titration calorimetry, and optical titrations. These data illustrate the potential of combining small molecule engineering with de novo protein design to develop sensors whose conformation, association state, and optical properties respond to multiple environmental cues.}, archive = {J_PNAS}, author = {Khaleel, Zinah Hilal and No, Young Hyun and Kim, Nam Hyeong and Bae, Do Hyun and Wu, Yibing and Kim, Suhyeon and Choi, Hojae and Lee, Da Eun and Jeong, Se Yun and Ko, Yoon-Joo and Kim, Seong-Gi and Suh, Minah and Kim, Jin-Chul and DeGrado, William F. and Kim, Ki Hyun and Kim, Yong Ho}, doi = {10.1073/pnas.2411316122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2411316122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Design of a light and ca2+ switchable organic–peptide hybrid}, volume = {122}, year = {2025}, }
• (2025). Strong precursor softening in cubic CaSiO3 perovskite. PNAS, 122(5), e2410910122. (www)

  @article{ , abstract = {CaSiO 3 perovskite (CaPv) is the last major mineral in the Earth’s lower mantle whose elasticity remains largely unresolved. Here, we investigate the elasticity of CaPv using ab initio machine-learning force fields (MLFF). At room temperature, the elasticity of tetragonal CaPv determined by MLFF molecular dynamics (MD) agrees well with experimental measurements after considering temperature induced variations in the hydrostatic structure, proving the effectiveness of the method. We use the MLFF MD in the NPT ensemble to establish the tetragonal–cubic phase boundary and confirm that in the lower mantle CaPv is in the cubic phase. The elasticity of cubic CaPv shows distinct temperature dependence at different ranges: it is linear at high temperatures, whereas it exhibits anomalous precursor softening near the tetragonal–cubic phase boundary. The temperature interval of precursor softening widens as the pressure increases and overlaps with the temperature profile of subducted cold slabs near the core–mantle boundary. While cubic CaPv is seismically invisible along the average mantle geotherm, it may induce low-velocity zones with negative temperature anomaly, leading to the view that the large low shear velocity provinces (LLSVPs) may be caused by subducted oceanic crust rich in CaPv with temperature lower than ambient mantle. A cool, rigid LLSVP may help explain the preferential formation of mantle plumes at its margins, as well as its weaker seismic anisotropy.}, archive = {J_PNAS}, author = {Zhang, Chi and Yang, Jin-Yuan and Sun, Tao and Zhang, Huai and Brodholt, John P.}, doi = {10.1073/pnas.2410910122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2410910122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Strong precursor softening in cubic CaSiO3 perovskite}, volume = {122}, year = {2025}, }
• (2025). Bacterial sensor evolved by decreasing complexity. PNAS, 122(5), e2409881122. (www)

  @article{ , abstract = {Bacterial receptors feed into multiple signal transduction pathways that regulate a variety of cellular processes including gene expression, second messenger levels, and motility. Receptors are typically activated by signal binding to ligand-binding domains (LBDs). Cache domains are omnipresent LBDs found in bacteria, archaea, and eukaryotes, including humans. They form the predominant family of extracytosolic bacterial LBDs and were identified in all major receptor types. Cache domains are composed of either a single (sCache) or a double (dCache) structural module. The functional relevance of bimodular LBDs remains poorly understood. Here, we identify the PacF chemoreceptor in the phytopathogen Pectobacterium atrosepticum that recognizes formate at the membrane-distal module of its dCache domain, triggering chemoattraction. We further demonstrate that a family of formate-specific sCache domains has evolved from a dCache domain, exemplified by PacF, by losing the membrane-proximal module. By solving high-resolution structures of two family members in complex with formate, we show that the molecular basis for formate binding at sCache and dCache domains is highly similar, despite their low sequence identity. The apparent loss of the membrane-proximal module may be related to the observation that dCache domains bind ligands typically at the membrane-distal module, whereas studies have failed to find ligands bound in the membrane-proximal module. This work advances our understanding of signal sensing in bacterial receptors and suggests that evolution by reducing complexity may be a route for shaping diversity.}, archive = {J_PNAS}, author = {Monteagudo-Cascales, Elizabet and Gavira, José A. and Xing, Jiawei and Velando, Félix and Matilla, Miguel A. and Zhulin, Igor B. and Krell, Tino}, doi = {10.1073/pnas.2409881122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2409881122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Bacterial sensor evolved by decreasing complexity}, volume = {122}, year = {2025}, }
• (2025). Vulnerability to natural disasters and sustainable consumption: Unraveling political and regional differences. PNAS, 122(5), e2409851122. (www)

  @article{ , abstract = {The urgent calls for action on climate change underscore the importance of increasing sustainable behavior among individuals who have traditionally veered away from it, such as those on the political right. Utilizing data from four geopolitical regions across 24 countries, we explore whether vulnerability to natural disasters, brought on by either experiencing or anticipating a natural disaster, is a crucial factor. We find that as vulnerability to natural disasters increases, sustainable consumption intentions significantly increase among rightists in Western Europe, Israel, and the United States. Environmental motives, rather than economic or trend motives, are found to drive this effect. This suggests that, for rightists, the expectation of being directly impacted by climate change can override their established attitudes and foster more sustainable behavior with the goal of helping the environment. In contrast, the same increase in sustainable consumption intentions is weaker among leftists, who already embrace sustainable behavior. Interestingly, in Central and Eastern Europe, this interplay between political ideology and vulnerability to natural disasters is absent, highlighting the unique postcommunist context of this region. These findings underscore the necessity of tailored strategies for promoting sustainable behavior across regional contexts and provide vital insight into how sustainable consumption may increase among groups that have traditionally resisted it. In a quasiexperiment, we test the potential of an intervention using messages that highlight recent natural disasters in one’s locality and demonstrate its effectiveness in pushing rightists toward sustainable consumption.}, archive = {J_PNAS}, author = {Chae, Rebecca L. and Siddiqui, Rafay and Xu, Yan}, doi = {10.1073/pnas.2409851122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2409851122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Vulnerability to natural disasters and sustainable consumption: Unraveling political and regional differences}, volume = {122}, year = {2025}, }
• (2025). Rational design and modular synthesis of biodegradable ionizable lipids via the passerini reaction for mRNA delivery. PNAS, 122(5), e2409572122. (www)

  @article{ , abstract = {The ionizable lipid component of lipid nanoparticle (LNP) formulations is essential for mRNA delivery by facilitating endosomal escape. Conventionally, these lipids are synthesized through complex, multistep chemical processes that are both time-consuming and require significant engineering. Furthermore, the development of new ionizable lipids is hindered by a limited understanding of the structure-activity relationships essential for effective mRNA delivery. In this work, we have developed a modular platform utilizing the Passerini reaction to rapidly generate large, chemically diverse libraries of biodegradable ionizable lipids. This high-throughput approach enables the systematic exploration of various lipid components–head groups, tails, and spacers–and their impacts on mRNA delivery efficiency. By investigating the hydrogen bonding potential between the lipid’s head groups and the mRNA’s ribose phosphate complex, we found that optimizing the methylene units between the lipid’s head groups and linkages could enhance endosomal escape and, consequently, mRNA delivery efficiencies. Leveraging this insight, our platform has led to the identification of the biodegradable ionizable lipid A4B4-S3, which outperforms the current clinical benchmark, SM-102, in gene editing efficacy in mouse liver following systemic administration and demonstrates the promise for repeat-dose protein replacement treatments. This work not only offers a rapid, scalable method for ionizable lipid synthesis but also deepens our understanding of their structure-activity relationships, paving the way for more effective mRNA therapeutics.}, archive = {J_PNAS}, author = {Xu, Yue and Gong, Fanglin and Golubovic, Alex and Strilchuk, Amy and Chen, Jingan and Zhou, Muye and Dong, Songtao and Seto, Breanna and Li, Bowen}, doi = {10.1073/pnas.2409572122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2409572122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Rational design and modular synthesis of biodegradable ionizable lipids via the passerini reaction for mRNA delivery}, volume = {122}, year = {2025}, }
• (2025). Plastic responses to past environments shape adaptation to novel selection pressures. PNAS, 122(5), e2409541122. (www)

  @article{ , abstract = {Phenotypic plasticity may pave the way for rapid adaptation to newly encountered environments. Although it is often contested, there is growing evidence that initial plastic responses of ancestral populations to new environmental cues may promote subsequent adaptation. However, we do not know whether plasticity to cues present in the ancestral habitat (past-cue plasticity) can facilitate adaptation to novel cues. Conceivably, this could occur if plastic responses are coincidentally optimal to both past and novel cues (i.e., are preadaptive) or if they are transferred to novel cues during adaptation. Past plastic phenotype values could also become fixed during adaptation to the new environment. To uncover the role of past-cue plasticity in adaptation, we tested gene expression plasticity responses of two parallel mine-waste-adapted Silene uniflora populations and their closest coastal relatives. Plants were exposed to the past and novel cues of salt and zinc, which revealed that during adaptation to mine waste, plasticity to salt diminishes. Despite this, our results show that ancestral plasticity to salt has a substantial impact on subsequent adaptation to zinc. For a third of genes that have evolved zinc plasticity in mine populations, salt plasticity has been transferred to the zinc response. Furthermore, a quarter of fixed expression differences between mine and coastal populations were similar to ancestral salt responses. Alongside evidence that ancestral plasticity to novel cues can facilitate adaptation, our results provide a clear indication that ancestral past-cue plasticity can also play a key role in rapid, parallel adaptation to novel habitats.}, archive = {J_PNAS}, author = {Coates, Sarah E. R. and Comeault, Aaron A. and Wood, Daniel P. and Fay, Michael F. and Creer, Simon and Osborne, Owen G. and Dunning, Luke T. and Papadopulos, Alexander S. T.}, doi = {10.1073/pnas.2409541122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2409541122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Plastic responses to past environments shape adaptation to novel selection pressures}, volume = {122}, year = {2025}, }
• (2025). Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation. PNAS, 122(5), e2408582122. (www)

  @article{ , abstract = {The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 in the active state has been well studied, the role of the reduced cysteine residues, Cys6 and Cys111, in SOD1 filament formation remains unclear. In this study, we investigated the role of reduced cysteine residues by determining and comparing cryoelectron microscopy (cryo-EM) structures of wild-type (WT) and C6A/C111A SOD1 filaments under thiol-based reducing and metal-depriving conditions, starting with protein samples possessing enzymatic activity. The C6A/C111A mutant SOD1 formed filaments more rapidly than the WT protein. The mutant structure had a unique paired-protofilament arrangement, with a smaller filament core than that of the single-protofilament structure observed in WT SOD1. Although the single-protofilament form developed more slowly, cross-seeding experiments demonstrated the predominance of single-protofilament morphology over paired protofilaments, regardless of the presence of the Cys6 and Cys111 mutations. These findings highlight the importance of the number of amino acid residues within the filament core in determining the energy requirements for assembly. Our study provides insights into ALS pathogenesis by elucidating the initiation and propagation of filament formation, which potentially leads to deleterious amyloid filaments.}, archive = {J_PNAS}, author = {Baek, Yeongjin and Kim, Hyunmin and Lee, Dukwon and Kim, Doyeon and Jo, Eunbyul and Roh, Soung-Hun and Ha, Nam-Chul}, doi = {10.1073/pnas.2408582122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2408582122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation}, volume = {122}, year = {2025}, }
• (2025). Carbonate fluorapatite coatings on phillipsite represent a significant sink of phosphorus in abyssal plains of the western pacific ocean. PNAS, 122(5), e2407683122. (www)

  @article{ , abstract = {As an essential micronutrient, phosphorus plays a key role in oceanic biogeochemistry, with its cycling intimately connected to the global carbon cycle and climate change. Authigenic carbonate fluorapatite (CFA) has been suggested to represent a significant phosphorus sink in the deep ocean, but its formation mechanisms in oceanic low-productivity settings remain poorly constrained. Applying X-ray absorption near edge structure, transmission electron microscopy, and laser ablation inductively coupled plasma mass spectrometer analyses, we report a unique mineral assemblage where CFA crystals coat phillipsite in abyssal sediments of the East Mariana Basin and the Philippine Sea. This finding suggests that phillipsite provides an ideal microenvironment for CFA formation due to its ability to release calcium cations and its strong adsorption capacity for phosphate anions. The feasibility of such a mechanism was confirmed by long-term (10 mo) laboratory experiments. Furthermore, the CFA forming in the sediment of abyssal plains is found to be enriched in rare earth elements (REE). The previously unrecognized mechanism of CFA formation may therefore not only contribute to the cycling of phosphorus in oceanic low-productivity environments but may also represent a significant sink of REE.}, archive = {J_PNAS}, author = {Fan, Wenxiao and Zhou, Junming and Jiang, Xiaodong and Zhang, Huan and Mi, Mei and Yuan, Peng and Dong, Yanhui and Liu, Dong and Wei, Yanfu and Peckmann, Jörn}, doi = {10.1073/pnas.2407683122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2407683122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Carbonate fluorapatite coatings on phillipsite represent a significant sink of phosphorus in abyssal plains of the western pacific ocean}, volume = {122}, year = {2025}, }
• (2025). SIV monoclonal antibody administration spanning treatment interruption in macaques delays viral rebound and selects escape variants. PNAS, 122(5), e2404767122. (www)

  @article{ , abstract = {HIV-1 envelope broadly neutralizing antibodies represent a promising component of HIV-1 cure strategies. To evaluate the therapeutic efficacy of combination monoclonal antibodies (mAbs) in a rigorous nonhuman primate model, we tested different combinations of simian immunodeficiency virus (SIV) neutralizing mAbs in SIVmac251-infected rhesus macaques. Antiretroviral therapy-suppressed animals received anti-SIV mAbs targeting multiple Env epitopes spanning analytical treatment interruption (ATI) in 3 groups (n = 7 each): i) no mAb; ii) 4-mAb combination; and iii) 2-mAb combination. Each mAb was administered at 15 mg/kg, and both mAb-treated groups received ITS103.01, a highly potent CD4-binding site targeting antibody. mAb treatment delayed viral rebound, lowered rebound viremia setpoint and viral diversity, and extended animal lifespan. Compared to controls, for which viremia rebounded 2 wk following ATI, mAb infusion delayed rebound for both groups ( P = 0.0003). Animals that received the 4-mAb regimen rebounded 3 to 6 wk post-ATI while the 2-mAb regimen rebounded 5 to 22 wk post-ATI. Envelope escape mutations emerged in rebound virus of mAb-treated animals that abrogated neutralization by ITS103.01, the most potent in the cocktail. These data demonstrate in vivo antiviral activity of SIV mAbs in the context of ATI via immune pressure dominated by the most potent mAb and highlight their potential in adjunctive therapeutic studies.}, archive = {J_PNAS}, author = {King, Hannah A. D. and Brammer, Daniel and Lewitus, Eric and Fennessey, Christine M. and Manalang, Kimberly M. and Shrader, Hannah R. and Andrew, Shayne and Kuri, Phillip and Lind, Matthew and Pham, Phuc and Sanders-Buell, Eric and Bai, Hongjun and Mason, Rosemarie and Song, Kaimei and McCarthy, Elizabeth and Helmold Hait, Sabrina and Todd, John-Paul and Pegu, Amarendra and Foulds, Kathryn E. and Lifson, Jeffrey D. and Keele, Brandon F. and Rolland, Morgane and Roederer, Mario and Bolton, Diane L.}, doi = {10.1073/pnas.2404767122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2404767122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {SIV monoclonal antibody administration spanning treatment interruption in macaques delays viral rebound and selects escape variants}, volume = {122}, year = {2025}, }
• (2025). Organismal complexity strongly correlates with the number of protein families and domains. PNAS, 122(5), e2404332122. (www)

  @article{ , abstract = {In the pregenomic era, scientists were puzzled by the observation that haploid genome size (the C-value) did not correlate well with organismal complexity. This phenomenon, called the “C-value paradox,” is mostly explained by the fact that protein-coding genes occupy only a small fraction of eukaryotic genomes. When the first genome sequences became available, scientists were even more surprised by the fact that the number of genes (G-value) was also a poor predictor of complexity, which gave rise to the “G-value paradox.” The proposed explanations usually invoke mechanisms that increase the information content of each individual gene (protein–protein interactions, intrinsic disorder, posttranslational modifications, alternative splicing, etc.). Less attention has been paid to mechanisms that increase the amount of genetic material but do not increase (or not to the same extent) the amount of information encoded in the genome, such as gene duplication and domain shuffling. Proteins belonging to the same family and/or sharing the same domains often carry out similar or even redundant functions. We thus hypothesized that an organism’s number of different protein families and domains should be suitable predictors of organismal complexity. In agreement with our hypothesis, we observed that the number of protein families, clans, domains, and motifs increases from simple to progressively more complex organisms. In addition, these metrics correlate with the number of cell types better than and independently of the number of protein-coding genes and several previously proposed predictors of organismal complexity. Our observations have the potential to represent a resolution to the G-value paradox.}, archive = {J_PNAS}, author = {Alvarez-Ponce, David and Krishnamurthy, Subramanian}, doi = {10.1073/pnas.2404332122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2404332122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Organismal complexity strongly correlates with the number of protein families and domains}, volume = {122}, year = {2025}, }
• (2025). Cryo-ET suggests tubulin chaperones form a subset of microtubule lumenal particles with a role in maintaining neuronal microtubules. PNAS, 122(5), e2404017121. (www)

  @article{ , abstract = {The functional architecture of the long-lived neuronal microtubule (MT) cytoskeleton is maintained by various MT-associated proteins (MAPs), most of which are known to bind to the MT outer surface. However, electron microscopy (EM) has long ago revealed the presence of particles inside the lumens of neuronal MTs, of yet unknown identity and function. Here, we use cryogenic electron tomography (cryo-ET) to analyze the three-dimensional (3D) organization and structures of MT lumenal particles in primary hippocampal neurons, human induced pluripotent stem cell–derived neurons, and pluripotent and differentiated P19 cells. We obtain in situ density maps of several lumenal particles from the respective cells and detect common structural features underscoring their potential overarching functions. Mass spectrometry-based proteomics combined with structural modeling suggest that a subset of lumenal particles could be tubulin-binding cofactors (TBCs) bound to tubulin monomers. A different subset of smaller particles, which remains unidentified, exhibits densities that bridge across the MT protofilaments. We show that increased lumenal particle concentration within MTs is concomitant with neuronal differentiation and correlates with higher MT curvatures. Enrichment of lumenal particles around MT lattice defects and at freshly polymerized MT open-ends suggests a MT protective role. Together with the identified structural resemblance of a subset of particles to TBCs, these results hint at a role in local tubulin proteostasis for the maintenance of long-lived neuronal MTs.}, archive = {J_PNAS}, author = {Chakraborty, Saikat and Martinez-Sanchez, Antonio and Beck, Florian and Toro-Nahuelpan, Mauricio and Hwang, In-Young and Noh, Kyung-Min and Baumeister, Wolfgang and Mahamid, Julia}, doi = {10.1073/pnas.2404017121}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2404017121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Cryo-ET suggests tubulin chaperones form a subset of microtubule lumenal particles with a role in maintaining neuronal microtubules}, volume = {122}, year = {2025}, }
• (2025). The chloroplast RNA–binding protein CP29A supports rbcL expression during cold acclimation. PNAS, 122(5), e2403969122. (www)

  @article{ , abstract = {The chloroplast genome encodes key components of the photosynthetic light reaction machinery as well as the large subunit of the enzyme central for carbon fixation, Ribulose-1,5-bisphosphat-carboxylase/-oxygenase (RuBisCo). Its expression is predominantly regulated posttranscriptionally, with nuclear-encoded RNA-binding proteins (RBPs) playing a key role. Mutants of chloroplast gene expression factors often exhibit impaired chloroplast biogenesis, especially in cold conditions. Low temperatures pose a challenge for plants as this leads to electron imbalances and oxidative damage. A well-known response of plants to this problem is to increase the production of RuBisCo and other Calvin Cycle enzymes in the cold, but how this is achieved is unclear. The chloroplast RBP CP29A has been shown to be essential for cold resistance in growing leaf tissue of Arabidopsis thaliana . Here, we examined CP29A–RNA interaction sites at nucleotide resolution. We found that CP29A preferentially binds to the 5′-untranslated region of rbcL , downstream of the binding site of the pentatricopeptide repeat protein MATURATION OF RBCL 1 (MRL1). MRL1 is an RBP known to be necessary for the accumulation of rbcL . In Arabidopsis mutants lacking CP29A, we were unable to observe significant effects on rbcL , possibly due to CP29A’s restricted role in a limited number of cells at the base of leaves. In contrast, CRISPR/Cas9-induced mutants of tobacco NtCP29A exhibit cold-dependent photosynthetic deficiencies throughout the entire leaf blade. This is associated with a parallel reduction in rbcL mRNA and RbcL protein accumulation. Our work indicates that a chloroplast RNA–binding protein contributes to cold acclimation of RbcL production.}, archive = {J_PNAS}, author = {Lenzen, Benjamin and Rösch, Florian and Legen, Julia and Ruwe, Hannes and Kachariya, Nitin and Sattler, Michael and Small, Ian and Schmitz-Linneweber, Christian}, doi = {10.1073/pnas.2403969122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2403969122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The chloroplast RNA–binding protein CP29A supports rbcL expression during cold acclimation}, volume = {122}, year = {2025}, }
• (2025). Environmental variability across space and time drives the recolonization pattern of a historically persecuted large carnivore. PNAS, 122(5), e2401679122. (www)

  @article{ , abstract = {Wildlife populations are not static. Intrinsic and extrinsic factors affect individuals, which lead to spatiotemporal variation in population density and range. Yet, dynamics in density and their drivers are rarely documented, due in part to the inherent difficulty of studying long-term population-level phenomena at ecologically meaningful scales. We studied the spatiotemporal density dynamics in a recolonizing large carnivore population, the wolverine Gulo gulo , across the Scandinavian Peninsula over nine years. We fitted open-population spatial capture-recapture models to noninvasive genetic sampling data collected across Norway and Sweden to estimate annual density surfaces and their drivers. This approach allowed us to model sex-specific changes in wolverine density and the effect of landscape-level environmental determinants over time. Our results revealed that, as wolverines successfully recolonized many parts of their historical range in Scandinavia, the relationship with spatial determinants of density has changed over time. We also found support for sex-specific responses of the Scandinavian wolverine to the environmental determinants of density and differences in the temporal dynamics of their relationships, indicating disproportionate recolonization ability and anthropogenic pressures. We observed significant changes in the relationship of female wolverine density with several determinants during the study period, suggesting still ongoing expansion of female wolverines whereas males might have already reached the range limits. These findings show that the Scandinavian wolverine population is still recovering from centuries of persecution and severe range contraction. Our study sheds light on the dynamics and challenges of recolonizing large carnivores in human-dominated landscapes across time and space.}, archive = {J_PNAS}, author = {Moqanaki, Ehsan and Milleret, Cyril and Dupont, Pierre and Mattisson, Jenny and Dey, Soumen and Brøseth, Henrik and Aronsson, Malin and Persson, Jens and Wabakken, Petter and Flagstad, Øystein and Bischof, Richard}, doi = {10.1073/pnas.2401679122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2401679122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Environmental variability across space and time drives the recolonization pattern of a historically persecuted large carnivore}, volume = {122}, year = {2025}, }
• (2025). Lost opportunities: How gendered arrangements harm men. PNAS, 122(5), e2320788122. (www)

  @article{ , abstract = {Traditional gendered arrangements—norms, roles, prejudices, and hierarchies—shape every human life. Associated harms are primarily framed as women’s issues due to more severe consequences women face. Yet, gendered arrangements also shape men ’s relationships, career paths, and health. Current work on gender equity overlooks men’s perspectives. Despite benefits they gain from out-ranking women, men’s position paradoxically entraps them in restrictive roles, compelling them to prioritize dominance. An inclusive framework challenges prevailing narratives by considering personal costs borne by men. Identifying with a man’s traditional role is a mixed privilege, as five gendered arrangements show for men who subscribe to them: 1. Masculine norms can restrict men’s choices and are associated with adverse health trajectories; 2. Some men’s disengagement from communal roles denies them positive outcomes associated with caring for others; 3. Hostile sexism fosters antipathy, fueling tension in some men’s interactions with women; 4. Benevolent sexism forces some men into scripted interactions, preventing genuine connections and burdening them with unrealistic breadwinner and protector roles; 5. Societal shifts in gender hierarchies can elicit threat responses in men, depending on intersections with social class and racial identities. Understanding costs to men calls for more empirical research. Gender equity for men, whose circumstances differ from those of women, would enable men to make informed choices and achieve better outcomes for themselves—paralleling the progress women have made in many areas of life. Striving for equity for all genders can ultimately enhance overall human well-being.}, archive = {J_PNAS}, author = {Bareket, Orly and Fiske, Susan T.}, doi = {10.1073/pnas.2320788122}, journal = {Proceedings of the National Academy of Sciences}, month = {2}, number = {5}, pages = {e2320788122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Lost opportunities: How gendered arrangements harm men}, volume = {122}, year = {2025}, }
• (2025). Correction for zioga et al., observed carbon decoupling of subnational production insufficient for net-zero goal by 2050. PNAS, 122(4), e2425516121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2425516121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {4}, pages = {e2425516121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for zioga et al., observed carbon decoupling of subnational production insufficient for net-zero goal by 2050}, volume = {122}, year = {2025}, }
• (2025). Correction for austin et al., death-receptor activation halts clathrin-dependent endocytosis. PNAS, 122(4), e2425433121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2425433121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {4}, pages = {e2425433121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for austin et al., death-receptor activation halts clathrin-dependent endocytosis}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for sutter et al., electrochemical cofactor recycling of bacterial microcompartments. PNAS, 122(4), e2425332121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2425332121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {4}, pages = {e2425332121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for sutter et al., electrochemical cofactor recycling of bacterial microcompartments}, volume = {122}, year = {2025}, }
• (2025). Correction for khadim et al., continental freshwater discharge influences sea surface salinity variability near world’s megadeltas. PNAS, 122(4), e2425315121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2425315121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {4}, pages = {e2425315121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for khadim et al., continental freshwater discharge influences sea surface salinity variability near world’s megadeltas}, volume = {122}, year = {2025}, }
• (2025). Correction for toubdji et al., exploring a unique class of flavoenzymes: Identification and biochemical characterization of ribosomal RNA dihydrouridine synthase. PNAS, 122(4), e2424888121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424888121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {4}, pages = {e2424888121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for toubdji et al., exploring a unique class of flavoenzymes: Identification and biochemical characterization of ribosomal RNA dihydrouridine synthase}, volume = {122}, year = {2025}, }
• (2025). Correction for thompson and fronhofer, the conflict between adaptation and dispersal for maintaining biodiversity in changing environments. PNAS, 122(4), e2424469121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424469121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {4}, pages = {e2424469121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for thompson and fronhofer, the conflict between adaptation and dispersal for maintaining biodiversity in changing environments}, volume = {122}, year = {2025}, }
• (2025). Hidden artistic complexity of peru’s chancay culture discovered in tattoos by laser-stimulated fluorescence. PNAS, 122(4), e2421517122. (www)

  @article{ , abstract = {Tattoos were a prevalent art form in pre-Hispanic South America exemplified by mummified human remains with preserved skin decoration that reflects the personal and cultural representations of their times. Tattoos are known to fade and bleed over time and this is compounded in mummies by the decay of the body, inhibiting the ability to examine the original art. Laser-stimulated fluorescence (LSF) produces images based on fluorescence emitted from within the target. Here, we present the first results of applying LSF to tattoos on human remains from the pre-Columbian Chancay culture of coastal Peru. We find that the preserved skin fluoresced strongly underneath the black tattoo ink yielding a high-contrast image that virtually eliminates the ink bleed, revealing the exceptionally fine details of the original artwork. The level of detail and precision of the artwork was found to be higher than associated pottery, textiles, and rock art suggesting special effort was expended by the Chancay on at least some of their tattoos. This suggests artistic complexity in pre-Columbian Peru was at a higher level than previously known, expanding the degree of artistic development found in South America at this time. LSF expands the scope of tattoo analysis and the level of detail this can yield providing a new technique to gain further insights into this important art form.}, archive = {J_PNAS}, author = {Kaye, Thomas G. and Bąk, Judyta and Marcelo, Henry William and Pittman, Michael}, doi = {10.1073/pnas.2421517122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {4}, pages = {e2421517122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hidden artistic complexity of peru’s chancay culture discovered in tattoos by laser-stimulated fluorescence}, volume = {122}, year = {2025}, }
• (2025). Hydrated cable bacteria exhibit protonic conductivity over long distances. PNAS, 122(4), e2416008122. (www)

  @article{ , abstract = {This study presents the direct measurement of proton transport along filamentous Desulfobulbaceae , or cable bacteria. Cable bacteria are filamentous multicellular microorganisms that have garnered much interest due to their ability to serve as electrical conduits, transferring electrons over several millimeters. Our results indicate that cable bacteria can also function as protonic conduits because they contain proton wires that transport protons at distances >100 µm. We find that protonic conductivity (σ P ) along cable bacteria varies between samples and is measured as high as 114 ± 28 µS cm −1 at 25 °C and 70% relative humidity (RH). For cable bacteria, the protonic conductance (G P ) and σ P are dependent upon the RH, increasing by as much as 26-fold between 60% and 80% RH. This observation implies that proton transport occurs via the Grotthuss mechanism along water associated with cable bacteria, forming proton wires. In order to determine σ P and G P along cable bacteria, we implemented a protocol using a modified transfer-printing technique to deposit either palladium interdigitated protodes (IDP), palladium transfer length method (TLM) protodes, or gold interdigitated electrodes (IDE) on top of cable bacteria. Due to the relatively mild nature of the transfer-printing technique, this method should be applicable to a broad array of biological samples and curved materials. The observation of protonic conductivity in cable bacteria presents possibilities for investigating the importance of long-distance proton transport in microbial ecosystems and to potentially build biotic or biomimetic scaffolds to interface with materials via proton-mediated gateways or channels.}, archive = {J_PNAS}, author = {Lusk, Bradley G. and Morgan, Sheba and Mulvaney, Shawn P. and Blue, Brandon and LaGasse, Sam W. and Cress, Cory D. and Bjerg, Jesper T. and Lee, Woo K. and Eddie, Brian J. and Robinson, Jeremy T.}, doi = {10.1073/pnas.2416008122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {4}, pages = {e2416008122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hydrated cable bacteria exhibit protonic conductivity over long distances}, volume = {122}, year = {2025}, }
• (2025). Correction for gadea et al., the smallest electrochemical bubbles. PNAS, 122(3), e2426052122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2426052122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {3}, pages = {e2426052122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for gadea et al., the smallest electrochemical bubbles}, volume = {122}, year = {2025}, }
• (2025). Correction for zhang et al., facet-switching of rate-determining step on copper in CO2-to-ethylene electroreduction. PNAS, 122(3), e2425969122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2425969122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {3}, pages = {e2425969122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for zhang et al., facet-switching of rate-determining step on copper in CO2-to-ethylene electroreduction}, volume = {122}, year = {2025}, }
• (2025). Correction for matsuzaki et al., transcriptional drift in aging cells: A global decontroller. PNAS, 122(3), e2425894122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2425894122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {3}, pages = {e2425894122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for matsuzaki et al., transcriptional drift in aging cells: A global decontroller}, volume = {122}, year = {2025}, }
• (2025). Correction for D’Angelo et al., a paradoxical misperception of relative motion. PNAS, 122(3), e2425771122. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2425771122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {3}, pages = {e2425771122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for D’Angelo et al., a paradoxical misperception of relative motion}, volume = {122}, year = {2025}, }
• (2025). Profile of bruce e. tabashnik. PNAS, 122(2), e2425448121. (www)

  @article{ , archive = {J_PNAS}, author = {Ravindran, Sandeep}, doi = {10.1073/pnas.2425448121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2425448121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profile of bruce e. tabashnik}, volume = {122}, year = {2025}, }
• (2025). Correction to supporting information for le et al., motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations. PNAS, 122(2), e2424914121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424914121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2424914121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction to supporting information for le et al., motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations}, volume = {122}, year = {2025}, }
• (2025). Correction for tran-kiem and bedford, estimating the reproduction number and transmission heterogeneity from the size distribution of clusters of identical pathogen sequences. PNAS, 122(2), e2424815121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424815121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2424815121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for tran-kiem and bedford, estimating the reproduction number and transmission heterogeneity from the size distribution of clusters of identical pathogen sequences}, volume = {122}, year = {2025}, }
• (2025). Correction for mehmood et al., teacher vaccinations enhance student achievement in pakistan: The role of role models and theory of mind. PNAS, 122(2), e2424809121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424809121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2424809121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for mehmood et al., teacher vaccinations enhance student achievement in pakistan: The role of role models and theory of mind}, volume = {122}, year = {2025}, }
• (2025). Correction for alboreggia et al., targeted degradation of pin1 by protein-destabilizing compounds. PNAS, 122(2), e2424805121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424805121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2424805121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for alboreggia et al., targeted degradation of pin1 by protein-destabilizing compounds}, volume = {122}, year = {2025}, }
• (2025). Correction for orellana et al., childhood maltreatment influences adult brain structure through its effects on immune, metabolic, and psychosocial factors. PNAS, 122(2), e2424380121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424380121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2424380121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for orellana et al., childhood maltreatment influences adult brain structure through its effects on immune, metabolic, and psychosocial factors}, volume = {122}, year = {2025}, }
• (2025). Correction for jury et al., experimental coral reef communities transform yet persist under mitigated future ocean warming and acidification. PNAS, 122(2), e2424162121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424162121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2424162121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for jury et al., experimental coral reef communities transform yet persist under mitigated future ocean warming and acidification}, volume = {122}, year = {2025}, }
• (2025). Reply to lockhart et al.: Advancing the understanding of sex differences in functional brain organization with innovative AI tools. PNAS, 122(2), e2419736121. (www)

  @article{ , archive = {J_PNAS}, author = {Ryali, Srikanth and Zhang, Yuan and Supekar, Kaustubh and Menon, Vinod}, doi = {10.1073/pnas.2419736121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2419736121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to lockhart et al.: Advancing the understanding of sex differences in functional brain organization with innovative AI tools}, volume = {122}, year = {2025}, }
• (2025). The interaction of serratia bacteria and harmonine in harlequin ladybird confers an interspecies competitive edge. PNAS, 122(2), e2417873121. (www)

  @article{ , abstract = {The harlequin ladybird, Harmonia axyridis , is a predatory beetle used globally to control pests such as aphids and scale insects. Originating from East Asia, this species has become highly invasive since its introduction in the late 19th century to Europe and North America, posing a threat to local biodiversity. Intraguild predation is hypothesized to drive the success of this invasive species, but the underlying mechanisms remain unknown. In this study, a feeding assay revealed that while harlequin ladybirds survive feeding on seven-spotted ladybird eggs, the reverse is not true. However, seven-spotted ladybirds that had fed on harlequin ladybird eggs were able to survive the feeding assay when treated with penicillin. Microbiome sequencing and whole genome analysis of harlequin ladybird eggs revealed a newly discovered pathogenic bacterium strain named Serratia harmoniae. The median lethal concentration (LC50) of S. harmoniae was found to be 2.1 × 10 5 times higher in the harlequin ladybird compared to the seven-spotted ladybird. The high tolerance observed in harlequin ladybirds was attributed to harmonine, specifically produced in the fat body of this species. Silencing three key genes in the harmonine biosynthesis pathway— Spidey , Sca2 , and Desat— reduced the production of the compound, leading to increased S. harmoniae levels and higher mortality. Treating RNAi-altered individuals with penicillin reversed this effect, successfully reducing S. harmoniae presence and increasing insect survival. Taken together, these findings demonstrate that S. harmoniae , a newly identified pathogenic bacterium carried by harlequin ladybirds, interacts with harmonine to confer an interspecies competitive advantage over native ladybird species in nonnative regions.}, archive = {J_PNAS}, author = {Zhang, Chaowei and Zhou, Hang and He, Kang and Xiao, Yiqi and Chen, Mengyao and Zuo, Zhangqi and Shu, Runguo and Geng, Yuhang and Jin, Shuo and Mei, Yang and He, Bingbing and Li, Fei}, doi = {10.1073/pnas.2417873121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2417873121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The interaction of serratia bacteria and harmonine in harlequin ladybird confers an interspecies competitive edge}, volume = {122}, year = {2025}, }
• (2025). Concomitant formation of protocells and prebiotic compounds under a plausible early earth atmosphere. PNAS, 122(2), e2413816122. (www)

  @article{ , abstract = {Revealing the origin of life and unambiguously detecting fossil remains of the earliest organisms are closely related aspects of the same scientific research. The synthesis of prebiotic molecular building blocks of life and the first compartmentalization into protocells have been considered two events apart in time, space, or both. We conducted lightning experiments in borosilicate reactors filled with a mixture of gases mimicking plausible geochemical conditions of early Earth. In addition to the variety of prebiotic organic molecules synthesized in these experiments, we investigated the micrometer-thick silica-induced organic film that covers the walls of the reactors and floats at the water–gas interface. We found that the film is formed by aggregation of HCN-polymer nanoclusters whenever water is present, either in the liquid or vapor phase. The organic film morphs into micrometer-scale biomorphic vesicular structures hanging from the organic film into the water. We also show that these structures are hollow and may act as microreactors facilitating chemical pathways toward increasing complexity. We propose that these organic biomorphs form through a bubble-driven mechanism and interfacial precipitation of HCN-polymers. The concomitant synthesis of biomorphic poly-HCN protocells and prebiotic molecules under plausible geochemical conditions of early Earth-like planets and moons and opens a different geochemical scenario for the emergence of life. Our results suggest that the coexistence of molecular building blocks of life and submicron biomorphic structures in the oldest rocks on Earth or any other celestial body does not necessarily mean evidence of life.}, archive = {J_PNAS}, author = {Jenewein, Christian and Maíz-Sicilia, Aurora and Rull, Fernando and González-Souto, Lorena and García-Ruiz, Juan Manuel}, doi = {10.1073/pnas.2413816122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2413816122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Concomitant formation of protocells and prebiotic compounds under a plausible early earth atmosphere}, volume = {122}, year = {2025}, }
• (2025). Dynamic treeline and cryosphere response to pronounced mid-holocene climatic variability in the US rocky mountains. PNAS, 122(2), e2412162121. (www)

  @article{ , abstract = {Climate-driven changes in high-elevation forest distribution and reductions in snow and ice cover have major implications for ecosystems and global water security. In the Greater Yellowstone Ecosystem of the Rocky Mountains (United States), recent melting of a high-elevation (3,091 m asl) ice patch exposed a mature stand of whitebark pine ( Pinus albicaulis ) trees, located ~180 m in elevation above modern treeline, that date to the mid-Holocene (c. 5,950 to 5,440 cal y BP). Here, we used this subfossil wood record to develop tree-ring-based temperature estimates for the upper-elevation climate conditions that resulted in ancient forest establishment and growth and the subsequent regional ice-patch growth and downslope shift of treeline. Results suggest that mid-Holocene forest establishment and growth occurred under warm-season (May-Oct) mean temperatures of 6.2 °C (±0.2 °C), until a multicentury cooling anomaly suppressed temperatures below 5.8 °C, resulting in stand mortality by c. 5,440 y BP. Transient climate model simulations indicate that regional cooling was driven by changes in summer insolation and Northern Hemisphere volcanism. The initial cooling event was followed centuries later (c. 5,100 y BP) by sustained Icelandic volcanic eruptions that forced a centennial-scale 1.0 °C summer cooling anomaly and led to rapid ice-patch growth and preservation of the trees. With recent warming (c. 2000–2020 CE), warm-season temperatures now equal and will soon exceed those of the mid-Holocene period of high treeline. It is likely that perennial ice cover will again disappear from the region, and treeline may expand upslope so long as plant-available moisture and disturbance are not limiting.}, archive = {J_PNAS}, author = {Pederson, Gregory T. and Stahle, Daniel and McWethy, David B. and Toohey, Matthew and Jungclaus, Johann and Lee, Craig and Martin, Justin and Alt, Mio and Kichas, Nickolas and Chellman, Nathan and McConnell, Joseph R. and Whitlock, Cathy}, doi = {10.1073/pnas.2412162121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2412162121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic treeline and cryosphere response to pronounced mid-holocene climatic variability in the US rocky mountains}, volume = {122}, year = {2025}, }
• (2025). Not so binary or generalizable: Brain sex differences with artificial neural networks. PNAS, 122(2), e2411917121. (www)

  @article{ , archive = {J_PNAS}, author = {Lockhart, Jeffrey W. and Fuentes, Agustín and Rippon, Gina and Eliot, Lise}, doi = {10.1073/pnas.2411917121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2411917121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Not so binary or generalizable: Brain sex differences with artificial neural networks}, volume = {122}, year = {2025}, }
• (2025). A conifer metabolite corrects episodic ataxia type 1 by voltage sensor-mediated ligand activation of kv1.1. PNAS, 122(2), e2411816122. (www)

  @article{ , abstract = {Loss-of-function sequence variants in KCNA1 , which encodes the voltage-gated potassium channel Kv1.1, cause Episodic Ataxia Type 1 (EA1) and epilepsy. Due to a paucity of drugs that directly rescue mutant Kv1.1 channel function, current therapeutic strategies for KCNA1 -linked disorders involve indirect modulation of neuronal excitability. Native Americans have traditionally used conifer extracts to treat paralysis, weakness, and pain, all of which may involve altered electrical activity and/or Kv1.1 dysfunction specifically. Here, screening conifer extracts, we found that Chamaecyparis pisifera increases wild-type (WT) Kv1.1 activity, as does its prominent metabolite, the abietane diterpenoid pisiferic acid. Uniquely, pisiferic acid also restored function in 12/12 EA1-linked mutant Kv1.1 channels tested in vitro. Crucially, pisiferic acid (1 mg/kg) restored WT function in Kv1.1 E283K/+ mice, a model of human EA1. Experimentally validated all-atom molecular dynamics simulations in a neuron-like membrane revealed that the Kv1.1 voltage-sensing domain (VSD) also acts as a ligand-binding domain akin to those of classic ligand-gated channels; binding of pisiferic acid induces a conformational shift in the VSD that ligand-dependently opens the pore. Conifer metabolite pisiferic acid is a promising and versatile therapeutic lead for EA1 and other Kv1.1-linked disorders.}, archive = {J_PNAS}, author = {Manville, Rían W. and Foglia, Lorenzo and Yoshimura, Ryan F. and Hogenkamp, Derk J. and Nguyen, Amy and Yu, Alvin and Abbott, Geoffrey W.}, doi = {10.1073/pnas.2411816122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2411816122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A conifer metabolite corrects episodic ataxia type 1 by voltage sensor-mediated ligand activation of kv1.1}, volume = {122}, year = {2025}, }
• (2025). Reply to kaestner et al.: Activation of PIEZO1 is not significant for the passage of red blood cells through biomimetic splenic slits. PNAS, 122(2), e2411469121. (www)

  @article{ , archive = {J_PNAS}, author = {Moreau, Alexis and Yaya, François and Lu, Huijie and Surendranath, Anagha and Charrier, Anne and Dehapiot, Benoit and Helfer, Emmanuèle and Viallat, Annie and Peng, Zhangli}, doi = {10.1073/pnas.2411469121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2411469121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to kaestner et al.: Activation of PIEZO1 is not significant for the passage of red blood cells through biomimetic splenic slits}, volume = {122}, year = {2025}, }
• (2025). Splenic filtration of red blood cells: Physics, chemistry, and biology need to go hand in hand. PNAS, 122(2), e2405086121. (www)

  @article{ , archive = {J_PNAS}, author = {Kaestner, Lars and Egée, Stephane and Connes, Philippe and Bogdanova, Anna Yu. and Simmonds, Michael J.}, doi = {10.1073/pnas.2405086121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2405086121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Splenic filtration of red blood cells: Physics, chemistry, and biology need to go hand in hand}, volume = {122}, year = {2025}, }
• (2025). Boreal forests are heading for an open state. PNAS, 122(2), e2404391121. (www)

  @article{ , abstract = {The boreal forest biome is warming four times faster than the global average. Changes so far are moderate, but time lags in responses may transiently maintain forest states which are no longer supported by current environmental conditions. Here, we explore whether tree cover dynamics hint at the state to which the biome may be shifting. Our results suggest that global boreal tree cover is heading for a unimodal state of open forest (30 to 50%), contrasting starkly to the bimodal distribution of dense forests (>60%) and sparse woodlands (5 to 15%) found today. A future open forest in a warmer world would likely increase the risk of forest fires, leading to potentially substantial releases of stored carbon.}, archive = {J_PNAS}, author = {Rotbarth, Ronny and van Nes, Egbert H. and Scheffer, Marten and Holmgren, Milena}, doi = {10.1073/pnas.2404391121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2404391121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Boreal forests are heading for an open state}, volume = {122}, year = {2025}, }
• (2025). Beyond despair: Leveraging ecosystem restoration for psychosocial resilience. PNAS, 122(2), e2307082121. (www)

  @article{ , abstract = {Ecosystem restoration has historically been viewed as an ecological endeavor, but restoration possesses significant, yet largely untapped, potential as a catalyst for personal and social transformation. We highlight the opportunity for restoration to enhance community resilience by increasing agency and collective action and countering the pervasive perception that we are powerless witnesses to environmental decline. In this perspective, we take a “bright spots” approach and highlight successful examples of ecosystem restoration that have helped to nurture a sense of place, foster optimism, and cultivate stronger and more diverse social networks. These three individual- and community-level capacities have the potential to lead to increased psychosocial resilience, which is a key component of community resilience. Our aim is to spark discussion and research to better understand how we can transform restoration from a largely technical endeavor to a practice and process through which human–nature relationships are infused with deliberate meaning and human well-being is improved. With current calls to upscale and technologize restoration to meet sustainable development goals, we cannot lose sight of the value of community-engaged ecosystem restoration as a strategy with great potential for psychosocial benefits.}, archive = {J_PNAS}, author = {Smith, Carter S. and DeMattia, Elizabeth A. and Albright, Elizabeth and Bromberger, Abigail F. and Hayward, Olivia G. and Mackinson, India J. and Mantell, Sydney A. and McAdoo, Brian G. and McAfee, Dominic and McCollum, Aurora and Paxton, Avery B. and Roderer, Anne and Stevenson, Kathryn and Vidra, Rebecca L. and Zhao, Zixin}, doi = {10.1073/pnas.2307082121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {2}, pages = {e2307082121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Beyond despair: Leveraging ecosystem restoration for psychosocial resilience}, volume = {122}, year = {2025}, }
• (2025). Correction for armstrong et al., genetic differentiation and precolonial indigenous cultivation of hazelnut (Corylus cornuta, betulaceae) in western north america. PNAS, 122(1), e2424806121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424806121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2424806121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for armstrong et al., genetic differentiation and precolonial indigenous cultivation of hazelnut (Corylus cornuta, betulaceae) in western north america}, volume = {122}, year = {2025}, }
• (2025). Correction for bartesaghi et al., inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells. PNAS, 122(1), e2424656121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424656121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2424656121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for bartesaghi et al., inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells}, volume = {122}, year = {2025}, }
• (2025). Correction for yun et al., GPCR targeting of e3 ubiquitin ligase MDM2 by inactive β-arrestin. PNAS, 122(1), e2424650121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424650121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2424650121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for yun et al., GPCR targeting of e3 ubiquitin ligase MDM2 by inactive β-arrestin}, volume = {122}, year = {2025}, }
• (2025). Correction for ritz et al., social anxiety disorder-associated gut microbiota increases social fear. PNAS, 122(1), e2424381121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424381121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2424381121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for ritz et al., social anxiety disorder-associated gut microbiota increases social fear}, volume = {122}, year = {2025}, }
• (2025). Profile of stefan w. hell. PNAS, 122(1), e2424369121. (www)

  @article{ , archive = {J_PNAS}, author = {Ravindran, Sandeep}, doi = {10.1073/pnas.2424369121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2424369121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Profile of stefan w. hell}, volume = {122}, year = {2025}, }
• (2025). Correction for huo et al., hierarchical behavior control by a single class of interneurons. PNAS, 122(1), e2424365121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424365121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2424365121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for huo et al., hierarchical behavior control by a single class of interneurons}, volume = {122}, year = {2025}, }
• (2025). Correction for zhou et al., a genome-wide microRNA screen identifies the microRNA-183/96/182 cluster as a modulator of circadian rhythms. PNAS, 122(1), e2424179121. (www)

  @article{ , archive = {J_PNAS}, doi = {10.1073/pnas.2424179121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2424179121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Correction for zhou et al., a genome-wide microRNA screen identifies the microRNA-183/96/182 cluster as a modulator of circadian rhythms}, volume = {122}, year = {2025}, }
• (2025). Development of precision medicine approaches to advance clinical trials for autism and social behavior: A research imperative. PNAS, 122(1), e2424066122. (www)

  @article{ , archive = {J_PNAS}, author = {Boulton, Kelsie A. and Guastella, Adam J.}, doi = {10.1073/pnas.2424066122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2424066122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Development of precision medicine approaches to advance clinical trials for autism and social behavior: A research imperative}, volume = {122}, year = {2025}, }
• (2025). CryoSeek II: Cryo-EM analysis of glycofibrils from freshwater reveals well-structured glycans coating linear tetrapeptide repeats. PNAS, 122(1), e2423943122. (www)

  @article{ , abstract = {Despite the recent breakthrough in structure determination and prediction of proteins, the structural investigation of carbohydrates remains a challenge. Here, we report the cryo-EM analysis of a glycofibril found in the freshwater in the Tsinghua Lotus Pond. The fibril, which we name TLP-4, is made of a linear chain of tetrapeptide repeats coated with >4 nm thick glycans. In each repeat, two glycans are O-linked to a 3,4-dihydroxyproline and another glycan attaches to the adjacent Ser or Thr. The fibril structure is entirely maintained through glycan packing. Bioinformatic analysis confirms the conservation of the TLP-4 repeats across species, suggesting the existence of a large number of glycofibrils to be discovered. Our findings not only provide valuable insights into the structural roles of glycans in bio-assemblies but also demonstrate the potential of our recently formulated research strategy of CryoSeek to find bioentities and establish prototypes for structural studies of carbohydrates.}, archive = {J_PNAS}, author = {Wang, Tongtong and Huang, Wenze and Xu, Kui and Sun, Yitong and Zhang, Qiangfeng Cliff and Yan, Chuangye and Li, Zhangqiang and Yan, Nieng}, doi = {10.1073/pnas.2423943122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2423943122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {CryoSeek II: Cryo-EM analysis of glycofibrils from freshwater reveals well-structured glycans coating linear tetrapeptide repeats}, volume = {122}, year = {2025}, }
• (2025). Electrochemical NAD+ regeneration in bacterial organelles. PNAS, 122(1), e2423449122. (www)

  @article{ , archive = {J_PNAS}, author = {Mills, Carolyn E.}, doi = {10.1073/pnas.2423449122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2423449122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electrochemical NAD+ regeneration in bacterial organelles}, volume = {122}, year = {2025}, }
• (2025). Reply to zhang et al.: Parallel vector memories are required to explain all behavioral data in navigating bumblebees. PNAS, 122(1), e2423197121. (www)

  @article{ , archive = {J_PNAS}, author = {Patel, Rickesh N. and Roberts, Natalie S. and Kempenaers, Julian and Zadel, Ana and Heinze, Stanley}, doi = {10.1073/pnas.2423197121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2423197121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to zhang et al.: Parallel vector memories are required to explain all behavioral data in navigating bumblebees}, volume = {122}, year = {2025}, }
• (2025). Multitude of glasses of water. PNAS, 122(1), e2423093121. (www)

  @article{ , archive = {J_PNAS}, author = {Sciortino, Francesco}, doi = {10.1073/pnas.2423093121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2423093121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Multitude of glasses of water}, volume = {122}, year = {2025}, }
• (2025). Parallel vector memories or single memory updating?. PNAS, 122(1), e2422788121. (www)

  @article{ , archive = {J_PNAS}, author = {Zhang, Fengxiang and Pu, Yi and Kong, Xiang-Zhen}, doi = {10.1073/pnas.2422788121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2422788121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Parallel vector memories or single memory updating?}, volume = {122}, year = {2025}, }
• (2025). Income inequality and the erosion of democracy in the twenty-first century. PNAS, 122(1), e2422543121. (www)

  @article{ , abstract = {Among the most pressing problems societies face today are economic inequality and the erosion of democratic norms and institutions. In fact the two problems—inequality and democratic erosion—are linked. In a large cross-national statistical study of risk factors for democratic erosion, we establish that economic inequality is one of the strongest predictors of where and when democracy erodes. Even wealthy and longstanding democracies are vulnerable if they are highly unequal (though national wealth might provide some resiliency). The association between inequality and risk of democratic backsliding is robust, and holds under different measures and structures of both income inequality and wealth inequality. The association is unlikely to be a case of reverse causation. For concerned citizens seeking to understand why so many democracies are eroding and how to stop this process, our study indicates that policies for ameliorating inequality are a promising path forward.}, archive = {J_PNAS}, author = {Rau, Eli G. and Stokes, Susan}, doi = {10.1073/pnas.2422543121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2422543121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Income inequality and the erosion of democracy in the twenty-first century}, volume = {122}, year = {2025}, }
• (2025). Carbon gain in upper but loss in deeper cropland soils across china over the last four decades. PNAS, 122(1), e2422371122. (www)

  @article{ , abstract = {Increasing soil organic carbon (SOC) in agricultural systems is a primary nature-based option for mitigating climate change, improving soil fertility, and ensuring food security. However, the consequences of global warming and increases in carbon inputs on cropland SOC stocks over the last few decades remain largely unknown, particularly in deeper soil layers. Here, by using repeated measurements, we reassess variations in SOC stocks across a 0 to 100 cm soil profile at the same locations in China’s upland croplands in 1980 and 2023. We observe an overall net accumulation of 0.74 Pg SOC (7%) with a mean sequestration rate of 13.7 g SOC m −2 y −1 . This accumulation results from 0.86 Pg SOC gains at upper soil depths (0 to 60 cm) induced by carbon inputs, alongside 0.12 Pg SOC losses at deeper soil layers (60 to 100 cm) prompted by warming-enhanced decomposition. While our findings indicate a successful, though lower than expected, increase in overall net SOC stocks, the loss of more recalcitrant deeper SOC warrants further consideration of its effects on enhancing cropland SOC accumulation to achieve carbon neutrality over the long term.}, archive = {J_PNAS}, author = {Zhou, Zhenghu and Wang, Chuankuan and Li, Yu’e and Wang, Xuhui and He, Xinhua and Xu, Minggang and Cai, Andong}, doi = {10.1073/pnas.2422371122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2422371122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Carbon gain in upper but loss in deeper cropland soils across china over the last four decades}, volume = {122}, year = {2025}, }
• (2025). Quantifying the genetic origins of body plan scaling. PNAS, 122(1), e2422340121. (www)

  @article{ , archive = {J_PNAS}, author = {Galstyan, Vahe and ten Wolde, Pieter Rein}, doi = {10.1073/pnas.2422340121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2422340121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Quantifying the genetic origins of body plan scaling}, volume = {122}, year = {2025}, }
• (2025). Deletion of metal transporter zip14 reduces major histocompatibility complex II expression in murine small intestinal epithelial cells. PNAS, 122(1), e2422321121. (www)

  @article{ , abstract = {Documented worldwide, impaired immunity is a cardinal signature resulting from loss of dietary zinc, an essential micronutrient. A steady supply of zinc to meet cellular requirements is regulated by an array of zinc transporters. Deletion of the transporter Zip14 (Slc39a14) in mice produced intestinal inflammation. Elevated fecal lipocalin-2, calprotectin, IgG levels, and dysbiosis support the inflammatory phenotype. Here, we show through RNA-sequencing, using purified intestinal epithelial cells (IECs), that Zip14 deletion produces markedly reduced expression of major histocompatibility complex class II (MHCII) molecules and the master MHCII transactivator ( Ciita ). qPCR, western analysis, and immunohistochemistry confirmed loss of MHCII. Spectrofluorimetry with zinc probe FluoZin-3 showed reduced labile zinc in IECs from knockout mice. Chromatin immunoprecipitation assays, using Ciita antibody and IEC chromatin, suggest decreased transcription accounts for depressed expression of specific MHCII genes. Assay for Transposase-Accessible Chromatin (ATAC) sequencing (ATAC-seq) demonstrated that H2-Aa , H2-Ab1 and other MHCII genes result from chromatin remodeling yielding closed chromatin at regulatory regions of these genes. In agreement, ATAC-seq showed peak density of the chromosomal regulatory region of Ciita is consistent with down regulation of specific MHCII genes in IECs with Zip14 loss. Finally, dietary zinc supplementation of knockout mice and zinc supplementation of intestinal organoids with Zip14 deletion restored transcript levels. Taken together, our data suggest that cellular zinc delivery, via Zip14, is necessary for proper chromatin occupancy, required for normal MHCII expression and effective immune functions, and to preclude inflammatory disorders of the small intestine.}, archive = {J_PNAS}, author = {Jimenez-Rondan, Felix R. and Ruggiero, Courtney H. and Riva, Alberto and Yu, Fahong and Stafford, Lauren S. and Cross, Tyler R. and Larkin, Joseph and Cousins, Robert J.}, doi = {10.1073/pnas.2422321121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2422321121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deletion of metal transporter zip14 reduces major histocompatibility complex II expression in murine small intestinal epithelial cells}, volume = {122}, year = {2025}, }
• (2025). Deciphering the artificial evolution of domesticated plants within dynamic habitats. PNAS, 122(1), e2422179121. (www)

  @article{ , archive = {J_PNAS}, author = {Lentz, David L. and Pohl, Mary E. D.}, doi = {10.1073/pnas.2422179121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2422179121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deciphering the artificial evolution of domesticated plants within dynamic habitats}, volume = {122}, year = {2025}, }
• (2025). Reply to caruso bavisotto et al.: Toward exploring the potential of muscle-secreting exosomes in the muscle–brain axis. PNAS, 122(1), e2421378121. (www)

  @article{ , archive = {J_PNAS}, author = {Huang, Kai-Yu and Chung, Hee Jung and Kong, Hyunjoon}, doi = {10.1073/pnas.2421378121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2421378121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reply to caruso bavisotto et al.: Toward exploring the potential of muscle-secreting exosomes in the muscle–brain axis}, volume = {122}, year = {2025}, }
• (2025). Higher-order transient structures and the principle of dynamic connectivity in membrane signaling. PNAS, 122(1), e2421280121. (www)

  @article{ , abstract = {We examine the role of higher-order transient structures (HOTS) in M2R regulation of GIRK channels. Electron microscopic membrane protein location maps show that both proteins form HOTS that exhibit a statistical bias to be near each other. Theoretical calculations and electrophysiological measurements suggest that channel activity is isolated near larger M2R HOTS. By invoking weak interactions that permit transient binding of M2R to M2R and GIRK to GIRK ( i-i interactions) and M2R to GIRK ( i-j interactions), the distribution patterns and electrophysiological properties of HL-1 cells are replicated in a reaction-diffusion simulation. We propose the principle of dynamic connectivity to explain communication between protein components of a membrane signaling pathway. Dynamic connectivity is mediated by weak, transient interactions between proteins. HOTS created by weak i-i interactions, and statistical biases created by weak i-j interactions promoted by the multivalence of HOTS, are the key elements of dynamic connectivity.}, archive = {J_PNAS}, author = {Zhang, Yuxi and MacKinnon, Roderick}, doi = {10.1073/pnas.2421280121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2421280121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Higher-order transient structures and the principle of dynamic connectivity in membrane signaling}, volume = {122}, year = {2025}, }
• (2025). Higher-order transient membrane protein structures. PNAS, 122(1), e2421275121. (www)

  @article{ , abstract = {This study shows that five membrane proteins—three GPCRs, an ion channel, and an enzyme—form self-clusters under natural expression levels in a cardiac-derived cell line. The cluster size distributions imply that these proteins self-oligomerize reversibly through weak interactions. When the concentration of the proteins is increased through heterologous expression, the cluster size distributions approach a critical distribution at which point a phase transition occurs, yielding larger bulk phase clusters. A thermodynamic model like that explaining micellization of amphiphiles and lipid membrane formation accounts for this behavior. We propose that many membrane proteins exist as oligomers that form through weak interactions, which we call higher-order transient structures (HOTS). The key characteristics of HOTS are transience, molecular specificity, and a monotonically decreasing size distribution that may become critical at high concentrations. Because molecular specificity invokes self-recognition through protein sequence and structure, we propose that HOTS are genetically encoded supramolecular units.}, archive = {J_PNAS}, author = {Zhang, Yuxi and Mazal, Hisham and Mandala, Venkata Shiva and Pérez-Mitta, Gonzalo and Sondoghdar, Vahid and Haselwandter, Christoph A. and MacKinnon, Roderick}, doi = {10.1073/pnas.2421275121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2421275121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Higher-order transient membrane protein structures}, volume = {122}, year = {2025}, }
• (2025). Evidence for a metal–bosonic insulator–superconductor transition in compressed sulfur. PNAS, 122(1), e2420904122. (www)

  @article{ , abstract = {The abrupt drop of resistance to zero at a critical temperature is a key signature of the current paradigm of the metal–superconductor transition. However, the emergence of an intermediate bosonic insulating state characterized by a resistance peak preceding the onset of the superconducting transition has challenged this traditional understanding. Notably, this phenomenon has been predominantly observed in disordered or chemically doped low-dimensional systems, raising intriguing questions about the generality of the effect and its underlying fundamental physics. Here, we present a systematic experimental study of compressed elemental sulfur, an undoped three-dimensional (3D) high-pressure superconductor, with detailed measurements of electrical resistance as a function of temperature, magnetic field, and current. The anomalous resistance peak observed in this 3D system is interpreted based on an empirical model of a metal–bosonic insulator–superconductor transition, potentially driven by vortex dynamics under magnetic field and energy dissipation processes. These findings offer a fresh platform for theoretical analysis of the decades-long enigmatic of the underlying mechanism of this phenomenon.}, archive = {J_PNAS}, author = {Wang, Kui and Zhao, Hongjian and Liu, Guangtao and Zhou, Mi and Chen, Yinqi and Li, Qiushi and Ma, Guangchen and Wang, Hongbo and Hemley, Russell J. and Ma, Yanming}, doi = {10.1073/pnas.2420904122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2420904122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evidence for a metal–bosonic insulator–superconductor transition in compressed sulfur}, volume = {122}, year = {2025}, }
• (2025). The unexplored potential of exosomes in the muscle–brain axis. PNAS, 122(1), e2420766121. (www)

  @article{ , archive = {J_PNAS}, author = {Caruso Bavisotto, Celeste and Bucchieri, Fabio and Cappello, Francesco}, doi = {10.1073/pnas.2420766121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2420766121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The unexplored potential of exosomes in the muscle–brain axis}, volume = {122}, year = {2025}, }
• (2025). Complex tissue regeneration in lophuromys reveals a phylogenetic signal for enhanced regenerative ability in deomyine rodents. PNAS, 122(1), e2420726122. (www)

  @article{ , abstract = {Identifying why complex tissue regeneration is present or absent in specific vertebrate lineages has remained elusive. One also wonders whether the isolated examples where regeneration is observed represent cases of convergent evolution or are instead the product of phylogenetic inertia from a common ancestral program. Testing alternative hypotheses to identify genetic regulation, cell states, and tissue physiology that explain how regenerative healing emerges in some species requires sampling multiple species among which there is variation in regenerative ability across a phylogenetic framework. Here, we interrogate tissue healing across eleven rodents and show that brush-furred mice ( Lophuromys zena ) are capable of musculoskeletal regeneration where new tissue faithfully maintains axial polarity and tissue identity as previously observed in spiny mice ( Acomys spp. ). In contrast, we find that all nondeomyine rodents heal identical ear pinna injuries via fibrotic repair with scar tissue. Together, these data reveal a phylogenetic signal for enhanced regenerative ability in Deomyinae which is key to testing evolutionary hypotheses about the emergence of regenerative ability in mammals.}, archive = {J_PNAS}, author = {Riddell, Brennan and McDonough, Molly and Ferguson, Adam and Kimani, John M. and Gawriluk, Thomas R. and Peng, Chi and Kiama, Stephen G. and Ezenwa, Vanessa O. and Seifert, Ashley W.}, doi = {10.1073/pnas.2420726122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2420726122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Complex tissue regeneration in lophuromys reveals a phylogenetic signal for enhanced regenerative ability in deomyine rodents}, volume = {122}, year = {2025}, }
• (2025). Across the firewall: Foreign media’s role in shaping chinese social media narratives on the russo-ukrainian war. PNAS, 122(1), e2420607122. (www)

  @article{ , abstract = {There is a widespread perception that China’s digital censorship distances its people from the global internet, and the Chinese Communist Party, through state-controlled media, is the main gatekeeper of information about foreign affairs. Our analysis of narratives about the Russo-Ukrainian War circulating on the Chinese social media platform Weibo challenges this view. Comparing narratives on Weibo with 8.26 million unique news articles from 2,500 of some of the most trafficked websites in China, Russia, Ukraine, and the United States (totaling 10,000 sites), we find that Russian news websites published more articles matching narratives found on Weibo than news websites from China, Ukraine, or the United States. Similarly, a plurality of Weibo narratives were most associated with narratives found on Russian news websites while less than ten percent were most associated with narratives from Chinese news sites. Narratives later appearing on Weibo were more likely to first appear on Russian rather than Chinese, Ukrainian, or US news websites, and Russian websites were highly influential for narratives appearing on Weibo. Altogether, these results show that Chinese state media was not the main gatekeeper of information about Russia’s invasion of Ukraine for Weibo users.}, archive = {J_PNAS}, author = {Hanley, Hans W. A. and Lu, Yingdan and Pan, Jennifer}, doi = {10.1073/pnas.2420607122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2420607122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Across the firewall: Foreign media’s role in shaping chinese social media narratives on the russo-ukrainian war}, volume = {122}, year = {2025}, }
• (2025). Integrin-activating yersinia protein invasin sustains long-term expansion of primary epithelial cells as 2D organoid sheets. PNAS, 122(1), e2420595121. (www)

  @article{ , abstract = {Matrigel ® /BME ® , a basement membrane-like preparation, supports long-term growth of epithelial 3D organoids from adult stem cells [T. Sato et al. , Nature 459 , 262–265 (2009); T. Sato et al. , Gastroenterology 141 , 1762–1772 (2011)]. Here, we show that interaction between Matrigel’s major component laminin-111 with epithelial α6β1-integrin is crucial for this process. The outer membrane protein Invasin of Yersinia is known to activate multiple integrin–β1 complexes, including integrin α6β1. A C-terminal integrin-binding fragment of Invasin, coated on culture plates, mediated gut epithelial cell adhesion. Addition of organoid growth factors allowed multipassage expansion in 2D. Polarization, junction formation, and generation of enterocytes, goblet cells, Paneth cells, and enteroendocrine cells were stable over time. Sustained expansion of other human, mouse, and even snake epithelia was accomplished under comparable conditions. The 2D “organoid sheet” format holds advantages over the 3D “in gel” format in terms of imaging, accessibility of basal and apical domains, and automation for high-throughput screening. Invasin represents a fully defined, affordable, versatile, and animal-free complement to Matrigel ® /BME ® .}, archive = {J_PNAS}, author = {Wijnakker, Joost J.A.P.M. and van Son, Gijs J.F. and Krueger, Daniel and van de Wetering, Willine J. and Lopez-Iglesias, Carmen and Schreurs, Robin and van Rijt, Fenna and Lim, Sangho and Lin, Lin and Peters, Peter J. and Isberg, Ralph R. and Janda, Claudia Y. and de Lau, Wim and Clevers, Hans}, doi = {10.1073/pnas.2420595121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2420595121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Integrin-activating yersinia protein invasin sustains long-term expansion of primary epithelial cells as 2D organoid sheets}, volume = {122}, year = {2025}, }
• (2025). Synapse-specific catecholaminergic modulation of neuronal glutamate release. PNAS, 122(1), e2420496121. (www)

  @article{ , abstract = {Norepinephrine in vertebrates and its invertebrate analog, octopamine, regulate the activity of neural circuits. We find that, when hungry, Drosophila larvae switch activity in type II octopaminergic motor neurons (MNs) to high-frequency bursts, which coincide with locomotion-driving bursts in type I glutamatergic MNs that converge on the same muscles. Optical quantal analysis across hundreds of synapses simultaneously reveals that octopamine potentiates glutamate release by tonic type Ib MNs, but not phasic type Is MNs, and occurs via the G q -coupled octopamine receptor (OAMB). OAMB is more abundant in type Ib terminals and acts through diacylglycerol and its target Unc13A, a key component of the glutamate release machinery. Potentiation varies significantly—by up to 1,000%—across synapses of a single Ib axon, with synaptic Unc13A levels determining both release probability and potentiation. We propose that a dual molecular mechanism—an upstream neuromodulator receptor and a downstream transmitter release controller—fine-tunes catecholaminergic modulation so that strong tonic synapses exhibit large potentiation, while weaker tonic and all phasic synapses maintain consistency, yielding a sophisticated regulation of locomotor behavior.}, archive = {J_PNAS}, author = {Bakshinska, Dariya and Liu, William YuChen and Schultz, Ryan and Stowers, R. Steven and Hoagland, Adam and Cypranowska, Caroline and Stanley, Cherise and Younger, Susan H. and Newman, Zachary L. and Isacoff, Ehud Y.}, doi = {10.1073/pnas.2420496121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2420496121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Synapse-specific catecholaminergic modulation of neuronal glutamate release}, volume = {122}, year = {2025}, }
• (2025). Structure-guided design and synthesis of c22- and c32-modified FK520 analogs with enhanced activity against human pathogenic fungi. PNAS, 122(1), e2419883121. (www)

  @article{ , abstract = {Invasive fungal infections are a leading cause of death worldwide. Translating molecular insights into clinical benefits is challenging because fungal pathogens and their hosts share similar eukaryotic physiology. Consequently, current antifungal treatments have limited efficacy, may be poorly fungicidal in the host, can exhibit toxicity, and are increasingly compromised by emerging resistance. We have established that the phosphatase calcineurin (CaN) is required for invasive fungal disease and an attractive target for antifungal drug development. CaN is a druggable target, and there is vast clinical experience with the CaN inhibitors FK506 and cyclosporin A (CsA). However, while FK506 and its natural analog FK520 exhibit antifungal activity, they are also immunosuppressive in the host and thus not fungal-selective. We leverage our pathogenic fungal CaN-FK506-FKBP12 complex X-ray structures and biophysical data to support structure-based ligand design as well as structure–activity relationship analyses of broad-spectrum FK506/FK520 derivatives with potent antifungal activity and reduced immunosuppressive activity. Here, we apply molecular docking studies to develop antifungal C22- or C32-modified FK520 derivatives with improved therapeutic index scores. Among them, the C32-modified FK520 derivative JH-FK-44 ( 7 ) demonstrates a significantly improved therapeutic index compared to JH-FK-08, our lead compound to date. NMR binding studies with C32-derivatives are consistent with our hypothesis that C32 modifications disrupt the hydrogen bonding network in the human complex while introducing favorable electrostatic and cation–π interactions with the fungal FKBP12 R86 residue. These findings further reinforce calcineurin inhibition as a promising strategy for antifungal therapy.}, archive = {J_PNAS}, author = {Dome, Patrick A. and Jeong, Pyeonghwa and Nam, Gibeom and Jang, Hongjun and Rivera, Angela and Floyd Averette, Anna and Park, Eunchong and Liao, Tzu-Chieh and Ciofani, Maria and Wu, Jianli and Chi, Jen-Tsan Ashley and Venters, Ronald A. and Park, Hyun-Ju and Steinbach, William J. and Juvvadi, Praveen R. and Heitman, Joseph and Hong, Jiyong}, doi = {10.1073/pnas.2419883121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2419883121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structure-guided design and synthesis of c22- and c32-modified FK520 analogs with enhanced activity against human pathogenic fungi}, volume = {122}, year = {2025}, }
• (2025). Structural and functional dynamics of human cone cGMP-phosphodiesterase important for photopic vision. PNAS, 122(1), e2419732121. (www)

  @article{ , abstract = {Cone cGMP-phosphodiesterase (PDE6) is the key effector enzyme for daylight vision, and its properties are critical for shaping distinct physiology of cone photoreceptors. We determined the structures of human cone PDE6C in various liganded states by single-particle cryo-EM that reveal essential functional dynamics and adaptations of the enzyme. Our analysis exposed the dynamic nature of PDE6C association with its regulatory γ-subunit (Pγ) which allows openings of the catalytic pocket in the absence of phototransduction signaling, thereby controlling photoreceptor noise and sensitivity. We demonstrate evolutionarily recent adaptations of PDE6C stemming from residue substitutions in the Pγ subunit and the noncatalytic cGMP binding site and influencing the Pγ dynamics in holoPDE6C. Thus, our structural analysis sheds light on the previously unrecognized molecular evolution of the effector enzyme in cones that advances adaptation for photopic vision.}, archive = {J_PNAS}, author = {Singh, Sneha and Srivastava, Dhiraj and Boyd, Kimberly and Artemyev, Nikolai O.}, doi = {10.1073/pnas.2419732121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2419732121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural and functional dynamics of human cone cGMP-phosphodiesterase important for photopic vision}, volume = {122}, year = {2025}, }
• (2025). Deciphering the role of the MALT1–RC3H1 axis in regulating GPX4 protein stability. PNAS, 122(1), e2419625121. (www)

  @article{ , abstract = {Ferroptosis, a unique form of iron-dependent cell death triggered by lipid peroxidation accumulation, holds great promise for cancer therapy. Despite the crucial role of GPX4 in regulating ferroptosis, our understanding of GPX4 protein regulation remains limited. Through FACS-based genome-wide CRISPR screening, we identified MALT1 as a regulator of GPX4 protein. Inhibition of MALT1 expression enhances GPX4 ubiquitination-mediated degradation by up-regulating the E3 ubiquitin ligase RC3H1. Using both rescue assays and functional genetic screening, we demonstrate that pharmacologically targeting MALT1 triggers ferroptosis in liver cancer cells. Moreover, we show that targeting MALT1 synergizes with sorafenib or regorafenib to induce ferroptosis across multiple cancer types. These findings elucidate the modulatory effects of the MALT1–RC3H1 axis on GPX4 stability, revealing a molecular mechanism that could be exploited to induce ferroptosis for cancer therapy.}, archive = {J_PNAS}, author = {Wang, Jun and Liao, Long and Miao, Beiping and Yang, Bo and Li, Botai and Ma, Xuhui and Fitz, Annika and Wu, Shanshan and He, Jia and Zhang, Qianqian and Ji, Shuyi and Jin, Guangzhi and Zhang, Jianming and Cao, Ying and Wang, Hui and Qin, Wenxin and Sun, Chong and Bernards, René and Wang, Cun}, doi = {10.1073/pnas.2419625121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2419625121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deciphering the role of the MALT1–RC3H1 axis in regulating GPX4 protein stability}, volume = {122}, year = {2025}, }
• (2025). In situ architecture of a nucleoid-associated biomolecular co-condensate that regulates bacterial cell division. PNAS, 122(1), e2419610121. (www)

  @article{ , abstract = {In most bacteria, cell division depends on the tubulin-homolog FtsZ that polymerizes in a GTP-dependent manner to form the cytokinetic Z-ring at the future division site. Subsequently, the Z-ring recruits, directly or indirectly, all other proteins of the divisome complex that executes cytokinesis. A critical step in this process is the precise positioning of the Z-ring at the future division site. While the divisome proteins are generally conserved, the regulatory systems that position the Z-ring are more diverse. However, these systems have in common that they modulate FtsZ polymerization. In Myxococcus, PomX, PomY, and PomZ form precisely one MDa-sized, nonstoichiometric, nucleoid-associated assembly that spatiotemporally guides Z-ring formation. Here, using cryo-correlative light and electron microscopy together with in situ cryoelectron tomography, we determine the PomXYZ assembly’s architecture at close-to-live conditions. PomX forms a porous meshwork of randomly intertwined filaments. Templated by this meshwork, the phase-separating PomY protein forms a biomolecular condensate that compacts and bends the PomX filaments, resulting in the formation of a selective PomXYZ co-condensate that is associated to the nucleoid by PomZ. These studies reveal a hitherto undescribed supramolecular structure and provide a framework for understanding how a nonstoichiometric co-condensate forms, maintains number control, and nucleates GTP-dependent FtsZ polymerization to precisely regulate cell division.}, archive = {J_PNAS}, author = {Xu, Peng and Schumacher, Dominik and Liu, Chuan and Harms, Andrea and Dickmanns, Marcel and Beck, Florian and Plitzko, Jürgen M. and Baumeister, Wolfgang and Søgaard-Andersen, Lotte}, doi = {10.1073/pnas.2419610121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2419610121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {In situ architecture of a nucleoid-associated biomolecular co-condensate that regulates bacterial cell division}, volume = {122}, year = {2025}, }
• (2025). Tsg101 mimicry of canonical e2 enzymes underlies its role in ubiquitin signaling. PNAS, 122(1), e2419542121. (www)

  @article{ , abstract = {Tsg101 is a highly conserved protein best known as an early-functioning component of cellular ESCRT machinery participating in recognition, sorting, and trafficking of cellular cargo to various intracellular destinations. It shares sequence and structural homology to canonical ubiquitin-conjugating (E2) enzymes and is linked to diverse events regulated by Ub signaling. How it might fulfill these roles is unclear. Here, we show that Tsg101 E2 mimicry permits interactions with diverse ubiquitin ligating (E3) enzymes and underlies its multifunctional capabilities. Coexpression of Tsg101 with the E3 ligase NNedd4-2s protected the enzyme from degradation and, remarkably, other widely divergent ligases as well. Structural alignment with UbcH5, a canonical E2 enzyme, revealed that recognition at the E2-E3 interface, a region broadly conserved despite sequence and structural differences in both E2 and E3 enzymes, was critical for protection. Nevertheless, UbcH5 failed to protect NNedd4-2s, indicating that the UEV chaperone function is unique to the variant. Studies using Cy5-Ub-VME showed that Tsg101-mediated protection reduced accessibility to Cys residues in the ligase. Access to Tsg101 Ub-binding sites was critical: Rabeprazole, which interferes with Tsg101 Ub-binding, diminished E3 ligase protection. Thus, E2 mimicry permitting control of E3 ligase ubiquitin signaling underlies Tsg101’s broad ability to participate in multiple cellular functions. The study provides mechanistic insight into how Tsg101, by partnering with diverse E3 ligases, can contribute to a broad range of cellular activities.}, archive = {J_PNAS}, author = {Nyenhuis, David A. and Watanabe, Susan M. and Tjandra, Nico and Carter, Carol A.}, doi = {10.1073/pnas.2419542121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2419542121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tsg101 mimicry of canonical e2 enzymes underlies its role in ubiquitin signaling}, volume = {122}, year = {2025}, }
• (2025). A hybrid meta on-top functional for multiconfiguration pair-density functional theory. PNAS, 122(1), e2419413121. (www)

  @article{ , abstract = {Multiconfiguration pair-density functional theory (MC-PDFT) was proposed a decade ago, but it is still in the early stage of density functional development. MC-PDFT uses functionals that are called on-top functionals; they depend on the density and the on-top pair density. Most MC-PDFT calculations to date have been unoptimized translations of generalized gradient approximations (GGAs) of Kohn–Sham density functional theory (KS-DFT). A hybrid MC-PDFT has also been developed, in which one includes a fraction of the complete active space self-consistent-field wave function energy in the total energy. Meta-GGA functionals, which use kinetic-energy densities in addition to GGA ingredients, have shown higher accuracy than GGAs in KS-DFT, yet the translation of meta-GGAs has not been previously proposed for MC-PDFT. In this paper, we propose a way to include kinetic energy density in a hybrid on-top functional for MC-PDFT, and we optimize the parameters of the resulting functional by training with a database developed as part of the present work that contains a wide variety of systems with diverse characters. The resulting hybrid meta functional is called the MC23 functional. We find that MC23 has improved performance as compared to KS-DFT functionals for both strongly and weakly correlated systems. We recommend MC23 for future MC-PDFT calculations.}, archive = {J_PNAS}, author = {Bao, Jie J. and Zhang, Dayou and Zhang, Shaoting and Gagliardi, Laura and Truhlar, Donald G.}, doi = {10.1073/pnas.2419413121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2419413121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A hybrid meta on-top functional for multiconfiguration pair-density functional theory}, volume = {122}, year = {2025}, }
• (2025). Learning the language of antibody hypervariability. PNAS, 122(1), e2418918121. (www)

  @article{ , abstract = {Protein language models (PLMs) have demonstrated impressive success in modeling proteins. However, general-purpose “foundational” PLMs have limited performance in modeling antibodies due to the latter’s hypervariable regions, which do not conform to the evolutionary conservation principles that such models rely on. In this study, we propose a transfer learning framework called Antibody Mutagenesis-Augmented Processing (AbMAP), which fine-tunes foundational models for antibody-sequence inputs by supervising on antibody structure and binding specificity examples. Our learned feature representations accurately predict mutational effects on antigen binding, paratope identification, and other key antibody properties. We experimentally validate AbMAP for antibody optimization by applying it to refine a set of antibodies that bind to a SARS-CoV-2 peptide, and obtain an 82% hit-rate and up to 22-fold increase in binding affinity. AbMAP also unlocks large-scale analyses of immune repertoires, revealing that B-cell receptor repertoires of individuals, while remarkably different in sequence, converge toward similar structural and functional coverage. Importantly, AbMAP’s transfer learning approach can be readily adapted to advances in foundational PLMs. We anticipate AbMAP will accelerate the efficient design and modeling of antibodies, expedite the discovery of antibody-based therapeutics, and deepen our understanding of humoral immunity.}, archive = {J_PNAS}, author = {Singh, Rohit and Im, Chiho and Qiu, Yu and Mackness, Brian and Gupta, Abhinav and Joren, Taylor and Sledzieski, Samuel and Erlach, Lena and Wendt, Maria and Fomekong Nanfack, Yves and Bryson, Bryan and Berger, Bonnie}, doi = {10.1073/pnas.2418918121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2418918121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Learning the language of antibody hypervariability}, volume = {122}, year = {2025}, }
• (2025). Palmitoylation-dependent association with annexin II directs hepatitis e virus ORF3 sorting into vesicles and quasi-enveloped virions. PNAS, 122(1), e2418751122. (www)

  @article{ , abstract = {Historically considered to be nonenveloped, hepatitis E virus (HEV), an important zoonotic pathogen, has recently been discovered to egress from infected cells as quasi-enveloped virions. These quasi-enveloped virions circulating in the blood are resistant to neutralizing antibodies, thereby facilitating the stealthy spread of infection. Despite abundant evidence of the essential role of the HEV-encoded ORF3 protein in quasi-enveloped virus formation, the underlying mechanism remains unclear. Here, we demonstrate that the HEV ORF3 protein possesses an inherent capacity for self-secretion and that palmitoylation at two cysteine residues within the ORF3 N-terminal region is essential for its secretion and quasi-enveloped virus formation. We further found that only palmitoylated ORF3 proteins hijacked Annexin II for transport to the cytoskeleton and are then directed into multivesicular bodies through the nSMase-endosomal sorting complexes required for transport-III pathway for secretion. Finally, we show that infection of gerbils with HEV mutants harboring mutations at palmitoylation sites within ORF3 showed no fecal viral shedding but competent replication in the liver. Our study fills a gap in the understanding of the assembly and release of quasi-enveloped virions mediated by ORF3 and offers the potential for designing therapeutic strategies to control HEV infection.}, archive = {J_PNAS}, author = {Liu, Xing and Liu, Tianxu and Shao, Zhen and Xiong, Xiaoyan and Qi, Shuhui and Guan, Junyong and Wang, Menghang and Tang, Yan-Dong and Feng, Zongdi and Wang, Lin and Yin, Xin}, doi = {10.1073/pnas.2418751122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2418751122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Palmitoylation-dependent association with annexin II directs hepatitis e virus ORF3 sorting into vesicles and quasi-enveloped virions}, volume = {122}, year = {2025}, }
• (2025). Moisture-driven carbonation kinetics for ultrafast CO2 mineralization. PNAS, 122(1), e2418239121. (www)

  @article{ , abstract = {CO 2 mineralization, a process where CO 2 reacts with minerals to form stable carbonates, presents a sustainable approach for CO 2 sequestration and mitigation of global warming. While the crucial role of water in regulating CO 2 mineralization efficiency is widely acknowledged, a comprehensive understanding of the underlying mechanisms remains elusive. This study employs a combined experimental and atomistic simulation approach to elucidate the intricate mechanisms governing moisture-driven carbonation kinetics of calcium-bearing minerals. A self-designed carbonation reactor equipped with an ultrasonic atomizer is used to meticulously control the water content during carbonation experiments. Grand Canonical Monte Carlo simulations reveal that maximum CO 2 uptake occurs at a critical water content where the initiation of capillary condensation significantly enhanced liquid–gas interactions. This phenomenon leads to CO 2 adsorption–driven ultrafast carbonation at an optimal moisture content (0.1 to 0.2 g/g, water mass ratio to total wet mass of the mineral). A higher moisture content decimates the carbonation rate by crippling CO 2 intake within mineral pores. However, at exceptionally high moisture levels, the carbonation reaction sites shift from internal mesopores to the grain surface. This results in surface dissolution–driven ultrafast carbonation, attributed to the monotonically decreasing free energy of dissolution with increasing surface water thickness, as revealed by metadynamics simulations. This study provides a fundamental and unified understanding of the multifaceted role of water in mineral carbonation, paving the way for optimizing ultrafast CO 2 mineralization strategies for global decarbonization efforts.}, archive = {J_PNAS}, author = {Gao, Yining and Tao, Yong and Li, Gen and Shen, Peiliang and Pellenq, Roland J.-M. and Poon, Chi Sun}, doi = {10.1073/pnas.2418239121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2418239121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Moisture-driven carbonation kinetics for ultrafast CO2 mineralization}, volume = {122}, year = {2025}, }
• (2025). Structures of methane and ammonia monooxygenases in native membranes. PNAS, 122(1), e2417993121. (www)

  @article{ , abstract = {Methane- and ammonia-oxidizing bacteria play key roles in the global carbon and nitrogen cycles, respectively. These bacteria use homologous copper membrane monooxygenases to accomplish the defining chemical transformations of their metabolisms: the oxidations of methane to methanol by particulate methane monooxygenase (pMMO) and ammonia to hydroxylamine by ammonia monooxygenase (AMO), enzymes of prime interest for applications in mitigating climate change. However, investigations of these enzymes have been hindered by the need for disruptive detergent solubilization prior to structure determination, confounding studies of pMMO and precluding studies of AMO. Here, we overcome these challenges by using cryoEM to visualize pMMO and AMO directly in their native membrane arrays at 2.4 to 2.8 Å resolution. These structures reveal details of the copper centers, numerous bound lipids, and previously unobserved components, including identifiable and distinct supernumerary helices interacting with pMMO and AMO, suggesting a widespread role for these helices in copper membrane monooxygenases. Comparisons between these structures, their metallocofactors, and their unexpected protein–protein interactions highlight features that may govern activity or the formation of higher-order arrays in native membranes. The ability to obtain molecular insights within the native membrane will enable further understanding of these environmentally important enzymes.}, archive = {J_PNAS}, author = {Tucci, Frank J. and Rosenzweig, Amy C.}, doi = {10.1073/pnas.2417993121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2417993121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structures of methane and ammonia monooxygenases in native membranes}, volume = {122}, year = {2025}, }
• (2025). A lever hypothesis for synaptotagmin-1 action in neurotransmitter release. PNAS, 122(1), e2417941121. (www)

  @article{ , abstract = {Neurotransmitter release is triggered in microseconds by Ca 2+ -binding to the Synaptotagmin-1 C 2 -domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca 2+ -sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 C 2 B domain to SNARE complexes through a “primary interface” comprising two regions (I and II). The Synaptotagmin-1 Ca 2+ -binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers, or helping bridge the membranes, but SNARE complex binding through the primary interface orients the Ca 2+ -binding loops away from the fusion site, hindering these putative activities. To clarify this paradox, we have used NMR and fluorescence spectroscopy. NMR experiments reveal that binding of C 2 B domain arginines to SNARE acidic residues at region II remains after disruption of region I, and that a mutation that impairs spontaneous and Ca 2+ -triggered neurotransmitter release enhances binding through region I. Moreover, fluorescence assays show that Ca 2+ does not induce dissociation of Synaptotagmin-1 from membrane-anchored SNARE complex but causes reorientation of the C 2 B domain. Based on these results and electrophysiological data described by Toulme et al. ( https://doi.org/10.1073/pnas.2409636121 ), we propose that upon Ca 2+ binding the Synaptotagmin-1 C 2 B domain reorients on the membrane and dissociates from the SNAREs at region I but not region II, acting remotely as a lever that pulls the SNARE complex and facilitates linker zippering or other SNARE structural changes required for fast membrane fusion.}, archive = {J_PNAS}, author = {Jaczynska, Klaudia and Esser, Victoria and Xu, Junjie and Sari, Levent and Lin, Milo M. and Rosenmund, Christian and Rizo, Josep}, doi = {10.1073/pnas.2417941121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2417941121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A lever hypothesis for synaptotagmin-1 action in neurotransmitter release}, volume = {122}, year = {2025}, }
• (2025). Metastable state preceding shear zone instability: Implications for earthquake-accelerated landslides and dynamic triggering. PNAS, 122(1), e2417840121. (www)

  @article{ , abstract = {Understanding the dynamic response of granular shear zones under cyclic loading is fundamental to elucidating the mechanisms triggering earthquake-induced landslides, with implications for broader fields such as seismology and granular physics. Existing prediction methods struggle to accurately predict many experimental and in situ landslide observations due to inadequate consideration of the underlying physical mechanisms. The mechanisms that influence landslide dynamic triggering, a transition from static (or extremely slow creeping) to rapid runout, remain elusive. Herein, we focus on the inherent physics of granular shear zones under dynamic loading using ring shear experiments. Except for coseismic slip caused by the dynamic load, varying magnitudes of postseismic creep with increasing cycles of dynamic loading are observed, highlighting the effects of coseismic weakening (shear zone fatigue) and subsequent postseismic healing. A metastable state, characterized by a significant increase in postseismic creep, typically precedes shear zone instability. The metastable state may arise as weakened shear resistance approaches the applied shear stress, demonstrating a phase transition from a solid-like state to a fluid state (plastic granular flow). The metastable state may potentially indicate the shear zone’s stress state and serve as a precursor to impending instability. Furthermore, the proposed mechanisms offer a compelling explanation for the widespread postseismic landslide movement following earthquakes. Incorporating these mechanisms into the Newmark method has the potential to improve the prediction of earthquake-induced landslide displacement and enhance our understanding of dynamic triggering.}, archive = {J_PNAS}, author = {Li, Yan and Hu, Wei and Xu, Qiang and Luo, Hui and Chang, Chingshung and Jia, Xiaoping}, doi = {10.1073/pnas.2417840121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2417840121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Metastable state preceding shear zone instability: Implications for earthquake-accelerated landslides and dynamic triggering}, volume = {122}, year = {2025}, }
• (2025). Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies. PNAS, 122(1), e2417544121. (www)

  @article{ , abstract = {The emergence of SARS-CoV-2 variants of concern (VOCs) has greatly diminished the neutralizing activity of previously FDA-approved monoclonal antibodies (mAbs), including that of antibody cocktails and of first-generation broadly neutralizing antibodies such as S309 (Sotrovimab). In contrast, antibodies targeting cryptic conformational epitopes of the receptor binding domain (RBD) have demonstrated broad activity against emerging variants, but exert only moderate neutralizing activity, which has so far hindered clinical development. Here, we utilize in vitro display technology to identify and affinity-mature antibodies targeting the cryptic class 6 epitope, accessible only in the “up” conformation of the SARS-CoV-2 spike trimer. Increasing antibody affinity into the low picomolar range endowed potent neutralization of VOCs and protection of hACE2 mice from viral challenge. Cryoelectron microscopy and crystal structures of two affinity-matured antibodies (4C12-B12 and 4G1-C2) in complex with RBD highlighted binding modes and epitopes distal from mutational hotspots commonly overserved in VOCs, providing direct structural insights into the observed mutational resistance. Moreover, we further demonstrate that antibodies targeting the class 6 epitope, rather than being an artifact of in vitro selection, are common in the IgG1 + memory B cell repertoire of convalescent patients and can be induced in human antibody V-gene transgenic mice through immunization. Our results highlight the importance of very high (picomolar) affinity in the development of neutralizing antibodies and vaccines and suggest an affinity threshold in the provision of broad and long-lasting immunity against SARS-CoV-2.}, archive = {J_PNAS}, author = {Mazigi, Ohan and Langley, David B. and Henry, Jake Y. and Burnett, Deborah L. and Sobti, Meghna and Walker, Gregory J. and Rouet, Romain and Balachandran, Harikrishnan and Lenthall, Helen and Jackson, Jennifer and Ubiparipovic, Stephanie and Schofield, Peter and Brown, Simon H. J. and Schulz, Sebastian R. and Hoffmann, Markus and Pöhlmann, Stefan and Post, Jeffrey and Martinello, Marianne and Ahlenstiel, Golo and Kelleher, Anthony and Rawlinson, William D. and Turville, Stuart G. and Bull, Rowena A. and Stewart, Alastair G. and Jäck, Hans-Martin and Goodnow, Christopher C. and Christ, Daniel}, doi = {10.1073/pnas.2417544121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2417544121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies}, volume = {122}, year = {2025}, }
• (2025). Liquid-nano-liquid interface–oriented anisotropic encapsulation. PNAS, 122(1), e2417292121. (www)

  @article{ , abstract = {Emulsion interface engineering has been widely employed for the synthesis of nanomaterials with various morphologies. However, the instability of the liquid–liquid interface and uncertain interfacial interactions impose significant limitations on controllable fabrications. Here, we developed a liquid-nano-liquid interface–oriented anisotropic encapsulation strategy for fabricating asymmetric nanohybrids. Specifically, functional nanoparticles such as magnetic nanoparticles, lanthanide fluorescent nanoparticles, and Au nanorods were anisotropically encapsulated by mesoporous polydopamine (mPDA). In this emulsion system, the wetting behavior of functional nanoparticles at the water/oil interface could be manipulated by the stabilizer of the emulsion (surfactant), leading to the anisotropic assembly of mPDA shell and resulting in various nanostructures, including core–shell, yolk–shell with small opening, ball-in-bowl, and multipetal structures. Due to their structural asymmetry, inherent magnetic properties, and photothermal properties, the ball-in-bowl structured Fe 3 O 4 @SiO 2 &mPDA nanohybrids, serving as proof of concept for nanomotors, demonstrated effective penetration of bacterial biofilm and promotion of infected wound healing. Overall, our approach offers a different perspective for designing morphologically controllable asymmetric structures based on liquid-nano-liquid interface in microemulsion systems that hold great potential for establishing innovative functional nanomaterials.}, archive = {J_PNAS}, author = {Zhan, Yating and Huang, Xirui and Liu, Minchao and Lin, Runfeng and Yu, Hongyue and Kou, Yufang and Xing, Enyun and Elzatahry, Ahmed A. and Mady, Mohamed F. and Zhao, Dongyuan and Zhao, Tiancong and Li, Xiaomin}, doi = {10.1073/pnas.2417292121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2417292121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Liquid-nano-liquid interface–oriented anisotropic encapsulation}, volume = {122}, year = {2025}, }
• (2025). Mitochondrial DNA lineages determine tumor progression through t cell reactive oxygen signaling. PNAS, 122(1), e2417252121. (www)

  @article{ , abstract = {Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA–cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, mtDNA B6 and mtDNA NZB , where mtDNA NZB mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, mtDNA B6 Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas mtDNA NZB Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection. When challenged with melanoma or colon cancer cells, the mtDNA NZB mice exhibited strikingly impaired tumor growth while mtDNA B6 mice showed Treg-dependent inhibition of Teff cells and allowed rapid tumor growth. Transcriptional analysis showed that activation of mtDNA NZB Teff cells increased mitochondrial gene expression while activation of mtDNA NZB Treg cells impaired mitochondrial gene expression and resulted in mtDNA NZB Treg cell exhaustion. Induction of the mitochondrially targeted catalytic antioxidant, mCAT, in hematopoietic cells normalized mtDNA NZB Treg function in both transplant and tumor models, indicating a key role for mROS in promoting Treg dysfunction. Anti-PD-L1 therapy did not modulate these effects, indicating that modulation of host mitochondrial function provides an independent approach for enhancing tumor cell destruction.}, archive = {J_PNAS}, author = {Yardeni, Tal and Olali, Arnold Z. and Chen, Hsiao-Wen and Wang, Liqing and Halton, Jeffrey A. and Zenab, Angi and Morrow, Ryan and Butic, Arrienne and Murdock, Deborah G. and Waymire, Katrina G. and MacGregor, Grant R. and Boursi, Ben and Beier, Ulf H. and Hancock, Wayne W. and Wallace, Douglas C.}, doi = {10.1073/pnas.2417252121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2417252121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mitochondrial DNA lineages determine tumor progression through t cell reactive oxygen signaling}, volume = {122}, year = {2025}, }
• (2025). Fast-chargeable lithium-ion batteries by μ-si anode-tailored full-cell design. PNAS, 122(1), e2417053121. (www)

  @article{ , abstract = {Silicon (Si) anodes have long been recognized to significantly improve the energy density and fast-charging capability of lithium-ion batteries (LIBs). However, the implementation of these anodes in commercial LIB cells has progressed incrementally due to the immense volume change of Si across its full state-of-charge (SOC) range. Here, we report an anode-tailored full-cell design (ATFD), which incorporates micrometer-sized silicon (μ-Si) alone, for operation over a limited, prespecified SOC range identified as 30−70%. This range allows homogeneous (de)lithiation throughout the electrode, accompanied by an acceptable level of volume change. The ATFD-based cell exhibits 21.3% higher gravimetric energy density than that of its graphite-based counterpart in a commercial 18650 cylindrical cell and 84.6% capacity retention after 500 cycles even at a fast-charging rate of 3 C. This study indicates that the partial, intermediate SOC operation of the μ-Si anode can markedly increase the energy density and boost the fast-charging capability of a LIB cell, a challenging task in traditional cell engineering.}, archive = {J_PNAS}, author = {Lee, Taeyong and Seong, Min Ji and Ahn, Hyo Chul and Baek, Minsung and Park, Kiho and Oh, Jihoon and Choi, Taehoon and Choi, Jang Wook}, doi = {10.1073/pnas.2417053121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2417053121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Fast-chargeable lithium-ion batteries by μ-si anode-tailored full-cell design}, volume = {122}, year = {2025}, }
• (2025). Dissecting the cellular architecture and genetic circuitry of the soybean seed. PNAS, 122(1), e2416987121. (www)

  @article{ , abstract = {Seeds are complex structures composed of three regions, embryo, endosperm, and seed coat, with each further divided into subregions that consist of tissues, cell layers, and cell types. Although the seed is well characterized anatomically, much less is known about the genetic circuitry that dictates its spatial complexity. To address this issue, we profiled mRNAs from anatomically distinct seed subregions at several developmental stages. Analyses of these profiles showed that all subregions express similar diverse gene numbers and that the small gene numbers expressed subregion specifically provide information about the biological processes that occur in these seed compartments. In parallel, we profiled RNAs in individual nuclei and identified nuclei clusters representing distinct cell identities. Integrating single-nucleus RNA and subregion mRNA transcriptomes allowed most cell identities to be assigned to specific subregions and cell types and/or cell states. The number of cell identities exceeds the number of anatomically distinguishable cell types, emphasizing the spatial complexity of seeds. We defined gene coexpression networks that underlie distinct biological processes during seed development. We showed that network distribution among subregions and cell identities is highly variable. Some networks operate in single subregions and/or cell identities, and many coexpression networks operate in multiple subregions and/or cell identities. We also showed that single subregions and cell identities possess several networks. Together, our studies provide unique insights into the biological processes and genetic circuitry that underlie the spatial landscape of the seed.}, archive = {J_PNAS}, author = {Pelletier, Julie M. and Chen, Min and Lin, Jer-Young and Le, Brandon and Kirkbride, Ryan C. and Hur, Jungim and Wang, Tina and Chang, Shu-Heng and Olson, Alexander and Nikolov, Lachezar and Goldberg, Robert B. and Harada, John J.}, doi = {10.1073/pnas.2416987121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2416987121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dissecting the cellular architecture and genetic circuitry of the soybean seed}, volume = {122}, year = {2025}, }
• (2025). Personality differences between birth order categories and across sibship sizes. PNAS, 122(1), e2416709121. (www)

  @article{ , abstract = {We examined associations of self-reports on the HEXACO Personality Inventory—Revised (HEXACO-PI-R) with birth order category and sibship size, controlling for participant sex and age. In a first sample ( N > 700,000 online adults, mainly from English-speaking countries), Honesty-Humility and Agreeableness both showed the highest means for middle-borns, followed in order by last-borns (youngests), firstborns (oldests), and only children, with differences between middles and onlys of d ≥ 0.20. The same result was replicated in a similar but smaller second sample ( N > 70,000) in which sibship size was also assessed, thereby allowing birth order differences to be separated from sibship size differences. In that sample, Honesty-Humility and Agreeableness showed higher means with larger sibship sizes, with differences between sibship sizes of 1 and 6+ of d = 0.30 and d = 0.36, respectively. Controls for upbringing religiousness and current religiousness reduced these differences by about 25%. Within sibship sizes, birth order differences in these dimensions were considerably smaller but oldests remained up to d = 0.10 lower than middles and youngests. Openness was d ≈ 0.10 higher for onlys than for non-onlys collectively, and within sibship sizes, Openness was d ≈ 0.10 higher for oldests than for middles and youngests.}, archive = {J_PNAS}, author = {Ashton, Michael C. and Lee, Kibeom}, doi = {10.1073/pnas.2416709121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2416709121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Personality differences between birth order categories and across sibship sizes}, volume = {122}, year = {2025}, }
• (2025). The 1831 CE mystery eruption identified as zavaritskii caldera, simushir island (Kurils). PNAS, 122(1), e2416699122. (www)

  @article{ , abstract = {Polar ice cores and historical records evidence a large-magnitude volcanic eruption in 1831 CE. This event was estimated to have injected ~13 Tg of sulfur (S) into the stratosphere which produced various atmospheric optical phenomena and led to Northern Hemisphere climate cooling of ~1 °C. The source of this volcanic event remains enigmatic, though one hypothesis has linked it to a modest phreatomagmatic eruption of Ferdinandea in the Strait of Sicily, which may have emitted additional S through magma–crust interactions with evaporite rocks. Here, we undertake a high-resolution multiproxy geochemical analysis of ice-core archives spanning the 1831 CE volcanic event. S isotopes confirm a major Northern Hemisphere stratospheric eruption but, importantly, rule out significant contributions from external evaporite S. In multiple ice cores, we identify cryptotephra layers of low K andesite-dacite glass shards occurring in summer 1831 CE and immediately prior to the stratospheric S fallout. This tephra matches the chemistry of the youngest Plinian eruption of Zavaritskii, a remote nested caldera on Simushir Island (Kurils). Radiocarbon ages confirm a recent (<300 y) eruption of Zavaritskii, and erupted volume estimates are consistent with a magnitude 5 to 6 event. The reconstructed radiative forcing of Zavaritskii (−2 ± 1 W m −2 ) is comparable to the 1991 CE Pinatubo eruption and can readily account for the climate cooling in 1831–1833 CE. These data provide compelling evidence that Zavaritskii was the source of the 1831 CE mystery eruption and solve a confounding case of multiple closely spaced observed and unobserved volcanic eruptions.}, archive = {J_PNAS}, author = {Hutchison, William and Sugden, Patrick and Burke, Andrea and Abbott, Peter and Ponomareva, Vera V. and Dirksen, Oleg and Portnyagin, Maxim V. and MacInnes, Breanyn and Bourgeois, Joanne and Fitzhugh, Ben and Verkerk, Magali and Aubry, Thomas J. and Engwell, Samantha L. and Svensson, Anders and Chellman, Nathan J. and McConnell, Joseph R. and Davies, Siwan and Sigl, Michael and Plunkett, Gill}, doi = {10.1073/pnas.2416699122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2416699122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The 1831 CE mystery eruption identified as zavaritskii caldera, simushir island (Kurils)}, volume = {122}, year = {2025}, }
• (2025). Deep conservation complemented by novelty and innovation in the insect eye ground plan. PNAS, 122(1), e2416562122. (www)

  @article{ , abstract = {A spectacular diversity of forms and features allow species to thrive in different environments, yet some structures remain relatively unchanged. Insect compound eyes are easily recognizable despite dramatic differences in visual abilities across species. It is unknown whether distant insect species use similar or different mechanisms to pattern their eyes or what types of genetic changes produce diversity of form and function. We find that flies, mosquitos, butterflies, moths, beetles, wasps, honeybees, and crickets use homologous developmental programs to pattern their retinas. Transcription factor expression can be used to establish homology of different photoreceptor (PR) types across the insects: Prospero (Pros) for R7, Spalt (Sal) for R7+R8, and Defective proventriculus (Dve) for R1-6. Using gene knockout (CRISPR/Cas9) in houseflies, butterflies, and crickets and gene knockdown (RNAi) in beetles, we found that like Drosophila , EGFR and Sevenless (Sev) signaling pathways are required to recruit motion and color vision PRs, though Drosophila have a decreased reliance on Sev signaling relative to other insects. Despite morphological and physiological variation across species, retina development passes through a highly conserved phylotypic stage when the unit eyes (ommatidia) are first patterned. This patterning process likely represents an “insect eye ground plan” that is established by an ancient developmental program. We identify three types of developmental patterning modifications (ground plan modification, nonstochastic patterns, and specialized regions) that allow for the diversification of insect eyes. We suggest that developmental divergence after the ground plan is established is responsible for the exceptional diversity observed across insect visual systems.}, archive = {J_PNAS}, author = {Gao, Ke and Donati, Antoine and Ainsworth, Julia and Wu, Di and Terner, Eleanor R. and Perry, Michael W.}, doi = {10.1073/pnas.2416562122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2416562122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deep conservation complemented by novelty and innovation in the insect eye ground plan}, volume = {122}, year = {2025}, }
• (2025). Family relations of moche elite burials on the north coast of peru (~500 CE): Analyses of the señora de cao and relatives. PNAS, 122(1), e2416321121. (www)

  @article{ , abstract = {The Moche archaeological culture flourished along Peru’s North Coast between the 4th and 10th centuries CE and was characterized by a complex social hierarchy dominated by political and religious elites. Previous archaeological evidence suggests kinship was a key factor in maintaining political authority within Moche society. To test this hypothesis, we applied archaeological, genetic, and isotopic methods to examine familial relationships between six individuals, including the prominent Señora de Cao ( ~500 CE ), buried together in a pyramid-like, painted temple, Huaca Cao Viejo, in the Chicama Valley, Peru. Our findings reveal that all six individuals were biologically related, with varying degrees of kinship. The Señora de Cao was interred with a sacrificed juvenile, identified as a possible niece, and at least one, and potentially two siblings and a grandparent in separate tombs nearby. One of the male siblings was accompanied in death by his sacrificed son. Isotopic analysis indicates that while most individuals had diets rich in maize and animal protein and spent their childhoods in or near the Chicama Valley, the sacrificed juvenile accompanying the Señora had a distinct diet and geographic origin. These results demonstrate that Moche elites were interred with family members, including some raised far from their parental homes. This supports the hypothesis that kinship was central to transmitting status and authority. Moreover, sacrificing family members to accompany deceased elites underscores the significance of ritual sacrifice in reinforcing familial ties and linking the deceased to both ancestors and the divine.}, archive = {J_PNAS}, author = {Quilter, Jeffrey and Harkins, Kelly and Fanco Jordan, Régulo and Marsh, Erik and Prieto, Gabriel and Verano, John and LeBlanc, Steven and Broomandkhoshbacht, Nasreen and Krigbaum, John and Fehren-Schmitz, Lars}, doi = {10.1073/pnas.2416321121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2416321121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Family relations of moche elite burials on the north coast of peru (~500 CE): Analyses of the señora de cao and relatives}, volume = {122}, year = {2025}, }
• (2025). PhiSiCal-checkup: A bayesian framework to validate amino acid conformations within experimental protein structures. PNAS, 122(1), e2416301121. (www)

  @article{ , abstract = {As structural biology and drug discovery depend on high-quality protein structures, assessment tools are essential. We describe a new method for validating amino-acid conformations: “PhiSiCal ( ϕ ψ χ al) Checkup.” Twenty new joint probability distributions in the form of statistical mixture models explain the empirical distributions of dihedral angles ω , ϕ , ψ , χ 1 , χ 2 , … of canonical amino acids in experimental protein structures. Marginal and conditional probability distributions for subsets of dihedral angles are derived from these joint mixture models. Together, these distributions are employed to measure rapidly the information-theoretic “favorability” of any proposed experimental protein structure. The inferred statistical models and measures overcome several shortcomings and afford improvements over the current state of the art in amino-acid conformation verification. Experimental comparisons are made against current protein conformation verification software. In a number of examples, we pick up outliers that are invisible to current methods. We also calculate, as part of verification, the sensitivity of favorability to small changes in a proposed structure accounting for the precision of coordinates. In some cases a near neighbor of a proposed amino-acid conformation may be either less or more favorable. This raises the question, is the current reliance on fixed “thresholds” for validation a good thing? PhiSiCal-Checkup is freely available for online and offline (open-source) use from https://lcb.infotech.monash.edu.au/phisical/checkup .}, archive = {J_PNAS}, author = {Amarasinghe, Piyumi R. and Allison, Lloyd and Morton, Craig J. and Stuckey, Peter J. and Garcia de la Banda, Maria and Lesk, Arthur M. and Konagurthu, Arun S.}, doi = {10.1073/pnas.2416301121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2416301121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PhiSiCal-checkup: A bayesian framework to validate amino acid conformations within experimental protein structures}, volume = {122}, year = {2025}, }
• (2025). Elucidation of a distinct photoreduction pathway in class II arabidopsis thaliana photolyase. PNAS, 122(1), e2416284121. (www)

  @article{ , abstract = {Class II photolyases (PLs) are a distant subclade in the photolyase/cryptochrome superfamily, displaying a unique Trp–Tyr tetrad for photoreduction and exhibiting a lower quantum yield (QY) of DNA repair (49%) than class I photolyases (82%) [M. Zhang, L. Wang, S. Shu, A. Sancar, D. Zhong, Science 354 , 209–213 (2016)]. Using layer-by-layer mutant design and femtosecond spectroscopy, we have successfully determined the rates of electron transfer and proton transfer, driving force, and reorganization energy for nine elementary steps involved in the initial photoreduction of class II Arabidopsis thaliana photolyase (AtPL), thereby constructing the photoreduction network specific to class II PLs. Several dynamic features have been revealed including a slow-rise (172 ps) and fast-decay (26 ps) kinetics between the excited lumiflavin and adenine groups within the flavin adenine dinucleotide cofactor, a slower electron transfer (ET) (22 ps) between the excited lumiflavin and the nearest Trp in the Trp triad (W a ) as compared to reported class I PL (0.8 ps), and a rapid deprotonation of the distal Trp in the Trp triad (W c ). Most strikingly, we captured a slightly energetically unfavorable ET step between W a and the center Trp (W b ), as opposed to the decreasing reduction potential observed in class I PL that drives the electron flow unidirectionally. Such an energetically uphill ET step leads to a lower photoreduction quantum yield (~34%) in class II AtPL compared to that of class I PL (~45%), raising an important question on the evolutionary implications of various photoreduction networks in photolyases and cryptochromes.}, archive = {J_PNAS}, author = {Zhou, Zhongneng and Chen, Zijing and Kang, Xiu-Wen and Ding, Bei and Zou, Shuhua and Tang, Siwei and Zhou, Yalin and Wang, Bingyao and Zhong, Dongping}, doi = {10.1073/pnas.2416284121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2416284121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Elucidation of a distinct photoreduction pathway in class II arabidopsis thaliana photolyase}, volume = {122}, year = {2025}, }
• (2025). Genesis and regulation of C-terminal cyclic imides from protein damage. PNAS, 122(1), e2415976121. (www)

  @article{ , abstract = {C-Terminal cyclic imides are posttranslational modifications that can arise from spontaneous intramolecular cleavage of asparagine or glutamine residues resulting in a form of irreversible protein damage. These protein damage events are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN), indicating that these aging-related modifications may require cellular quality control mechanisms to prevent deleterious effects. However, the factors that determine protein or peptide susceptibility to C-terminal cyclic imide formation or their effect on protein stability have not been explored in detail. Here, we characterize the primary and secondary structures of peptides and proteins that promote intrinsic formation of C-terminal cyclic imides in comparison to deamidation, a related form of protein damage. Extrinsic effects from solution properties and stressors on the cellular proteome additionally promote C-terminal cyclic imide formation on proteins like glutathione synthetase that are susceptible to aggregation if the protein damage products are not removed by CRBN. This systematic investigation provides insight into the regions of the proteome that are prone to these unexpectedly frequent modifications, the effects of this form of protein damage on protein stability, and the biological role of CRBN.}, archive = {J_PNAS}, author = {Xu, Wenqing and Zhao, Zhenguang and Su, Matthew and Jain, Atul D. and Lloyd, Hannah C. and Feng, Ethan Yang and Cox, Nick and Woo, Christina M.}, doi = {10.1073/pnas.2415976121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2415976121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Genesis and regulation of C-terminal cyclic imides from protein damage}, volume = {122}, year = {2025}, }
• (2025). Stochastic morphological swings in hydra regeneration: A manifestation of noisy canalized morphogenesis. PNAS, 122(1), e2415736121. (www)

  @article{ , abstract = {Animal morphogenesis, the development of an organism’s body form, is commonly perceived as a directed and almost deterministic process. However, noise and stochastic fluctuations are ubiquitous in biological systems. The questions on the role of fluctuations in morphogenesis and what ensures the robustness of this process under noisy conditions remain elusive. Here, we utilize Hydra regeneration, subjected to an external electric field, to provide unique insights into these questions. We found that during Hydra morphogenesis, a phase can be induced where fluctuations lead to stochastic morphological swings, back and forth, between a nearly spherical structure (the incipient tissue’s state) and an elongated cylindrical shape (the final body form of a mature Hydra ). Despite these prolonged swings, the tissue regenerates into a normal Hydra . The stochastic transitions between two well-defined shapes imply that morphological development occurs through an activation process. Indeed, by introducing a periodic perturbation through modulation of the electric field, we were able to demonstrate morphogenesis dynamics with characteristics of stochastic resonance —the tissue’s response to the perturbation displayed a resonance-like behavior as a function of the noise level. Our findings add a dynamic layer to the problem of morphogenesis and offer an unconventional physical framework based on an activation transition in a slowly varying double-well potential that ensures a canalized regeneration of the body form under fluctuations.}, archive = {J_PNAS}, author = {Agam, Oded and Braun, Erez}, doi = {10.1073/pnas.2415736121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2415736121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Stochastic morphological swings in hydra regeneration: A manifestation of noisy canalized morphogenesis}, volume = {122}, year = {2025}, }
• (2025). Metabolic enhancement contributed by horizontal gene transfer is essential for dietary specialization in leaf beetles. PNAS, 122(1), e2415717122. (www)

  @article{ , abstract = {Horizontal gene transfer (HGT) from bacteria to insects is widely reported and often associated with the adaptation and diversification of insects. However, compelling evidence demonstrating how HGT-conferred metabolic adjustments enable species to adapt to surrounding environment remains scarce. Dietary specialization is an important ecological strategy adopted by animals to reduce inter- and intraspecific competition for limited resources. Adults of the leaf beetle Plagiodera versicolora (Coleoptera) preferentially consume new leaves; nevertheless, we found that they selectively oviposit on mature leaves, thereby establishing a distinct dietary niche separation between adults and larvae. Based on the de novo assembled chromosome-level genome, we identified two horizontally transferred genes with cellulose degradation potential, belonging to the glycosyl hydrolase 48 family ( GH48-1 and GH48-2 ). Prokaryotic expression of the HGTs confirmed the cellulose degradation capability of the two genes. Knockdown of GH48 significantly hampered the growth and survival rate of larvae feeding on mature leaves compared to wild-type larvae, with no similar effect observed in adults. Replenishing the GH48-expressing bacteria compensated for the knockdown of these two genes and recurred larval adaptability to mature leaves. Taken together, our results highlight the advantage and metabolic enhancement conferred by the two cellulose-degrading HGTs in P. versicolora larvae, enabling their development on cellulose-enriched mature leaves and underscoring the indispensable role of HGTs in facilitating the adaptation of leaf beetles to plants.}, archive = {J_PNAS}, author = {Zhang, Yuxin and Tu, Chengjie and Bai, Jianyang and Li, Xiayu and Sun, Ziyue and Xu, Letian}, doi = {10.1073/pnas.2415717122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2415717122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Metabolic enhancement contributed by horizontal gene transfer is essential for dietary specialization in leaf beetles}, volume = {122}, year = {2025}, }
• (2025). Structural insight into sodium ion pathway in the bacterial flagellar stator from marine vibrio. PNAS, 122(1), e2415713122. (www)

  @article{ , abstract = {Many bacteria swim in liquid or swarm on surface using the flagellum rotated by a motor driven by specific ion flow. The motor consists of the rotor and stator, and the stator converts the energy of ion flow to mechanical rotation. However, the ion pathway and the mechanism of stator rotation coupled with specific ion flow are still obscure. Here, we determined the structures of the sodium-driven stator of Vibrio , namely PomAB, in the presence and absence of sodium ions and the structure with its specific inhibitor, phenamil, by cryo-electron microscopy. The structures and following functional analysis revealed the sodium ion pathway, the mechanism of ion selectivity, and the inhibition mechanism by phenamil. We propose a model of sodium ion flow coupled with the stator rotation based on the structures. This work provides insights into the molecular mechanisms of ion specificity and conversion of the electrochemical potential into mechanical functions.}, archive = {J_PNAS}, author = {Nishikino, Tatsuro and Takekawa, Norihiro and Kishikawa, Jun-ichi and Hirose, Mika and Kojima, Seiji and Homma, Michio and Kato, Takayuki and Imada, Katsumi}, doi = {10.1073/pnas.2415713122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2415713122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural insight into sodium ion pathway in the bacterial flagellar stator from marine vibrio}, volume = {122}, year = {2025}, }
• (2025). RNAi of the elastomeric protein resilin reduces jump velocity and resilience to damage in locusts. PNAS, 122(1), e2415625121. (www)

  @article{ , abstract = {Resilin, an elastomeric protein with remarkable physical properties that outperforms synthetic rubbers, is a near-ubiquitous feature of the power amplification mechanisms used by jumping insects. Catapult-like mechanisms, which incorporate elastic energy stores formed from a composite of stiff cuticle and resilin, are frequently used by insects to translate slow muscle contractions into rapid-release recoil movements. The precise role of resilin in these jumping mechanisms remains unclear, however. We used RNAi to reduce resilin deposition in the principal energy-storing springs of the desert locust ( Schistocerca gregaria ) before measuring jumping performance. Knockdown reduced the amount of resilin-associated fluorescence in the semilunar processes (SLPs) by 44% and reduced the cross-sectional area of the tendons of the hind leg extensor-tibiae muscle by 31%. This affected jumping in three ways: First, take-off velocity was reduced by 15% in knockdown animals, which could be explained by a change in the extrinsic stiffness of the extensor-tibiae tendon caused by the decrease in its cross-sectional area. Second, knockdown resulted in permanent breakages in the hind legs of 29% of knockdown locusts as tested by electrical stimulation of the extensor muscle, but none in controls. Third, knockdown locusts exhibited a greater decline in distance jumped when made to jump in rapid succession than did controls. We conclude that stiff cuticle acts as the principal elastic energy store for insect jumping, while resilin protects these more brittle structures against breakage from repeated use.}, archive = {J_PNAS}, author = {Rogers, Stephen M. and Cullen, Darron A. and Labonte, David and Sutton, Gregory P. and Vanden Broeck, Jozef J. M. and Burrows, Malcolm}, doi = {10.1073/pnas.2415625121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2415625121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RNAi of the elastomeric protein resilin reduces jump velocity and resilience to damage in locusts}, volume = {122}, year = {2025}, }
• (2025). Time evolution of a pumped molecular magnet—A time-resolved inelastic neutron scattering study. PNAS, 122(1), e2415300121. (www)

  @article{ , abstract = {Introducing an experimental technique of time-resolved inelastic neutron scattering (TRINS), we explore the time-dependent effects of resonant pulsed microwaves on the molecular magnet Cr 8 F 8 Piv 16 . The octagonal rings of magnetic Cr 3+ atoms with antiferromagnetic interactions form a singlet ground state with a weakly split triplet of excitations at 0.8 meV. A 4.6 tesla field was applied to tune the splitting between two members of the triplet excited level | 1 ⟩ ↔ | 2 ⟩ to resonance with 105 GHz (0.434 meV) microwaves. The time-dependent occupations of the ground state | 0 ⟩ , lower lying levels | 1 ⟩ and | 2 ⟩ , and higher energy states | λ ≥ 3 ⟩ were extracted during and after 20 s long microwave pulses incident along the (101) direction of a Cr 8 F 8 Piv 16 crystal held at 1.9 K. At significantly elevated spin temperatures, we found underpopulation relative to thermal equilibrium of | 2 ⟩ and spin-lattice thermalization time scales ranging from 1.6(2) s to 5.7(2) s depending on the power level. This contrasts with the relaxation time τ 1 ( T → 0 ) = 27 ( 5 ) μ s inferred for | 2 ⟩ from in situ Electron Spin Resonance measurements. By probing a broad range of excited states during intense microwave pumping, TRINS thus provides a first view of long lived excited states in a molecular antiferromagnet.}, archive = {J_PNAS}, author = {Reeder, T. R. and Titum, Paraj and Kindervater, J. and Stewart, V. J. and Ye, Q. and Rodriguez-Rivera, J. A. and Qiu, Y. and Maliszewskyj, N. and McQueen, T. M. and Broholm, C. L.}, doi = {10.1073/pnas.2415300121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2415300121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Time evolution of a pumped molecular magnet—A time-resolved inelastic neutron scattering study}, volume = {122}, year = {2025}, }
• (2025). Persistent humid climate favored the qin and western han dynasties in china around 2,200 y ago. PNAS, 122(1), e2415294121. (www)

  @article{ , abstract = {The Qin and Western Han dynasties (221 BCE to 24 CE) represent an era of societal prosperity in China. However, due to a lack of high-resolution paleoclimate records it is still unclear whether the agricultural boost documented for this period was associated with more favorable climatic conditions. Here, multiparameter analysis of annually resolved tree-ring records and process-based physiological modeling provide evidence of stable and consistently humid climatic conditions during 270 to 77 BCE in northern China. Precipitation in the Asian summer monsoon region during the Qin–Western Han Dynasties was ~18 to 34% higher compared to present-day conditions. In shifting agricultural and pastoral boundaries ~60 to 100 km northwestward, possibility up to 200 km at times, persistently wetter conditions arguably increased food production, contributing to the socioeconomic prosperity around 2,200 y ago. A gradual wetting trend in the western part of arid northwestern China since the 1980s resembles the historical climate analogue, suggesting that similar benefits for regional environmental and agricultural systems may reoccur under current climate change, at least in the near term.}, archive = {J_PNAS}, author = {Qin, Chun and Yang, Bao and Bräuning, Achim and Charpentier Ljungqvist, Fredrik and Osborn, Timothy J. and Shishov, Vladimir and He, Minhui and Kang, Shuyuan and Schneider, Lea and Esper, Jan and Büntgen, Ulf and Grießinger, Jussi and Huang, Danqing and Zhang, Peng and Talento, Stefanie and Xoplaki, Elena and Luterbacher, Jürg and Stenseth, Nils Chr.}, doi = {10.1073/pnas.2415294121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2415294121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Persistent humid climate favored the qin and western han dynasties in china around 2,200 y ago}, volume = {122}, year = {2025}, }
• (2025). Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: Implications for prion diseases. PNAS, 122(1), e2415250121. (www)

  @article{ , abstract = {Protein misfolding and aggregation are a hallmark of various neurodegenerative disorders. However, the underlying mechanisms driving protein misfolding in the cellular context are incompletely understood. Here, we show that the two-dimensional confinement imposed by a membrane anchor stabilizes the native protein conformation and suppresses liquid–liquid phase separation (LLPS) and protein aggregation. Inherited prion diseases in humans and neurodegeneration in transgenic mice are linked to the expression of anchorless prion protein (PrP), suggesting that the C-terminal glycosylphosphatidylinositol (GPI) anchor of native PrP impedes spontaneous formation of neurotoxic and infectious PrP species. Combining unique in vitro and in vivo approaches, we demonstrate that anchoring to membranes prevents LLPS and spontaneous aggregation of PrP. Upon release from the membrane, PrP undergoes a conformational transition to detergent-insoluble aggregates. Our study demonstrates an essential role of the GPI anchor in preventing spontaneous misfolding of PrP C and provides a mechanistic basis for inherited prion diseases associated with anchorless PrP.}, archive = {J_PNAS}, author = {Gogte, Kalpshree and Mamashli, Fatemeh and Herrera, Maria Georgina and Kriegler, Simon and Bader, Verian and Kamps, Janine and Grover, Prerna and Winter, Roland and Winklhofer, Konstanze F. and Tatzelt, Jörg}, doi = {10.1073/pnas.2415250121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2415250121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: Implications for prion diseases}, volume = {122}, year = {2025}, }
• (2025). Retinal ganglion cells encode the direction of motion outside their classical receptive field. PNAS, 122(1), e2415223122. (www)

  @article{ , abstract = {Retinal ganglion cells (RGCs) typically respond to light stimulation over their spatially restricted receptive field. Using large-scale recordings in the mouse retina, we show that a subset of non- direction-selective (DS) RGCs exhibit asymmetric activity, selective to motion direction, in response to a stimulus crossing an area far beyond the classic receptive field. The extraclassical response arises via inputs from an asymmetric distal zone and is enhanced by desensitization mechanisms and an inherent DS component, creating a network of neurons responding to motion toward the optic disc. Pharmacological manipulations revealed the necessity of glycinergic amacrine cells for this response. Using in vivo recordings, we identified similar extraclassical responses in lateral geniculate nucleus neurons, suggesting such non conventional DS information is transferred to downstream structures. Our results suggest a complex integration of motion direction processing across the visual field, which arises beyond the classical receptive field boundaries.}, archive = {J_PNAS}, author = {Riccitelli, Serena and Yaakov, Hadar and Heukamp, Alina S. and Ankri, Lea and Rivlin-Etzion, Michal}, doi = {10.1073/pnas.2415223122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2415223122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Retinal ganglion cells encode the direction of motion outside their classical receptive field}, volume = {122}, year = {2025}, }
• (2025). Dual-action kinase inhibitors influence p38α MAP kinase dephosphorylation. PNAS, 122(1), e2415150122. (www)

  @article{ , abstract = {Reversible protein phosphorylation directs essential cellular processes including cell division, cell growth, cell death, inflammation, and differentiation. Because protein phosphorylation drives diverse diseases, kinases and phosphatases have been targets for drug discovery, with some achieving remarkable clinical success. Most protein kinases are activated by phosphorylation of their activation loops, which shifts the conformational equilibrium of the kinase toward the active state. To turn off the kinase, protein phosphatases dephosphorylate these sites, but how the conformation of the dynamic activation loop contributes to dephosphorylation was not known. To answer this, we modulated the activation loop conformational equilibrium of human p38α ΜΑP kinase with existing kinase inhibitors that bind and stabilize specific inactive activation loop conformations. From this, we identified three inhibitors that increase the rate of dephosphorylation of the activation loop phospho-threonine by the PPM serine/threonine phosphatase WIP1. Hence, these compounds are “dual-action” inhibitors that simultaneously block the active site and promote p38α dephosphorylation. Our X-ray crystal structures of phosphorylated p38α bound to the dual-action inhibitors reveal a shared flipped conformation of the activation loop with a fully accessible phospho-threonine. In contrast, our X-ray crystal structure of phosphorylated apo human p38α reveals a different activation loop conformation with an inaccessible phospho-threonine, thereby explaining the increased rate of dephosphorylation upon inhibitor binding. These findings reveal a conformational preference of phosphatases for their targets and suggest a unique approach to achieving improved potency and specificity for therapeutic kinase inhibitors.}, archive = {J_PNAS}, author = {Stadnicki, Emily J. and Ludewig, Hannes and Kumar, Ramasamy P. and Wang, Xicong and Qiao, Youwei and Kern, Dorothee and Bradshaw, Niels}, doi = {10.1073/pnas.2415150122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2415150122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dual-action kinase inhibitors influence p38α MAP kinase dephosphorylation}, volume = {122}, year = {2025}, }
• (2025). Human brain dynamics are shaped by rare long-range connections over and above cortical geometry. PNAS, 122(1), e2415102122. (www)

  @article{ , abstract = {A fundamental topological principle is that the container always shapes the content. In neuroscience, this translates into how the brain anatomy shapes brain dynamics. From neuroanatomy, the topology of the mammalian brain can be approximated by local connectivity, accurately described by an exponential distance rule (EDR). The compact, folded geometry of the cortex is shaped by this local connectivity, and the geometric harmonic modes can reconstruct much of the functional dynamics. However, this ignores the fundamental role of the rare long-range (LR) cortical connections, crucial for improving information processing in the mammalian brain, but not captured by local cortical folding and geometry. Here, we show the superiority of harmonic modes combining rare LR connectivity with EDR (EDR+LR) in capturing functional dynamics (specifically LR functional connectivity and task-evoked brain activity) compared to geometry and EDR representations. Importantly, the orchestration of dynamics is carried out by a more efficient manifold made up of a low number of fundamental EDR+LR modes. Our results show the importance of rare LR connectivity for capturing the complexity of functional brain activity through a low-dimensional manifold shaped by fundamental EDR+LR modes.}, archive = {J_PNAS}, author = {Vohryzek, Jakub and Sanz-Perl, Yonatan and Kringelbach, Morten L. and Deco, Gustavo}, doi = {10.1073/pnas.2415102122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2415102122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Human brain dynamics are shaped by rare long-range connections over and above cortical geometry}, volume = {122}, year = {2025}, }
• (2025). TRAMP assembly alters the conformation and RNA binding of mtr4 and trf4-air2. PNAS, 122(1), e2414980121. (www)

  @article{ , abstract = {The TRAMP complex contains two enzymatic activities essential for RNA processing upstream of the nuclear exosome. Within TRAMP, RNA is 3′ polyadenylated by a subcomplex of Trf4/5 and Air1/2 and unwound 3′ to 5′ by Mtr4, a DExH helicase. The molecular mechanisms of TRAMP assembly and RNA shuffling between the two TRAMP catalytic sites are poorly understood. Here, we report solution hydrogen–deuterium exchange data with thermodynamic and functional assays to uncover these mechanisms for yeast TRAMP with Trf4 and Air2 homologs. We show that TRAMP assembly constrains RNA-recognition motifs that are peripheral to catalytic sites. These include the Mtr4 Arch and Air2 zinc knuckles 1, 2, and 3. While the Air2 Arch-interacting motif likely constrains the Mtr4 Arch via transient interactions, these do not fully account for the importance of the Mtr4 Arch in TRAMP assembly. We further show that tRNA binding by single active-site subunits, Mtr4 and Trf4-Air2, differs from the double active-site TRAMP. TRAMP has reduced tRNA binding on the Mtr4 Fist and RecA2 domains, offset by increased tRNA binding on Air2 zinc knuckles 2 and 3. Competition between these RNA-binding sites may drive tRNA transfer between TRAMP subunits. We identify dynamic changes upon TRAMP assembly and RNA-recognition motifs that transfer RNA between TRAMP catalytic sites.}, archive = {J_PNAS}, author = {Denson, Joshua M. and Zhang, Naifu and Ball, Darby and Thompson, Kayla and Johnson, Sean J. and D’Arcy, Sheena}, doi = {10.1073/pnas.2414980121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2414980121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {TRAMP assembly alters the conformation and RNA binding of mtr4 and trf4-air2}, volume = {122}, year = {2025}, }
• (2025). The unequal adoption of ChatGPT exacerbates existing inequalities among workers. PNAS, 122(1), e2414972121. (www)

  @article{ , abstract = {We study the adoption of ChatGPT, the icon of Generative AI, using a large-scale survey linked to comprehensive register data in Denmark. Surveying 18,000 workers from 11 exposed occupations, we document that ChatGPT is widespread, especially among younger and less-experienced workers. However, substantial inequalities have emerged. Women are 16 percentage points less likely to have used the tool for work. Furthermore, despite its potential to lift workers with less expertise, users of ChatGPT earned slightly more already before its arrival, even given their lower tenure. Workers see a substantial productivity potential in ChatGPT but are often hindered by employer restrictions and a perceived need for training.}, archive = {J_PNAS}, author = {Humlum, Anders and Vestergaard, Emilie}, doi = {10.1073/pnas.2414972121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2414972121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The unequal adoption of ChatGPT exacerbates existing inequalities among workers}, volume = {122}, year = {2025}, }
• (2025). MYO7A is required for the functional integrity of the mechanoelectrical transduction complex in hair cells of the adult cochlea. PNAS, 122(1), e2414707122. (www)

  @article{ , abstract = {Myosin-VIIA (MYO7A) is an unconventional myosin responsible for syndromic (Usher 1B) or nonsyndromic forms of deafness in humans when mutated. In the cochlea, MYO7A is expressed in hair cells, where it is believed to act as the motor protein tensioning the mechanoelectrical transducer (MET) channels, thus setting their resting open probability ( P o ). However, direct evidence for this unique role for an unconventional myosin in mature hair cells is lacking. Here, we show that MYO7A has a distinct role in hair cells, being crucial for the structural integrity of hair bundles. Postnatal deletion of Myo7a leads to 87 to 96% reduction in MYO7A from hair cells by postnatal day 20 (P20), without affecting hearing function. During the following week, mice showed progressive decline in both hearing function and MET current amplitude in hair cells without affecting the resting P o and calcium sensitivity of the MET channel. Hair-bundle stiffness was normal at P20 but halved at P30, despite it having a normal staircase morphology and tip links. The reduction of MYO7A in the stereocilia (>87%) increased their vulnerability to sound-induced damage, with significantly more hearing loss and hair bundle deterioration than in control mice. RNA-sequencing identified a downregulation of several stereociliary genes in the Myo7a -deficient cochlea, indicating the presence of indirect compensatory mechanisms. This study reveals that mature hair cells seem to use a MYO7A-independent mechanism to maintain the resting P o of the MET channels. Instead, MYO7A is essential for maintaining the structural and functional integrity of the hair bundles.}, archive = {J_PNAS}, author = {Underhill, Anna and Webb, Samuel and Grandi, Fiorella C. and Jeng, Jing-Yi and de Monvel, Jacques B. and Plion, Baptiste and Carlton, Adam J. and Amariutei, Ana E. and Voulgari, Niovi and De Faveri, Francesca and Ceriani, Federico and Mustapha, Mirna and Johnson, Stuart L. and Safieddine, Saaid and Kros, Corné J. and Marcotti, Walter}, doi = {10.1073/pnas.2414707122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2414707122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {MYO7A is required for the functional integrity of the mechanoelectrical transduction complex in hair cells of the adult cochlea}, volume = {122}, year = {2025}, }
• (2025). The return of stagnant slab recorded by intraplate volcanism. PNAS, 122(1), e2414632122. (www)

  @article{ , abstract = {Subducted plates often stagnate in the mantle transition zone (MTZ), and the fate of the stagnant slabs is still debatable. They may sink into the lower mantle, or remain partially trapped in the MTZ, but it is uncertain whether they can return to the upper mantle. We report geochemical evidence of late-Miocene (~6 Ma) basalts from, and upper mantle seismic evidence beneath Shuangyashan, an area above the slab tear of the stagnant Pacific plate in eastern Asia, to show how the slab returns to the upper mantle from the MTZ. Remarkably high δ 57 Fe, Gd/Yb and low δ 26 Mg, Ti/Eu, CaO/Al 2 O 3 values of Shuangyashan basalts suggest that the subducted Pacific oceanic crust had been entrained to their upper mantle source. Therefore, the return of oceanic crust from the MTZ to the upper mantle appears to have been driven by upwelling triggered by tearing of the stagnant slab right beneath this area. Meanwhile, local shear splitting measurements reveal a circular pattern of anisotropy in the upper mantle with delay times diminishing toward the slab tear, suggesting that the slab-fragment-bearing upwelling subsequently turned into lateral flows in the upper mantle, and contributed to a wider intraplate magmatism above the stagnant slab. This finding, together with other widespread intraplate volcanism from eastern Asia, extending for approximately 6,000 km, demonstrates that a subduction-induced tear can lead to the destruction and partial return of stagnant slab material, and thus lead to the cycling of subducted crustal materials and the generation of subduction-induced intraplate magmatism.}, archive = {J_PNAS}, author = {Zhou, Zhong-Biao and Chen, Li-Hui and Huang, Zhou-Chuan and Hofmann, Albrecht W. and Wang, Xiao-Jun and Zeng, Gang and Bi, Ya-Jing and Zhao, Jian}, doi = {10.1073/pnas.2414632122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2414632122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The return of stagnant slab recorded by intraplate volcanism}, volume = {122}, year = {2025}, }
• (2025). Zoos must embrace animal death for education and conservation. PNAS, 122(1), e2414565121. (www)

  @article{ , archive = {J_PNAS}, author = {Clauss, Marcus and Roller, Marco and Bertelsen, Mads Frost and Rudolf von Rohr, Claudia and Müller, Dennis W. H. and Schiffmann, Christian and Kummrow, Maya and Encke, Dag and Ferreira, Sam and Duvall, Ethan S. and Maré, Celesté and Abraham, Andrew J.}, doi = {10.1073/pnas.2414565121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2414565121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Zoos must embrace animal death for education and conservation}, volume = {122}, year = {2025}, }
• (2025). RAP-2 and CNH-MAP4 kinase MIG-15 confer resistance in bystander epithelium to cell-fate transformation by excess ras or notch activity. PNAS, 122(1), e2414321121. (www)

  @article{ , abstract = {Induction of cell fates by growth factors impacts many facets of developmental biology and disease. LIN-3/EGF induces the equipotent vulval precursor cells (VPCs) in Caenorhabditis elegans to assume the 3˚−3˚−2˚−1˚−2˚−3˚ pattern of cell fates. 1˚ and 2˚ cells become specialized epithelia and undergo stereotyped series of cell divisions to form the vulva. Conversely, 3˚ cells are relatively quiescent and nonspecialized; they divide once and fuse with the surrounding epithelium. 3˚ cells have thus been characterized as passive, uninduced, or ground state. Based on our previous studies, we hypothesized that a 3˚-promoting program would confer resistance to cell fate-transformation by inappropriately activated 1˚ and 2˚ fate-promoting LET-60/Ras and LIN-12/Notch, respectively. Deficient MIG-15/CNH-MAP4 Kinase meets the expectations of genetic interactions for a 3˚-promoting protein. Moreover, endogenous MIG-15 is required for expression of a fluorescent biomarker of 3˚ cell fate, is expressed in VPCs, and functions cell autonomously in VPCs. The Ras family small GTPase RAP-2, orthologs of which activate orthologs of MIG-15 in other systems, emulates these functions of MIG-15. However, gain of RAP-2 function has no effect on patterning, suggesting its activity is constitutive in VPCs. The 3˚ biomarker is expressed independently of the AC, raising questions about the cellular origin of 3˚-promoting activity. Activated LET-60/Ras and LIN-12/Notch repress expression of the 3˚ biomarker, suggesting that the 3˚-promoting program is both antagonized by as well as antagonizes 1˚- and 2˚- promoting programs. This study provides insight into developmental properties of cells historically considered to be nonresponding to growth factor signals.}, archive = {J_PNAS}, author = {Fakieh, Razan A. and Reiner, David J.}, doi = {10.1073/pnas.2414321121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2414321121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {RAP-2 and CNH-MAP4 kinase MIG-15 confer resistance in bystander epithelium to cell-fate transformation by excess ras or notch activity}, volume = {122}, year = {2025}, }
• (2025). Comparing cooperative geometric puzzle solving in ants versus humans. PNAS, 122(1), e2414274121. (www)

  @article{ , abstract = {Biological ensembles use collective intelligence to tackle challenges together, but suboptimal coordination can undermine the effectiveness of group cognition. Testing whether collective cognition exceeds that of the individual is often impractical since different organizational scales tend to face disjoint problems. One exception is the problem of navigating large loads through complex environments and toward a given target. People and ants stand out in their ability to efficiently perform this task not just individually but also as a group. This provides a rare opportunity to empirically compare problem-solving skills and cognitive traits across species and group sizes. Here, we challenge people and ants with the same “piano-movers” load maneuvering puzzle and show that while ants perform more efficiently in larger groups, the opposite is true for humans. We find that although individual ants cannot grasp the global nature of the puzzle, their collective motion translates into emergent cognitive skills. They encode short-term memory in their internally ordered state and this allows for enhanced group performance. People comprehend the puzzle in a way that allows them to explore a reduced search space and, on average, outperform ants. However, when communication is restricted, groups of people resort to the most obvious maneuvers to facilitate consensus. This is reminiscent of ant behavior, and negatively impacts their performance. Our results exemplify how simple minds can easily enjoy scalability while complex brains require extensive communication to cooperate efficiently.}, archive = {J_PNAS}, author = {Dreyer, Tabea and Haluts, Amir and Korman, Amos and Gov, Nir and Fonio, Ehud and Feinerman, Ofer}, doi = {10.1073/pnas.2414274121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2414274121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Comparing cooperative geometric puzzle solving in ants versus humans}, volume = {122}, year = {2025}, }
• (2025). VCP controls KCC2 degradation through FAF1 recruitment and accelerates emergence from anesthesia. PNAS, 122(1), e2414016122. (www)

  @article{ , abstract = {Ubiquitin-proteasomal degradation of K + /Cl − cotransporter 2 (KCC2) in the ventral posteromedial nucleus (VPM) has been demonstrated to serve as a common mechanism by which the brain emerges from anesthesia and regains consciousness. Ubiquitin-proteasomal degradation of KCC2 during anesthesia is driven by E3 ligase Fbxl4. However, the mechanism by which ubiquitinated KCC2 is targeted to the proteasome has not been elucidated. We report in cultured neuro-2a cells that the valosin-containing protein (VCP) transported ubiquitinated KCC2 to the proteasome and in mice in vivo experiments that inhibition of VCP restored KCC2 expression in the VPM and enhanced the effects of anesthesia. In cultured neuro-2a cells, propofol-induced degradation of KCC2 was inhibited by VCP inhibitor DBeQ and VCP knockout plasmid sgRNA(VCP). Propofol-induced enhanced interaction between VCP and KCC2 was inhibited by knockout of Fbxl4 or Fas-associated factor 1 (FAF1). In in vivo studies, pharmacological or genetic inhibition of VCP in the VPM significantly prevented KCC2 degradation and enhanced propofol anesthesia; these effects were abrogated by a KCC2 antagonist VU0463271. These results demonstrate that the VCP controls ubiquitin-proteasomal degradation of KCC2 dependent on FAF1 recruitment and serves as a mechanism for the ubiquitin-proteasomal degradation of KCC2, which is responsible for the subsequent emergence from anesthesia.}, archive = {J_PNAS}, author = {Chen, Peng and Hu, Jiang-Jian and Liu, Yuexin and Cao, Boxu and Song, Xue-Jun}, doi = {10.1073/pnas.2414016122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2414016122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {VCP controls KCC2 degradation through FAF1 recruitment and accelerates emergence from anesthesia}, volume = {122}, year = {2025}, }
• (2025). Confined cell migration along extracellular matrix space in vivo. PNAS, 122(1), e2414009121. (www)

  @article{ , abstract = {Collective migration of cancer cells is often interpreted using concepts derived from the physics of active matter, but the experimental evidence is mostly restricted to observations made in vitro. Here, we study collective invasion of metastatic cancer cells injected into the mouse deep dermis using intravital multiphoton microscopy combined with a skin window technique and three-dimensional quantitative image analysis. We observe a multicellular but low-cohesive migration mode characterized by rotational patterns which self-organize into antiparallel persistent tracks with orientational nematic order. We analyze the deformations induced by the cells in the extracellular matrix and find broadly distributed strain bands with a prevalence of compression. A model of active nematic hydrodynamics is able to describe several statistical features of the experimentally observed flow, suggesting that collective cancer cell invasion can be interpreted as a nematic active fluid in the turbulent regime. Our results help elucidate the migration patterns of cancer cells in vivo and provide quantitative guidance for the development of realistic in vitro and in silico models for collective cell migration.}, archive = {J_PNAS}, author = {Chepizhko, Oleksandr and Armengol-Collado, Josep-Maria and Alexander, Stephanie and Wagena, Esther and Weigelin, Bettina and Giomi, Luca and Friedl, Peter and Zapperi, Stefano and La Porta, Caterina A. M.}, doi = {10.1073/pnas.2414009121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2414009121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Confined cell migration along extracellular matrix space in vivo}, volume = {122}, year = {2025}, }
• (2025). Earliest evidence of sedentism in the antilles: Multiple isotope data from canímar abajo, cuba. PNAS, 122(1), e2413963121. (www)

  @article{ , abstract = {The early populations that inhabited the Antilles were traditionally understood as highly mobile groups of hunters/fishers and gatherers. Although more recent data have demonstrated that some populations engaged in the production of domestic plants and cultivars, questions remain about other aspects of their lifeways, including whether the adoption of domesticates was accompanied by a decrease in residential mobility. The level of sedentism in a population is an instrumental variable to understand community social relations and complexity, adaptations, and lifeways. Here, we combined enamel strontium ( 87 Sr/ 86 Sr), oxygen (δ 18 O en ), and carbon (δ 13 C en ) isotopes of 44 human teeth from the site of Canímar Abajo—where the oldest human remains from the insular Caribbean have been reported—to examine the mobility patterns of early Antillean groups. In contrast with traditional narratives, the homogeneous strontium isotope values observed in most individuals from the older funerary area of the site (cal. BC 2237–790) were consistent with the pattern expected for a sedentary population subsisting primarily on local resources obtained close to the coast. The isotopic evidence reveals that between cal. AD 403–1282, the mound was reused for funerary practices by both local communities and nonlocal individuals. The evidence suggests that this period saw higher population mobility, with influxes of individuals from more distant locations and diverse dietary and burial traditions. The isotope results from Canímar Abajo provide the earliest isotopic evidence of populations with low-level residential mobility in the Antilles.}, archive = {J_PNAS}, author = {Chinique de Armas, Yadira and Hernández Godoy, Silvia Teresita and Viera Sanfiel, Luis M. and Buhay, William M. and Laffoon, Jason E.}, doi = {10.1073/pnas.2413963121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2413963121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Earliest evidence of sedentism in the antilles: Multiple isotope data from canímar abajo, cuba}, volume = {122}, year = {2025}, }
• (2025). Evolution takes multiple paths to evolvability when facing environmental change. PNAS, 122(1), e2413930121. (www)

  @article{ , abstract = {Life at all scales is surprisingly effective at exploiting new opportunities, as demonstrated by the rapid emergence of antimicrobial resistance and novel pathogens. How populations acquire this level of evolvability and the various ways it aids survival are major open questions with direct implications for human health. Here, we use digital evolution to show that changing environments facilitate the simultaneous evolution of high mutation rates and a distribution of mutational effects skewed toward beneficial phenotypes. The evolved mutational neighborhoods allow rapid adaptation to previously encountered environments, whereas higher mutation rates aid adaptation to completely new environmental conditions. By precisely tracking evolving lineages and the phenotypes of their mutants, we show that evolving populations localize on phenotypic boundaries between distinct regions of genotype space. Our results demonstrate how evolution shapes multiple determinants of evolvability concurrently, fine-tuning a population’s adaptive responses to unpredictable or recurrent environmental shifts.}, archive = {J_PNAS}, author = {Kumawat, Bhaskar and Lalejini, Alexander and Acosta, Monica M. and Zaman, Luis}, doi = {10.1073/pnas.2413930121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2413930121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Evolution takes multiple paths to evolvability when facing environmental change}, volume = {122}, year = {2025}, }
• (2025). The CYLD–PARP1 feedback loop regulates DNA damage repair and chemosensitivity in breast cancer cells. PNAS, 122(1), e2413890121. (www)

  @article{ , abstract = {Poly(ADP-ribose) polymerase 1 (PARP1) plays a crucial role in DNA repair and genomic stability maintenance. However, the regulatory mechanisms governing PARP1 activity, particularly through deubiquitination, remain poorly elucidated. Using a deubiquitinase (DUB) library binding screen, we identified cylindromatosis (CYLD) as a bona fide DUB for PARP1 in breast cancer cells. Mechanistically, CYLD is recruited by PARP1 to DNA lesions upon genotoxic stress, where it cleaves K63-linked polyubiquitin chains on PARP1 at residues K748, K940, and K949, resulting in compromised PARP1 activation. In a reciprocal manner, PARP1 PARylates CYLD at sites E191, E231, E259, and E509, thereby enhancing its DUB activity. Consequently, depletion of CYLD leads to increased efficiency in base excision repair and confers breast cancer cells with resistance to alkylating agents. Conversely, overexpression of CYLD enhances sensitivity to PARP inhibitors (PARPi) even in homologous recombination-proficient breast cancer cells. These findings offer unique insights into the intricate interplay between CYLD and PARP1 in DNA repair, underscoring the pivotal role of targeting this regulatory axis for breast cancer chemotherapy.}, archive = {J_PNAS}, author = {Zheng, Miaomiao and Wang, Shuo and Tang, Kexin and Kong, Ruixue and Wang, Xuemeng and Zhou, Jun and Chen, Yan and Wang, Yijie}, doi = {10.1073/pnas.2413890121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2413890121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The CYLD–PARP1 feedback loop regulates DNA damage repair and chemosensitivity in breast cancer cells}, volume = {122}, year = {2025}, }
• (2025). Computational-aided rational mutation design of pertuzumab to overcome active HER2 mutation S310F through antibody–drug conjugates. PNAS, 122(1), e2413686122. (www)

  @article{ , abstract = {Recurrent missense mutations in the human epidermal growth factor receptor 2 (HER2) have been identified across various human cancers. Among these mutations, the active S310F mutation in the HER2 extracellular domain stands out as not only oncogenic but also confers resistance to pertuzumab, an antibody drug widely used in clinical cancer therapy, by impeding its binding. In this study, we have successfully employed computational-aided rational design to undertake directed evolution of pertuzumab, resulting in the creation of an evolved pertuzumab variant named Ptz-SA. This variant, with only two mutations (T30S/D31A) located on its heavy chain, effectively reinstates binding to the mutated antigen, at the expense of a 35-fold reduction in binding affinity to HER2 (S310F) compared to the wild-type pair. Subsequently, Ptz-SA demonstrates potent killing capacity through antigen-dependent cytotoxicity. Moreover, upon engineering Ptz-SA into antibody–drug conjugates, such as Ptz-SA-MMAE, it manifests notable in vitro and in vivo antitumor efficacy by efficiently delivering cytotoxic payload into tumor cells expressing HER2 (S310F). Cryoelectron microscopy studies elucidate the molecular mechanism underlying the restored binding ability of Ptz-SA toward the S310F mutation. The steric hindrance induced by the S310F mutation is efficiently circumvented by the T30S and D31A mutations, which provides adequate space to accommodate the larger phenylalanine. Additionally, Ptz-SA also exhibits binding capacity to HER2 (S310Y), another mutation occurring at the S310 site of HER2 with high frequency. The computational-aided evolution of pertuzumab provides an alternative strategy for overcoming point mutation-mediated resistance to therapeutic antibodies.}, archive = {J_PNAS}, author = {Bai, Xuefei and Xu, Lingyi and Wang, Zhe and Zhuang, Xinlei and Ning, Jiangtao and Sun, Yanping and Wang, Haibin and Guo, Yugang and Xu, Yingchun and Guo, Jiangtao and Chen, Shuqing and Pan, Liqiang}, doi = {10.1073/pnas.2413686122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2413686122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Computational-aided rational mutation design of pertuzumab to overcome active HER2 mutation S310F through antibody–drug conjugates}, volume = {122}, year = {2025}, }
• (2025). Mechanism-guided engineering of a minimal biological particle for genome editing. PNAS, 122(1), e2413519121. (www)

  @article{ , abstract = {The widespread application of genome editing to treat and cure disease requires the delivery of genome editors into the nucleus of target cells. Enveloped delivery vehicles (EDVs) are engineered virally derived particles capable of packaging and delivering CRISPR-Cas9 ribonucleoproteins (RNPs). However, the presence of lentiviral genome encapsulation and replication proteins in EDVs has obscured the underlying delivery mechanism and precluded particle optimization. Here, we show that Cas9 RNP nuclear delivery is independent of the native lentiviral capsid structure. Instead, EDV-mediated genome editing activity corresponds directly to the number of nuclear localization sequences on the Cas9 enzyme. EDV structural analysis using cryo-electron tomography and small molecule inhibitors guided the removal of ~80% of viral residues, creating a minimal EDV (miniEDV) that retains full RNP delivery capability. MiniEDVs are 25% smaller yet package equivalent amounts of Cas9 RNPs relative to the original EDVs and demonstrated increased editing in cell lines and therapeutically relevant primary human T cells. These results show that virally derived particles can be streamlined to create efficacious genome editing delivery vehicles with simpler production and manufacturing.}, archive = {J_PNAS}, author = {Ngo, Wayne and Peukes, Julia and Baldwin, Alisha and Xue, Zhiwei Wayne and Hwang, Sidney and Stickels, Robert R. and Lin, Zhi and Satpathy, Ansuman T. and Wells, James A. and Schekman, Randy and Nogales, Eva and Doudna, Jennifer A.}, doi = {10.1073/pnas.2413519121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2413519121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Mechanism-guided engineering of a minimal biological particle for genome editing}, volume = {122}, year = {2025}, }
• (2025). Moiré magnetism and moiré excitons in twisted CrSBr bilayers. PNAS, 122(1), e2413326121. (www)

  @article{ , abstract = {Moiré excitons and moiré magnetism are essential to semiconducting van der Waals magnets. In this work, we perform a comprehensive first-principles study to elucidate the interplay of electronic excitation and magnetism in twisted magnetic CrSBr bilayers. We predict a twist-induced quantum phase transition for interlayer magnetic coupling and estimate the critical twist angle below which moiré magnetism with mixed ferromagnetic and antiferromagnetic domains could emerge. Localized one-dimensional moiré excitons are stable if the interlayer coupling is ferromagnetic and become unstable if the coupling turns to antiferromagnetic. Exciton energy modulation by magnons is estimated and dependence of exciton oscillator strength on the twist angle and interlayer coupling is analyzed. An orthogonally twisted bilayer is revealed to exhibit layer-dependent, anisotropic optical transitions. Electric field is shown to induce net magnetic moments in moiré excitons, endowing them with exceedingly long lifetimes. Our work lays the foundation for using magnetic moiré bilayers in spintronic, optoelectronic, and quantum information applications.}, archive = {J_PNAS}, author = {Liu, Junyi and Zhang, Xu and Lu, Gang}, doi = {10.1073/pnas.2413326121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2413326121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Moiré magnetism and moiré excitons in twisted CrSBr bilayers}, volume = {122}, year = {2025}, }
• (2025). A mutant ASXL1-BAP1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic monomyelocytic leukemia. PNAS, 122(1), e2413302121. (www)

  @article{ , abstract = {ASXL transcriptional regulator 1 (ASXL1) is one of the three most frequently mutated genes in age-related clonal hematopoiesis (CH), alongside DNA methyltransferase 3 alpha (DNMT3A) and Tet methylcytosine dioxygenase 2 ( TET2) . CH can progress to myeloid malignancies including chronic monomyelocytic leukemia (CMML) and is also strongly associated with inflammatory cardiovascular disease and all-cause mortality in humans. DNMT3A and TET2 regulate DNA methylation and demethylation pathways, respectively, and loss-of-function mutations in these genes reduce DNA methylation in heterochromatin, allowing derepression of silenced elements in heterochromatin. In contrast, the mechanisms that connect mutant ASXL1 and CH are not yet fully understood. CH/CMML-associated ASXL1 mutations encode C-terminally truncated proteins that enhance the deubiquitinase activity of the ASXL-BAP1 “PR-DUB” deubiquitinase complex, which removes monoubiquitin from H2AK119Ub. Here, we show that ASXL1 mutant proteins interact with the euchromatic histone lysine methyltransferases 1 and 2 (EHMT1–EHMT2) complex, which generates H3K9me1 and me2, the latter a repressive modification in constitutive heterochromatin. Compared to cells from age-matched wild-type mice, we found that expanded myeloid cells from old (≥18-mo-old) Asxl1tm/+ mice, a heterozygous knock-in mouse model of CH, display genome-wide decreases of H3K9me2, H3K9me3, and H2AK119Ub as well as an associated increase in expression of transposable elements (TEs) and satellite repeats. Increased TE expression was also observed in monocytes from ASXL1 -mutant CMML patients compared to monocytes from healthy controls. Our data suggest that mutant ASXL1 proteins compromise the integrity of both constitutive and facultative heterochromatin in an age-dependent manner by reducing the levels of H3K9me2/3 and H2AK119Ub. This increase in TE expression correlated with increased expression of nearby genes, including many interferon-inducible (inflammation-associated) genes (ISGs).}, archive = {J_PNAS}, author = {Dong, Zhen and Sepulveda, Hugo and Arteaga-Vazquez, Leo J. and Blouin, Chad and Fernandez, Jenna and Binder, Moritz and Chou, Wen-Chien and Tien, Hwei-Fang and Patnaik, Mrinal M. and Faulkner, Geoffrey J. and Myers, Samuel A. and Rao, Anjana}, doi = {10.1073/pnas.2413302121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2413302121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A mutant ASXL1-BAP1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic monomyelocytic leukemia}, volume = {122}, year = {2025}, }
• (2025). Gonadal sex and temperature independently influence germ cell differentiation and meiotic progression in trachemys scripta. PNAS, 122(1), e2413191121. (www)

  @article{ , abstract = {In species with genetic sex determination (GSD), the sex identity of the soma determines germ cell fate. For example, in mice, XY germ cells that enter an ovary differentiate as oogonia, whereas XX germ cells that enter a testis initiate differentiation as spermatogonia. However, numerous species lack a GSD system and instead display temperature-dependent sex determination (TSD). In the red-eared slider turtle, Trachemys scripta , a TSD model species with a warm female promoting temperature (FPT) and cool male promoting temperature (MPT) system, temperature directly affects germ cell number. In this study, we examined whether temperature directly affects other aspects of germ cell differentiation/sex identity. We uncoupled temperature and the sexual fate of the gonad by incubating eggs at MPT and treating with 17β-estradiol, a scheme that invariably produces ovaries. Through analysis of meiotic spreads, we showed that germ cells in FPT ovaries follow the typical pattern of initiating meiosis and progress through prophase I. However, in E2-induced ovaries that incubated at MPT, germ cells entered prophase I yet fail to exhibit synapsis. These results, combined with our single-cell transcriptome analysis, reveal a direct effect of temperature on germ cell sexual differentiation independent of its effect on the gonadal soma. These results imply that not all events of meiosis are under somatic control, at least not in this TSD species.}, archive = {J_PNAS}, author = {Hatkevich, Talia and Tezak, Boris M. and Acemel, Rafael D. and Yee Chung, Vicky Wai and Lupiáñez, Dario G. and Capel, Blanche}, doi = {10.1073/pnas.2413191121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2413191121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Gonadal sex and temperature independently influence germ cell differentiation and meiotic progression in trachemys scripta}, volume = {122}, year = {2025}, }
• (2025). PsDMAP1/PsTIP60-regulated H4K16ac is required for ROS-dependent virulence adaptation of phytophthora sojae on host plants. PNAS, 122(1), e2413127122. (www)

  @article{ , abstract = {Host plants and various fungicides inhibit plant pathogens by inducing the release of excessive reactive oxygen species (ROS) and causing DNA damage, either directly or indirectly leading to cell death. The mechanisms by which the oomycete Phytophthora sojae manages ROS stress resulting from plant immune responses and fungicides remains unclear. This study elucidates the role of histone acetylation in ROS-induced DNA damage responses (DDR) to adapt to stress. Mechanistically, the P. sojae DNA methyltransferase 1-associated protein (PsDMAP1) binds Tat-interactive protein 60 (PsTIP60) to comediate histone H4 acetylation on lysine 16 (H4K16ac). This regulation affects RNA polymerase II (pol II) recruitment, transcriptional induction of DDR-related genes, and the enrichment of histone H2Ax phosphorylated on serine 137 (γH2Ax) in response to both plant immunity and fungicide stress. The resulting H4K16ac serves as a crucial transgenerational epigenetic signal for virulence adaptation of P. sojae on plants, as a result of adaptation to ROS stress.}, archive = {J_PNAS}, author = {Zhang, Fan and Chen, Shanshan and Zhang, Can and Wang, Zhiwen and Miao, Jianqiang and Dai, Tan and Hao, Jianjun and Liu, Xili}, doi = {10.1073/pnas.2413127122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2413127122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {PsDMAP1/PsTIP60-regulated H4K16ac is required for ROS-dependent virulence adaptation of phytophthora sojae on host plants}, volume = {122}, year = {2025}, }
• (2025). The effect of job loss on risky financial decision-making. PNAS, 122(1), e2412760121. (www)

  @article{ , abstract = {Job loss is a common and disruptive life event. It is known to have numerous long-term negative effects on financial, health, and social outcomes. While the negative effects of becoming unemployed on health and well-being are well understood, the influence of job loss on financial decisions has received little attention. Across a large-scale survey ( N = 37 , 854 ), spending data from a bank ( N = 404 , 470 ), and two online experiments (total N = 1 , 403 ), we find that job loss increases financial risk-taking. First, in survey data, job loss is associated with elevated levels of self-reported financial risk-taking and lottery ticket purchases. Next, using administrative data from a large bank, we find consistent causal evidence of the influence of job loss on gambling spending. Although total spending decreases after job loss, gambling spending is less affected than our control categories. Finally, we turn to two incentive-compatible manipulations of job loss operationalized in a lab setting. We find that this experimental manipulation increases the take-up of financial risks. The current finding that job loss increases financial risk-taking could accentuate long-term negative financial effects of job loss.}, archive = {J_PNAS}, author = {Hirshman, Samuel D. and Sussman, Abigail B. and Vazquez-Hernandez, Carlos and O’Leary, Daniel and Trueblood, Jennifer S.}, doi = {10.1073/pnas.2412760121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2412760121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The effect of job loss on risky financial decision-making}, volume = {122}, year = {2025}, }
• (2025). X*Y females exhibit steeper reproductive senescence in the african pygmy mouse. PNAS, 122(1), e2412609121. (www)

  @article{ , abstract = {A wave of studies has recently emphasized the influence of sex chromosomes on both lifespan and actuarial senescence patterns across vertebrates and invertebrates. Basically, the heterogametic sex (XY males in XX/XY systems or ZW females in ZW/ZZ systems) typically displays a lower lifespan and a steeper rate of actuarial senescence than the homogametic sex. However, whether these effects extend to the senescence patterns of other phenotypic traits or physiological functions is yet to be determined. Here, we investigated whether sex chromosomes modulate reproductive senescence using females from the African pygmy mouse ( Mus minutoides ). This biological model exhibits an odd sex determining system with a third, feminizing sex chromosome, X*, resulting in three distinct female genotypes (XX, X*X, or X*Y) that coexist in natural populations. We found that the rate of senescence in litter size at birth is much more pronounced in heterogametic X*Y females than in homogametic XX or X*X females that may support the unguarded X or toxic Y hypotheses and can be directly linked to the complex and unique X*Y phenotype. A decrease in neonatal survival with mother’s age has also been found, but this decline is not different between the three female genotypes.}, archive = {J_PNAS}, author = {Lemaître, Jean-François and Voituron, Yann and Herpe, Léa and Veyrunes, Frédéric}, doi = {10.1073/pnas.2412609121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2412609121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {X*Y females exhibit steeper reproductive senescence in the african pygmy mouse}, volume = {122}, year = {2025}, }
• (2025). Tetrameric PilZ protein stabilizes stator ring in complex flagellar motor and is required for motility in campylobacter jejuni. PNAS, 122(1), e2412594121. (www)

  @article{ , abstract = {Rotation of the bacterial flagellum, the first identified biological rotary machine, is driven by its stator units. Knowledge gained about the function of stator units has increasingly led to studies of rotary complexes in different cellular pathways. Here, we report that a tetrameric PilZ family protein, FlgX, is a structural component underneath the stator units in the flagellar motor of Campylobacter jejuni . FlgX forms a stable tetramer that does not bind cyclic di-GMP (c-di-GMP), unlike other canonical PilZ domain–containing proteins. Cryoelectron tomography and subtomogram averaging of flagellar motors in situ provide evidence that FlgX interacts with each stator unit and plays a critical role in stator ring assembly and stability. Furthermore, FlgX is conserved and was most likely present in the common ancestor of the phylum Campylobacterota . Overall, FlgX represents a divergence in function for PilZ superfamily proteins as well as a player in the key stator–rotor interaction of complex flagellar motors.}, archive = {J_PNAS}, author = {Chen, Yuanyuan and Tachiyama, Shoichi and Li, Yuqian and Feng, Xueyin and Zhao, Hang and Wu, Yanmin and Guo, Yu and Lara-Tejero, María and Hua, Canfeng and Liu, Jun and Gao, Beile}, doi = {10.1073/pnas.2412594121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2412594121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tetrameric PilZ protein stabilizes stator ring in complex flagellar motor and is required for motility in campylobacter jejuni}, volume = {122}, year = {2025}, }
• (2025). Comparing integrative ventilatory and renal acid–base acclimatization in lowlanders and tibetan highlanders during ascent to 4,300 m. PNAS, 122(1), e2412561121. (www)

  @article{ , abstract = {With over 14 million people living above 3,500 m, the study of acclimatization and adaptation to high altitude in human populations is of increasing importance, where exposure to high altitude (HA) imposes a blood oxygenation and acid–base challenge. A sustained and augmented hypoxic ventilatory response protects oxygenation through ventilatory acclimatization, but elicits hypocapnia and respiratory alkalosis. A subsequent renally mediated compensatory metabolic acidosis corrects pH toward baseline values, with a high degree of interindividual variability. Differential renal compensation between acclimatizing lowlanders (LL) and Tibetan highlanders (TH; Sherpa) with ascent was previously unknown. We assessed ventilatory and renal acclimatization between unacclimatized LL and TH during incremental ascent from 1,400 m to 4,300 m in age- and sex-matched groups of 15-LL (8F) and 14-TH (7F) of confirmed Tibetan ancestry. We compared respiratory and renally mediated blood acid–base acclimatization (PCO 2 , [HCO 3 − ], pH) in both groups before (1,400 m) and following day 8 to 9 of incremental ascent to 4,300 m. We found that following ascent to 4,300 m, LL had significantly lower PCO 2 ( P <0.0001) and [HCO 3 − ] ( P <0.0001), and higher pH ( P = 0.0037) than 1,400 m, suggesting respiratory alkalosis and only partial renal compensation. Conversely, TH had significantly lower PCO 2 ( P < 0.0001) and [HCO 3 − ] ( P < 0.0001), but unchanged pH ( P = 0.1), suggesting full renal compensation, with significantly lower PCO 2 ( P = 0.01), [HCO 3 − ] ( P < 0.0001) and pH ( P = 0.005) than LL at 4,300 m. This demonstration of differential integrative respiratory–renal responses between acclimatizing LL and TH may indicate selective pressure on TH, and highlights the important role of the kidneys in acclimatization.}, archive = {J_PNAS}, author = {Johnson, Nicole A. and Dickenson, Jessica A. and MacKenzie, Benjamin W.L. and Isakovich, Rodion and Kalker, Anne and Bouten, Janne and Strzalkowski, Nicholas D.J. and Harman, Taylor S. and Holmström, Pontus and Kunwar, Ajaya J. and Thakur, Nilam and Dhungel, Sunil and Sherpa, Nima and Bigham, Abigail W. and Brutsaert, Tom D. and Day, Trevor A.}, doi = {10.1073/pnas.2412561121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2412561121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Comparing integrative ventilatory and renal acid–base acclimatization in lowlanders and tibetan highlanders during ascent to 4,300 m}, volume = {122}, year = {2025}, }
• (2025). Aberrant neuronal hyperactivation causes an age-dependent behavioral decline in caenorhabditis elegans. PNAS, 122(1), e2412391122. (www)

  @article{ , abstract = {Age-dependent sensory impairment, memory loss, and cognitive decline are generally attributed to neuron loss, synaptic dysfunction, and decreased neuronal activities over time. Concurrently, increased neuronal activity is reported in humans and other organisms during aging. However, it is unclear whether neuronal hyperactivity is the cause of cognitive impairment or a compensatory mechanism of circuit dysfunction. The roundworm Caenorhabditis elegans exhibits age-dependent declines in an associative learning behavior called thermotaxis, in which its temperature preference on a thermal gradient is contingent on food availability during its cultivation. Cell ablation and calcium imaging demonstrate that the major thermosensory circuit consisting of AFD thermosensory neuron and AIY interneuron is relatively intact in aged animals. On the other hand, ablation of either AWC sensory neurons or AIA interneurons ameliorates the age-dependent thermotaxis decline. Both neurons showed spontaneous and stochastic hyperactivity in aged animals, enhanced by reciprocal communication between AWC and AIA via neurotransmitters and neuropeptides. Our findings suggest that AWC and AIA hyperactivity mediates thermotaxis decline in aged animals. Furthermore, dietary modulation could ameliorate age-dependent thermotaxis decline by suppressing neuronal hyperactivity. We propose that aberrantly enhanced, not diminished, neuronal activities can impair the behavior of aged animals.}, archive = {J_PNAS}, author = {Aleogho, Binta Maria and Mohri, Mizuho and Jang, Moon Sun and Tsukada, Sachio and Al-Hebri, Yana and Matsuyama, Hironori J. and Tsukada, Yuki and Mori, Ikue and Noma, Kentaro}, doi = {10.1073/pnas.2412391122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2412391122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Aberrant neuronal hyperactivation causes an age-dependent behavioral decline in caenorhabditis elegans}, volume = {122}, year = {2025}, }
• (2025). Chromatin enables precise and scalable gene regulation with factors of limited specificity. PNAS, 122(1), e2411887121. (www)

  @article{ , abstract = {Biophysical constraints limit the specificity with which transcription factors (TFs) can target regulatory DNA. While individual nontarget binding events may be low affinity, the sheer number of such interactions could present a challenge for gene regulation by degrading its precision or possibly leading to an erroneous induction state. Chromatin can prevent nontarget binding by rendering DNA physically inaccessible to TFs, at the cost of energy-consuming remodeling orchestrated by pioneer factors (PFs). Under what conditions and by how much can chromatin reduce regulatory errors on a global scale? We use a theoretical approach to compare two scenarios for gene regulation: one that relies on TF binding to free DNA alone and one that uses a combination of TFs and chromatin-regulating PFs to achieve desired gene expression patterns. We find, first, that chromatin effectively silences groups of genes that should be simultaneously OFF, thereby allowing more accurate graded control of expression for the remaining ON genes. Second, chromatin buffers the deleterious consequences of nontarget binding as the number of OFF genes grows, permitting a substantial expansion in regulatory complexity. Third, chromatin-based regulation productively co-opts nontarget TF binding for ON genes in order to establish a “leaky” baseline expression level, which targeted activator or repressor binding subsequently up- or down-modulates. Thus, on a global scale, using chromatin simultaneously alleviates pressure for high specificity of regulatory interactions and enables an increase in genome size with minimal impact on global expression error.}, archive = {J_PNAS}, author = {Perkins, Mindy Liu and Crocker, Justin and Tkačik, Gašper}, doi = {10.1073/pnas.2411887121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411887121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Chromatin enables precise and scalable gene regulation with factors of limited specificity}, volume = {122}, year = {2025}, }
• (2025). Molecular basis of hemoglobin binding and heme removal in corynebacterium diphtheriae. PNAS, 122(1), e2411833122. (www)

  @article{ , abstract = {To successfully mount infections, nearly all bacterial pathogens must acquire iron, a key metal cofactor that primarily resides within human hemoglobin. Corynebacterium diphtheriae causes the life-threatening respiratory disease diphtheria and captures hemoglobin for iron scavenging using the surface-displayed receptor HbpA. Here, we show using X-ray crystallography, NMR, and in situ binding measurements that C. diphtheriae selectively captures iron-loaded hemoglobin by partially ensconcing the heme molecules of its α subunits. Quantitative growth and heme release measurements are compatible with C. diphtheriae acquiring heme passively released from hemoglobin’s β subunits. We propose a model in which HbpA and heme-binding receptors collectively function on the C. diphtheriae surface to capture hemoglobin and its spontaneously released heme. Acquisition mechanisms that exploit the propensity of hemoglobin’s β subunit to release heme likely represent a common strategy used by bacterial pathogens to obtain iron during infections.}, archive = {J_PNAS}, author = {Mahoney, Brendan J. and Lyman, Lindsey R. and Ford, Jordan and Soule, Jess and Cheung, Nicole A. and Goring, Andrew K. and Ellis-Guardiola, Kat and Collazo, Michael J. and Cascio, Duilio and Ton-That, Hung and Schmitt, Michael P. and Clubb, Robert T.}, doi = {10.1073/pnas.2411833122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411833122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular basis of hemoglobin binding and heme removal in corynebacterium diphtheriae}, volume = {122}, year = {2025}, }
• (2025). Tungsten is utilized for lactate consumption and SCFA production by a dominant human gut microbe eubacterium limosum. PNAS, 122(1), e2411809121. (www)

  @article{ , abstract = {Eubacterium limosum is a dominant member of the human gut microbiome and produces short-chain fatty acids (SCFAs). These promote immune system function and inhibit inflammation, making this microbe important for human health. Lactate is a primary source of gut SCFAs but its utilization by E. limosum has not been explored. We show that E. limosum growing on lactate takes up added tungstate rather than molybdate and produces the SCFAs acetate and butyrate, but not propionate. The genes encoding an electron bifurcating, tungsten-containing oxidoreductase (WOR1) and a tungsten-containing formate dehydrogenase (FDH), along with an electron bifurcating lactate dehydrogenase (LCT), lactate permease, and enzymes of the propanediol pathway, are all up-regulated on lactate compared to growth on glucose. Lactate metabolism is controlled by a GntR-family repressor (LctR) and two global regulators, Rex and CcpA, where Rex in part controls W storage and tungstopyranopterin (Tuco) biosynthesis. Tuco-dependent riboswitches, along with CcpA, also control two iron transporters, consistent with the increased iron demand for many iron-containing enzymes, including WOR1 and FDH, involved in SCFA production. From intracellular aldehyde concentrations and the substrate specificity of WOR1, we propose that WOR1 is involved in detoxifying acetaldehyde produced during lactate degradation. Lactate to SCFA conversion by E. limosum is clearly highly tungstocentric and tungsten might be an overlooked micronutrient in the human microbiome and in overall human health.}, archive = {J_PNAS}, author = {Putumbaka, Saisuki and Schut, Gerrit J. and Thorgersen, Michael P. and Poole, Farris L. and Shao, Nana and Rodionov, Dmitry A. and Adams, Michael W. W.}, doi = {10.1073/pnas.2411809121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411809121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tungsten is utilized for lactate consumption and SCFA production by a dominant human gut microbe eubacterium limosum}, volume = {122}, year = {2025}, }
• (2025). Reconciling heterogeneous dengue virus infection risk estimates from different study designs. PNAS, 122(1), e2411768121. (www)

  @article{ , abstract = {Uncovering rates at which susceptible individuals become infected with a pathogen, i.e., the force of infection (FOI), is essential for assessing transmission risk and reconstructing distribution of immunity in a population. For dengue, reconstructing exposure and susceptibility statuses from the measured FOI is of particular significance as prior exposure is a strong risk factor for severe disease. FOI can be measured via many study designs. Longitudinal serology is considered gold standard measurements, as they directly track the transition of seronegative individuals to seropositive due to incident infections (seroincidence). Cross-sectional serology can provide estimates of FOI by contrasting seroprevalence across ages. Age of reported cases can also be used to infer FOI. Agreement of these measurements, however, has not been assessed. Using 26 y of data from cohort studies and hospital-attended cases from Kamphaeng Phet province, Thailand, we found FOI estimates from the three sources to be highly inconsistent. Annual FOI estimates from seroincidence were 1.75 to 4.05 times higher than case-derived FOI. Seroprevalence-derived was moderately correlated with case-derived FOI (correlation coefficient = 0.47) with slightly lower estimates. Through extensive simulations and theoretical analysis, we show that incongruences between methods can result from failing to account for dengue antibody kinetics, assay noise, and heterogeneity in FOI across ages. Extending standard inference models to include these processes reconciled the FOI and susceptibility estimates. Our results highlight the importance of comparing inferences across multiple data types to uncover additional insights not attainable through a single data type/analysis.}, archive = {J_PNAS}, author = {Huang, Angkana T. and Buddhari, Darunee and Kaewhiran, Surachai and Iamsirithaworn, Sopon and Khampaen, Direk and Farmer, Aaron and Fernandez, Stefan and Thomas, Stephen J. and Rodriguez-Barraquer, Isabel and Hunsawong, Taweewun and Srikiatkhachorn, Anon and Ribeiro dos Santos, Gabriel and O’Driscoll, Megan and Hamins-Puertolas, Marco and Endy, Timothy and Rothman, Alan L. and Cummings, Derek A. T. and Anderson, Kathryn and Salje, Henrik}, doi = {10.1073/pnas.2411768121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411768121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Reconciling heterogeneous dengue virus infection risk estimates from different study designs}, volume = {122}, year = {2025}, }
• (2025). Binding mode–guided development of high-performance antibodies targeting site-specific posttranslational modifications. PNAS, 122(1), e2411720121. (www)

  @article{ , abstract = {Posttranslational modifications (PTMs) of proteins play critical roles in regulating many cellular events. Antibodies targeting site-specific PTMs are essential tools for detecting and enriching PTMs at sites of interest. However, fundamental difficulties in molecular recognition of both PTM and surrounding peptide sequence have hindered the efficient generation of highly sequence-specific anti-PTM antibodies. Furthermore, the widespread use of potentially inconsistent, nonrenewable, and molecularly undefined antibodies presents experimental challenges thought to contribute to the reproducibility problem in biomedical research. In this study, we describe the binding mode-guided development of a platform that efficiently generates potent and selective recombinant antibodies to PTMs that are molecularly defined and renewable. Our platform is built on our previous discovery of an unconventional binding mode of anti-PTM antibodies, antigen clasping, where two antigen binding sites cooperatively sandwich a single antigen, creating extensive interactions with the antigen and leading to high selectivity and potency. We designed the platform that generates clasping antibodies with two distinct binding units, resulting in efficient generation of antibodies to a set of trimethylated histone H3 with high levels of specificity and affinity. Performance comparison in chromatin immunoprecipitation, a common application in epigenomics, revealed that a clasping antibody to trimethylated histone H3 at lysine 27 exhibited superior specificity to a widely used conventional antibody and captured symmetric and asymmetric nucleosomes in a less biased manner. We further generated clasping antibodies to phosphotyrosine antigens by using the same principle. These results suggest the broad applicability of our platform to generating high-performance clasping antibodies to diverse PTMs.}, archive = {J_PNAS}, author = {Riso, Mariapia and Shah, Rohan N. and Koide, Akiko and Ruthenburg, Alexander J. and Koide, Shohei and Hattori, Takamitsu}, doi = {10.1073/pnas.2411720121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411720121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Binding mode–guided development of high-performance antibodies targeting site-specific posttranslational modifications}, volume = {122}, year = {2025}, }
• (2025). Geometrically modulated contact forces enable hula hoop levitation. PNAS, 122(1), e2411588121. (www)

  @article{ , abstract = {Mechanical systems with moving points of contact—including rolling, sliding, and impacts—are common in engineering applications and everyday experiences. The challenges in analyzing such systems are compounded when an object dynamically explores the complex surface shape of a moving structure, as arises in familiar but poorly understood contexts such as hula hooping. We study this activity as a unique form of mechanical levitation against gravity and identify the conditions required for the stable suspension of an object rolling around a gyrating body. We combine robotic experiments involving hoops twirling on surfaces of various geometries and a model that links the motions and shape to the contact forces generated. The in-plane motions of the hoop involve synchronization to the body gyration that is shown to require damping and sufficiently high launching speed. Further, vertical equilibrium is achieved only for bodies with “hips” or a critical slope of the surface, while stability requires an hourglass shape with a “waist” and whose curvature exceeds a critical value. Analysis of the model reveals dimensionless factors that successfully organize and unify observations across a wide range of geometries and kinematics. By revealing and explaining the mechanics of hula hoop levitation, these results motivate strategies for motion control via geometry-dependent contact forces and for accurately predicting the resulting equilibria and their stability.}, archive = {J_PNAS}, author = {Zhu, Xintong and Pomerenk, Olivia and Ristroph, Leif}, doi = {10.1073/pnas.2411588121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411588121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Geometrically modulated contact forces enable hula hoop levitation}, volume = {122}, year = {2025}, }
• (2025). ANAC044 orchestrates mitochondrial stress signaling to trigger iron-induced stem cell death in root meristems. PNAS, 122(1), e2411579122. (www)

  @article{ , abstract = {While iron (Fe) is essential for life and plays important roles for almost all growth related processes, it can trigger cell death in both animals and plants. However, the underlying mechanisms for Fe-induced cell death in plants remain largely unknown. S-nitrosoglutathione reductase (GSNOR) has previously been reported to regulate nitric oxide homeostasis to prevent Fe-induced cell death within root meristems. Here, we found that in the absence of GSNOR , exposure to high Fe treatment results in DNA damage–dependent cell death specifically in vascular stem cells in root meristems within 48 h. Through a series of time-course transcriptomic analyses, we unveil that in the absence of GSNOR , mitochondrial dysfunction emerges as the most prominent response to high Fe treatment. Consistently, the application of mitochondrial respiratory inhibitors leads to stem cell death in root meristems, and pharmacological blockage of the voltage-dependent anion channel that is responsible for the release of mitochondrial-derived molecules into the cytosol or genetic changes that abolish the ANAC017- and ANAC013-mediated mitochondrial retrograde signaling effectively eliminate Fe-induced stem cell death in gsnor root meristems. We further identify the nuclear transcription factor ANAC044 as a mediator of this mitochondrial retrograde signaling. Disruption of ANAC044 completely abolishes the GSNOR-dependent, Fe-induced stem cell death in root meristems, while ectopic expression of ANAC044 causes severe root stem cell death. Collectively, our findings reveal a mechanism responsible for initiating Fe-induced stem cell death in the root meristem, which is the ANAC044-mediated GSNOR-regulated mitochondrial stress signaling pathway.}, archive = {J_PNAS}, author = {Yan, Juanmei and Feng, Zhihang and Xiao, Yihui and Zhou, Ming and Zhao, Xiaobo and Lin, Xianyong and Shi, Weiming and Busch, Wolfgang and Li, Baohai}, doi = {10.1073/pnas.2411579122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411579122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {ANAC044 orchestrates mitochondrial stress signaling to trigger iron-induced stem cell death in root meristems}, volume = {122}, year = {2025}, }
• (2025). The changing relationship between racial identity and skin color in brazil. PNAS, 122(1), e2411495121. (www)

  @article{ , abstract = {In recent years, Brazil’s non-White (Brown and Black) population became a numerical majority for the first time since the 19th century. Although we know this change was mostly due to racial reclassification, we do not know how such changes are related to skin color, the primary marker of race in Brazil. Using data from six Latin American Public Opinion Project (LAPOP), or America’s Barometer, surveys from 2010 to 2023, we examine how changes in racial self-identification (White, Brown, or Black) are related to respondent skin color (light, medium, or dark). We ask how the association between self-identified race and skin color changed over the 13-y period and to what extent these trends varied by educational level. We found a “darkening” of racial identification over time, especially among those with medium and dark skin, who increasingly identified as Black. Brazilians with light skin increasingly identified as Brown, but this was partly explained by changes in interviewer reporting of skin color in the same period. We found only minor evidence that education level was related to changing racial classification over time. Our findings further understanding of recent trends in racial reclassification, which may reflect growing Black consciousness and the extension of racial quotas to both Brown and Black Brazilians in federal universities and public sector jobs.}, archive = {J_PNAS}, author = {Freeman, Nicholas C. and Telles, Edward E. and Goldberg, Rachel E.}, doi = {10.1073/pnas.2411495121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411495121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The changing relationship between racial identity and skin color in brazil}, volume = {122}, year = {2025}, }
• (2025). The effect of CO2 ramping rate on the transient weakening of the atlantic meridional overturning circulation. PNAS, 122(1), e2411357121. (www)

  @article{ , abstract = {The Atlantic Meridional Overturning Circulation (AMOC) is a key component of the global climate that is projected to weaken under future anthropogenic climate change. While many studies have investigated the AMOC’s response to different levels and types of forcing in climate models, relatively little attention has been paid to the AMOC’s sensitivity to the rate of forcing change, despite it also being highly uncertain in future emissions scenarios. In this study, I isolate the AMOC’s response to different rates of CO 2 increase in a state-of-the-art global climate model and find that the AMOC undergoes more severe weakening under faster rates of CO 2 change, even when the magnitude of CO 2 change is the same. I then propose an AMOC-ocean heat transport-sea ice feedback that enhances the decline of the circulation and explains the dependence on the rate of forcing change. The AMOC’s rate-sensitive behavior leads to qualitatively different climates (including differing Arctic sea ice evolution) at the same CO 2 concentration, highlighting how the rate of forcing change is itself a key driver of global climatic change.}, archive = {J_PNAS}, author = {Hankel, Camille}, doi = {10.1073/pnas.2411357121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411357121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The effect of CO2 ramping rate on the transient weakening of the atlantic meridional overturning circulation}, volume = {122}, year = {2025}, }
• (2025). Collaborative management partnerships strongly decreased deforestation in the most at-risk protected areas in africa since 2000. PNAS, 122(1), e2411348121. (www)

  @article{ , abstract = {Collaborative management partnerships (CMPs) between state wildlife authorities and nonprofit conservation organizations to manage protected areas (PAs) have been used increasingly across Sub-Saharan Africa since the 2000s. They aim to attract funding, build capacity, and increase the environmental effectiveness of PAs. Our study documents the rise of CMPs, examines their current extent, and measures their effectiveness in protecting habitats. We combine statistical matching and Before-After-Control-Intervention regressions to quantify the impact of CMPs, using tree cover loss as a proxy. We identify 127 CMPs located in 16 countries. CMPs are more often located in remote PAs, with habitats that are least threatened by human activity. Our results indicate that, on average, each year in a CMP results in an annual decrease in tree cover loss of about 55% compared to PAs without CMPs. Where initial anthropogenic pressure was low, we measure no effect. Where it was high, we see a 66% decrease in tree cover loss. This highly heterogeneous effect illustrates the importance of moving beyond average effect size when assessing conservation interventions, as well as the need for policy makers to invest public funds to protect the areas the most at risk.}, archive = {J_PNAS}, author = {Desbureaux, Sébastien and Kabore, Ibrahim and Vaglietti, Giulia and Baghai, Mujon and Lindsey, Peter and Robson, Ashley and Delacote, Philippe and Leblois, Antoine}, doi = {10.1073/pnas.2411348121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411348121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Collaborative management partnerships strongly decreased deforestation in the most at-risk protected areas in africa since 2000}, volume = {122}, year = {2025}, }
• (2025). Endonuclease g promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNAThr production. PNAS, 122(1), e2411298122. (www)

  @article{ , abstract = {Mitochondrial endonuclease G (EndoG) contributes to chromosomal degradation when it is released from mitochondria during apoptosis. It is presumed to also have a mitochondrial function because EndoG deficiency causes mitochondrial dysfunction. However, the mechanism by which EndoG regulates mitochondrial function is not known. Fat accumulation in metabolic dysfunction–associated steatotic liver disease (MASLD), which is more common in men, is caused in part by mitochondrial dysfunction. EndoG expression is reduced in MASLD liver, and EndoG deficiency causes MASLD in an obesity-independent manner but only in males. EndoG promotes mitochondrial respiration by resolving mitochondrial tRNA/DNA hybrids formed during mtDNA transcription by recruiting RNA helicase DHX30 to unwind them. EndoG also cleaves off the 3′-end of the H-strand transcript that can prevent mt-tRNA Thr precursor cloverleaf-folding, and processing, which increases mt-tRNA Thr production and mitochondrial translation. Using fluorescent lifetime imaging microscopy technology to visualize oxygen consumption at the individual mitochondrion level, we found that EndoG deficiency leads to the selective loss of a mitochondrial subpopulation with high-oxygen consumption. This defect was reversed with mt-tRNA Thr supplementation. Thus, EndoG promotes mitochondrial respiration by selectively regulating the production of mt-tRNA Thr in male mice.}, archive = {J_PNAS}, author = {Xu, Xihui and Penjweini, Rozhin and Székvölgyi, Lóránt and Karányi, Zsolt and Heckel, Anne-Marie and Gurusamy, Devikala and Varga, Dóra and Yang, Shutong and Brown, Alexandra L. and Cui, Wenqi and Park, Jinsung and Nagy, Dénes and Podszun, Maren C. and Yang, Sarah and Singh, Komudi and Ashcroft, Stephen P. and Kim, Jeonghan and Kim, Myung K. and Tarassov, Ivan and Zhu, Jun and Philp, Andrew and Rotman, Yaron and Knutson, Jay R. and Entelis, Nina and Chung, Jay H.}, doi = {10.1073/pnas.2411298122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411298122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Endonuclease g promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNAThr production}, volume = {122}, year = {2025}, }
• (2025). Electron transfer in polysaccharide monooxygenase catalysis. PNAS, 122(1), e2411229121. (www)

  @article{ , abstract = {Polysaccharide monooxygenase (PMO) catalysis involves the chemically difficult hydroxylation of unactivated C–H bonds in carbohydrates. The reaction requires reducing equivalents and will utilize either oxygen or hydrogen peroxide as a cosubstrate. Two key mechanistic questions are addressed here: 1) How does the enzyme regulate the timely and tightly controlled electron delivery to the mononuclear copper active site, especially when bound substrate occludes the active site? and 2) How does this electron delivery differ when utilizing oxygen or hydrogen peroxide as a cosubstrate? Using a computational approach, potential paths of electron transfer (ET) to the active site copper ion were identified in a representative AA9 family PMO from Myceliophthora thermophila ( Mt PMO9E). When Y62, a buried residue 12 Å from the active site, is mutated to F, lower activity is observed with O 2 . However, a WT-level activity is observed with H 2 O 2 as a cosubstrate indicating an important role in ET for O 2 activation. To better understand the structural effects of mutations to Y62 and axial copper ligand Y168, crystal structures were solved of the wild type Mt PMO9E and the variants Y62W, Y62F, and Y168F. A bioinformatic analysis revealed that position 62 is conserved as either Y or W in the AA9 family. The Mt PMO9E Y62W variant has restored activity with O 2 . Overall, the use of redox-active residues to supply electrons for the reaction with O 2 appears to be widespread in the AA9 family. Furthermore, the results provide a molecular framework to understand catalysis with O 2 versus H 2 O 2 .}, archive = {J_PNAS}, author = {Sayler, Richard I. and Thomas, William C. and Rose, Alexander J. and Marletta, Michael A.}, doi = {10.1073/pnas.2411229121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411229121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Electron transfer in polysaccharide monooxygenase catalysis}, volume = {122}, year = {2025}, }
• (2025). Molecular mechanism governing the plasticity of use-dependent spike broadening in dorsal root ganglion neurons. PNAS, 122(1), e2411033121. (www)

  @article{ , abstract = {Use-dependent spike broadening (UDSB) results from inactivation of the voltage-gated K + (Kv) channels that regulate the repolarization of the action potential. However, the specific signaling and molecular processes that modulate UDSB have remained elusive. Here, we applied an adeno-associated viral vector approach and dynamic clamping to conclusively demonstrate how multisite phosphorylation of the N-terminal inactivation domain (NTID) of the Kv3.4 channel modulates UDSB in rat dorsal root ganglion (DRG) neurons. The Kv3.4 phosphonull variant promotes slow recovery from inactivation, cumulative inactivation, and UDSB. In contrast, the Kv3.4 phosphomimic variant promotes fast recovery from inactivation and robust resistance to cumulative inactivation and UDSB. Furthermore, knocking down Kv3.4 maximizes AP width and eliminates UDSB modulation. Together with the evidence from previous work, the results concretely suggest how dynamic UDSB modulation governed by multisite phosphorylation of the NTID of Kv3.4 in DRG neurons may play a significant role in mechanosensory transduction and pain modulation.}, archive = {J_PNAS}, author = {Alexander, Tyler D. and Tymanskyj, Stephen and Kennedy, Kyle J. and Kaczmarek, Leonard K. and Covarrubias, Manuel}, doi = {10.1073/pnas.2411033121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2411033121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular mechanism governing the plasticity of use-dependent spike broadening in dorsal root ganglion neurons}, volume = {122}, year = {2025}, }
• (2025). Integrating climate and physical constraints into assessments of net capture from direct air capture facilities. PNAS, 122(1), e2410824121. (www)

  @article{ , abstract = {Limiting climate change to targets enshrined in the Paris Agreement will require both deep decarbonization of the energy system and the deployment of carbon dioxide removal at potentially large scale (gigatons of annual removal). Nations are pursuing direct air capture to compensate for inertia in the expansion of low-carbon energy systems, decarbonize hard-to-abate sectors, and address legacy emissions. Global assessments of this technology have failed to integrate factors that affect net capture and removal cost, including ambient conditions like temperature and humidity, as well as emission factors of electricity and natural gas systems. We present an integrated assessment of the global deployment potential of this technology. Employing a chemical process model, climate data, grid emission factors, and fugitive methane emission factors, we predict critical performance metrics, including carbon dioxide capture rates, and water-, energy-, and emissions-intensity of capture. Our results support investors and policy makers as they site facilities and develop credible policy instruments to support expansion.}, archive = {J_PNAS}, author = {Shorey, Patrick and Abdulla, Ahmed}, doi = {10.1073/pnas.2410824121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2410824121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Integrating climate and physical constraints into assessments of net capture from direct air capture facilities}, volume = {122}, year = {2025}, }
• (2025). A detailed spatiotemporal atlas of the white matter tracts for the fetal brain. PNAS, 122(1), e2410341121. (www)

  @article{ , abstract = {This study presents the construction of a comprehensive spatiotemporal atlas of white matter tracts in the fetal brain for every gestational week between 23 and 36 wk using diffusion MRI (dMRI). Our research leverages data collected from fetal MRI scans, capturing the dynamic changes in the brain’s architecture and microstructure during this critical period. The atlas includes 60 distinct white matter tracts, including commissural, projection, and association fibers. We employed advanced fetal dMRI processing techniques and tractography to map and characterize the developmental trajectories of these tracts. Our findings reveal that the development of these tracts is characterized by complex patterns of fractional anisotropy (FA) and mean diffusivity (MD), coinciding with the intensity of histogenic processes such as axonal growth, involution of the radial-glial scaffolding, and synaptic pruning. This atlas can serve as a useful resource for neuroscience research and clinical practice, improving our understanding of the fetal brain and potentially aiding in the early diagnosis of neurodevelopmental disorders. By detailing the normal progression of white matter tract development, the atlas can be used as a benchmark for identifying deviations that may indicate neurological anomalies or predispositions to disorders.}, archive = {J_PNAS}, author = {Calixto, Camilo and Dorigatti Soldatelli, Matheus and Jaimes, Camilo and Pierotich, Lana and Warfield, Simon K. and Gholipour, Ali and Karimi, Davood}, doi = {10.1073/pnas.2410341121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2410341121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A detailed spatiotemporal atlas of the white matter tracts for the fetal brain}, volume = {122}, year = {2025}, }
• (2025). Predicting gene sequences with AI to study codon usage patterns. PNAS, 122(1), e2410003121. (www)

  @article{ , abstract = {Selective pressure acts on the codon use, optimizing multiple, overlapping signals that are only partially understood. We trained AI models to predict codons given their amino acid sequence in the eukaryotes Saccharomyces cerevisiae and Schizosaccharomyces pombe and the bacteria Escherichia coli and Bacillus subtilis to study the extent to which we can learn patterns in naturally occurring codons to improve predictions. We trained our models on a subset of the proteins and evaluated their predictions on large, separate sets of proteins of varying lengths and expression levels. Our models significantly outperformed naïve frequency-based approaches, demonstrating that there are learnable dependencies in evolutionary-selected codon usage. The prediction accuracy advantage of our models is greater for highly expressed genes and is greater in bacteria than eukaryotes, supporting the hypothesis that there is a monotonic relationship between selective pressure for complex codon patterns and effective population size. In S . cerevisiae and bacteria, our models were more accurate for longer proteins, suggesting that the learned patterns may be related to cotranslational folding. Gene functionality and conservation were also important determinants that affect the performance of our models. Finally, we showed that using information encoded in homologous proteins has only a minor effect on prediction accuracy, perhaps due to complex codon-usage codes in genes undergoing rapid evolution. Our study employing contemporary AI methods offers a unique perspective and a deep-learning-based prediction tool for evolutionary-selected codons. We hope that these can be useful to optimize codon usage in endogenous and heterologous proteins.}, archive = {J_PNAS}, author = {Sidi, Tomer and Bahiri-Elitzur, Shir and Tuller, Tamir and Kolodny, Rachel}, doi = {10.1073/pnas.2410003121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2410003121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Predicting gene sequences with AI to study codon usage patterns}, volume = {122}, year = {2025}, }
• (2025). Molecular basis of spns1-mediated lysophospholipid transport from the lysosome. PNAS, 122(1), e2409596121. (www)

  @article{ , abstract = {Spns1 mediates the rate-limiting efflux of lysophospholipids from the lysosome to the cytosol. Deficiency of Spns1 is associated with embryonic senescence, as well as liver and skeletal muscle atrophy in animal models. However, the mechanisms by which Spns1 transports lysophospholipid and proton sensing remain unclear. Here, we present a cryogenic electron microscopy structure of human Spns1 in lysophosphatidylcholine (LPC)-bound lumen-facing conformation. Notably, LPC snugly binds within the luminal-open cavity, where the molecular dynamics simulations reveal that LPC presents a propensity to enter between transmembrane-helices (TM) 5 and 8. Structural comparisons and cell-based transport assays uncover several pivotal residues at TM 5/8 that orchestrate the transport cycle, which are unique to Spns1. Furthermore, we identify a five-residue network that is crucial for proton-sensing by Spns1. Transference of these network residues to Spns2, a sphingosine-1-phosphate uniporter, causes the chimeric Spns2 to be low pH dependent. Our results reveal molecular insights into lysosomal LPC transport and the proton-sensing mechanism by Spns1.}, archive = {J_PNAS}, author = {Chen, Hongwen and Ha, Hoa T. T. and Elghobashi-Meinhardt, Nadia and Le, Nhung A. and Schmiege, Philip and Nguyen, Long N. and Li, Xiaochun}, doi = {10.1073/pnas.2409596121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2409596121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Molecular basis of spns1-mediated lysophospholipid transport from the lysosome}, volume = {122}, year = {2025}, }
• (2025). Dynamic binding of the bacterial chaperone trigger factor to translating ribosomes in escherichia coli. PNAS, 122(1), e2409536121. (www)

  @article{ , abstract = {The bacterial chaperone Trigger factor (TF) binds to ribosome-nascent chain complexes (RNCs) and cotranslationally aids the folding of proteins in bacteria. Decades of studies have given a broad, but often conflicting, description of the substrate specificity of TF, its RNC-binding dynamics, and competition with other RNC-binding factors, such as the Signal Recognition Particle (SRP). Previous RNC-binding kinetics experiments were commonly conducted on stalled RNCs in reconstituted systems, and consequently, may not be representative of the interaction of TF with ribosomes translating mRNA in the cytoplasm of the cell. Here, we used single-particle tracking (SPT) to measure TF binding to actively translating ribosomes inside living Escherichia coli . In cells, TF displays distinct binding modes—longer (ca 1 s) and shorter (ca 50 ms) RNC bindings. Consequently, we conclude that TF, on average, stays bound to the RNC for only a fraction of the translation cycle. Further, binding events are interrupted only by transient excursions to a freely diffusing state (ca 40 ms), suggesting a highly dynamic binding and unbinding cycle of TF in vivo. We also show that TF competes with SRP for RNC binding, and in doing so, tunes the binding selectivity of SRP.}, archive = {J_PNAS}, author = {Hävermark, Tora and Metelev, Mikhail and Lundin, Erik and Volkov, Ivan L. and Johansson, Magnus}, doi = {10.1073/pnas.2409536121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2409536121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Dynamic binding of the bacterial chaperone trigger factor to translating ribosomes in escherichia coli}, volume = {122}, year = {2025}, }
• (2025). The carnivorous plant genlisea harnesses active particle dynamics to prey on microfauna. PNAS, 122(1), e2409510121. (www)

  @article{ , abstract = {Carnivory in plants is an unusual trait that has arisen multiple times, independently, throughout evolutionary history. Plants in the genus Genlisea are carnivorous and feed on microorganisms that live in soil using modified subterranean leaf structures (rhizophylls). A surprisingly broad array of microfauna has been observed in the plants’ digestive chambers, including ciliates, amoebae, and soil mites. Here, we show, through experiments and simulations, that Genlisea exploit active matter physics to “rectify” bacterial swimming and establish a local flux of bacteria through the structured environment of the rhizophyll toward the plant’s digestion vesicle. In contrast, macromolecular digestion products are free to diffuse away from the digestion vesicle and establish a concentration gradient of carbon sources to draw larger microorganisms further inside the plant. Our experiments and simulations show that this mechanism is likely to be a localized one and that no large-scale efflux of digested matter is present.}, archive = {J_PNAS}, author = {Martín-Roca, José and Barriuso G., C. Miguel and Martínez Fernández, Raúl and Betterelli Giuliano, Camila and Zhang, Rongjing and Valeriani, Chantal and Wilson, Laurence G.}, doi = {10.1073/pnas.2409510121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2409510121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The carnivorous plant genlisea harnesses active particle dynamics to prey on microfauna}, volume = {122}, year = {2025}, }
• (2025). Unlocking the catalytic precision of ligand-controlled enzymatic halogenation. PNAS, 122(1), e2409479122. (www)

  @article{ , abstract = {A single-component flavin-dependent halogenase, AetF, has emerged as an attractive biocatalyst for catalyzing halogenation. However, its flavin chemistry remains unexplored and cannot be predicted due to its uniqueness in sequence and structure compared to other flavin-dependent monooxygenases. Here, we investigated the flavin reactions of AetF using transient kinetics. Our data revealed that NADP + binding is required for formation of C4a-hydroperoxy flavin adenine dinucleotide (FAD) (FAD C4aOOH ), a key flavin-oxygen adduct required for generating a halogenating species. In the presence of NaBr without L-tryptophan, the flavin oxygen adduct intermediates [possibly FAD C4aOOH and C4a-hydroxy FAD (FAD C4aOH )] are highly stabilized (>4,000 s) before returning to the oxidized FAD state. In the presence of L-tryptophan, the rate of FAD C4aOH dehydration to form oxidized FAD increased by ~825-fold. These data suggest that the presence of all substrates is required for speeding up AetF’s catalytic cycle. Our findings underscore the adeptness of AetF in managing its reactivity through ligand control. Structural and tunnel analyses revealed that the binding of NADP + and L-tryptophan induces changes in protein tunnels which may potentially link to the ligand-controlled mechanisms. Leveraging these catalytic insights, we employed light-induced flavin reduction and NADP + stimulation to enable AetF halogenation of various compounds. Our findings demonstrate the mechanisms of precise control over flavin chemistry by AetF. These mechanistic insights may be useful for the biocatalytic development of single-component flavin-dependent halogenases.}, archive = {J_PNAS}, author = {Phintha, Aisaraphon and Lukowski, April L. and Chaiyen, Pimchai}, doi = {10.1073/pnas.2409479122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2409479122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unlocking the catalytic precision of ligand-controlled enzymatic halogenation}, volume = {122}, year = {2025}, }
• (2025). Diverse plant RNAs coat arabidopsis leaves and are distinct from apoplastic RNAs. PNAS, 122(1), e2409090121. (www)

  @article{ , abstract = {Transgenic expression of a double-stranded RNA in plants can induce silencing of homologous mRNAs in fungal pathogens. Although such host-induced gene silencing is well documented, the molecular mechanisms by which RNAs can move from the cytoplasm of plant cells across the plasma membrane of both the host cell and fungal cell are poorly understood. Indirect evidence suggests that this RNA transfer may occur at a very early stage of the infection process, prior to breach of the host cell wall, suggesting that silencing RNAs might be secreted onto leaf surfaces. To assess whether Arabidopsis plants possess a mechanism for secreting RNA onto leaf surfaces, we developed a protocol for isolating leaf surface RNA separately from intercellular (apoplastic) RNA. This protocol yielded abundant leaf surface RNA that displayed an RNA banding pattern distinct from apoplastic RNA, suggesting that it may be secreted directly onto the leaf surface rather than exuded through stomata or hydathodes. Notably, this RNA was not associated with either extracellular vesicles or protein complexes; however, RNA species longer than 100 nucleotides could be pelleted by ultracentrifugation. Furthermore, pelleting was inhibited by the divalent cation chelator EGTA, suggesting that these RNAs may form condensates on the leaf surface. These leaf surface RNAs are derived almost exclusively from Arabidopsis, but come from diverse genomic sources, including rRNA, tRNA, mRNA, intergenic RNA, microRNAs, and small interfering RNAs, with tRNAs especially enriched. We speculate that endogenous leaf surface RNA plays an important role in the assembly of distinct microbial communities on leaf surfaces.}, archive = {J_PNAS}, author = {Borniego, M. Lucía and Singla-Rastogi, Meenu and Baldrich, Patricia and Sampangi-Ramaiah, Megha Hastantram and Zand Karimi, Hana and McGregor, Madison and Meyers, Blake C. and Innes, Roger W.}, doi = {10.1073/pnas.2409090121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2409090121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Diverse plant RNAs coat arabidopsis leaves and are distinct from apoplastic RNAs}, volume = {122}, year = {2025}, }
• (2025). Structural basis of nearest-neighbor cooperativity in the ring-shaped gene regulatory protein TRAP from protein engineering and cryo-EM. PNAS, 122(1), e2409030121. (www)

  @article{ , abstract = {The homo-dodecameric ring-shaped trp RNA binding attenuation protein (TRAP) from Alkalihalobacillus halodurans (Aha) binds up to twelve tryptophan ligands (Trp) and becomes activated to bind a specific sequence in the 5’ leader region of the trp operon mRNA, thereby downregulating biosynthesis of Trp. Thermodynamic measurements of Trp binding have revealed a range of cooperative behavior for different TRAP variants, even if the averaged apparent affinities for Trp have been found to be similar. Proximity between the ligand binding sites, and the ligand-coupled disorder-to-order transition has implicated nearest-neighbor interactions in cooperativity. To establish a solid basis for describing nearest-neighbor cooperativity in TRAP, we engineered variants constructed with two subunits connected by a flexible linker (dTRAP). We mutated the binding sites of alternating protomers such that only every other site was competent for Trp binding (WT-Mut dTRAP). Ligand binding monitored by NMR, calorimetry, and native mass spectrometry revealed strong cooperativity in dTRAP containing adjacent binding-competent sites, but a severe binding defect when the wild-type sites were separated by mutated sites. Cryo-EM experiments of dTRAP in its ligand-free apo state, and both dTRAP and WT-Mut dTRAP in the presence of Trp, revealed progressive stabilization of loops that gate the Trp binding site and participate in RNA binding. These studies provide important insights into the thermodynamic and structural basis for the observed ligand binding cooperativity in TRAP. Such insights can be useful for understanding allosteric control networks and for the development of those with defined ligand sensitivity and regulatory control.}, archive = {J_PNAS}, author = {Li, Weicheng and Yang, Haoyun and Stachowski, Kye and Norris, Andrew S. and Lichtenthal, Katie and Kelly, Skyler and Gollnick, Paul and Wysocki, Vicki H. and Foster, Mark P.}, doi = {10.1073/pnas.2409030121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2409030121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Structural basis of nearest-neighbor cooperativity in the ring-shaped gene regulatory protein TRAP from protein engineering and cryo-EM}, volume = {122}, year = {2025}, }
• (2025). A phase transition in diffusion models reveals the hierarchical nature of data. PNAS, 122(1), e2408799121. (www)

  @article{ , abstract = {Understanding the structure of real data is paramount in advancing modern deep-learning methodologies. Natural data such as images are believed to be composed of features organized in a hierarchical and combinatorial manner, which neural networks capture during learning. Recent advancements show that diffusion models can generate high-quality images, hinting at their ability to capture this underlying compositional structure. We study this phenomenon in a hierarchical generative model of data. We find that the backward diffusion process acting after a time t is governed by a phase transition at some threshold time, where the probability of reconstructing high-level features, like the class of an image, suddenly drops. Instead, the reconstruction of low-level features, such as specific details of an image, evolves smoothly across the whole diffusion process. This result implies that at times beyond the transition, the class has changed, but the generated sample may still be composed of low-level elements of the initial image. We validate these theoretical insights through numerical experiments on class-unconditional ImageNet diffusion models. Our analysis characterizes the relationship between time and scale in diffusion models and puts forward generative models as powerful tools to model combinatorial data properties.}, archive = {J_PNAS}, author = {Sclocchi, Antonio and Favero, Alessandro and Wyart, Matthieu}, doi = {10.1073/pnas.2408799121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2408799121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A phase transition in diffusion models reveals the hierarchical nature of data}, volume = {122}, year = {2025}, }
• (2025). A mechanosensitive circuit of FAK, ROCK, and ERK controls biomineral growth and morphology in the sea urchin embryo. PNAS, 122(1), e2408628121. (www)

  @article{ , abstract = {Biomineralization is the utilization of different minerals by a vast array of organisms to form hard tissues and shape them in various forms. Within this diversity, a common feature of all mineralized tissues is their high stiffness, implying that mechanosensing could be commonly used in biomineralization. Yet, the role of mechanosensing in biomineralization is far from clear. Here, we use the sea urchin larval skeletogenesis to investigate the role of substrate stiffness and focal adhesion kinase (FAK) in biomineralization. We demonstrate that substrate stiffness alters spicule morphology and growth, indicating a mechanosensitive response during skeletogenesis. We show that active FAK, F-actin, and vinculin are enriched around the spicules, indicating the formation of focal adhesion complexes and suggesting that the cells sense the mechanical properties of the biomineral. Furthermore, we find that FAK activity is regulated by Rho-associated protein kinase (ROCK) and is crucial for skeletal growth and normal branching. FAK and ROCK activate extracellular signal-regulated kinase (ERK), which regulates skeletogenic gene expression at the tips of the spicules. Thus, the FAK-ROCK-ERK circuit seems to provide essential mechanical feedback on spicule elongation to the skeletogenic gene regulatory network, enabling skeletal growth. Remarkably, the same factors govern mammalian osteoblast differentiation in vitro and pathological calcification in vivo. Thus, this study highlights a common mechanotransduction pathway in biomineralization that was probably independently co-opted across different organisms to shape mineralized structures in metazoans.}, archive = {J_PNAS}, author = {Layous, Majed and Gildor, Tsvia and Nehrer, Tovah and Qassem, Areen and Wolfenson, Haguy and Ben-Tabou de-Leon, Smadar}, doi = {10.1073/pnas.2408628121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2408628121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A mechanosensitive circuit of FAK, ROCK, and ERK controls biomineral growth and morphology in the sea urchin embryo}, volume = {122}, year = {2025}, }
• (2025). Conservation of symbiotic signaling since the most recent common ancestor of land plants. PNAS, 122(1), e2408539121. (www)

  @article{ , abstract = {Plants have colonized lands 450 million years ago. This terrestrialization was facilitated by developmental and functional innovations. Recent evo-devo approaches have demonstrated that one of these innovations was the mutualistic arbuscular mycorrhizal symbiosis (AMS). The genetic pathways that have been involved in the establishment and functioning of AMS since its evolution remain poorly described. Here, we found that intracellular colonization by AM fungi induces a transcriptional reporter of the common symbiosis pathway, well-described in angiosperms, in the liverwort Marchantia paleacea . Mutants of either of the three main genes of this pathway, SYMRK , CCaMK, and CYCLOPS, disrupt the ability of M. paleacea to associate with AM fungi. Finally, overexpressing gain-of-function CCaMK or CYCLOPS leads to convergent transcriptomic signatures that partially overlap with AMS. Altogether, our data indicate that plants have maintained three genes of the common symbiotic pathway to support symbiotic interactions since their most recent common ancestor.}, archive = {J_PNAS}, author = {Vernié, Tatiana and Rich, Mélanie and Pellen, Tifenn and Teyssier, Eve and Garrigues, Vincent and Chauderon, Lucie and Medioni, Lauréna and van Beveren, Fabian and Libourel, Cyril and Keller, Jean and Girou, Camille and Lefort, Corinne and Le Ru, Aurélie and Martinez, Yves and Reinhardt, Didier and Kodama, Kyoichi and Shimazaki, Shota and Morel, Patrice and Kyozuka, Junko and Mbengue, Malick and Vandenbussche, Michiel and Delaux, Pierre-Marc}, doi = {10.1073/pnas.2408539121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2408539121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Conservation of symbiotic signaling since the most recent common ancestor of land plants}, volume = {122}, year = {2025}, }
• (2025). Energy–poverty–inequality SDGs: A large-scale household analysis and forecasting in china. PNAS, 122(1), e2408167121. (www)

  @article{ , abstract = {Affordable and clean energy, eliminating poverty, and reducing inequality are important goals of the United Nations Sustainable Development Goals (SDGs). This paper examines the role of access to clean cooking fuels in promoting income growth and reducing income inequality. Using data from Chinese households, we show that a 10% increase in the adoption of clean cooking fuels would result in an increase in total annual household income of US$37 billion nationwide. Income growth from access to clean cooking fuels is greater for lower-income groups due to a shift to higher household income and reduced downward household income mobility, which contributes to a reduction in income inequality. The effect of access to clean cooking fuels on household income growth is primarily driven by improved health and increased labor supply. The use of clean cooking fuels also saves fuel collection time and cooking time, reducing time spent on household chores by about 0.4 h per day, thereby increasing labor supply in the job market and improving wage income. Improvements in income due to clean cooking fuels are influenced by external conditions, urbanization, education, employment opportunities, and good market conditions. With further promotion of clean cooking fuels, household income and inequality in China are expected to improve further by 2030 and contribute more widely to human well-being and achievement of the SDGs.}, archive = {J_PNAS}, author = {Li, Cong and Li, Minglai and Zhang, Lin and Li, Qiang and Zheng, Hua and Feldman, Marcus W.}, doi = {10.1073/pnas.2408167121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2408167121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Energy–poverty–inequality SDGs: A large-scale household analysis and forecasting in china}, volume = {122}, year = {2025}, }
• (2025). Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors. PNAS, 122(1), e2407745121. (www)

  @article{ , abstract = {Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). These malignancies develop within preexisting benign lesions called plexiform neurofibromas (PNs). PNs are solely driven by biallelic NF1 loss eliciting RAS pathway activation, and they respond favorably to MEK inhibitor therapy. MPNSTs harbor additional mutations and respond poorly to MEK inhibition. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST models indicates that MEK inhibition has poor antitumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors were performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining SHP2 inhibition with hydroxychloroquine (HQ) resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies could be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with HQ as a unique treatment approach for NF1 MPNSTs.}, archive = {J_PNAS}, author = {Sait, Sameer Farouk and Tang, Kwan Ho and Angus, Steven P. and Brown, Rebecca and Sun, Daochun and Xie, Xuanhua and Iltis, Charlene and Lien, Michelle and D. Socci, Nicholas and Bale, Tejus A. and Davis, Christopher and Dixon, Shelley A. H. and Zhang, Chi and Wade Clapp, D. and Neel, Benjamin G. and Parada, Luis F.}, doi = {10.1073/pnas.2407745121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2407745121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors}, volume = {122}, year = {2025}, }
• (2025). Tamsulosin ameliorates bone loss by inhibiting the release of cl− through wedging into an allosteric site of TMEM16A. PNAS, 122(1), e2407493121. (www)

  @article{ , abstract = {TMEM16A, a key calcium-activated chloride channel, is crucial for many physiological and pathological processes such as cancer, hypertension, and osteoporosis, etc. However, the regulatory mechanism of TMEM16A is poorly understood, limiting the discovery of effective modulators. Here, we unveil an allosteric gating mechanism by presenting a high-resolution cryo-EM structure of TMEM16A in complex with a channel inhibitor that we identified, Tamsulosin, which is resolved at 2.93 Å. Tamsulosin wedges itself into a pocket within the extracellular domain of TMEM16A, surrounded by α1-α2, α5-α6, and α9-α10 loops. This binding stabilizes a transient preopen conformation of TMEM16A, which is activated by Ca 2+ ions while still preserving a closed pore to prevent Cl − permeation. Validation of this binding site through computational, electrophysiological, and functional experiments, along with site-directed mutagenesis, confirmed the pivotal roles of the pocket-lining residues R605 and E624 on α5-α6 loop in modulating Tamsulosin binding and pore activity. Tamsulosin induces significant positional shifts in extracellular loops, particularly the α5-α6 loop, which moves toward the extracellular exit of the pore, leading to noticeable structural rearrangements in pore-lining helices. The hinges induced by P595 in α5 and G711 in α7 introduce flexibility to the transmembrane helices, orienting Y593 to collaborate with I641 in effectively gating the preopening pore. Notably, Tamsulosin demonstrates significant antiosteoporotic effects by inhibiting TMEM16A, suggesting potential for its repurposing in new therapeutic indications. Our study not only enhances our understanding of the gating mechanism of TMEM16A inhibition but also facilitates structure-based drug design targeting TMEM16A.}, archive = {J_PNAS}, author = {Li, Shiliang and Sun, Weijia and Li, Shuang and Zhu, Lili and Guo, Shuai and He, Jiaqi and Li, Yuheng and Tian, Chaoquan and Zhao, Zhenjiang and Yu, Tao and Li, Jianwei and Zhang, Yiqing and Hai, Youlong and Wang, Jiawen and Zheng, Yongjun and Wang, Rui and Hu, Xiaoyong and Ling, Shukuan and Li, Honglin and Li, Yingxian}, doi = {10.1073/pnas.2407493121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2407493121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Tamsulosin ameliorates bone loss by inhibiting the release of cl− through wedging into an allosteric site of TMEM16A}, volume = {122}, year = {2025}, }
• (2025). Nocturnal camouflage through background matching against moonlight. PNAS, 122(1), e2406808121. (www)

  @article{ , abstract = {Camouflage is often considered a daytime phenomenon based on light and shade. Nocturnal camouflage can also occur, but its mechanistic basis remains unclear. Here, we analyze the conditions for background matching (BM) of avian predators against the night sky. Such concealment is achieved when the contrast between the predator and the sky is smaller than the contrast detection threshold of prey. This condition cannot be fulfilled under isotropic skies, as in fully overcast or moonless nights. However, on clear moonlit nights, the isotropy of the sky radiance is broken due to the presence of the Moon, and the conditions for BM can be met for a wide range of sky directions. This effect is mainly dependent on the altitude of the Moon above the horizon, rather than on Moon phase. We have modeled the feasibility of concealment through BM of a typically white barn owl ( Tyto alba ) when hunting rodents, based on its contrast against the moonlit sky. We considered the radiometric quantities of the sky, the ground, and the bird’s undersides. Our results show that a barn owl with highly reflecting underparts may approach a rodent from broad regions of the moonlit sky while keeping itself below the contrast detection threshold of the mouse M-cones and rods. S-cones, in turn, remain below their excitation threshold for most of the lunar cycle. Our results demonstrate that the white color of barn owls serves as camouflage tailored to the moonlit sky background, providing a mechanistic basis for understanding nocturnal camouflage.}, archive = {J_PNAS}, author = {Negro, Juan J. and Bará, Salvador and Galadí-Enríquez, David and Nieves, Juan Luis and Martínez-Domingo, Miguel A. and Ferrero, Alejandro and Campos, Joaquín and Bao-Varela, Carmen and Masana, Eduard and Camacho, Carlos}, doi = {10.1073/pnas.2406808121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2406808121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nocturnal camouflage through background matching against moonlight}, volume = {122}, year = {2025}, }
• (2025). Pseudogap in electron-doped cuprates: Strong correlation leading to band splitting. PNAS, 122(1), e2406624122. (www)

  @article{ , abstract = {The pseudogap phenomena have been a long-standing mystery of the cuprate high-temperature superconductors. The pseudogap in the electron-doped cuprates has been attributed to band folding due to antiferromagnetic (AFM) long-range order or short-range correlation. We performed an angle-resolved photoemission spectroscopy study of the electron-doped cuprates Pr 1.3− x La 0.7 Ce x CuO 4 showing spin-glass, disordered AFM behaviors, and superconductivity at low temperatures and, by measurements with fine momentum cuts, found that the gap opens on the unfolded Fermi surface rather than the AFM Brillouin zone boundary. The gap did not show a node, following the full symmetry of the Brillouin zone, and its magnitude decreased from the zone-diagonal to ( π ,0) directions, opposite to the hole-doped case. These observations were reproduced by cluster dynamical-mean-field-theory calculation, which took into account electron correlation precisely within a (CuO 2 ) 4 cluster. The present experimental and theoretical results are consistent with the mechanism that electron or hole doping into a Mott insulator creates an in-gap band that is separated from the upper or lower Hubbard band by the pseudogap.}, archive = {J_PNAS}, author = {Horio, Masafumi and Sakai, Shiro and Suzuki, Hakuto and Nonaka, Yosuke and Hashimoto, Makoto and Lu, Donghui and Shen, Zhi-Xun and Ohgi, Taro and Konno, Takuya and Adachi, Tadashi and Koike, Yoji and Imada, Masatoshi and Fujimori, Atsushi}, doi = {10.1073/pnas.2406624122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2406624122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Pseudogap in electron-doped cuprates: Strong correlation leading to band splitting}, volume = {122}, year = {2025}, }
• (2025). Unveiling hidden reaction kinetics of carbon dioxide in supercritical aqueous solutions. PNAS, 122(1), e2406356121. (www)

  @article{ , abstract = {Dissolution of CO 2 in water followed by the subsequent hydrolysis reactions is of great importance to the global carbon cycle, and carbon capture and storage. Despite numerous previous studies, the reactions are still not fully understood at the atomistic scale. Here, we combined ab initio molecular dynamics (AIMD) simulations with Markov state models to elucidate the reaction mechanisms and kinetics of CO 2 in supercritical water both in the bulk and nanoconfined states. The integration of unsupervised learning with first-principles data allows us to identify complex reaction coordinates and pathways automatically instead of a priori human speculation. Interestingly, our unbiased modeling found an unknown pathway of dissolving CO 2 (aq) under graphene nanoconfinement, involving the pyrocarbonate anion [C 2 O 5 2 − (aq)] as an intermediate state. The pyrocarbonate anion was previously hypothesized to have a fleeting existence in water; however, our study reveals that it is a crucial reaction intermediate and stable carbon species in the nanoconfined solutions. We even observed the formation of pyrocarbonic acid [H 2 C 2 O 5 (aq)], which was unknown in water, in our AIMD simulations. The unexpected appearance of pyrocarbonates is related to the superionic behavior of the confined solutions. We also found that carbonation reactions involve collective proton transfer along transient water wires, which exhibits concerted behavior in the bulk solution but proceeds stepwise under nanoconfinement. The first-principles Markov state models show substantial promise for elucidating complex reaction kinetics in aqueous solutions. Our study highlights the importance of large oxocarbons in aqueous carbon reactions, with great implications for the deep carbon cycle and the sequestration of CO 2 .}, archive = {J_PNAS}, author = {Li, Chu and Yao, Yuan and Pan, Ding}, doi = {10.1073/pnas.2406356121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2406356121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Unveiling hidden reaction kinetics of carbon dioxide in supercritical aqueous solutions}, volume = {122}, year = {2025}, }
• (2025). Protein dynamics underlies strong temperature dependence of heat receptors. PNAS, 122(1), e2406318121. (www)

  @article{ , abstract = {Ion channels are generally allosteric proteins, involving specialized stimulus sensor domains conformationally linked to the gate to drive channel opening. Temperature receptors are a group of ion channels from the transient receptor potential family. They exhibit an unprecedentedly strong temperature dependence and are responsible for temperature sensing in mammals. Despite intensive studies, however, the nature of the temperature sensor domain in these channels remains elusive. By direct calorimetry of TRPV1 proteins, we have recently provided a proof of principle that temperature sensing by ion channels may diverge from the conventional allosterity theory; rather it is intimately linked to inherent thermal instability of channel proteins. Here, we tackle the generality of the hypothesis and provide key molecular pieces of evidence on the coupling of thermal transitions in the channels. We show that while wild-type channels possess a single concerted thermal transition peak, the chimera, in which strong temperature dependence becomes disrupted, results in multitransition peaks, and the activation enthalpies are accordingly reduced. The data show that the coupling with protein unfolding drives up the energy barrier of activation, leading to a strong temperature dependence of opening. Furthermore, we pinpoint the proximal N-terminus of the channels as a linchpin in coalescing different parts of the channels into concerted activation. Thus, we suggest that coupled interaction networks in proteins underlie the strong temperature dependence of temperature receptors.}, archive = {J_PNAS}, author = {Mugo, Andrew Njagi and Chou, Ryan and Qin, Feng}, doi = {10.1073/pnas.2406318121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2406318121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Protein dynamics underlies strong temperature dependence of heat receptors}, volume = {122}, year = {2025}, }
• (2025). Nucleation mechanism of multiple-order parameter ferroelectric domain wall motion in hafnia. PNAS, 122(1), e2406316122. (www)

  @article{ , abstract = {Ferroelectric hafnia exhibits promising robust polarization and silicon compatibility for ferroelectric devices. Unfortunately, it suffers from difficult polarization switching. Methods to enable easier polarization switching are needed, and the underlying reason for this switching difficulty is not understood. Here, we investigated the 180 ° domain walls of hafnia and their motion through nucleation. We found that the domains of multiple-order parameter hafnia possess complicated three-dimensional dipole patterns and lead to domain walls of different symmetry. The most common domain wall type is a complex domain wall involving reversal of both polarization and tetragonality order parameters. This domain wall symmetry ensures a good matching of the dipoles perpendicular to the domain wall, which leads to low domain wall energy. However, this ensures a sharp, high-energy, charged domain wall on the edges of nuclei that results in difficult nucleation. Thus, this domain wall is too stable to move, which explains the switching difficulty of hafnia. By contrast, another simple domain wall, involving only polarization reversal, has a poor matching of dipoles perpendicular to the domain wall. This leads to higher domain wall energy and ensures a diffusive and low-energy charged domain wall that enables easier nucleation. This simple domain wall is thus not too stable and easier to move. Our theory advances domain wall nucleation theory from the field of conventional single-order parameter to multiple-order parameters. We propose controlling the populations of different domain wall types in hafnia as a way to enable fast polarization switching and lower coercive fields.}, archive = {J_PNAS}, author = {Zhou, Songsong and Rappe, Andrew M.}, doi = {10.1073/pnas.2406316122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2406316122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Nucleation mechanism of multiple-order parameter ferroelectric domain wall motion in hafnia}, volume = {122}, year = {2025}, }
• (2025). Climate change could amplify weak synchrony in large marine ecosystems. PNAS, 122(1), e2404155121. (www)

  @article{ , abstract = {Climate change is increasing the frequency of large-scale, extreme environmental events and flattening environmental gradients. Whether such changes will cause spatially synchronous, large-scale population declines depends on mechanisms that limit metapopulation synchrony, thereby promoting rescue effects and stability. Using long-term data and empirical dynamic models, we quantified spatial heterogeneity in density dependence, spatial heterogeneity in environmental responses, and environmental gradients to assess their role in inhibiting synchrony across 36 marine fish and invertebrate species. Overall, spatial heterogeneity in population dynamics was as important as environmental drivers in explaining population variation. This heterogeneity leads to weak synchrony in the California Current Ecosystem, where populations exhibit diverse responses to shared, large-scale environmental change. In contrast, in the Northeast U.S. Shelf Ecosystem, gradients in average environmental conditions among locations, filtered through nonlinear environmental response curves, limit synchrony. Simulations predict that environmental gradients and response diversity will continue to inhibit synchrony even if large-scale environmental extremes become common. However, if environmental gradients weaken, synchrony and periods of large-scale population decline may rise sharply among commercially important species on the Northeast Shelf. Our approach thus allows ecologists to 1) quantify how differences among local communities underpin landscape-scale resilience and 2) identify the kinds of future climatic changes most likely to amplify synchrony and erode species stability.}, archive = {J_PNAS}, author = {Karatayev, Vadim A. and Munch, Stephan B. and Rogers, Tanya L. and Reuman, Daniel C.}, doi = {10.1073/pnas.2404155121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2404155121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Climate change could amplify weak synchrony in large marine ecosystems}, volume = {122}, year = {2025}, }
• (2025). The proteome is a terminal electron acceptor. PNAS, 122(1), e2404048121. (www)

  @article{ , abstract = {Microbial metabolism is impressively flexible, enabling growth even when available nutrients differ greatly from biomass in redox state. Escherichia coli , for example, rearranges its physiology to grow on reduced and oxidized carbon sources through several forms of fermentation and respiration. To understand the limits on and evolutionary consequences of this metabolic flexibility, we developed a coarse-grained mathematical framework coupling redox chemistry with principles of cellular resource allocation. Our models inherit key qualities from both of their antecedents: i) describing diverse metabolic chemistries and ii) enforcing the simultaneous balancing of atom (e.g., carbon), electron, and energy (adenosine triphosphate) flows, as in redox models, while iii) treating biomass as both the product and catalyst of the growth process, as in resource allocation models. Assembling integrated models of respiration, fermentation, and photosynthesis clarified key microbiological phenomena, including demonstrating that autotrophs grow more slowly than heterotrophs because of constraints imposed by the intracellular production of reduced carbon. Our model further predicted that heterotrophic growth is improved by matching the redox state of biomass to the nutrient environment. Through analysis of ≈ 60,000 genomes and diverse proteomic datasets, we found evidence that proteins indeed accumulate amino acid substitutions promoting redox matching. We therefore propose an unexpected mode of genome evolution where substitutions neutral or even deleterious to the individual biochemical or structural functions of proteins can nonetheless be selected due to a redox-chemical benefit to the population.}, archive = {J_PNAS}, author = {Flamholz, Avi I. and Goyal, Akshit and Fischer, Woodward W. and Newman, Dianne K. and Phillips, Rob}, doi = {10.1073/pnas.2404048121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2404048121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The proteome is a terminal electron acceptor}, volume = {122}, year = {2025}, }
• (2025). Oncogenic IDH1mut drives robust loss of histone acetylation and increases chromatin heterogeneity. PNAS, 122(1), e2403862122. (www)

  @article{ , abstract = {Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2 mut ) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype. Yet, the complete depiction of the epigenetic alterations in IDH mut cells has not been thoroughly explored. Here, we applied an unbiased approach, leveraging epigenetic-focused cytometry by time-of-flight (CyTOF) analysis, to systematically profile the effect of mutant-IDH1 expression on a broad panel of histone modifications at single-cell resolution. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH1, with the most prominent being deregulation of histone acetylation marks. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Notably, the changes in acetylation are not predominantly driven by 2-HG, can be rescued by pharmacological inhibition of mutant-IDH1, and reversed by acetate supplementations. Furthermore, cells expressing mutant-IDH1 show higher epigenetic and transcriptional heterogeneity and upregulation of oncogenes such as KRAS and MYC, highlighting its tumorigenic potential. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma and highlights epigenetic and oncogenic pathways affected by mutant-IDH1-driven metabolic rewiring.}, archive = {J_PNAS}, author = {Furth, Noa and Cohen, Niv and Spitzer, Avishay and Salame, Tomer-Meir and Dassa, Bareket and Mehlman, Tevie and Brandis, Alexander and Moussaieff, Arieh and Friedmann-Morvinski, Dinorah and Castro, Maria G. and Fortin, Jerome and Suvà, Mario L. and Tirosh, Itay and Erez, Ayelet and Ron, Guy and Shema, Efrat}, doi = {10.1073/pnas.2403862122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2403862122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Oncogenic IDH1mut drives robust loss of histone acetylation and increases chromatin heterogeneity}, volume = {122}, year = {2025}, }
• (2025). Salmonella infection accelerates postnatal maturation of the intestinal epithelium. PNAS, 122(1), e2403344122. (www)

  @article{ , abstract = {Postnatal establishment of enteric metabolic, host–microbial and immune homeostasis is the result of precisely timed and tightly regulated developmental and adaptive processes. Here, we show that infection with the invasive enteropathogen Salmonella Typhimurium results in accelerated maturation of the neonatal epithelium with premature appearance of antimicrobial, metabolic, developmental, and regenerative features of the adult tissue. Using conditional Myd88-deficient mice, we identify the critical contribution of immune cell-derived mediators. Cytokine stimulation of neonatal intestinal epithelial stem cell organoids suggests a network of synergistic and antagonistic cytokine effects with a significant contribution of IL-22, IL-4/IL-13, TNF, and IL-6 to infection-induced enterocyte reprogramming. Our findings demonstrate that the infection-associated immune cell activation disrupts physiological postnatal tissue maturation and may thereby worsen clinical outcomes and alter the neonatal-adult transition.}, archive = {J_PNAS}, author = {Schlößer, Stefan and Ullrich, Anna-Lena and Modares, Nastaran Fazel and Schmitz, Matthias A. and Schöneich, Johannes and Zhang, Kaiyi and Richter, Isabel and Robrahn, Laura and Schraven, Sarah and Nagai, James S. and Haange, Sven-Bastiaan and Jennings, Susan A. V. and Clavel, Thomas and Rolle-Kampczyk, Ulrike and Kiessling, Fabian and Costa, Ivan G. and Muncan, Vanesa and Repnik, Urska and von Bergen, Martin and Dupont, Aline and Hornef, Mathias W.}, doi = {10.1073/pnas.2403344122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2403344122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Salmonella infection accelerates postnatal maturation of the intestinal epithelium}, volume = {122}, year = {2025}, }
• (2025). Deriving a genetic regulatory network from an optimization principle. PNAS, 122(1), e2402925121. (www)

  @article{ , abstract = {Many biological systems operate near the physical limits to their performance, suggesting that aspects of their behavior and underlying mechanisms could be derived from optimization principles. However, such principles have often been applied only in simplified models. Here, we explore a detailed mechanistic model of the gap gene network in the Drosophila embryo, optimizing its 50+ parameters to maximize the information that gene expression levels provide about nuclear positions. This optimization is conducted under realistic constraints, such as limits on the number of available molecules. Remarkably, the optimal networks we derive closely match the architecture and spatial gene expression profiles observed in the real organism. Our framework quantifies the tradeoffs involved in maximizing functional performance and allows for the exploration of alternative network configurations, addressing the question of which features are necessary and which are contingent. Our results suggest that multiple solutions to the optimization problem might exist across closely related organisms, offering insights into the evolution of gene regulatory networks.}, archive = {J_PNAS}, author = {Sokolowski, Thomas R. and Gregor, Thomas and Bialek, William and Tkačik, Gašper}, doi = {10.1073/pnas.2402925121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2402925121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Deriving a genetic regulatory network from an optimization principle}, volume = {122}, year = {2025}, }
• (2025). Restart uncertainty relation for monitored quantum dynamics. PNAS, 122(1), e2402912121. (www)

  @article{ , abstract = {We introduce a time-energy uncertainty relation within the context of restarts in monitored quantum dynamics. Previous studies have established that the mean recurrence time, which represents the time taken to return to the initial state, is quantized as an integer multiple of the sampling time, displaying pointwise discontinuous transitions at resonances. Our findings demonstrate that the natural utilization of the restart mechanism in laboratory experiments, driven by finite data collection time spans, leads to a broadening effect on the transitions of the mean recurrence time. Our proposed uncertainty relation captures the underlying essence of these phenomena, by connecting the broadening of the mean hitting time near resonances, to the intrinsic energies of the quantum system and to the fluctuations of recurrence time. Our uncertainty relation has also been validated through remote experiments conducted on an International Business Machines Corporation (IBM) quantum computer. This work not only contributes to our understanding of fundamental aspects related to quantum measurements and dynamics, but also offers practical insights for the design of efficient quantum algorithms with mid-circuit measurements.}, archive = {J_PNAS}, author = {Yin, Ruoyu and Wang, Qingyuan and Tornow, Sabine and Barkai, Eli}, doi = {10.1073/pnas.2402912121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2402912121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Restart uncertainty relation for monitored quantum dynamics}, volume = {122}, year = {2025}, }
• (2025). Integration of basal and apical embryo lineage regulators controls F-actin cable integrity and zygote asymmetry in arabidopsis. PNAS, 122(1), e2402720122. (www)

  @article{ , abstract = {In many plants, the asymmetric division of the zygote sets up the apical–basal body axis. In the cress Arabidopsis , the zygote coexpresses regulators of the apical and basal embryo lineages, the transcription factors WOX2 and WRKY2/WOX8, respectively. WRKY2/WOX8 activity promotes nuclear migration, cellular polarity, and mitotic asymmetry of the zygote, which are hallmarks of axis formation in many plant species. However, the role of WOX2 and how the antagonistic WOX2 and WRKY2/WOX8 functions are integrated in the zygote have remained a long-standing question. Here, we report that WOX2 loss-of-function completely suppresses the reduced zygote asymmetry of wrky2 mutants and that WOX2 overexpression mimics the wrky2 phenotype. At the molecular level, WRKY2 downregulates WOX2 transcription in the zygote and the basal embryo lineage, in addition to promoting WOX8 expression. WOX2 antagonizes WRKY2 function by repressing WOX8 transcription. As a physiological readout, the WRKY2/WOX8-WOX2 balance regulates the integrity of F-actin cables in the zygote, providing a mechanistic framework for the role of WRKY2/WOX8-WOX2-mediated zygote asymmetry.}, archive = {J_PNAS}, author = {Xiong, Feng and Zhang, Zhongjuan and Gong, Wen and Hermann, Marita and Bak, Deniz Tiambeng and Garbsch, Frauke and Laux, Thomas}, doi = {10.1073/pnas.2402720122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2402720122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Integration of basal and apical embryo lineage regulators controls F-actin cable integrity and zygote asymmetry in arabidopsis}, volume = {122}, year = {2025}, }
• (2025). US corn belt enhances regional precipitation recycling. PNAS, 122(1), e2402656121. (www)

  @article{ , abstract = {Precipitation recycling, where evapotranspiration (ET) from the land surface contributes to precipitation within the same region, is a critical component of the water cycle. This process is especially important for the US Corn Belt, where extensive cropland expansions and irrigation activities have significantly transformed the landscape and affected the regional climate. Previous studies investigating precipitation recycling typically relied on analytical models with simplifying assumptions, overlooking the complex interactions between groundwater hydrology and agricultural management. In this study, we use high-resolution climate models coupled with an explicit water vapor tracer algorithm to quantify the impacts of shallow groundwater, dynamic crop growth, and irrigation on regional precipitation recycling in the US Corn Belt. We find that these coupled groundwater–crop–irrigation processes reduce surface temperatures and increase the growing season precipitation. The increase in precipitation is attributed to a significant enhancement of the precipitation recycling ratio from 14 to 18%. This enhanced precipitation recycling is stronger in a dry year than normal and wet years, depending on both large-scale moisture transport and local ET. Our study underscores the critical role of groundwater hydrology and agricultural management in altering the regional water cycle, with important implications for regional climate predictions and food and water security.}, archive = {J_PNAS}, author = {Zhang, Zhe and He, Cenlin and Chen, Fei and Miguez-Macho, Gonzalo and Liu, Changhai and Rasmussen, Roy}, doi = {10.1073/pnas.2402656121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2402656121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {US corn belt enhances regional precipitation recycling}, volume = {122}, year = {2025}, }
• (2025). Oppositional and competitive instigation of hippocampal synaptic plasticity by the VTA and locus coeruleus. PNAS, 122(1), e2402356122. (www)

  @article{ , abstract = {The novelty, saliency, and valency of ongoing experiences potently influence the firing rate of the ventral tegmental area (VTA) and the locus coeruleus (LC). Associative experience, in turn, is recorded into memory by means of hippocampal synaptic plasticity that is regulated by noradrenaline sourced from the LC, and dopamine, sourced from both the VTA and LC. Two persistent forms of synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD) support the encoding of different kinds of spatial experience. To what extent the VTA and the LC influence the direction of change of synaptic plasticity and therefore the content of stored experience is not clear. Here, we report that test-pulse activation of Schaffer-collateral–CA1 synapses of freely behaving male rats, in conjunction with VTA stimulation, results in LTP (>24 h), whereas concomitant hippocampal afferent and LC stimulation results in LTD (>24 h). Effects are frequency-dependent (1 to 50 Hz) and competitive: high-frequency (25 Hz), but not low-frequency (5 Hz) optogenetic activation of tyrosine hydroxylase-positive (TH+) neurons in the VTA, results in D1/D5R-dependent LTP, whereas 5 Hz (but not 1, or 25 Hz) activation of TH+ neurons in the LC results in hippocampal LTD that is both D1/D5 and β-AR-dependent. These results suggest that the VTA and LC do not work in synergy, but rather function in a competing fashion to drive different forms of information encoding through synaptic plasticity. Our findings indicate that information transmitted by the VTA and LC is likely to play a decisive role in the shaping of hippocampal information storage and the nature of learned experience.}, archive = {J_PNAS}, author = {Hagena, Hardy and Manahan-Vaughan, Denise}, doi = {10.1073/pnas.2402356122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2402356122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Oppositional and competitive instigation of hippocampal synaptic plasticity by the VTA and locus coeruleus}, volume = {122}, year = {2025}, }
• (2025). An exchangeable SIM probe for monitoring organellar dynamics of necrosis cells and intracellular water heterogeneity in kidney repair. PNAS, 122(1), e2402348121. (www)

  @article{ , abstract = {Monitoring subcellular organelle dynamics in real time and precisely assessing membrane heterogeneity in living cells are very important for studying fundamental biological mechanisms and gaining a comprehensive understanding of cellular processes. However, there remains a shortage of effective tools for these purposes. Herein, we propose a strategy to develop the exchangeable water-sensing probeAPBD for time-lapse imaging of dynamics in cellular membrane-bound organelle morphology with structured illumination microscopy at the nanoscale. In this work, our results reveal mitochondria as the first organelle to undergo morphological changes through swelling, fission, and fusion in cell necrosis, leading to the rupture of the endoplasmic reticulum (ER) sheet adhered to the mitochondria. Meanwhile, the ER tubules are then reconstructed by stretching and fusion of autophagosomes. Moreover, APBD allows us to directly visualize spatially resolved distribution of biomembranes vs. water inside single mammalian cells. Our findings show that the renal ischemia–reperfusion injury (IRI) model results in the increased biomembrane to cytoplasmic water ratio in the tissue. This reveals intracellular water heterogeneity between the nucleus and the cytoplasm during the IRI process. Overall, this study presents a strategy for development of the molecular tools for cellular water heterogeneity and organelle dynamics.}, archive = {J_PNAS}, author = {Lai, Youbo and Zhang, Tengteng and Huang, Ling and Klymchenko, Andrey S. and Lin, Weiying}, doi = {10.1073/pnas.2402348121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2402348121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An exchangeable SIM probe for monitoring organellar dynamics of necrosis cells and intracellular water heterogeneity in kidney repair}, volume = {122}, year = {2025}, }
• (2025). Aerosol light absorption alleviates particulate pollution during wintertime haze events. PNAS, 122(1), e2402281121. (www)

  @article{ , abstract = {Aerosol light absorption has been widely considered as a contributing factor to the worsening of particulate pollution in large urban areas, primarily through its role in stabilizing the planetary boundary layer (PBL). Here, we report that absorption-dominated aerosol–radiation interaction can decrease near-surface fine particulate matter concentrations ([PM 2.5 ]) at a large-scale during wintertime haze events. A “warm bubble” effect by the significant heating rate of absorbing aerosols above the PBL top generates a secondary circulation, enhancing the upward motion (downward motion) and the convergence (divergence) in polluted (relatively clean) areas, with a net effect of lowering near-surface [PM 2.5 ]. Furthermore, aerosol absorption of ultraviolet-wave light effectively reduces the photolysis of chemical species, i.e., aerosol–photolysis interaction, hindering ozone formation, reducing atmospheric oxidizing capability, and suppressing secondary aerosol concentrations. Our model assessment reveals that the synergetic two effects decrease near-surface [PM 2.5 ] by around 7.4%, so the presence of light-absorbing aerosols can considerably alleviate particulate pollution during wintertime haze events. Such negative feedbacks to the aerosol loading should be considered in weather/climate prediction and health assessment models.}, archive = {J_PNAS}, author = {Wu, Jiarui and Bei, Naifang and Wang, Yuan and Su, Xiaoli and Zhang, Ningning and Wang, Lili and Hu, Bo and Wang, Qiyuan and Jiang, Qian and Zhang, Chenchong and Liu, Yangfan and Wang, Ruonan and Li, Xia and Lu, Yuxuan and Liu, Zirui and Cao, Junji and Tie, Xuexi and Li, Guohui and Seinfeld, John}, doi = {10.1073/pnas.2402281121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2402281121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Aerosol light absorption alleviates particulate pollution during wintertime haze events}, volume = {122}, year = {2025}, }
• (2025). How and why funders support engaged research. PNAS, 122(1), e2400931121. (www)

  @article{ , abstract = {Research that better aligns policy, practice, and research communities is gaining momentum around the world. This includes engaged research strategies that bring partners, and their diverse perspectives and kinds of knowledge, together to shape research agendas with on-the-ground-needs and to create dynamic problem-solving processes. These approaches aim to generate more equitable and effective solutions to societal challenges. Although many of these partnered strategies have a longstanding history, entrenched research cultures, practices, and institutional structures stand in the way of scaling them. Given the outsized role funders play in shaping research efforts, funders are a critical lever for change. This perspective describes the efforts of a global collaborative of philanthropic and public funders who are adapting their practices, supporting the development of infrastructure (e.g., capacity-strengthening, facilitation expertise, processes to guide relational work, etc.), and targeting system-level challenges to enable engaged research to maximize its potential. The authors integrate insights from different issue areas, geographies, and funding areas to provide concrete examples of funder activities that support engaged research and to suggest areas for further action. Recommendations include scaling changes in funding practices, deepening understanding of how and when engaged research leads to improved outcomes, and reshaping how success is defined and measured.}, archive = {J_PNAS}, author = {Bednarek, Angela T. and Miyamoto, Ben and Corbett, Kristin and Hudson, Charlotte and Scarrow, Gayle and Brass, Maeghan and DuMont, Kim and Holmes, Bev and Supplee, Lauren and McLean, Robert and Bhatia, Jaspal and Chappell, Shamira and Gorman Vélez, Maggie and Kolavalli, Chhaya}, doi = {10.1073/pnas.2400931121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2400931121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {How and why funders support engaged research}, volume = {122}, year = {2025}, }
• (2025). Memory control deficits in the sleep-deprived human brain. PNAS, 122(1), e2400743122. (www)

  @article{ , abstract = {Sleep disturbances are associated with intrusive memories, but the neurocognitive mechanisms underpinning this relationship are poorly understood. Here, we show that sleep deprivation disrupts prefrontal inhibition of memory retrieval, and that the overnight restoration of this inhibitory mechanism is associated with time spent in rapid eye movement (REM) sleep. The functional impairments arising from sleep deprivation are linked to a behavioral deficit in the ability to downregulate unwanted memories, and coincide with a deterioration of deliberate patterns of self-generated thought. We conclude that sleep deprivation gives rise to intrusive memories via the disruption of neural circuits governing mnemonic inhibitory control, which may rely on REM sleep.}, archive = {J_PNAS}, author = {Harrington, Marcus O. and Karapanagiotidis, Theodoros and Phillips, Lauryn and Smallwood, Jonathan and Anderson, Michael C. and Cairney, Scott A.}, doi = {10.1073/pnas.2400743122}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2400743122}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Memory control deficits in the sleep-deprived human brain}, volume = {122}, year = {2025}, }
• (2025). The origin of color categories. PNAS, 122(1), e2400273121. (www)

  @article{ , abstract = {To what extent does concept formation require language? Here, we exploit color to address this question and ask whether macaque monkeys have color concepts evident as categories. Macaques have similar cone photoreceptors and central visual circuits to humans, yet they lack language. Whether Old World monkeys such as macaques have consensus color categories is unresolved, but if they do, then language cannot be required. If macaques do not have color categories, then color categories in humans are unlikely to derive from innate properties of visual encoding and likely to depend on cognitive abilities such as language that differ between monkeys and humans. We tested macaques by adapting a match-to-sample paradigm used in humans to uncover color categories from errors in matches, and we analyzed the data using computational simulations that assess the possibility of unrecognized distortions in the perceptual uniformity of color space. The results provide evidence that humans have consensus cognitive color categories and macaques do not. One animal showed evidence for a private color category, demonstrating that monkeys have the capacity to form color categories even if they do not form consensus color categories. Taken together, the results imply that consensus color categories in humans, for which there is ample evidence, must depend upon language or other cognitive abilities.}, archive = {J_PNAS}, author = {Garside, Daniel J. and Chang, Audrey L. Y. and Selwyn, Hannah M. and Conway, Bevil R.}, doi = {10.1073/pnas.2400273121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2400273121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {The origin of color categories}, volume = {122}, year = {2025}, }
• (2025). A minimal vertex model explains how the amnioserosa avoids fluidization during drosophila dorsal closure. PNAS, 122(1), e2322732121. (www)

  @article{ , abstract = {Dorsal closure is a process that occurs during embryogenesis of Drosophila melanogaster . During dorsal closure, the amnioserosa (AS), a one-cell thick epithelial tissue that fills the dorsal opening, shrinks as the lateral epidermis sheets converge and eventually merge. During this process, both shape index and aspect ratio of amnioserosa cells increase markedly. The standard 2-dimensional vertex model, which successfully describes tissue sheet mechanics in multiple contexts, would in this case predict that the tissue should fluidize via cell neighbor changes. Surprisingly, however, the amnioserosa remains an elastic solid with no such events. We here present a minimal extension to the vertex model that explains how the amnioserosa can achieve this unexpected behavior. We show that continuous shrinkage of the preferred cell perimeter and cell perimeter polydispersity lead to the retention of the solid state of the amnioserosa. Our model accurately captures measured cell shape and orientation changes and predicts nonmonotonic junction tension that we confirm with laser ablation experiments.}, archive = {J_PNAS}, author = {Tah, Indrajit and Haertter, Daniel and Crawford, Janice M. and Kiehart, Daniel P. and Schmidt, Christoph F. and Liu, Andrea J.}, doi = {10.1073/pnas.2322732121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2322732121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {A minimal vertex model explains how the amnioserosa avoids fluidization during drosophila dorsal closure}, volume = {122}, year = {2025}, }
• (2025). Image segmentation with traveling waves in an exactly solvable recurrent neural network. PNAS, 122(1), e2321319121. (www)

  @article{ , abstract = {We study image segmentation using spatiotemporal dynamics in a recurrent neural network where the state of each unit is given by a complex number. We show that this network generates sophisticated spatiotemporal dynamics that can effectively divide an image into groups according to a scene’s structural characteristics. We then demonstrate a simple algorithm for object segmentation that generalizes across inputs ranging from simple geometric objects in grayscale images to natural images. Using an exact solution of the recurrent network’s dynamics, we present a precise description of the mechanism underlying object segmentation in the network dynamics, providing a clear mathematical interpretation of how the algorithm performs this task. Object segmentation across all images is accomplished with one recurrent neural network that has a single, fixed set of weights. This demonstrates the expressive potential of recurrent neural networks when constructed using a mathematical approach that brings together their structure, dynamics, and computation.}, archive = {J_PNAS}, author = {Liboni, Luisa H. B. and Budzinski, Roberto C. and Busch, Alexandra N. and Löwe, Sindy and Keller, Thomas A. and Welling, Max and Muller, Lyle E.}, doi = {10.1073/pnas.2321319121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2321319121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Image segmentation with traveling waves in an exactly solvable recurrent neural network}, volume = {122}, year = {2025}, }
• (2025). Divergence time and environmental similarity predict the strength of morphological convergence in stick and leaf insects. PNAS, 122(1), e2319485121. (www)

  @article{ , abstract = {Independent evolution of similar traits in lineages inhabiting similar environments (convergent or repeated evolution) is often taken as evidence for adaptation by natural selection, and used to illustrate the predictability of evolution. Yet convergence is rarely perfect for two reasons. First, environments may not be as similar as they appear. Second, responses to selection are contingent upon available genetic variation and independent lineages may differ in the alleles, genetic backgrounds, and even the developmental mechanisms responsible for the phenotypes in question. Both impediments to convergence are predicted to increase as the length of time separating two lineages increases, making it difficult to discern their relative importance. We quantified environmental similarity and the extent of convergence to show how habitat and divergence time each contribute to observed patterns of morphological evolution in 212 species of stick and leaf insects (order Phasmatodea). Dozens of phasmid lineages independently colonized similar habitats, repeatedly evolving in parallel directions on a 23-trait morphospace, though the magnitude and direction of these shifts varied. Lineages converging toward more similar environments ended up closer on the morphospace, as did closely related lineages, and closely related lineages followed more parallel evolutionary trajectories to arrive there than more distantly related ones. Remarkably, after accounting for habitat similarity, we show that divergence time reduced the extent of convergence at a constant rate across more than 100 My of separation, suggesting even the magnitude of contingency can be predictable, given sufficient spans of time.}, archive = {J_PNAS}, author = {Boisseau, Romain P. and Bradler, Sven and Emlen, Douglas J.}, doi = {10.1073/pnas.2319485121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2319485121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Divergence time and environmental similarity predict the strength of morphological convergence in stick and leaf insects}, volume = {122}, year = {2025}, }
• (2025). Trojan horse peptide conjugates remodel the activity spectrum of clinical antibiotics. PNAS, 122(1), e2319483121. (www)

  @article{ , abstract = {Infections caused by gram-negative pathogens continue to be a major risk to human health because of the innate antibiotic resistance endowed by their unique cell membrane architecture. Nature has developed an elegant solution to target gram-negative strains, namely by conjugating toxic antibiotic warheads to a suitable carrier to facilitate the active import of the drug to a specific target organism. Microcin C7 (McC) is a Trojan horse peptide–conjugated antibiotic that specifically targets enterobacteria by exploiting active import through oligopeptide transport systems. Here, we characterize the molecular mechanism of McC recognition by YejA, the solute binding protein of the Escherichia coli oligopeptide transporter. Structure-guided mutational and functional analysis elucidates the determinants of substrate recognition. We demonstrate that the peptide carrier can serve as a passport for the entry of molecules that are otherwise not taken into E. coli cells. We show that peptide conjugation can remodel the antibiotic spectrum of clinically relevant parent compounds. Bioinformatics analysis reveals a broad distribution of YejA-like transporters in only the Proteobacteria, underscoring the potential for the development of Trojan horse antibiotics that are actively imported into such gram-negative bacteria.}, archive = {J_PNAS}, author = {Luo, Shangwen and Li, Xin-Rong and Gong, Xiao-Tong and Kulikovsky, Alexey and Qu, Feng and Beis, Konstantinos and Severinov, Konstantin and Dubiley, Svetlana and Feng, Xinxin and Dong, Shi-Hui and Nair, Satish K.}, doi = {10.1073/pnas.2319483121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2319483121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Trojan horse peptide conjugates remodel the activity spectrum of clinical antibiotics}, volume = {122}, year = {2025}, }
• (2025). Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction. PNAS, 122(1), e2318833121. (www)

  @article{ , abstract = {Dysregulation of GABAergic inhibition is associated with pathological pain. Consequently, enhancement of GABAergic transmission represents a potential analgesic strategy. However, therapeutic potential of current GABA agonists and modulators is limited by unwanted side effects. We postulated that inhibition of GABA’s degradation enzyme, GABA aminotransferase (GABA-AT), would increase endogenous GABA levels and produce analgesia. We evaluated antinociceptive efficacy of the potent GABA-AT inhibitor OV329 in rodent models of neuropathic and inflammatory pain and assessed possible side effects (i.e., reward and motor impairment). OV329 attenuated the development and maintenance of mechanical and cold hypersensitivities induced by the chemotherapeutic agent paclitaxel. Prophylactic OV329, administered systemically, normalized paclitaxel-induced increases in glutamate levels and suppressed neuropathic nociception. Intrathecal OV329 suppressed paclitaxel-induced mechanical hypersensitivity, elevating GABA, and reducing glutamate levels in the lumbar spinal cord, consistent with a spinal site of action. Furthermore, OV329 largely synergized with paclitaxel to enhance 4T1 tumor cell line cytotoxicity without altering viability of nontumor cells. OV329 also attenuated inflammation-induced mechanical hypersensitivity induced by intraplanar injection of complete Freund’s adjuvant (CFA) with efficacy comparable to morphine. Unlike morphine, OV329 did not produce reward in a conditioned place preference assay in mice and was not self-administered intravenously by rats. Antinociceptive efficacy of OV329 was observed at doses that did not impair motor function or produce tolerance following chronic dosing. Thus, inhibition of GABA-AT with OV329 represents a unique therapeutic strategy to alleviate neuropathic and inflammatory pain with no apparent abuse liability, potentially producing a beneficial spectrum of pharmacological effects through enzymatic regulation.}, archive = {J_PNAS}, author = {Wirt, Jonah L. and Assis Ferreira, Luana and Jesus, Carlos Henrique Alves and Woodward, Taylor J. and Oliva, Idaira and Xu, Zhili and Crystal, Jonathon D. and Pepin, Robert H. and Silverman, Richard B. and Hohmann, Andrea G.}, doi = {10.1073/pnas.2318833121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2318833121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction}, volume = {122}, year = {2025}, }
• (2025). An animal model recapitulates human hepatic diseases associated with GATA6 mutations. PNAS, 122(1), e2317801121. (www)

  @article{ , abstract = {Heterozygotic GATA6 mutations are responsible for various congenital diseases in the heart, pancreas, liver, and other organs in humans. However, there is lack of an animal that can comprehensively model these diseases since GATA6 is essential for early embryogenesis. Here, we report the establishment of a gata6 knockout zebrafish which recapitulates most of the symptoms in patients with GATA6 mutations, including cardiac outflow tract defects, pancreatic hypoplasia/agenesis, gallbladder agenesis, and various liver diseases. Particularly in the liver, the zebrafish gata6 model exhibits the paucity of intrahepatic bile ducts, disrupted bile canaliculi, cholestasis, resembling the liver diseases associated with GATA6 mutations. Moreover, an unreported phenotype, hepatic cysts, has been also revealed in the model. Mechanistically, Gata6 interacts with Hhex and binds lrh-1 promoter to synergistically activate its expression, thereby enhancing the Lrh-1-mediated β-catenin signaling which is essential for liver development. This transcriptional activation of lrh-1 is tightly controlled by the negative feedback, in which Lrh1 interacts with Gata6 to weaken its transactivation ability. Moreover, Gata6 level is regulated by Hhex-mediated proteasomal degradation. The orchestration by these three transcription factors precisely modulates Gata6 activity, ensuring β-catenin signaling output and proper liver development in zebrafish. Importantly, the molecular mechanism identified in zebrafish is conserved in human cells. GATA6 mutant variants associated with hepatobiliary malformations in humans interact aberrantly with HHEX, resulting in subsequent impairments of LRH-1 activation. Conclusively, the disease model established here provides both phenotypic and mechanism insights into the human hepatic diseases associated with GATA6 mutations.}, archive = {J_PNAS}, author = {Shi, Wenpeng and Yi, Xiaogui and Ruan, Hua and Wang, Donglei and Wu, Dan and Jiang, Pengfei and Luo, Lisha and Ma, Xirui and Jiang, Faming and Li, Cairui and Wu, Weinan and Luo, Lingfei and Li, Li and Wang, Guixue and Qiu, Juhui and Huang, Honghui}, doi = {10.1073/pnas.2317801121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2317801121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {An animal model recapitulates human hepatic diseases associated with GATA6 mutations}, volume = {122}, year = {2025}, }
• (2025). Individual differences elucidate the perceptual benefits associated with robust temporal fine-structure processing. PNAS, 122(1), e2317152121. (www)

  @article{ , abstract = {The auditory system is unique among sensory systems in its ability to phase lock to and precisely follow very fast cycle-by-cycle fluctuations in the phase of sound-driven cochlear vibrations. Yet, the perceptual role of this temporal fine structure (TFS) code is debated. This fundamental gap is attributable to our inability to experimentally manipulate TFS cues without altering other perceptually relevant cues. Here, we circumnavigated this limitation by leveraging individual differences across 200 participants to systematically compare variations in TFS sensitivity to performance in a range of speech perception tasks. TFS sensitivity was assessed through detection of interaural time/phase differences, while speech perception was evaluated by word identification under noise interference. Results suggest that greater TFS sensitivity is not associated with greater masking release from fundamental-frequency or spatial cues but appears to contribute to resilience against the effects of reverberation. We also found that greater TFS sensitivity is associated with faster response times, indicating reduced listening effort. These findings highlight the perceptual significance of TFS coding for everyday hearing.}, archive = {J_PNAS}, author = {Borjigin, Agudemu and Bharadwaj, Hari M.}, doi = {10.1073/pnas.2317152121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2317152121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Individual differences elucidate the perceptual benefits associated with robust temporal fine-structure processing}, volume = {122}, year = {2025}, }
• (2025). Population encoding of observed and actual somatosensations in the human posterior parietal cortex. PNAS, 122(1), e2316012121. (www)

  @article{ , abstract = {Cognition relies on transforming sensory inputs into a generalizable understanding of the world. Mirror neurons have been proposed to underlie this process, mapping visual representations of others’ actions and sensations onto neurons that mediate our own, providing a conduit for understanding. However, this theory has limitations. Here, we hypothesize that mirror-like responses represent one facet of a broader framework in which our brains engage internal models for cognition. We recorded populations of single neurons in the human posterior parietal cortex (PPC) of a brain–machine interface clinical trial participant implanted with a microelectrode array while she either experienced actual touch, or observed diverse tactile stimuli applied to other individuals. Two body locations were tested, on each of the participant and other individuals. Some neurons exhibited mirror-like properties, consistent with earlier literature. However, they were fragile, breaking with increased task complexity. Population responses were better characterized by generalizable and compositional basic-level features encoded within neural subspaces. These features enable the population to respond to diverse actual and observed touch stimuli and are recruited similarly for similar forms of touch. Mirror-like neurons belong within these subspaces, contributing more globally to compositionality and generalizability. We speculate that at a population-level, human PPC manifests an internal model for touch, and that cognition unfolds in the high-level human cortex by versatility in its representational building blocks. In a broad sense, we speculate that the population features we demonstrate support a broad mechanism by which the high-level human cortex enables understanding.}, archive = {J_PNAS}, author = {Chivukula, Srinivas and Aflalo, Tyson and Zhang, Carey and Rosario, Emily R. and Bari, Ausaf and Pouratian, Nader and Andersen, Richard A.}, doi = {10.1073/pnas.2316012121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2316012121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Population encoding of observed and actual somatosensations in the human posterior parietal cortex}, volume = {122}, year = {2025}, }
• (2025). Modular DNA origami–based electrochemical detection of DNA and proteins. PNAS, 122(1), e2311279121. (www)

  @article{ , abstract = {The diversity and heterogeneity of biomarkers has made the development of general methods for single-step quantification of analytes difficult. For individual biomarkers, electrochemical methods that detect a conformational change in an affinity binder upon analyte binding have shown promise. However, because the conformational change must operate within a nanometer-scale working distance, an entirely new sensor, with a unique conformational change, must be developed for each analyte. Here, we demonstrate a modular electrochemical biosensor, built from DNA origami, which is easily adapted to diverse molecules by merely replacing its analyte binding domains. Instead of relying on a unique nanometer-scale movement of a single redox reporter, all sensor variants rely on the same 100-nm scale conformational change, which brings dozens of reporters close enough to a gold electrode surface that a signal can be measured via square-wave voltammetry, a standard electrochemical technique. To validate our sensor’s mechanism, we used single-stranded DNA as an analyte, and optimized the number of redox reporters and various linker lengths. Adaptation of the sensor to streptavidin and Platelet-Derived Growth Factor-BB (PDGF-BB) analytes was achieved by simply adding biotin or anti-PDGF aptamers to appropriate DNA linkers. Geometrically optimized streptavidin sensors exhibited signal gain and limit of detection markedly better than comparable reagentless electrochemical sensors. After use, the same sensors could be regenerated under mild conditions: Performance was largely maintained over four cycles of DNA strand displacement and rehybridization. By leveraging the modularity of DNA nanostructures, our work provides a straightforward route to the single-step quantification of arbitrary nucleic acids and proteins.}, archive = {J_PNAS}, author = {Jeon, Byoung-jin and Guareschi, Matteo M. and Stewart, Jaimie Marie and Wu, Emily and Gopinath, Ashwin and Arroyo-Currás, Netzahualcóyotl and Dauphin-Ducharme, Philippe and Plaxco, Kevin W. and Lukeman, Philip S. and Rothemund, Paul W. K.}, doi = {10.1073/pnas.2311279121}, journal = {Proceedings of the National Academy of Sciences}, month = {1}, number = {1}, pages = {e2311279121}, shortjournal = {Proc. Natl. Acad. Sci. USA}, title = {Modular DNA origami–based electrochemical detection of DNA and proteins}, volume = {122}, year = {2025}, }